Faculty Profiles - MIYOSHI Toru

Papers - MIYOSHI Toru

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Impact of High-Sensitivity Cardiac Troponin T on Clinical Outcomes in Patients With Cardiac Sarcoidosis.

Yoichi Takaya, Koji Nakagawa, Toru Miyoshi, Nobuhiro Nishii, Hiroshi Morita, Kazufumi Nakamura, Shinsuke Yuasa

Circulation journal : official journal of the Japanese Circulation Society 2025.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The prognostic utility of high-sensitivity cardiac troponin T (hs-cTnT) on clinical outcomes in cardiac sarcoidosis (CS) remains unknown, so we evaluated hs-cTnT in the chronic phase of CS. METHODS AND RESULTS: We enrolled 92 consecutive patients with CS in the chronic phase after medical therapies. Patients were divided into 2 groups according to hs-cTnT level: 0.014 ng/mL: high hs-cTnT (n=37); normal hs-cTnT (n=55). The primary endpoint was cardiac death and the secondary endpoint was cardiac death, ventricular tachyarrhythmias, or hospitalization for heart failure. The mean age of patients was 63±11 years, and 75 received steroid treatment. During a median follow-up of 63 months, there were 9 cardiac deaths: 7 (19%) patients with high hs-cTnT and 2 (4%) patients with normal hs-cTnT. The rate of cardiac death was higher in patients with high hs-cTnT than in those with normal hs-cTnT (log-rank, P<0.01). Cox proportional hazard analysis showed that hs-cTnT was an independent predictor of cardiac death. The events rate was higher in patients with high hs-cTnT than in those with normal hs-cTnT (log-rank, P<0.01): cardiac death, ventricular tachyarrhythmias or hospitalization for heart failure occurred in 24 (65%) patients with high hs-cTnT and 11 (20%) patients with normal hs-cTnT. CONCLUSIONS: Elevated hs-cTnT was linked with adverse outcomes in CS patients, suggesting it is an effective prognostic biomarker.

DOI： 10.1253/circj.CJ-24-0801

Excessive supraventricular ectopic activity is a simple cutoff for predicting late recurrence of atrial fibrillation after ablation.

Tomoki Fujisawa, Hiroshi Kawakami, Shunsuke Tamaki, Shigehiro Miyazaki, Yusuke Akazawa, Toru Miyoshi, Akinori Higaki, Fumiyasu Seike, Haruhiko Higashi, Kazuhisa Nishimura, Katsuji Inoue, Shuntaro Ikeda, Osamu Yamaguchi

Heart and vessels 2024.12

Language：English Publishing type：Research paper (scientific journal)

The relationship between post-ablation excessive supraventricular ectopic activity (ESVEA), a new marker for new-onset atrial fibrillation (AF), and late AF recurrence is uncertain. We enrolled 469 patients with AF who underwent initial radiofrequency catheter ablation and 24-h Holter monitoring the day after. Early AF recurrence (n = 57; 12%) and ESVEA (n = 242; 52%) were noted. During a median follow-up of 25 months, 152 (32%) patients experienced late AF recurrence. Patients with early AF recurrence or ESVEA were significantly more likely to experience late recurrence (p = 0.02). Even without AF, ESVEA was associated with late recurrence following AF ablation.

DOI： 10.1007/s00380-024-02498-z

iPSC-Derived Biological Pacemaker—From Bench to Bedside

Quan Duy Vo, Kazufumi Nakamura, Yukihiro Saito, Toshihiro Iida, Masashi Yoshida, Naofumi Amioka, Satoshi Akagi, Toru Miyoshi, Shinsuke Yuasa

Cells 13 ( 24 ) 2045 - 2045 2024.12

Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Induced pluripotent stem cell (iPSC)-derived biological pacemakers have emerged as an alternative to traditional electronic pacemakers for managing cardiac arrhythmias. While effective, electronic pacemakers face challenges such as device failure, lead complications, and surgical risks, particularly in children. iPSC-derived pacemakers offer a promising solution by mimicking the sinoatrial node’s natural pacemaking function, providing a more physiological approach to rhythm control. These cells can differentiate into cardiomyocytes capable of autonomous electrical activity, integrating into heart tissue. However, challenges such as achieving cellular maturity, long-term functionality, and immune response remain significant barriers to clinical translation. Future research should focus on refining gene-editing techniques, optimizing differentiation, and developing scalable production processes to enhance the safety and effectiveness of these biological pacemakers. With further advancements, iPSC-derived pacemakers could offer a patient-specific, durable alternative for cardiac rhythm management. This review discusses key advancements in differentiation protocols and preclinical studies, demonstrating their potential in treating dysrhythmias.

DOI： 10.3390/cells13242045

Life-Threatening Ventricular Tachyarrhythmia in Isolated Cardiac Sarcoidosis Compared With Cardiac Sarcoidosis With Extracardiac Involvement

Yoichi Takaya, Koji Nakagawa, Toru Miyoshi, Nobuhiro Nishii, Hiroshi Morita, Kazufumi Nakamura, Shinsuke Yuasa

The American Journal of Cardiology 2024.12

Prognostic value of right atrial function in patients with significant tricuspid regurgitation. International journal

Takahiro Nishihara, Yoichi Takaya, Rie Nakayama, Yu Yoshida, Norihisa Toh, Toru Miyoshi, Kazufumi Nakamura, Shinsuke Yuasa

ESC heart failure 2024.8

Language：English Publishing type：Research paper (scientific journal)

AIMS: Although right ventricular (RV) dysfunction is associated with adverse outcomes in tricuspid regurgitation (TR), the potential role of right atrial (RA) function is unknown. We aimed to investigate the relationship between RA function and clinical outcomes in patients with significant TR. METHODS: This retrospective study included 169 outpatients with moderate or severe TR due to left-sided heart diseases who underwent transthoracic echocardiography between June 2020 and April 2023 (average age, 75 ± 10 years; male, 40%). Patients with atrial fibrillation were excluded from this study due to the inaccuracy of the evaluation using 2D speckle-tracking echocardiography. RA function was compared between patients with and without events, which were defined as all-cause mortality or hospitalization due to heart failure. RA function was calculated as RA global longitudinal strain (RAGLS) with the 2D speckle-tracking echocardiography. RESULTS: During a median follow-up of 13 months, 19 patients had events (all-cause mortality: 14 cases, hospitalization due to heart failure: 5 cases). RAGLS was lower in patients with events than in those without events (13% ± 10% vs. 18% ± 9%, P = 0.02). When the patients were categorized into two groups [low RAGLS ≤ 16.2% vs. high RAGLS > 16.2%, high RA volume index (RAVI) ≥ 50 mL/m2 vs. low RAVI < 50 mL/m2], Kaplan-Meier curves showed that patients with low RAGLS had higher event rates than those with high RAGLS (log-rank test, P = 0.003). Patients with high RAVI had higher event rates than those with low RAVI (log-rank test, P < 0.001). In the multivariate Cox regression analysis, low RAGLS (≤16.2%) was significantly associated with events in a model that included RV dysfunction (RV fractional area change ≤ 35%) or high RAVI (≥50 mL/m2) (hazard ratio: 4.55, 95% confidence interval: 1.51-13.71, P < 0.01; hazard ratio: 4.57, 95% confidence interval: 1.52-13.79, P < 0.01, respectively). CONCLUSIONS: RAGLS is associated with all-cause mortality and hospitalization due to heart failure in patients with significant TR. Our results suggest that RA function is a sensitive marker for identifying the risk stratification of significant TR.

DOI： 10.1002/ehf2.14846

Impact of extracardiac sarcoidosis on clinical outcomes in patients with cardiac sarcoidosis: Importance of continued screening for cardiac involvement. International journal

Yoichi Takaya, Koji Nakagawa, Toru Miyoshi, Nobuhiro Nishii, Hiroshi Morita, Kazufumi Nakamura, Shinsuke Yuasa

International journal of cardiology 413 132368 - 132368 2024.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The prognostic impact of extracardiac sarcoidosis remains unknown in cardiac sarcoidosis (CS). We aimed to evaluate the influence of extracardiac sarcoidosis on clinical outcomes and the effect of continued outpatient visits for screening of cardiac involvement. METHODS: Ninety-nine patients with CS were divided into two groups: patients with systemic CS who had prior extracardiac sarcoidosis, patients with isolated CS who had no prior extracardiac sarcoidosis. Patients with systemic CS were divided according to the continuation of outpatient visits. The endpoint was cardiac death, fatal ventricular arrhythmia, or hospitalization for heart failure. RESULTS: At the time of diagnosing CS, patients with isolated CS had a higher prevalence of high-grade atrioventricular block or fatal ventricular arrhythmia, and left ventricular contractile dysfunction than those with systemic CS. Over a median follow-up of 42 months, cardiac events occurred in 19 (37%) of 52 patients with systemic CS and in 27 (57%) of 47 patients with isolated CS. The event-free survival rate was worse in patients with isolated CS than in those with systemic CS. Cox proportional hazard analysis showed that the absence of prior extracardiac sarcoidosis was an independent predictor of adverse outcomes. Patients with systemic CS who ceased outpatient visits had a lower left ventricular ejection fraction with severe heart failure symptoms and a worse event-free survival rate than those who continued outpatient visits. CONCLUSIONS: The presence of extracardiac sarcoidosis is associated with clinical outcomes. The cessation of screening for cardiac involvement after diagnosing extracardiac sarcoidosis is associated with adverse outcomes.

DOI： 10.1016/j.ijcard.2024.132368

Prognostic Implications of Insulin Resistance in Heart Failure in Japan

Keiichiro Iwasaki, Kazufumi Nakamura, Satoshi Akagi, Yoichi Takaya, Hironobu Toda, Toru Miyoshi, Shinsuke Yuasa

Nutrients 16 ( 12 ) 1888 - 1888 2024.6

Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Diabetes mellitus (DM) is a major risk and prognostic factor for heart failure (HF). Insulin resistance (IR) is an important component of DM, but the relationship between IR and HF prognosis has not yet been established across a wide variety of HF populations. We retrospectively evaluated the relationship between IR and clinical outcomes of HF patients at our hospital between 2017 and 2021. IR was defined as a homeostatic model assessment of IR (HOMA-IR) index ≥ 2.5, calculated from fasting blood glucose and insulin concentrations. The primary outcome was a composite of all-cause death and hospitalisation for HF (HHF). Among 682 patients included in the analyses, 337 (49.4%) had IR. The median age was 70 [interquartile range (IQR): 59–77] years old, and 66% of the patients were men. Among the patients, 41% had a left ventricular ejection fraction below 40%, and 32% had DM. The median follow-up period was 16.5 [IQR: 4.4–37.3] months. IR was independently associated with the primary outcome (HR: 1.91, 95% CI: 1.39–2.62, p < 0.0001), death (hazard ratio [HR]: 1.86, 95% confidence interval [CI]: 1.28–2.83, p < 0.01), and HHF (HR: 1.91, 95% CI: 1.28–2.83, p < 0.01). HOMA-IR is an independent prognostic factor of HF in a wide variety of HF populations.

DOI： 10.3390/nu16121888

Efficacy and safety of intravenous versus oral tolvaptan in the acute phase of acute decompensated heart failure

Tomoaki Okada, Wataru Takagi, Toru Miyoshi, Akihiro Oka, Kosuke Seiyama, Satoko Ugawa, Kazumasa Nosaka, Masayuki Doi

Journal of Cardiology 2024.6

Prognostic value of metabolic dysfunction-associated steatotic liver disease over coronary computed tomography angiography findings: comparison with no-alcoholic fatty liver disease

Takahiro Nishihara, Toru Miyoshi, Mitsutaka Nakashima, Takashi Miki, Hironobu Toda, Masatoki Yoshida, Keishi Ichikawa, Kazuhiro Osawa, Shinsuke Yuasa

Cardiovascular Diabetology 23 ( 1 ) 2024.5

Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the proposed name change for non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the association of cardiovascular disease risk with MASLD and NAFLD in patients who underwent clinically indicated coronary computed tomography angiography (CCTA).

Methods

This retrospective study included 2289 patients (60% men; mean age: 68 years) with no history of coronary artery disease who underwent CCTA. The steatotic liver was defined as a hepatic-to-spleen attenuation ratio of < 1.0 on CT just before CCTA. MASLD is defined as the presence of hepatic steatosis along with at least one of the five cardiometabolic risk factors. Adverse CCTA findings were defined as obstructive and/or high-risk plaques. Major adverse cardiac events (MACE) encompassed composite coronary events, including cardiovascular death, acute coronary syndrome, and late coronary revascularization.

Results

MASLD and NAFLD were identified in 415 (18%) and 368 (16%) patients, respectively. Adverse CCTA findings were observed in 40% and 38% of the patients with MASLD and with NAFLD, respectively. Adverse CCTA findings were significantly associated with MASLD (p = 0.007) but not NAFLD (p = 0.253). During a median follow-up of 4.4 years, 102 (4.4%) MACE were observed. MASLD was significantly associated with MACE (hazard ratio 1.82, 95% CI 1.18–2.83, p = 0.007), while its association with NAFLD was not significant (p = 0.070). By incorporating MASLD into a prediction model of MACE, including the risk score and adverse CCTA findings, global chi-squared values significantly increased from 87.0 to 94.1 (p = 0.008).

Conclusions

Patients with MASLD are likely to have a higher risk of cardiovascular disease than those with NAFLD. Concurrent assessment of MASLD during CCTA improves the identification of patients at a higher risk of cardiovascular disease among those with clinically indicated CCTA.

DOI： 10.1186/s12933-024-02268-1

Other Link： https://link.springer.com/article/10.1186/s12933-024-02268-1/fulltext.html

Diagnostic improvements of calcium-removal image reconstruction algorithm using photon-counting detector CT for calcified coronary lesions. International journal

Takahiro Nishihara, Toru Miyoshi, Mitsutaka Nakashima, Noriaki Akagi, Yusuke Morimitsu, Tomohiro Inoue, Takashi Miki, Masatoki Yoshida, Hironobu Toda, Kazufumi Nakamura, Shinsuke Yuasa

European journal of radiology 172 111354 - 111354 2024.3

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: To investigate the diagnostic performance of a calcium-removal image reconstruction algorithm with photon-counting detector-computed tomography (PCD-CT), a technology that hides only the calcified plaque from the spectral data in coronary calcified lesions. METHODS: This retrospective study included 17 patients who underwent PCD-coronary CT angiography (CCTA) with at least one significant coronary stenosis (≥50 %) with calcified plaque by CCTA and invasive coronary angiography (ICA) performed within 60 days of CCTA. A total of 162 segments with calcified plaque were evaluated for subjective image quality using a 4-point scale. Their calcium-removal images were reconstructed from conventional images, and both images were compared with ICA images as the reference standard. The contrast-to noise ratios for both images were calculated. RESULTS: Conventional and calcium-removal images had a subjective image quality of 2.7 ± 0.5 and 3.2 ± 0.9, respectively (p < 0.001). The percentage of segments with a non-diagnostic image quality was 32.7 % for conventional images and 28.3 % for calcium-removal images (p < 0.001). The segment-based diagnostic accuracy revealed an area under the receiver operating characteristic curve of 0.87 for calcium-removal images and 0.79 for conventional images (p = 0.006). Regarding accuracy, the specificity and positive predictive value of calcium-removal images were significantly improved compared with those of conventional images (80.5 % vs. 69.5 %, p = 0.002 and 64.1 % vs. 52.0 %, p < 0.001, respectively). The objective image quality of the mean contrast-to-noise ratio did not differ between the images (13.9 ± 3.6 vs 13.3 ± 3.4, p = 0.356) CONCLUSIONS: Calcium-removal images with PCD-CT can potentially be used to evaluate diagnostic performance for calcified coronary artery lesions.

DOI： 10.1016/j.ejrad.2024.111354

Effect of Tafamidis on Serum Transthyretin Levels in Patients with Transthyretin Amyloidosis Cardiomyopathy(タイトル和訳中)

森淳史, 中村一文, 斎藤幸弘, 吉田賢司, 谷山真規子, 三好亨, 森田宏, 赤木禎治, 西井伸洋, 中川晃志

日本循環器学会学術集会抄録集 88回 PJ065 - 2 2024.3

Evaluation of Changes in Coronary Ischemia After Lipid-Lowering Therapy Using Computed Tomography Angiography.

Takahiro Nishihara, Mitsutaka Nakashima, Keishi Ichikawa, Toru Miyoshi

Circulation reports 6 ( 1 ) 16 - 17 2024.1

Association between Non-Lipid Residual Risk Factors and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Pitavastatin: An Observation from the REAL-CAD Study

Kiwamu Kamiya, Makoto Takei, Toshiyuki Nagai, Toru Miyoshi, Hiroshi Ito, Yoshihiro Fukumoto, Hitoshi Obara, Tatsuyuki Kakuma, Ichiro Sakuma, Hiroyuki Daida, Satoshi Iimuro, Hiroaki Shimokawa, Takeshi Kimura, Ryozo Nagai, Toshihisa Anzai

Journal of Atherosclerosis and Thrombosis 31 ( 1 ) 61 - 80 2024.1

Enhanced Production of EPA-Derived Anti-Inflammatory Metabolites after Oral Administration of a Novel Self-Emulsifying Highly Purified EPA Ethyl Ester Formulation (MND-2119)

Toru Miyoshi, Satoko Naoe, Hiroyuki Wakabayashi, Takashi Yano, Takuya Mori, Shingo Kanda, Makoto Arita, Hiroshi Ito

Journal of Atherosclerosis and Thrombosis 30 ( 12 ) 1927 - 1949 2023.12

Determination of lipid-rich plaques by artificial intelligence-enabled quantitative computed tomography using near-infrared spectroscopy as reference

Hiroyuki Omori, Hitoshi Matsuo, Shinichiro Fujimoto, Yoshihiro Sobue, Yui Nozaki, Gaku Nakazawa, Kuniaki Takahashi, Kazuhiro Osawa, Ryo Okubo, Umihiko Kaneko, Hideyuki Sato, Takashi Kajiya, Toru Miyoshi, Keishi Ichikawa, Mitsunori Abe, Toshiro Kitagawa, Hiroki Ikenaga, Mike Saji, Nobuo Iguchi, Takeshi Ijichi, Hiroshi Mikamo, Akira Kurata, Masao Moroi, Raisuke Iijima, Shant Malkasian, Tami Crabtree, James K. Min, James P. Earls, Rine Nakanishi

Atherosclerosis 386 117363 - 117363 2023.12

非動脈硬化性末梢血管疾患の診断と治療 Radiation-induced arteriopathyと考えられた症例に対して、医原性尿管腸骨動脈瘻を生じた1例

戸田洋伸, 吉田雅言, 中川晃志, 三好亨, 西井伸洋, 中村一文, 森田宏

脈管学 63 ( Suppl. ) S141 - S141 2023.10

Prognostic value of the liver fibrosis marker fibrosis-5 index in patients with severe isolated tricuspid regurgitation: comparison with fibrosis-4 index.

Mitsutaka Nakashima, Toru Miyoshi, Machiko Tanakaya, Takaaki Saito, Yusuke Katayama, Satoru Sakuragi, Yoichi Takaya, Hiroshi Ito

Heart and vessels 38 ( 9 ) 1181 - 1189 2023.9

Language：English Publishing type：Research paper (scientific journal)

The fibrosis-4 index (FIB4), a liver fibrosis maker, has been shown to be associated with the prognosis in patients with severe isolated tricuspid regurgitation (TR). Recent study showed that the fibrosis-5 index (FIB5), which was calculated by albumin, alkaline phosphatase, aspartate transaminase, alanine aminotransferase and platelet count, had better prognostic value than FIB4 in patients with heart failure. The aim of this study was to evaluate the usefulness of FIB5 index for predicting prognosis in patients with severe isolated TR and compare the prognostic value between the FIB4 and the FIB5 in those patients. This was a dual-center, retrospective study. 113 consecutive outpatients with severe isolated TR (mean age, 65.8 years; 47.8% male) were analyzed. Major adverse cardiovascular events (MACEs) were defined as the composite of cardiovascular death, hospitalization for heart failure, myocardial infarction, and stroke. During a median follow-up of 3.0 years, 41 MACEs occurred. Patients with MACEs had a lower the FIB5 than patients without MACEs. The multivariate Cox analysis revealed that the FIB5 < -4.30 was significantly associated with higher incidence of MACEs after adjusted by confounding factors. Receiver-operating characteristic curve analyses showed that prognostic values did not differ between the FIB5 and the FIB4 in whole patients and in patients aged ≥ 70 years; while, in patients aged < 70 years, the FIB5 had better prognostic value than the FIB4. The FIB5 may be a useful predictor of MACEs in patients with severe isolated TR.

DOI： 10.1007/s00380-023-02268-3

Rationale and design of the INVICTUS Registry: (Multicenter Registry of Invasive and Non-Invasive imaging modalities to compare Coronary Computed Tomography Angiography, Intravascular Ultrasound and Optical Coherence Tomography for the determination of Severity, Volume and Type of coronary atherosclerosiS)

Rine Nakanishi, Ryo Okubo, Yoshihiro Sobue, Umihiko Kaneko, Hideyuki Sato, Shinichiro Fujimoto, Yui Nozaki, Takashi Kajiya, Toru Miyoshi, Keishi Ichikawa, Mitsunori Abe, Toshiro Kitagawa, Hiroki Ikenaga, Kazuhiro Osawa, Mike Saji, Nobuo Iguchi, Gaku Nakazawa, Kuniaki Takahashi, Takeshi Ijich, Hiroshi Mikamo, Akira Kurata, Masao Moroi, Raisuke Iijima, Shant Malkasian, Tami Crabtree, Daniel Chamie, Lansky J. Alexandra, James K. Min, James P. Earls, Hitoshi Matsuo

Journal of Cardiovascular Computed Tomography 2023.9

Association of perivascular fat attenuation on computed tomography and heart failure with preserved ejection fraction. International journal

Takahiro Nishihara, Toru Miyoshi, Mitsutaka Nakashima, Keishi Ichikawa, Yoichi Takaya, Rie Nakayama, Takashi Miki, Hiroshi Ito

ESC heart failure 10 ( 4 ) 2447 - 2457 2023.8

Language：English Publishing type：Research paper (scientific journal)

AIMS: Heart failure with a preserved ejection fraction (HFpEF) is associated with chronic inflammation. We aimed to investigate the association between pericoronary adipose tissue attenuation (PCATA) on coronary computed tomography angiography as a novel noninvasive marker of pericoronary inflammation and the presence of HFpEF. METHODS AND RESULTS: This retrospective study included 607 outpatients (median age, 65 years; 50% male) who underwent both echocardiography and coronary computed tomography angiography. Patients with obstructive coronary artery disease were excluded from this study. PCATA was compared between patients with and without HFpEF, which was diagnosed according to the Heart Failure Association (HFA)-PEFF score. PCATA was assessed at the proximal 40-mm segments of all three major coronary arteries on coronary computed tomography angiography. Patients with HFpEF had higher PCATA in all coronary arteries compared to the control participants: left anterior descending artery (LAD), -65.2 ± 6.9 Hounsfield units (HU) vs. -68.1 ± 6.7 HU; left circumflex artery (LCX), -62.7 ± 6.8 HU vs. -65.4 ± 6.6 HU; and right coronary artery (RCA), -63.6 ± 8.5 HU vs. -65.5 ± 7.7 HU (P < 0.01). Multivariate logistic regression analysis, including conventional risk factors, revealed that PCATA per standard deviation in the LAD (odds ratio [OR], 1.449; 95% confidence interval [CI], 1.152-1.823), LCX (OR, 1.634; 95% CI, 1.283-2.081), and RCA (OR, 1.388; 95% CI, 1.107-1.740) were independently associated with HFpEF. The association between PCATA and HFpEF was mostly consistent across various patient clinical characteristics. The left ventricular mass and left atrial volume index showed a mild correlation with LAD-PCATA (ρ = 0.13 [P < 0.01] and ρ = 0.24 [P < 0.01]) and LCX-PCATA (ρ = 0.16 [P < 0.01] and ρ = 0.23 [P < 0.01]). CONCLUSIONS: High PCATA score was significantly associated with the presence of HFpEF. Our results suggest that inflammation in the pericoronary artery adipose tissue is one of the underlying mechanisms of HFpEF.

DOI： 10.1002/ehf2.14419

奇異性脳塞栓症を起こした卵円孔開存は心臓CTでどのように見えるのか?

三木崇史, 中川晃志, 辻真弘, 中島充貴, 西原大裕, 中山理絵, 高谷陽一, 三好亨, 赤木禎治, 伊藤浩

日本心血管インターベンション治療学会抄録集 31回 MO66 - 5 2023.8

Evidence for Hypoxia-Induced Shift in ATP Production from Glycolysis to Mitochondrial Respiration in Pulmonary Artery Smooth Muscle Cells in Pulmonary Arterial Hypertension International journal

Satoshi Akagi, Kazufumi Nakamura, Megumi Kondo, Satoshi Hirohata, Heiichiro Udono, Mikako Nishida, Yukihiro Saito, Masashi Yoshida, Toru Miyoshi, Hiroshi Ito

Journal of Clinical Medicine 12 ( 15 ) 5028 - 5028 2023.7

Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Background: The metabolic state of pulmonary artery smooth muscle cells (PASMCs) from patients with pulmonary arterial hypertension (PAH) is not well understood. In this study, we examined the balance between glycolysis and mitochondrial respiration in non-PAH-PASMCs and PAH-PASMCs under normoxia and hypoxia. Methods: We investigated the enzymes involved in glycolysis and mitochondrial respiration, and studied the two major energy-yielding pathways (glycolysis and mitochondrial respiration) by measuring extracellular acidification rate (ECAR) and cellular oxygen consumption rate (OCR) using the Seahorse extracellular flux technology. Results: Under both normoxia and hypoxia, the mRNA and protein levels of pyruvate dehydrogenase kinase 1 and pyruvate dehydrogenase were increased in PAH-PASMCs compared with non-PAH-PASMCs. The mRNA and protein levels of lactate dehydrogenase, as well as the intracellular lactate concentration, were also increased in PAH-PASMCs compared with non-PAH-PASMCs under normoxia. However, these were not significantly increased in PAH-PASMCs compared with non-PAH-PASMCs under hypoxia. Under normoxia, ATP production was significantly lower in PAH-PASMCs (59 ± 5 pmol/min) than in non-PAH-PASMCs (70 ± 10 pmol/min). On the other hand, ATP production was significantly higher in PAH-PASMCs (31 ± 5 pmol/min) than in non-PAH-PASMCs (14 ± 3 pmol/min) under hypoxia. Conclusions: There is an underlying change in the metabolic strategy to generate ATP production under the challenge of hypoxia.

DOI： 10.3390/jcm12155028

Myocardial Late Iodine Enhancement Using Photon-Counting Computed Tomography in Patients With Hypertrophic Cardiomyopathy

Takahiro Nishihara, Toru Miyoshi, Noriaki Akagi, Mitsutaka Nakashima, Kazufumi Nakamura, Hiroshi Ito

Circulation Reports 5 ( 6 ) 269 - 270 2023.6

Metabolic dysfunction associated fatty liver disease(MAFLD)における冠動脈プラーク性状の検討

西原大裕, 三好亨, 中島充貴, 三木崇史, 大澤和宏, 戸田洋伸, 吉田雅言, 中村一文, 伊藤浩

日本動脈硬化学会総会プログラム・抄録集 55回 235 - 235 2023.6

Effects of Agalsidase Alfa Enzyme Replacement Therapy on Left Ventricular Hypertrophy on Electrocardiogram in a Female Patient with Fabry Disease

Kazufumi Nakamura, Hiroshi Morita, Yoichi Takaya, Yukihiro Saito, Toru Miyoshi, Hiroshi Morinaga, Hitoshi Sugiyama, Jun Wada, Hiroshi Ito

International Heart Journal 64 ( 3 ) 502 - 505 2023.5

Diagnostic Performance of Cardiac Computed Tomography for Detecting Patent Foramen Ovale: Evaluation Using Transesophageal Echocardiography and Catheterization as Reference Standards. International journal

Takashi Miki, Koji Nakagawa, Keishi Ichikawa, Tomofumi Mizuno, Rie Nakayama, Kentaro Ejiri, Satoshi Kawada, Yoichi Takaya, Masakazu Miyamoto, Toru Miyoshi, Teiji Akagi, Hiroshi Ito

Journal of cardiovascular development and disease 10 ( 5 ) 2023.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Patent foramen ovale (PFO) is associated with various diseases such as cryptogenic stroke, migraine, and platypnea-orthodeoxia syndrome. This study aimed to evaluate the diagnostic performance of cardiac computed tomography (CT) for PFO detection. MATERIALS AND METHODS: Consecutive patients diagnosed with atrial fibrillation and who underwent catheter ablation with pre-procedural cardiac CT and transesophageal echocardiography (TEE) were enrolled in this study. The presence of PFO was defined as (1) the confirmation of PFO using TEE and/or (2) the catheter crossing the interatrial septum (IAS) into the left atrium during ablation. CT findings indicative of PFO included (1) the presence of a channel-like appearance (CLA) on the IAS and (2) a CLA with a contrast jet flow from the left atrium to the right atrium. The diagnostic performance of both a CLA alone and a CLA with a jet flow was evaluated for PFO detection. RESULTS: Altogether, 151 patients were analyzed in the study (mean age, 68 years; men, 62%). Twenty-nine patients (19%) had PFO confirmed by TEE and/or catheterization. The diagnostic performance of a CLA alone was as follows: sensitivity, 72.4%; specificity, 79.5%; positive predictive value (PPV), 45.7%; negative predictive value (NPV), 92.4%. The diagnostic performance of a CLA with a jet flow was as follows: sensitivity, 65.5%; specificity, 98.4%; PPV, 90.5%; NPV, 92.3%. The diagnostic performance of a CLA with a jet flow was statistically superior to that of a CLA alone (p = 0.045), and the C-statistics were 0.76 and 0.82, respectively. CONCLUSION: A CLA with a contrast jet flow in cardiac CT has a high PPV for PFO detection, and its diagnostic performance is superior to that of a CLA alone.

DOI： 10.3390/jcdd10050193

Association Between Aortic Valve Calcification and Severity of Concomitant Aortic Regurgitation in Patients With Severe Aortic Stenosis.

Fumi Yokohama, Yoichi Takaya, Keishi Ichikawa, Rie Nakayama, Takashi Miki, Hironobu Toda, Norihisa Toh, Toru Miyoshi, Kazufumi Nakamura, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society 2023.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Patients with severe aortic stenosis (AS) frequently have concomitant aortic regurgitation (AR), but the association between aortic valvular calcification (AVC) and the severity of AR remains unclear.Methods and Results: We retrospectively reviewed patients with severe AS who underwent transthoracic echocardiography and multidetector computed tomography (MDCT) within 1 month. The patients were divided into 3 groups according to the degree of concomitant AR. The association between AVC and the severity of concomitant AR was assessed in patients with severe AS. The study population consisted of 95 patients: 43 men and 52 women with a mean age of 82±7 years. Of the 95 patients with severe AS, 27 had no or trivial AR, 53 had mild AR, and 15 had moderate AR. The AVC score (AVCS) and AVC volume (AVCV) significantly increased as the severity of concomitant AR increased (P=0.014 for both), and similar findings were obtained for the AVCS and AVCV indexes (P=0.004 for both). CONCLUSIONS: The severity of AR correlated with AVCS and AVCV measured by MDCT in patients with severe AS. AVC may cause concomitant AR, leading to worsening of disease condition.

DOI： 10.1253/circj.CJ-22-0746

Association between High Pericoronary Adipose Tissue Computed Tomography Attenuation and Impaired Flow-Mediated Dilation of the Brachial Artery.

Keishi Ichikawa, Toru Miyoshi, Yuko Ohno, Kazuhiro Osawa, Mitsutaka Nakashima, Takahiro Nishihara, Takashi Miki, Hironobu Toda, Masatoki Yoshida, Hiroshi Ito

Journal of atherosclerosis and thrombosis 30 ( 4 ) 364 - 376 2023.4

Language：English Publishing type：Research paper (scientific journal)

AIMS: Pericoronary adipose tissue (PCAT) attenuation on coronary computed tomography angiography (CTA) is a noninvasive biomarker for pericoronary inflammation and is associated with cardiac mortality. We aimed to investigate the association between PCAT attenuation and endothelial dysfunction assessed using flow-mediated dilation (FMD). METHODS: A total of 119 outpatients who underwent both coronary CTA and FMD measurements were examined. PCAT attenuation values were assessed at the proximal 40-mm segments of all three major coronary arteries on coronary CTA. Endothelial function was assessed using FMD. Patients were then classified into two groups: those with endothelial dysfunction (FMD ＜4%, n=44) and those without endothelial dysfunction (FMD ≥ 4%, n=75). RESULTS: In all three coronary arteries, PCAT attenuation was significantly higher in patients with endothelial dysfunction than in those without endothelial dysfunction. Multivariate logistic regression analysis revealed that PCAT attenuation in the right coronary artery (odds ratio [OR]=1.543; 95% confidence interval [CI]=1.004-2.369, p=0.048) and left anterior descending artery (OR=1.525, 95% CI=1.004-2.369, p=0.049) was an independent predictor of endothelial dysfunction. Subgroup analysis of patients with adverse CTA findings (significant stenosis and/or high-risk plaque) and those with coronary artery calcium score ＞100 showed that high PCAT attenuation in all three coronary arteries was a significant predictor of endothelial dysfunction. CONCLUSION: High PCAT attenuation was significantly associated with FMD-assessed endothelial dysfunction in patients with suspected coronary artery disease. Our results suggest that endothelial dysfunction is one of the pathophysiological mechanisms linking pericoronary inflammation to cardiac mortality.

DOI： 10.5551/jat.63580

Feasibility of Fractional Flow Reserve Derived from CT as a Gatekeeper of Prior to Invasive Angiography in Clinical Practice(タイトル和訳中)

西原大裕, 三好亨, 中島充貴, 三木崇史, 吉田雅言, 戸田洋伸, 伊藤浩

日本循環器学会学術集会抄録集 87回 OJ55 - 1 2023.3

Feasibility of Fibrosis-4 Index for Screening Obstructive Coronary Artery Disease in Patients with Non-alcoholic Fatty Liver Disease(タイトル和訳中)

中島充貴, 三好亨, 西原大裕, 三木崇史, 戸田洋伸, 吉田雅言, 伊藤浩

日本循環器学会学術集会抄録集 87回 OJ55 - 9 2023.3

Morphological Features on Cardiac CT of Patent Foramen Ovale Causing Cryptogenic Stroke(タイトル和訳中)

三木崇史, 中川晃志, 辻真弘, 中島充貴, 西原大裕, 中山理絵, 高谷陽一, 三好亨, 赤木禎治, 伊藤浩

日本循環器学会学術集会抄録集 87回 PJ004 - 6 2023.3

Association of Perivascular Fat Attenuation on Computed Tomography and Heart Failure with Preserved Ejection Fraction(タイトル和訳中)

西原大裕, 三好亨, 中島充貴, 中山理絵, 三木崇史, 高谷陽一, 伊藤浩

日本循環器学会学術集会抄録集 87回 PJ113 - 6 2023.3

Utility of Plasm Volume Status Calculation in Adult Fontan Patients(タイトル和訳中)

中島充貴, 杜徳尚, 川田哲史, 高谷陽一, 中川晃志, 三好亨, 西井伸洋, 赤木禎治, 伊藤浩

日本循環器学会学術集会抄録集 87回 OJ62 - 6 2023.3

Association between Cardiovascular Disease and Liver Disease, from a Clinically Pragmatic Perspective as a Cardiologist. International journal

Mitsutaka Nakashima, Kazufumi Nakamura, Takahiro Nishihara, Keishi Ichikawa, Rie Nakayama, Yoichi Takaya, Norihisa Toh, Satoshi Akagi, Toru Miyoshi, Teiji Akagi, Hiroshi Ito

Nutrients 15 ( 3 ) 2023.2

Language：English Publishing type：Research paper (scientific journal)

Cardiovascular diseases and liver diseases are closely related. Non-alcoholic fatty liver disease has the same risk factors as those for atherosclerotic cardiovascular disease and may also be a risk factor for atherosclerotic cardiovascular disease on its own. Heart failure causes liver fibrosis, and liver fibrosis results in worsened cardiac preload and congestion. Although some previous reports regard the association between cardiovascular diseases and liver disease, the management strategy for liver disease in patients with cardiovascular diseases is not still established. This review summarized the association between cardiovascular diseases and liver disease. In patients with non-alcoholic fatty liver disease, the degree of liver fibrosis progresses with worsening cardiovascular prognosis. In patients with heart failure, liver fibrosis could be a prognostic marker. Liver stiffness assessed with shear wave elastography, the fibrosis-4 index, and non-alcoholic fatty liver disease fibrosis score is associated with both liver fibrosis in patients with liver diseases and worse prognosis in patients with heart failure. With the current population ageing, the importance of management for cardiovascular diseases and liver disease has been increasing. However, whether management and interventions for liver disease improve the prognosis of cardiovascular diseases has not been fully understood. Future investigations are needed.

DOI： 10.3390/nu15030748

Association between home-based exercise using a pedometer and clinical prognosis after endovascular treatment in patients with peripheral artery disease. International journal

Kohei Kawamura, Kentaro Ejiri, Hironobu Toda, Toshiaki Yamanaka, Masato Taniguchi, Kenji Kawamoto, Koji Tokioka, Yoichiro Naito, Ryo Yoshioka, Eiji Karashima, Hideki Fujio, Soichiro Fuke, Yasukazu Fujiwara, Atsushi Takaishi, Kosuke Seiyama, Toru Miyoshi, Kazufumi Nakamura, Hiroshi Ito

Journal of cardiology 81 ( 2 ) 222 - 228 2023.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Exercise therapy following endovascular treatment (EVT) is important for patients with peripheral artery disease (PAD); however, continuous exercise therapy is difficult to be performed in clinical practice. This study aimed to investigate the association between the implementation of home-based exercise using pedometers after EVT and 1-year clinical outcomes. METHODS: This multicenter observational prospective cohort registry included patients with PAD complaining of intermittent claudication who underwent EVT for aortoiliac and/or femoropopliteal artery lesions between January 2016 and March 2019. Patients were instructed to perform home-based exercises using a specific pedometer after EVT. The study population was divided into good and poor recording groups according to the frequency of the pedometer measurements. The good recording group was defined as those who completed ≥50 % of the prescribed daily pedometer recording during the follow-up period. The poor recording group was defined as those with an inability to use a pedometer and/or who completed <50 % of the prescribed daily pedometer recordings. The primary outcome was 1-year major adverse events (MAE), defined as a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, target vessel revascularization, and major amputation of the target limb. RESULTS: The mean age was 74.4 years; 78 % were male. A total of 623 lesions were analyzed (58.7 % aortoiliac, 41.3 % femoropopliteal). At 1 year, a lower cumulative incidence of MAE was observed in the good recording group compared to that in the poor recording group [10/233 (4.3 %) vs. 35/267 (13.7 %) patients, respectively; p < 0.001]. Multivariate Cox regression analysis showed that patients in the good recording group had a lower hazard ratio for 1-year MAE (0.33; 95 % confidence interval, 0.16-0.68; p = 0.004) than that in the poor recording group. CONCLUSIONS: Good self-recording of pedometer measurements was associated with favorable prognosis in patients with PAD following EVT.

DOI： 10.1016/j.jjcc.2022.09.005

Microcalcification and 99mTc-Pyrophosphate Uptake without Increased Bone Metabolism in Cardiac Tissue from Patients with Transthyretin Cardiac Amyloidosis. International journal

Atsushi Mori, Yukihiro Saito, Kazufumi Nakamura, Toshihiro Iida, Satoshi Akagi, Masashi Yoshida, Makiko Taniyama, Toru Miyoshi, Hiroshi Ito

International journal of molecular sciences 24 ( 3 ) 2023.1

Language：English Publishing type：Research paper (scientific journal)

Transthyretin cardiac amyloidosis (ATTR-CA) is characterized by high 99mTc-labeled bone tracer uptake in the heart. However, the mechanism of bone tracer uptake into the heart remains controversial. Since bone tracer uptake into metastatic bone tumors is thought to be associated with increased bone metabolism, we examined 99mTc-pyrophosphate (PYP) scintigraphy findings, endomyocardial biopsy (EMB) tissue findings, and the expression of bone metabolism-related genes in the EMB tissues in patients with ATTR-CA, amyloid light-chain cardiac amyloidosis (AL-CA), and noncardiac amyloidosis (non-CA) in this study. The uptake of 99mTc-PYP in the heart was significantly higher in the ATTR-CA patients than in the AL-CA and non-CA patients. A higher percentage of ATTR-CA EMB tissue showed von Kossa-positive microparticles: ATTR-CA, 62%; AL-CA, 33%; and non-CA, 0%. Calcified microparticles were identified using transmission electron microscopy. However, none of the osteogenic marker genes, osteoclastic marker genes, or phosphate/pyrophosphate-related genes were upregulated in the EMB samples from ATTR-CA patients compared to those from AL-CA and non-CA patients. These results suggest that active calcification-promoting mechanisms are not involved in the microcalcification observed in the heart in ATTR-CA. The mechanisms explaining bone tracer uptake in the heart, which is stronger than that in the ribs, require further investigation.

DOI： 10.3390/ijms24031921

奇異性脳塞栓症を起こした卵円孔開存は心臓CTでどう見えるのか?

三木崇史, 中川晃志, 辻真弘, 中島充貴, 西原大裕, 中山理絵, 高谷陽一, 三好亨, 赤木禎治, 伊藤浩

日本成人先天性心疾患学会雑誌 12 ( 1 ) 158 - 158 2023.1

In vivo tracking transplanted cardiomyocytes derived from human induced pluripotent stem cells using nuclear medicine imaging. International journal

Yukihiro Saito, Naoko Nose, Toshihiro Iida, Kaoru Akazawa, Takayuki Kanno, Yuki Fujimoto, Takanori Sasaki, Masaru Akehi, Takahiro Higuchi, Satoshi Akagi, Masashi Yoshida, Toru Miyoshi, Hiroshi Ito, Kazufumi Nakamura

Frontiers in cardiovascular medicine 10 1261330 - 1261330 2023

Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers Media SA

INTRODUCTION: Transplantation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a promising treatment for heart failure. Information on long-term cell engraftment after transplantation is clinically important. However, clinically applicable evaluation methods have not yet been established. METHODS: In this study, to noninvasively assess transplanted cell engraftment, human SLC5A5, which encodes a sodium/iodide symporter (NIS) that transports radioactive tracers such as 125I, 18F-tetrafluoroborate (TFB), and 99mTc-pertechnetate (99mTcO4-), was transduced into human induced pluripotent stem cells (iPSCs), and nuclear medicine imaging was used to track engrafted human iPSC-CMs. RESULTS: To evaluate the pluripotency of NIS-expressing human iPSCs, they were subcutaneously transplanted into immunodeficient rats. Teratomas were detected by 99mTcO4- single photon emission computed tomography (SPECT/CT) imaging. NIS expression and the uptake ability of 125I were maintained in purified human iPSC-CMs. NIS-expressing human iPSC-CMs transplanted into immunodeficient rats could be detected over time using 99mTcO4- SPECT/CT imaging. Unexpectedly, NIS expression affected cell proliferation of human iPSCs and iPSC-derived cells. DISCUSSION: Such functionally designed iPSC-CMs have potential clinical applications as a noninvasive method of grafted cell evaluation, but further studies are needed to determine the effects of NIS transduction on cellular characteristics and functions.

DOI： 10.3389/fcvm.2023.1261330

Premature atrial contraction immediately after catheter ablation was associated with late recurrence of atrial fibrillation. International journal

Tomoki Fujisawa, Hiroshi Kawakami, Takayuki Nagai, Shigehiro Miyazaki, Yusuke Akazawa, Toru Miyoshi, Akinori Higaki, Fumiyasu Seike, Haruhiko Higashi, Kazuhisa Nishimura, Katsuji Inoue, Shuntaro Ikeda, Osamu Yamaguchi

Pacing and clinical electrophysiology : PACE 46 ( 2 ) 152 - 160 2022.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Although premature atrial contractions (PACs) just after catheter ablation (CA) for atrial fibrillation (AF) are common, their clinical significance is uncertain. This study aimed to evaluate whether the PAC burden after an initial CA for AF was associated with late recurrence. METHODS: We enrolled 346 patients with AF (median age, 65 years; 30% female; 57% with paroxysmal AF) who underwent an initial radiofrequency CA and a 24-h Holter monitoring the day after the procedure. PAC was defined as supraventricular complexes occurring ≥30% earlier than expected compared with a previous RR interval, and the number of PAC/24 h during post-procedural Holter monitoring was analyzed. RESULTS: AF recurred in 106 patients (31%) during a median follow-up of 19 months. These patients had significantly more PAC/24 h than those without (median [interquartile range], 891 [316-4,351] beats vs. 409 [162-1,303] beats; P<0.01). The number of PACs was independently associated with AF recurrence after adjustment for clinical parameters and left atrial (LA) enlargement. Receiver operating characteristic curve analysis revealed that 1,431 PAC/24 h was the optimal cut-off value for predicting AF recurrence. ???Adding the PAC/24 h to the prediction model with LA diameter appeared to correctly reclassify patients who were thought to be at high risk for AF recurrence into the low-risk group and vice versa. CONCLUSIONS: The number of PACs was an independent risk factor for AF recurrence. A 24-h Holter recording the day after an initial CA is a simple and beneficial tool for the risk stratification of AF recurrence. This article is protected by copyright. All rights reserved.

DOI： 10.1111/pace.14648

Prognostic value of pericoronary adipose tissue attenuation in patients with non-alcoholic fatty liver disease with suspected coronary artery disease.

Keishi Ichikawa, Toru Miyoshi, Mitsutaka Nakashima, Takahiro Nishihara, Kazuhiro Osawa, Takashi Miki, Hironobu Toda, Masatoki Yoshida, Hiroshi Ito

Heart and vessels 37 ( 12 ) 1977 - 1984 2022.12

Language：English Publishing type：Research paper (scientific journal)

Pericoronary adipose tissue (PCAT) attenuation on coronary computed tomography angiography (CTA) has been emerged as a marker of pericoronary inflammation. We aimed to investigate the prognostic value of PCAT attenuation in patients with non-alcoholic fatty liver disease (NAFLD). We enrolled 232 NAFLD patients with suspected coronary artery disease and underwent coronary CTA. NAFLD was defined by abdominal CT as the ratio of hepatic attenuation to spleen attenuation less than 1.0. PCAT attenuation values were assessed by the crude analysis of mean CT attenuation value of the left anterior descending artery (LAD) and right coronary artery (RCA). As coronary CTA findings, luminal stenosis and high-risk plaque features were examined. Primary outcome was the composite of cardiovascular (CV) death, nonfatal acute coronary syndrome, and hospitalization for heart failure. During a median follow-up of 4.9 years, 17 patients had CV events. LAD-PCAT attenuation in patients with CV events was higher than that without CV events (-66.9 ± 7.0 versus -70.5 ± 6.6; p = 0.032), while RCA-PCAT attenuation was not. LAD-PCAT attenuation and high-risk plaque features were independent predictors of CV events. The addition of LAD-PCAT attenuation to high-risk plaque features increased the C-statistics and global chi-square from 0.66 to 0.75 (p = 0.042) and 6.8 to 12.7 (p = 0.015), respectively. The net reclassification achieved by adding LAD-PCAT attenuation to high-risk plaque features was 0.494 (p = 0.041). High-LAD-PCAT attenuation was an independent predictor of CV events in NAFLD patients, regardless of CTA-verified high-risk plaque features. In addition, LAD-PCAT attenuation had an incremental prognostic value over high-risk plaque features.

DOI： 10.1007/s00380-022-02107-x

Association between high oxidized high-density lipoprotein levels and increased pericoronary inflammation determined by coronary computed tomography angiography. International journal

Keishi Ichikawa, Toru Miyoshi, Kazuhiko Kotani, Kazuhiro Osawa, Mitsutaka Nakashima, Takahiro Nishihara, Hiroshi Ito

Journal of cardiology 80 ( 5 ) 410 - 415 2022.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Impaired high-density lipoprotein (HDL) function is a risk factor for cardiac mortality. We aimed to investigate the association between oxidized HDL (oxHDL) and pericoronary adipose tissue (PCAT) attenuation, a novel imaging biomarker of pericoronary inflammation, by using coronary computed tomography angiography (CTA). METHODS: A total of 287 outpatients with suspected coronary artery disease who had undergone both oxHDL measurement and coronary CTA were examined. PCAT attenuation values were assessed at the proximal 10-50 mm segments of the right coronary artery on coronary CTA. The presence of significant stenosis (luminal narrowing of >50 %) and high-risk plaque characteristics were also evaluated. Patients were then classified into tertiles according to their oxHDL level: low (n = 95), moderate (n = 96), and high (n = 96) groups. RESULTS: PCAT attenuation in the high oxHDL group was significantly higher than that in other groups after adjusting for age and apolipoprotein-A-I. Multivariate linear regression analysis revealed that oxHDL was significantly associated with PCAT attenuation in the right coronary artery (β = 3.832, p < 0.001), whereas HDL cholesterol was not. Furthermore, subgroup analyses demonstrated that the association between oxHDL and PCAT attenuation remained significant in older patients (β = 6.367, p < 0.001) and in those with hypertension (β = 4.922, p < 0.011), dyslipidemia (β = 3.264, p = 0.010), diabetes mellitus (β = 4.284, p = 0.015), and significant stenosis (β = 3.075, p = 0.021). CONCLUSIONS: High oxHDL levels were significantly associated with increased pericoronary inflammation, as assessed using coronary CTA. Our results may explain the association between impaired HDL function and the development of coronary atherosclerosis.

DOI： 10.1016/j.jjcc.2022.06.015

Cardio-Ankle Vascular Index as an Arterial Stiffness Marker Improves the Prediction of Cardiovascular Events in Patients without Cardiovascular Diseases. International journal

Yuko Okamoto, Toru Miyoshi, Keishi Ichikawa, Yoichi Takaya, Kazufumi Nakamura, Hiroshi Ito

Journal of cardiovascular development and disease 9 ( 11 ) 2022.10

Language：English Publishing type：Research paper (scientific journal)

Several studies have reported that the cardio-ankle vascular index (CAVI), a non-invasive measurement of arterial stiffness, is associated with the incidence of cardiovascular events. We investigated whether adding CAVI to a risk score improves the prediction of cardiovascular events in the setting of primary prevention. This retrospective observational study included consecutive 554 outpatients with cardiovascular disease risk factors but without known cardiovascular disease (68 ± 9 years, 64% men). The CAVI was measured using the VaSera vascular screening system. Major adverse cardiovascular events (MACE) included cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, and coronary revascularization. During a median follow-up of 4.3 years, cardiovascular events occurred in 65 patients (11.7%). Multivariate Cox analysis showed that abnormal CAVI (>9.0) was significantly associated with the incidence of MACE (hazard ratio 2.31, 95% confidence interval 1.27−4.18). The addition of CAVI to the Suita score, a conventional risk score for coronary heart disease in Japan, significantly improved the C statics from 0.642 to 0.713 (p = 0.04). In addition to a conventional risk score, CAVI improved the prediction of cardiovascular events in patients with cardiovascular disease risk factors but without known cardiovascular diseases.

DOI： 10.3390/jcdd9110368

The Fibrosis-4 Index Predicts Cardiovascular Prognosis in Patients With Severe Isolated Tricuspid Regurgitation.

Mitsutaka Nakashima, Machiko Tanakaya, Toru Miyoshi, Takaaki Saito, Yusuke Katayama, Satoru Sakuragi, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society 86 ( 11 ) 1777 - 1784 2022.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The fibrosis-4 (FIB-4) index is used to evaluate liver disease patients. It can also be used to evaluate the prognosis for heart disease patients; however, its ability to determine the prognosis of severe isolated tricuspid regurgitation (TR) patients is unclear. This study aimed to clarify the association between FIB-4 index scores and the cardiovascular prognosis for severe isolated TR patients.Methods and Results: This was a dual-center, retrospective study. From 2011 to 2019, 111 consecutive outpatients with severe isolated TR (mean age, 68.6 years; 53.2% male) were evaluated. Major adverse cardiovascular events (MACEs) were defined as the composite of cardiovascular death, hospitalization for heart failure, myocardial infarction, and stroke. The association between FIB-4 index scores and echocardiography was also evaluated. During a median follow up of 3.0 years, 24 patients were lost to follow up and 40 MACEs occurred. Baseline FIB-4 index scores for patients with MACEs were significantly higher than those for patients without MACEs. A multivariate analysis revealed that FIB-4 index scores are significantly associated with MACEs (hazard ratio, 1.89; 95% confidence interval, 1.01-3.54; P=0.046). A linear regression analysis indicated that FIB-4 index scores were correlated with echocardiographic parameters, including the left atrial volume index and left ventricular end-diastolic diameter. CONCLUSIONS: The FIB-4 index score may be a useful predictor of MACEs for patients with severe isolated TR.

DOI： 10.1253/circj.CJ-22-0109

The Association of Triglyceride to High-Density Lipoprotein Cholesterol Ratio with High-Risk Coronary Plaque Characteristics Determined by CT Angiography and Its Risk of Coronary Heart Disease. International journal

Yuji Koide, Toru Miyoshi, Takahiro Nishihara, Mitsutaka Nakashima, Keishi Ichikawa, Takashi Miki, Kazuhiro Osawa, Hiroshi Ito

Journal of cardiovascular development and disease 9 ( 10 ) 2022.9

Language：English Publishing type：Research paper (scientific journal)

The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio is an independent risk index for cardiovascular events. This study aimed to evaluate the association between TG/HDL-C ratio and coronary plaque characteristics as seen on coronary computed tomography angiography (CCTA) and the corresponding increase in the likelihood of cardiovascular events. A total of 935 patients who underwent CCTA for suspected coronary artery disease (CAD) were included. High-risk plaques (HRP) were defined based on three characteristics: positive remodeling, low-density plaques, and spotty calcification. Significant stenosis was defined as luminal narrowing of >70%. Patients with a higher TG/HDL-C ratio showed significantly greater prevalence of HRP and significant stenosis than patients with low TG/HDL-C ratios (p < 0.01). Multivariate logistic analysis demonstrated that the TG/HDL-C ratio was significantly associated with the presence of HRP (p < 0.01) but not with significant coronary stenosis (p = 0.24). During the median follow-up period of 4.1 years, 26 cardiovascular events including cardiovascular death and acute coronary syndrome occurred. The highest TG/HDL-C tertile was associated with cardiovascular events, with the lowest TG/HDL-C tertile as the reference (hazard ratio, 3.75; 95% confidence interval, 1.04−13.50). A high TG/HDL-C ratio is associated with the presence of CCTA-verified HRP, which can lead to cardiovascular events in patients with suspected CAD.

DOI： 10.3390/jcdd9100329

Effects of luseogliflozin and voglibose on high-risk lipid profiles and inflammatory markers in diabetes patients with heart failure. International journal

Kentaro Ejiri, Toru Miyoshi, Hajime Kihara, Yoshiki Hata, Toshihiko Nagano, Atsushi Takaishi, Hironobu Toda, Seiji Namba, Yoichi Nakamura, Satoshi Akagi, Satoru Sakuragi, Taro Minagawa, Yusuke Kawai, Nobuhiro Nishii, Soichiro Fuke, Masaki Yoshikawa, Kazufumi Nakamura, Hiroshi Ito

Scientific reports 12 ( 1 ) 15449 - 15449 2022.9

Language：English Publishing type：Research paper (scientific journal)

Sodium-glucose cotransporter 2 inhibitors could reduce cardiovascular events in patients with heart failure irrespective of diabetes status. In this prespecified sub-analysis of randomised-controlled trial, we investigated the efficacy of luseogliflozin (2.5 mg daily), a sodium-glucose cotransporter 2 inhibitor, with that of voglibose (0.6 mg daily), an alpha-glucosidase inhibitor, on high-risk lipid profile and inflammatory markers in patients with type-2 diabetes and heart failure. Among the 157 patients studied, there were no significant differences in the mean malondialdehyde LDL or small-dense LDL cholesterol levels between the luseogliflozin and voglibose groups (percent change: 0.2% vs. - 0.6%, p = 0.93; - 1.7% vs. - 8.6%, p = 0.21) after 12 weeks in comparison to levels at the baseline. No significant difference was observed between the two groups in the adiponectin and high-sensitivity C-reactive protein levels after 12 weeks compared to the baseline levels (percent change, - 1.6% vs. - 4.0% and 22.5% vs. 10.0%; p = 0.52 and p = 0.55, respectively). In conclusion, in patients with type-2 diabetes and heart failure, compared to voglibose, luseogliflozin did not significantly improve the high-risk lipoprotein profile including malondialdehyde LDL and small-dense LDL cholesterol or the levels of inflammatory markers, including adiponectin and high-sensitivity C-reactive protein.Trial registration: Trial number: UMIN-CTR, UMIN000018395; Registered 23 July 2015; URL: https://www.umin.ac.jp/ctr/index.htm .

DOI： 10.1038/s41598-022-19371-6

High platelet reactivity is a predictor of left ventricular remodelling in patients with acute myocardial infarction

Masahiro Tsuji, Yusuke Kawai, Toru Miyoshi, Eisuke Saito, Kohei Kawamura, Tamaki Ono, Koji Tokioka, Tohru Ohe, Kazufumi Nakamura, Hiroshi Ito

ESC Heart Failure 9 ( 5 ) 3565 - 3574 2022.7

Publishing type：Research paper (scientific journal) Publisher：Wiley

Abstract

Aims

Acute myocardial infarction (AMI) is associated with left ventricular remodelling (LVR), which leads to progressive heart failure. Platelets play a pivotal role in promoting systemic and cardiac inflammatory responses during the complex process of myocardial wound healing or repair following AMI. This study aimed to investigate the impact of platelet reactivity immediately after primary percutaneous coronary intervention (PCI) on LVR in AMI patients with ST‐segment (STEMI) and non‐ST‐segment elevation (NSTEMI).

Methods and results

This prospective, single‐centre, observational study included 182 patients with AMI who underwent primary PCI (107 patient with STEMI and 75 patients with NSTEMI). Patients were administered a loading dose of aspirin plus prasugrel before the procedure, and platelet reactivity was assessed using the VerifyNow P2Y12 assay immediately after PCI. Echocardiography was performed before discharge and during the chronic phase (8 ± 3 months after discharge). LVR was defined as a relative ≥20% increase in left ventricular end‐diastolic volume index (LVEDVI). LVR in chronic phase was found in 34 patients (18.7%) whose platelet reactivity was significantly higher than those without LVR (259.6 ± 61.5 and 213.1 ± 74.8 P2Y12 reaction units [PRU]; P = 0.001). The occurrence of LVR did not differ between patients with STEMI and patients with NSTEMI (21.5% and 14.7%; P = 0.33). The optimal cut‐off value of platelet reactivity for discriminating LVR was ≥245 PRU. LVEDVI significantly decreased at chronic phase in patients without high platelet reactivity (<245 PRU) (from 49.2 ± 13.5 to 45.4 ± 15.8 mL/m²; P = 0.02), but not in patients with high platelet reactivity (≥d245 PRU) (P = 0.06). Multivariate logistic analysis showed that high platelet reactivity was an independent predictor of LVR after adjusting for LVEDVI before discharge (odds ratio, 4.13; 95% confidence interval, 1.85–9.79).

Conclusions

High platelet reactivity measured immediately after PCI was a predictor of LVR in patients with AMI during the chronic phase. The role of antiplatelet therapy on inflammation in the myocardium is a promising area for further research.

DOI： 10.1002/ehf2.14100

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ehf2.14100

Overview of the 86th Annual Scientific Meeting of the Japanese Circulation Society - Cardiology Spreading Its Wings.

Kazufumi Nakamura, Toru Miyoshi, Satoshi Akagi, Norihisa Toh, Yukihiro Saito, Yoichi Takaya, Masatoki Yoshida, Koji Nakagawa, Satoshi Kawada, Hironobu Toda, Takashi Miki, Rie Nakayama, Fumi Yokohama, Keishi Ichikawa, Masashi Yoshida, Makiko Taniyama, Nobuhiro Nishii, Teiji Akagi, Hiroshi Morita, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society 86 ( 8 ) 1312 - 1318 2022.7

Language：English Publishing type：Research paper (scientific journal)

The 86thAnnual Scientific Meeting of the Japanese Circulation Society was held in a web-based format on March 11-13, 2022. In accordance with the internationalization policy of the JCS, the meeting was held with the Asian Pacific Society of Cardiology Congress 2022. The main theme was "Cardiology Spreading its Wings". The number of patients with heart failure and other cardiovascular diseases is increasing dramatically, and the fields dealt with by cardiovascular medicine are also greatly expanding. This conference was both intellectually satisfying and exciting for all participants, who numbered over 14,900. The meeting was completed with great success, and the enormous amount of cooperation and support from all involved was greatly appreciated.

DOI： 10.1253/circj.CJ-22-0349

冠動脈疾患を疑われた非アルコール性脂肪性肝疾患における冠動脈周囲脂肪炎症の予後予測効果への検討単施設後ろ向き研究

中島充貴, 三好亨, 市川啓之, 西原大裕, 三木崇史, 戸田洋伸, 吉田雅言, 伊藤浩

日本動脈硬化学会総会プログラム・抄録集 54回 229 - 229 2022.7

Impact of shear wave dispersion slope analysis for assessing the severity of myocarditis. International journal

Naofumi Amioka, Yoichi Takaya, Kazufumi Nakamura, Megumi Kondo, Kaoru Akazawa, Yuko Ohno, Keishi Ichikawa, Rie Nakayama, Yukihiro Saito, Satoshi Akagi, Toru Miyoshi, Masashi Yoshida, Hiroshi Morita, Hiroshi Ito

Scientific reports 12 ( 1 ) 8776 - 8776 2022.5

Language：English Publishing type：Research paper (scientific journal)

This study aimed to elucidate the utility of a novel ultrasound-based technique, shear wave dispersion slope (SWDS) analysis, which estimates tissue viscosity, for evaluating the severity of myocardial inflammation. Experimental autoimmune myocarditis (EAM) at different disease phases [3-week (acute phase): n = 10, 5-week (subacute phase): n = 9, and 7-week (late phase): n = 11] were developed in male Lewis rats. SWDS was measured in the right and the left ventricular free walls (RVFW and LVFW) under a retrograde perfusion condition. Histological myocardial inflammation was evaluated by CD68 staining. The accumulation of CD68-positive cells was severe in the myocardium of the EAM 3-week group. The median (interquartile range) SWDS of RVFW was significantly higher in the EAM 3-week group [9.9 (6.5-11.0) m/s/kHz] than in the control group [5.4 (4.5-6.8) m/s/kHz] (P = 0.034). The median SWDS of LVFW was also significantly higher in the EAM 3-week group [8.1 (6.4-11.0) m/s/kHz] than in the control group [4.4 (4.2-4.8) m/s/kHz] (P = 0.003). SWDS and the percentage of CD68-positive area showed a significant correlation in RVFW (R2 = 0.64, P < 0.001) and LVFW (R2 = 0.73, P < 0.001). This study showed that SWDS was elevated in ventricular walls with acute inflammation and also significantly correlated with the degree of myocardial inflammation. These results suggest the potential of SWDS in estimating the histological severity of acute myocarditis.

DOI： 10.1038/s41598-022-12935-6

Association of Oxidized Low-Density Lipoprotein in Nonalcoholic Fatty Liver Disease with High-Risk Plaque on Coronary Computed Tomography Angiography: A Matched Case-Control Study. International journal

Takahiro Nishihara, Toru Miyoshi, Keishi Ichikawa, Kazuhiro Osawa, Mitsutaka Nakashima, Takashi Miki, Hiroshi Ito

Journal of clinical medicine 11 ( 10 ) 2022.5

Language：English Publishing type：Research paper (scientific journal)

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for the development of atherosclerotic cardiovascular diseases (CVDs), and oxidative stress has been proposed as a shared pathophysiological condition. This study examined whether oxidized low-density lipoprotein (LDL) is involved in the underlying mechanism that links coronary atherosclerosis and NAFLD. This study included 631 patients who underwent coronary computed tomography angiography (CTA) for suspected coronary artery disease. NAFLD was defined on CT images as a liver-to-spleen attenuation ratio of <1.0. Serum-malondialdehyde-modified LDL (MDA-LDL) and coronary CTA findings were analyzed in a propensity-score-matched cohort of patients with NAFLD (n = 150) and those without NAFLD (n = 150). This study analyzed 300 patients (median age, 65 years; 64% men). Patients with NAFLD had higher MDA-LDL levels and a greater presence of CTA-verified high-risk plaques than those without NAFLD. In the multivariate linear regression analysis, MDA-LDL was independently associated with NAFLD (β = 11.337, p = 0.005) and high-risk plaques (β = 12.487, p = 0.007). Increased MDA-LDL may be a mediator between NAFLD and high-risk coronary plaque on coronary CTA. Increased oxidative stress in NAFLD, as assessed using MDA-LDL, may be involved in the development of CVDs.

DOI： 10.3390/jcm11102838

Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes. International journal

Yukihiro Saito, Kazufumi Nakamura, Masashi Yoshida, Hiroki Sugiyama, Satoshi Akagi, Toru Miyoshi, Hiroshi Morita, Hiroshi Ito

Stem cell research & therapy 13 ( 1 ) 141 - 141 2022.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The number of patients with bradyarrhythmia and the number of patients with cardiac pacemakers are increasing with the aging population and the increase in the number of patients with heart diseases. Some patients in whom a cardiac pacemaker has been implanted experience problems such as pacemaker infection and inconvenience due to electromagnetic interference. We have reported that overexpression of HCN channels producing a pacemaker current in mouse embryonic stem cell-derived cardiomyocytes showed enhanced pacing function in vitro and in vivo. The aim of this study was to determine whether HCN4 overexpression in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can strengthen the pacing function of the cells. METHODS: Human HCN4 was transduced in the AAVS1 locus of human induced pluripotent stem cells by nucleofection and HCN4-overexpressing iPSC-CMs were generated. Gene expression profiles, frequencies of spontaneous contraction and pacing abilities of HCN4-overexpressing and non-overexpressing iPSC-CMs in vitro were compared. RESULTS: HCN4-overexpressing iPSC-CMs showed higher spontaneous contraction rates than those of non-overexpressing iPSC-CMs. They responded to an HCN channel blocker and β adrenergic stimulation. The pacing rates against parent iPSC line-derived cardiomyocytes were also higher in HCN4-overexpressing iPSC-CMs than in non-overexpressing iPSC-CMs. CONCLUSIONS: Overexpression of HCN4 showed enhancement of If current, spontaneous firing and pacing function in iPSC-CMs. These data suggest this transgenic cell line may be useful as a cardiac pacemaker.

DOI： 10.1186/s13287-022-02818-y

Pathophysiology and Treatment of Diabetic Cardiomyopathy and Heart Failure in Patients with Diabetes Mellitus

Kazufumi Nakamura, Toru Miyoshi, Masashi Yoshida, Satoshi Akagi, Yukihiro Saito, Kentaro Ejiri, Naoaki Matsuo, Keishi Ichikawa, Keiichiro Iwasaki, Takanori Naito, Yusuke Namba, Masatoki Yoshida, Hiroki Sugiyama, Hiroshi Ito

International Journal of Molecular Sciences 23 ( 7 ) 3587 - 3587 2022.3

Publishing type：Research paper (scientific journal) Publisher：MDPI AG

There is a close relationship between diabetes mellitus and heart failure, and diabetes is an independent risk factor for heart failure. Diabetes and heart failure are linked by not only the complication of ischemic heart disease, but also by metabolic disorders such as glucose toxicity and lipotoxicity based on insulin resistance. Cardiac dysfunction in the absence of coronary artery disease, hypertension, and valvular disease is called diabetic cardiomyopathy. Diabetes-induced hyperglycemia and hyperinsulinemia lead to capillary damage, myocardial fibrosis, and myocardial hypertrophy with mitochondrial dysfunction. Lipotoxicity with extensive fat deposits or lipid droplets is observed on cardiomyocytes. Furthermore, increased oxidative stress and inflammation cause cardiac fibrosis and hypertrophy. Treatment with a sodium glucose cotransporter 2 (SGLT2) inhibitor is currently one of the most effective treatments for heart failure associated with diabetes. However, an effective treatment for lipotoxicity of the myocardium has not yet been established, and the establishment of an effective treatment is needed in the future. This review provides an overview of heart failure in diabetic patients for the clinical practice of clinicians.

DOI： 10.3390/ijms23073587

LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats. International journal

Toru Miyoshi, Kazufumi Nakamura, Naofumi Amioka, Omer F Hatipoglu, Tomoko Yonezawa, Yukihiro Saito, Masashi Yoshida, Satoshi Akagi, Hiroshi Ito

Scientific reports 12 ( 1 ) 4930 - 4930 2022.3

Language：English Publishing type：Research paper (scientific journal)

Doxorubicin (DOX)-based chemotherapy induces cardiotoxicity, which is considered the main bottleneck for its clinical application. In this study, we investigated the potential benefit of LCZ696, an angiotensin receptor-neprilysin inhibitor against DOX-induced cardiotoxicity in rats and H9c2 cells and determined whether the mechanism underlying any such effects involves its antioxidant activity. Male Sprague-Dawley rats were randomly separated into four groups, each consisting of 15 rats (DOX (1.5 mg/kg/day intraperitoneally for 10 days followed by non-treatment for 8 days); DOX + valsartan (31 mg/kg/day by gavage from day 1 to day 18); DOX + LCZ696 (68 mg/kg/day by gavage from day 1 to day 18); and control (saline intraperitoneally for 10 days). DOX-induced elevation of cardiac troponin T levels on day 18 was significantly reduced by LCZ696, but not valsartan. The DOX-induced increase in myocardial reactive oxygen species (ROS) levels determined using dihydroethidium was significantly ameliorated by LCZ696, but not valsartan, and was accompanied by the suppression of DOX-induced increase in p47phox. LCZ696 recovered the DOX-induced decrease in phosphorylation of adenosine monophosphate-activated protein kinase and increased the ratio of Bax and Bcl-2. In H9c2 cardiomyocytes, LCZ696 reduced DOX-induced mitochondrial ROS generation and improved cell viability more than valsartan. Our findings indicated that LCZ696 ameliorated DOX-induced cardiotoxicity in rat hearts in vivo and in vitro, possibly by mediating a decrease in oxidative stress.

DOI： 10.1038/s41598-022-09094-z

High pericoronary adipose tissue attenuation on computed tomography angiography predicts cardiovascular events in patients with type 2 diabetes mellitus: post-hoc analysis from a prospective cohort study. International journal

Keishi Ichikawa, Toru Miyoshi, Kazuhiro Osawa, Mitsutaka Nakashima, Takashi Miki, Takahiro Nishihara, Hironobu Toda, Masatoki Yoshida, Hiroshi Ito

Cardiovascular diabetology 21 ( 1 ) 44 - 44 2022.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Pericoronary adipose tissue (PCAT) attenuation on coronary computed tomography angiography (CTA) is a non-invasive biomarker for pericoronary inflammation. We aimed to investigate the prognostic value of PCAT attenuation in patients with type 2 diabetes mellitus (T2DM). METHODS: We included 333 T2DM patients (mean age, 66 years; male patients, 211; mean body mass index, 25 kg/m2) who underwent clinically indicated coronary CTA and examined their CT findings, coronary artery calcium score, pericardial fat volume, stenosis (> 50% luminal narrowing), high-risk plaque features of low-attenuation plaque and/or positive remodelling and/or spotty calcification, and PCAT attenuation. We assessed PCAT attenuation in Hounsfield units (HU) of proximal 40-mm segments of the left anterior descending artery (LAD) and right coronary artery (RCA). Cardiovascular events were defined as cardiac death, hospitalisation for acute coronary syndrome, late coronary revascularisation, and hospitalisation for heart failure. RESULTS: During a median follow-up of 4.0 years, we observed 31 cardiovascular events. LAD-PCAT attenuation was significantly higher in patients with cardiovascular events than in those without (- 68.5 ± 6.5 HU vs - 70.8 ± 6.1 HU, p = 0.045), whereas RCA-PCAT attenuation was not (p = 0.089). High LAD-PCAT attenuation (> - 70.7 HU; median value) was significantly associated with cardiovascular events in a model that included adverse CTA findings, such as significant stenosis and/or high-risk plaque (hazard ratio; 2.69, 95% confidence interval; 1.17-0.20, p = 0.020). After adding LAD-PCAT attenuation to the adverse CTA findings, the C-statistic and global chi-square values increased significantly from 0.65 to 0.70 (p = 0.037) and 10.9-15.0 (p = 0.043), respectively. CONCLUSIONS: In T2DM patients undergoing clinically indicated coronary CTA, high LAD-PCAT attenuation could significantly predict cardiovascular events. This suggests that assessing LAD-PCAT attenuation can help physicians identify high-risk T2DM patients.

DOI： 10.1186/s12933-022-01478-9

2型糖尿病および左室駆出率が保たれた心不全患者におけるLuseogliflozinの推定血漿量への影響(Effects of Luseogliflozin on Estimated Plasma Volume in Patients with Type 2 Diabetes and Heart Failure with Preserved Ejection Fraction)

中島充貴, 三好亨, 江尻健太郎, 木原一, 幡芳樹, 長野俊彦, 高石篤志, 戸田洋伸, 赤木達, 櫻木悟, 皆川太郎, 伊藤浩

日本循環器学会学術集会抄録集 86回 JO09 - 1 2022.3

CTにおけるPericoronary Fat Attenuation Indexは虚血性心疾患の既往がない患者における心不全入院を予測する(Pericoronary Fat Attenuation Index on Computed Tomography Predicts Hospitalization for Heart Failure in Patients without History of Ischemic Heart Disease)

中島充貴, 三好亨, 市川啓之, 西原大裕, 三木崇史, 高谷陽一, 横濱ふみ, 中山理絵, 杜徳尚, 伊藤浩

日本循環器学会学術集会抄録集 86回 MPJ05 - 2 2022.3

Effects of luseogliflozin on estimated plasma volume in patients with heart failure with preserved ejection fraction. International journal

Mitsutaka Nakashima, Toru Miyoshi, Kentaro Ejiri, Hajime Kihara, Yoshiki Hata, Toshihiko Nagano, Atsushi Takaishi, Hironobu Toda, Seiji Nanba, Yoichi Nakamura, Satoshi Akagi, Satoru Sakuragi, Taro Minagawa, Yusuke Kawai, Nobuhiro Nishii, Soichiro Fuke, Masaki Yoshikawa, Kazufumi Nakamura, Hiroshi Ito

ESC heart failure 9 ( 1 ) 712 - 720 2022.2

Language：English Publishing type：Research paper (scientific journal)

AIMS: Sodium glucose co-transporter 2 inhibitors have diuretic effects in both patients with glycosuria and with natriuresis. We sought to assess the effect of luseogliflozin on estimated plasma volume (ePV) in patients with type 2 diabetes and heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: This study was a post-hoc analysis of the MUSCAT-HF trial (UMIN000018395), a multicentre, prospective, open-label, randomized controlled trial that assessed the effect of 12 weeks of luseogliflozin (2.5 mg, once daily, n = 83) as compared with voglibose (0.2 mg, three times daily, n = 82) on the reduction in brain natriuretic peptide (BNP) in patients with type 2 diabetes and HFpEF. The analysis compared the change in ePV calculated by the Straus formula from baseline to Weeks 4, 12, and 24, using a mixed-effects model for repeated measures. We also estimated the association between changes in ePV and changes in other clinical parameters, including BNP levels. Luseogliflozin significantly reduced ePV as compared to voglibose at Week 4 {adjusted mean group-difference -6.43% [95% confidence interval (CI): -9.11 to -3.74]}, at Week 12 [-8.73% (95%CI: -11.40 to -6.05)], and at Week 24 [-11.02% (95%CI: -13.71 to -8.33)]. The effect of luseogliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in ePV at Week 12 was significantly associated with log-transformed BNP (r = 0.197, P = 0.015) and left atrial volume index (r = 0.283, P = 0.019). CONCLUSIONS: Luseogliflozin significantly reduced ePV in patients with type 2 diabetes and HFpEF, as compared with voglibose. The reduction of intravascular volume by luseogliflozin may provide clinical benefits to patients with type 2 diabetes and HFpEF.

DOI： 10.1002/ehf2.13683

2型糖尿病患者におけるCTを用いた冠動脈周囲脂肪の炎症イメージングによるリスク評価

市川啓之, 三好亨, 中島充貴, 西原大裕, 三木崇史, 中村一文, 森田宏, 伊藤浩

日本内科学会雑誌 111 ( 臨増 ) 158 - 158 2022.2

Pemafibrate Prevents Rupture of Angiotensin II-Induced Abdominal Aortic Aneurysms. International journal

Naofumi Amioka, Toru Miyoshi, Tomoko Yonezawa, Megumi Kondo, Satoshi Akagi, Masashi Yoshida, Yukihiro Saito, Kazufumi Nakamura, Hiroshi Ito

Frontiers in cardiovascular medicine 9 904215 - 904215 2022

Language：English Publishing type：Research paper (scientific journal)

Background: Abdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPARα) agonist, on AAA formation and rupture. Methods: Experimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE - / - mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS). Results: The size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-α in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPARα significantly attenuated the anti-oxidative effect of pemafibrate. Conclusion: Pemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells.

DOI： 10.3389/fcvm.2022.904215

Role of coronary computed tomography angiography (CTA) post the ISCHEMIA trial: Precision prevention based on coronary CTA-derived coronary atherosclerosis. International journal

Rine Nakanishi, Kazuhiro Osawa, Akira Kurata, Toru Miyoshi

Journal of cardiology 2021.12

Language：English Publishing type：Research paper (scientific journal)

The International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial has been recently published and suggested the importance of the selection of patients at high risk for future cardiovascular disease events and the enhancing optimal medical therapy. In the ISCHEMIA trial, coronary computed tomography angiography (CTA) was performed in most of the patients to exclude high-risk patients and those without obstructive coronary artery disease (CAD) who should not be randomized. Coronary CTA has been widely used as a non-invasive diagnostic modality to assess patients with suspected CAD. Currently, the international guidelines allow use of coronary CTA as a class I recommendation for patients with chest pain. Besides, in the numerous multicenter trials, the emerging role of coronary CTA has proven that it could soon become the standard for monitoring CAD and identifying patients at high risk of future cardiovascular events. In this review article, we summarize the current evidence on coronary CTA and the potential role of coronary CTA after the ISCHEMIA trial for patients with CAD. Risk assessment using detailed CAD data obtained non-invasively and prevention of future cardiovascular events through improved medical care will become increasingly essential for the precision treatment and prevention of CAD in patients.

DOI： 10.1016/j.jjcc.2021.12.006

Arterial stiffness in health and disease: The role of cardio-ankle vascular index. International journal

Toru Miyoshi, Hiroshi Ito

Journal of cardiology 78 ( 6 ) 493 - 501 2021.12

Language：English Publishing type：Research paper (scientific journal)

Arterial stiffness increases with age, as well as in various pathological states, including obesity, diabetes mellitus, smoking, and dyslipidemia, and it has important consequences for cardiovascular health. Arterial stiffness plays a central role in hemodynamic dysfunction characterized by excess pulsatility; specifically, it leads to heart failure, cerebrovascular disease, and renal failure. Among measures of arterial stiffness, carotid-femoral pulse wave velocity is considered as the reference standard; however, it has not been incorporated into routine clinical practice. Cardio-ankle vascular index (CAVI), which is a marker of arterial stiffness measured from the origin of the aorta to the ankle, was developed in 2004. CAVI is based on stiffness parameter β, which is theoretically independent of blood pressure at the time of measurement. CAVI applies stiffness parameter β to arterial segments between the heart and ankle. The measurement of CAVI is simple and well-standardized, and its reproducibility and accuracy are acceptable. Several studies have demonstrated that CAVI is high in patients with various atherosclerotic risk factors, and treatment of cardiovascular risk factors and lifestyle modifications improve CAVI. Several prospective studies have investigated the association between CAVI and future cardiovascular events in the general population and in patients with cardiovascular risk factors. A cut-off value of 9.0 is proposed for predicting patients at a high risk of cardiovascular events. From this review, it is clear that CAVI may be useful in the prevention of cardiovascular disease.

DOI： 10.1016/j.jjcc.2021.07.011

Usefulness of cardiac fusion imaging with computed tomography and Doppler echocardiography in the assessment of conduit stenosis in complex adult congenital heart disease. International journal

Nobuhisa Watanabe, Norihisa Toh, Yoichi Takaya, Rie Nakayama, Fumi Yokohama, Kazuhiro Osawa, Toru Miyoshi, Teiji Akagi, Susumu Kanazawa, Hiroshi Ito

Journal of cardiology 78 ( 6 ) 473 - 479 2021.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Noninvasive assessment of stenotic lesions in patients with complex adult congenital heart disease (ACHD) is challenging due to its complex morphology. The simultaneous two-screen display of multidetector-computed tomography (MDCT) and real-time echogram (STDME) technology can display a virtual multi-planar reconstruction from MDCT corresponding to the same cross-sectional image from transthoracic echocardiography (TTE). We investigated the usefulness of the STDME technology for stenosis severity assessment in complex ACHD patients. METHODS: Twenty-four complex ACHD patients with stenotic lesions were enrolled in this study. All patients underwent TTE and the STDME technology within a week after MDCT. Peak velocity and pressure gradient (PG) across the stenotic site were measured using continuous wave Doppler. Cardiac catheterization was performed in 17 patients. RESULTS: Nine out of the twenty-four patients had undergone repair with a conduit. Peak velocity and PG from the STDME technology were higher than those from TTE (peak velocity: 3.1 ± 1.1 vs. 2.8 ± 1.0 m/s; peak PG: 43 ± 28 vs. 34 ± 21 mmHg; both p < 0.01). Peak PG from the STDME technology showed significant correlations with those from catheterization in patients with a conduit (n=7) and those without a conduit (n=10) (r = 0.795 and 0.880, respectively; both p < 0.05), while peak PG from TTE was correlated with catheterization measurements only in patients without a conduit (r = 0.850, p < 0.05). CONCLUSIONS: The STDME technology enables more accurate assessment of conduit stenosis severity than does TTE in complex ACHD patients.

DOI： 10.1016/j.jjcc.2021.06.008

Efficacy of shear wave elasticity for evaluating myocardial hypertrophy in hypertensive rats. International journal

Yoichi Takaya, Kazufumi Nakamura, Rie Nakayama, Hiroaki Ohtsuka, Naofumi Amioka, Megumi Kondo, Kaoru Akazawa, Yuko Ohno, Keishi Ichikawa, Yukihiro Saito, Satoshi Akagi, Masashi Yoshida, Toru Miyoshi, Hiroshi Ito

Scientific reports 11 ( 1 ) 22812 - 22812 2021.11

Language：English Publishing type：Research paper (scientific journal)

Shear wave (SW) imaging is a novel ultrasound-based technique for assessing tissue characteristics. SW elasticity may be useful to assess the severity of hypertensive left ventricular (LV) hypertrophy. This study aimed to evaluate the efficacy of SW elasticity for assessing the degree of myocardial hypertrophy using hypertensive rats. Rats were divided into hypertension group and control group. SW elasticity was measured on the excised heart. Myocardial hypertrophy was assessed histologically. LV weight was greater in hypertension group. An increase in interventricular septum and LV free wall thicknesses was observed in hypertension group. SW elasticity was significantly higher in hypertension group than in control group (14.6 ± 4.3 kPa vs. 6.5 ± 1.1 kPa, P < 0.01). The cross-sectional area of cardiomyocytes was larger in hypertension group than in control group (397 ± 50 μm2 vs. 243 ± 14 μm2, P < 0.01), and SW elasticity was positively correlated with the cross-sectional area of cardiomyocytes (R = 0.96, P < 0.01). This study showed that SW elasticity was higher in hypertensive rats and was closely correlated with the degree of myocardial hypertrophy, suggesting the efficacy of SW elasticity for estimating the severity of hypertensive LV hypertrophy.

DOI： 10.1038/s41598-021-02271-6

The number of circulating CD34-positive cells is an independent predictor of coronary artery calcification progression: Sub-analysis of a prospective multicenter study. International journal

Keishi Ichikawa, Toru Miyoshi, Kazuhiro Osawa, Takashi Miki, Kunihisa Kohno, Kazufumi Nakamura, Yasushi Koyama, Hiroshi Ito

Cardiology journal 2021.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Decreases in circulating CD34-positive cells are associated with increases in cardiovascular events. We investigated the association between the number of CD34-positive cells and the progression of coronary artery calcification (CAC), a marker of atherosclerosis, in patients with hypercholesteremia under statin therapy in a sub-analysis of a multicenter study. METHODS: In the principal study, patients with CAC scores of 1-999 were treated with pitavastatin. Measurement of CAC by non-enhanced computed tomography and a blood test were performed at baseline and at 1-year follow-up. Patients were divided into two groups: CAC progression (change in CAC score > 0) and non-progression. The number of circulating CD34-positive cells was counted using flow cytometry. RESULTS: A total of 156 patients (mean age 67 years, 55% men) were included in this sub-analysis. CD34 positive cell numbers at baseline as a continuous variable was inversely correlated with annual change in the log-transformed CAC score (r = -0.19, p = 0.02). When patients were divided into high and low CD34 groups based on the median value of 0.8 cells/μL, the adjusted change in CAC score in the low-CD34 group was significantly greater than that in the high-CD34 group (54.2% vs. 20.8%, respectively, p = 0.04). In multiple logistic analysis, a low CD34-positive cell number was an independent predictor of CAC progression, with an odds ratio of 2.88 (95% confidence interval 1.28-6.49, p = 0.01). CONCLUSIONS: Low numbers of CD34-positive cells are associated with CAC progression in patients with hypercholesterolemia under statin therapy. The number of CD34-positive cells may help to identify patients at increased cardiovascular risk.

DOI： 10.5603/CJ.a2021.0151

Fragmented QRS as a predictor of cardiac events in patients with cardiac sarcoidosis. International journal

Soichiro Ogura, Kazufumi Nakamura, Hiroshi Morita, Koji Nakagawa, Nobuhiro Nishii, Satoshi Akagi, Norihisa Toh, Yoichi Takaya, Masashi Yoshida, Toru Miyoshi, Atsuyuki Watanabe, Hiroshi Ito

Journal of cardiology 79 ( 3 ) 446 - 452 2021.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Multiple spikes within the QRS complex, known as fragmented QRS (fQRS), are associated with the occurrences of ventricular arrhythmic events (VAEs) in patients with Brugada syndrome and hypertrophic cardiomyopathy. However, the association between fQRS and occurrence of VAEs in patients with cardiac sarcoidosis (CS) has not been elucidated. METHODS: We evaluated the associations between fQRS and cardiac events including VAEs [non-sustained ventricular tachycardia (NSVT), sustained ventricular tachycardia (VT), and ventricular fibrillation (VF)], hospitalization for heart failure, and all-cause death in 68 patients with CS (30 patients with fQRS vs. 38 patients without fQRS) over a 5-year period. RESULTS: Cardiac events occurred in 22 patients with fQRS and 18 patients without fQRS (73% vs. 47%, p=0.009). Of the cardiac events that occurred in CS patients, VAEs occurred more frequently in patients with fQRS than in patients without fQRS (VAEs: 70% vs. 45%, p=0.017; NSVT: 70% vs. 45%, p=0.010; VT: 43% vs. 18%, p=0.011, and VF: 6.7% vs. 2.6%, p=0.34), whereas there was no significant difference in hospitalization for heart failure or all-cause death between patients with and those without fQRS (hospitalization for heart failure: 6.7% vs. 5.3%, p=0.75; all-cause death: 6.7% vs. 5.3%, p=0.64). Multivariate analysis showed that fQRS in the baseline electrocardiogram was independently associated with VAEs (hazard ratio: 2.21, 95% confidence interval: 1.15-4.25, p=0.017). CONCLUSION: fQRS is a predictor of VAEs in patients with CS.

DOI： 10.1016/j.jjcc.2021.10.022

Clinical Applications Measuring Arterial Stiffness: An Expert Consensus for the Application of Cardio-Ankle Vascular Index (CAVI). International journal

Matthew J Budoff, Bruce Alpert, Julio A Chirinos, Bo Fernhall, Naomi Hamburg, Kazuomi Kario, Iftikhar Kullo, Kunihiro Matsushita, Toru Miyoshi, Hirofumi Tanaka, Ray Townsend, Paul Valensi

American journal of hypertension 2021.11

Language：English Publishing type：Research paper (scientific journal)

The purpose of this document is to provide clinicians with guidance, using expert consensus, to help summarize evidence and offer practiacl recommendations. Expert Consensus Documents are intended to provide guidance for clinicians in areas in which there are no clinical practice guidelines, especially for new and evolving tests such as arterial stiffness measurements, until any formal guidelines are released. This expert consensus document is intended as a source of information for decision making and to guide clinician-patient discussions in various clinical scenarios, and the goal is to help clinicians and patients make a more informed decision together.

DOI： 10.1093/ajh/hpab178

Preventative effects of bisoprolol transdermal patches on postoperative atrial fibrillation in high-risk patients undergoing non-cardiac surgery: A subanalysis of the MAMACARI study. International journal

Takayuki Iwano, Hironobu Toda, Kazufumi Nakamura, Kazuyoshi Shimizu, Kentaro Ejiri, Yoichiro Naito, Hisatoshi Mori, Takuro Masuda, Toru Miyoshi, Masashi Yoshida, Yukiko Hikasa, Hiroshi Morimatsu, Hiroshi Ito

Journal of cardiology 78 ( 5 ) 349 - 354 2021.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Perioperative atrial fibrillation (POAF) after non-cardiac surgery is a risk factor for cardiovascular events including stroke and death. The aim of this subanalysis of the MAMACARI study, a multicenter randomized control study on the effectiveness of a bisoprolol transdermal patch for prevention of perioperative myocardial injury in high-risk patients undergoing non-cardiac surgery, was to identify the predictors of POAF after non-cardiac surgery in high-risk patients and to determine changes in blood pressure and heart rate during bisoprolol patch administration in the perioperative period. METHODS AND RESULTS: Patients aged over 60 years with hypertension and a high revised cardiac risk index (≥2) who were scheduled to undergo non-cardiac surgery were randomly assigned to a bisoprolol patch group (n = 120) or a control group (n = 120). We divided the patients into two groups: patients with POAF (POAF group; n = 16) and patients without POAF (non-POAF group; n = 206). Multivariate analysis showed that bisoprolol patch therapy (OR: 0.30, 95% CI: 0.092-0.978) and surgery time of 250 min or more (OR: 4.99, 95% CI: 1.37-18.2) were independently associated with POAF. Although systolic blood pressure did not differ significantly between the two groups throughout the perioperative period, treatment with a bisoprolol patch significantly reduced heart rate throughout the perioperative period compared with that in the control group. CONCLUSIONS: Low dose of a bisoprolol patch in the perioperative period was effective for prevention of POAF after non-cardiac surgery in high-risk patients, while long surgery time was an independent risk factor for POAF. It is expected that low dose of a bisoprolol patch can prevent POAF without causing hypotension.

DOI： 10.1016/j.jjcc.2021.05.001

The utility of cardiac computed tomography in distinguishing a coumadin ridge. International journal

Keishi Ichikawa, Toru Miyoshi, Noriaki Akagi, Takashi Miki, Yoichi Takaya, Hiroshi Ito

Journal of cardiovascular computed tomography 2021.9

Association between higher pericoronary adipose tissue attenuation measured by coronary computed tomography angiography and nonalcoholic fatty liver disease: A matched case-control study. International journal

Keishi Ichikawa, Toru Miyoshi, Kazuhiro Osawa, Takashi Miki, Yusuke Morimitsu, Noriaki Akagi, Mitsutaka Nakashima, Hiroshi Ito

Medicine 100 ( 34 ) e27043 2021.8

Language：English Publishing type：Research paper (scientific journal)

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a risk factor for cardiac mortality. Pericoronary adipose tissue (PCAT) attenuation, expressed by the fat attenuation index on coronary computed tomography angiography, reflects pericoronary inflammation. We aimed to investigate the association between PCAT attenuation and NAFLD.This is a single-center cohort study comprising of patients who underwent coronary computed tomography angiography for suspected stable coronary artery disease between January and December 2020. Patient characteristics and coronary computed tomography angiography findings were analyzed between patients with NAFLD (n = 78) and a propensity score-matched cohort of patients without NAFLD (n = 78). PCAT attenuation was assessed in Hounsfield units (HU) of proximal 40-mm segments of the left anterior descending artery (LAD) and right coronary artery.The mean PCAT attenuation in LAD and right coronary artery were significantly higher in patients with NAFLD than those without NAFLD. When patients were divided into 2 groups using the median LAD-PCAT attenuation of -72.5 HU, the high PCAT attenuation group had more males (82% vs 67%, P = .028) and NAFLD patients (63% vs 37%, P = .001) compared to the low PCAT attenuation group. No differences in age, body mass index, conventional cardiovascular risk factors, or the presence of high-risk plaque were observed between the 2 groups. In the multivariate logistic analysis, NAFLD was independently associated with high PCAT attenuation (odds ratio 2.912, 95% confidence interval 1.386 to 6.118, P = .005).NAFLD is associated with high PCAT attenuation on coronary computed tomography angiography. This finding suggests that pericoronary inflammation is involved in the increased cardiac mortality in NAFLD patients.

DOI： 10.1097/MD.0000000000027043

Predictive Value of the Cardio-Ankle Vascular Index for Cardiovascular Events in Patients at Cardiovascular Risk. International journal

Toru Miyoshi, Hiroshi Ito, Kohji Shirai, Shigeo Horinaka, Jitsuo Higaki, Shigeo Yamamura, Atsuhito Saiki, Mao Takahashi, Mitsuru Masaki, Takafumi Okura, Kazuhiko Kotani, Takuro Kubozono, Ryo Yoshioka, Hajime Kihara, Koji Hasegawa, Noriko Satoh-Asahara, Hajime Orimo

Journal of the American Heart Association 10 ( 16 ) e020103 2021.8

Language：English Publishing type：Research paper (scientific journal)

Background Arterial stiffness is an important predictor of cardiovascular events; however, indexes for measuring arterial stiffness have not been widely incorporated into routine clinical practice. This study aimed to determine whether the cardio-ankle vascular index (CAVI), based on the blood pressure-independent stiffness parameter β and reflecting arterial stiffness from the origin of the ascending aorta, is a good predictor of cardiovascular events in patients with cardiovascular disease risk factors in a large prospective cohort. Methods and Results This multicenter prospective cohort study, commencing in May 2013, with a 5-year follow-up period, included patients (aged 40‒74 years) with cardiovascular disease risks. The primary outcome was the composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Among 2932 included patients, 2001 (68.3%) were men; the mean (SD) age at diagnosis was 63 (8) years. During the median follow-up of 4.9 years, 82 participants experienced primary outcomes. The CAVI predicted the primary outcome (hazard ratio, 1.38; 95% CI, 1.16‒1.65; P<0.001). In terms of event subtypes, the CAVI was associated with cardiovascular death and stroke but not with myocardial infarction. When the CAVI was incorporated into a model with known cardiovascular disease risks for predicting cardiovascular events, the global χ2 value increased from 33.8 to 45.2 (P<0.001), and the net reclassification index was 0.254 (P=0.024). Conclusions This large cohort study demonstrated that the CAVI predicted cardiovascular events. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01859897.

DOI： 10.1161/JAHA.120.020103

Pathological and clinical effects of interleukin-6 on human myocarditis. International journal

Naofumi Amioka, Kazufumi Nakamura, Tomonari Kimura, Keiko Ohta-Ogo, Takehiro Tanaka, Tomohiro Toji, Satoshi Akagi, Koji Nakagawa, Norihisa Toh, Masashi Yoshida, Toru Miyoshi, Nobuhiro Nishii, Atsuyuki Watanabe, Ryotaro Asano, Takeshi Ogo, Yoshikazu Nakaoka, Hiroshi Morita, Hiroyuki Yanai, Hiroshi Ito

Journal of cardiology 78 ( 2 ) 157 - 165 2021.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Numerous basic studies have shown a relationship between interleukin-6 (IL-6) and the development or severity of myocarditis. However, there has been no study in which the effect of IL-6 levels in patients with myocarditis was evaluated. METHODS: We enrolled control patients (n = 12) and consecutive patients with acute myocarditis (n = 13), including lymphocytic, eosinophilic, and giant cell myocarditis, and investigated the pathological and clinical effects of IL-6 on human myocarditis. RESULTS: The serum IL-6 level in patients with myocarditis (16.7 [9.9, 103.8] pg/mL) was significantly higher than that in the control patients (1.4 [1.0, 1.9] pg/mL) (P<0.001). Immunohistochemical analysis showed that IL-6 was expressed in infiltrating inflammatory cells of endomyocardial biopsy samples from all patients with myocarditis. Moreover, the log-transformed value of serum IL-6 level showed significant positive correlations with serum creatine kinase (CK) level, CK-MB level, peak CK level, peak CK-MB level and C-reactive protein level (all P ≤ 0.005) and a negative correlation with the left ventricular (LV) ejection fraction (p = 0.014). We divided the patients with myocarditis into a low IL-6 group (9.9 [4.5, 14.2] pg/dL, n = 7) and a high IL-6 group (108.9 [51.1, 130.9] pg/dL, n = 6). The degree of infiltration of IL-6-expressing inflammatory cells in myocardial samples obtained from patients in the high IL-6 group was significantly more severe than that in samples obtained from patients in the low IL-6 group. Furthermore, patients in the high IL-6 group significantly more frequently received catecholamine therapy (P = 0.005), venoarterial extracorporeal membrane oxygenation (P = 0.029), and artificial respirator support (P = 0.021) in the acute phase of myocarditis. CONCLUSION: The results suggest that there is a strong impact of IL-6 on cardiac injury and dysfunction in patients with myocarditis.

DOI： 10.1016/j.jjcc.2021.03.003

Restricted left atrial dilatation can visually differentiate cardiac amyloidosis from hypertrophic cardiomyopathy. International journal

Haruhiko Higashi, Katsuji Inoue, Shinji Inaba, Yasuhisa Nakao, Masaki Kinoshita, Shigehiro Miyazaki, Toru Miyoshi, Yusuke Akazawa, Hiroshi Kawakami, Teruyoshi Uetani, Jun Aono, Takayuki Nagai, Kazuhisa Nishimura, Shuntaro Ikeda, Makoto Saito, Osamu Yamaguchi

ESC heart failure 8 ( 4 ) 3198 - 3205 2021.8

Language：English Publishing type：Research paper (scientific journal)

AIMS: Cardiac amyloidosis (CA) is an infiltrative myocardial disease that occasionally mimics hypertrophic cardiomyopathy (HCM). The aim of this study is to investigate the discriminatory ability of visual assessment of left atrial (LA) function between CA and HCM on echocardiography. METHODS AND RESULTS: In total, 93 patients with cardiac magnetic resonance imaging (CMR)-confirmed HCM and 34 with cardiac biopsy-confirmed CA were retrospectively assessed. LA dilatation was assessed via echocardiography in an apical four-chamber view. Visual assessment was performed to identify LA dilatation grade (preserved = 1, abnormal = 2, and restricted = 3) based on the extent of outward expansion in the LA reservoir phase. Regarding the reproducibility of visually assessing LA dilatation grade, the kappa values between intra- and inter-observer measurements were 0.82 and 0.70, respectively. Of 127 participants, 57 (45%), 42 (33%), and 28 (22%) presented with LA dilatation Grades 1, 2, and 3, respectively. All 57 patients with preserved LA dilatation (Grade 1) had HCM, and 20 of 28 patients (71%) with restricted LA dilatation (Grade 3) presented with CA. Patients with CA had a higher LA dilatation grade than those with HCM (P < 0.01). LA emptying fraction and reservoir strain were also quantitatively evaluated. The area under the curves of LA dilatation grade (0.88) and LA emptying fraction (0.88) for differentiation of these two diseases were higher than that of LA reservoir strain (0.73) (P < 0.01, respectively). During follow-up, nine patients with HCM and 16 with CA experienced cardiac event (cardiac death or hospitalization due to heart failure). In Kaplan-Meier analysis including both groups of HCM and CA, the incidence of cardiac events was higher in patients with restricted LA dilatation than in those with preserved or abnormal LA dilatation (log-rank test, P < 0.01). CONCLUSIONS: Restricted LA dilatation is an indicator for the diagnosis of CA. Further, visual assessment of abnormal LA motion may facilitate diagnosis in patients with CA and high-risk patients with HCM.

DOI： 10.1002/ehf2.13442

Incremental prognostic value of non-alcoholic fatty liver disease over coronary computed tomography angiography findings in patients with suspected coronary artery disease. International journal

Keishi Ichikawa, Toru Miyoshi, Kazuhiro Osawa, Takashi Miki, Hironobu Toda, Kentaro Ejiri, Masashi Yoshida, Kazufumi Nakamura, Hiroshi Morita, Hiroshi Ito

European journal of preventive cardiology 2021.7

Language：English Publishing type：Research paper (scientific journal)

AIMS: This study aimed to investigate additional risk stratification benefits of hepatic steatosis (HS) concurrently assessed during coronary computed tomography angiography (CTA) in a large patient cohort with suspected stable coronary artery disease (CAD). METHODS AND RESULTS: In this prospective study, 1148 Japanese outpatients without a history of CAD who underwent coronary CTA for suspected stable CAD (mean age 64 ± 14 years) were included. HS, defined on CT as a hepatic-to-spleen attenuation ratio of <1.0, was examined just before the evaluation of adverse CTA findings, defined as obstructive and/or high-risk plaque. The major adverse cardiac events (MACE) were the composite of cardiac death, acute coronary syndrome, and late revascularization. The incremental predictive value of HS was evaluated using the global χ2 test and C-statistic. HS was identified in 247 (22%) patients. During a median follow-up of 3.9 years, MACE was observed in 40 (3.5%) patients. HS was significantly associated with MACE in a model that included adverse CTA findings (hazard ratio 4.01, 95% confidence interval 2.12-7.59, P < 0.001). By adding HS to the Framingham risk score and adverse CTA findings, the global χ2 score and C-statistic significantly increased from 29.0 to 49.5 (P < 0.001) and 0.74 to 0.81 (P = 0.026), respectively. In subgroup analyses in patients with diabetes mellitus and metabolic syndrome, HS had significant additive predictive value for MACE over the Framingham risk score and adverse CTA findings. CONCLUSION: In patients with suspected stable CAD, concurrent evaluation of HS during coronary CTA enables more accurate detection of patients at higher risk of MACE.

DOI： 10.1093/eurjpc/zwab120

Concerns in the use of adversarial learning for image synthesis in cardiovascular intervention International journal

Akinori Higaki, Toru Miyoshi, Osamu Yamaguchi

European Heart Journal - Digital Health 2 ( 4 ) 556 - 556 2021.7

Efficacy of shear wave elastography for evaluating right ventricular myocardial fibrosis in monocrotaline-induced pulmonary hypertension rats. International journal

Rie Nakayama, Yoichi Takaya, Kazufumi Nakamura, Megumi Kondo, Kaoru Kobayashi, Yuko Ohno, Naofumi Amioka, Satoshi Akagi, Masashi Yoshida, Toru Miyoshi, Hiroshi Ito

Journal of cardiology 78 ( 1 ) 17 - 23 2021.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Right ventricular (RV) function is important for outcomes in pulmonary hypertension. Evaluation of RV myocardial characteristics is useful to assess the disease severity. Shear wave elastography (SWE) provides information of shear wave (SW) elasticity, which is related to tissue hardness, and SW dispersion slope, which reflects tissue viscosity. This study aimed to test the hypothesis that SW elasticity is increased and SW dispersion slope is decreased in the right ventricle of monocrotaline (MCT)-induced pulmonary hypertension rats. METHODS: Rats were divided into MCT-induced pulmonary hypertension group (n = 10) and control group (n = 10). SW elasticity and SW dispersion slope were measured on excised hearts. Myocardial fibrosis was evaluated histologically. RESULTS: RV hypertrophy was observed in the MCT group. SW elasticity of right ventricle was higher in the MCT group than in the control group (3.5 ± 0.9 kPa vs. 2.5 ± 0.4 kPa, p < 0.01). SW dispersion slope of right ventricle was lower in the MCT group than in the control group (5.3 ± 1.7 m/s/kHz vs. 7.7 ± 1.5 m/s/kHz, p < 0.01). The fibrosis area of right ventricle was increased in MCT group compared with control group (18 ± 5% vs. 8 ± 3%, p < 0.01), and was positively related to SW elasticity and negatively related to SW dispersion slope. CONCLUSIONS: Higher SW elasticity and lower SW dispersion slope were observed in the fibrotic myocardium of right ventricle in MCT-induced pulmonary hypertension rats. SWE may have the potential to evaluate RV function by assessing myocardial characteristics.

DOI： 10.1016/j.jjcc.2021.01.015

Inhibitory effects of RAGE-aptamer on development of monocrotaline-induced pulmonary arterial hypertension in rats. International journal

Kazufumi Nakamura, Satoshi Akagi, Kentaro Ejiri, Masashi Yoshida, Toru Miyoshi, Masakiyo Sakaguchi, Naofumi Amioka, Luh Oliva Saraswati Suastika, Megumi Kondo, Rie Nakayama, Yoichi Takaya, Yuichiro Higashimoto, Kei Fukami, Hiromi Matsubara, Hiroshi Ito

Journal of cardiology 78 ( 1 ) 12 - 16 2021.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The receptor for advanced glycation end products (RAGE), a transmembrane receptor belonging to the immunoglobulin superfamily, is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with pulmonary arterial hypertension (PAH) and is implicated in the etiology of PAH. Recently, we reported that RAGE-aptamer, a short and single-stranded DNA directed against RAGE, inhibited an inappropriate increase in cultured PASMCs in PAH. The aim of this study was to determine the efficacy of RAGE-aptamer in monocrotaline-induced PAH in rats. METHODS AND RESULTS: Rats were assigned to either an untreated control group, a group that received continuous subcutaneous administration of RAGE-aptamer immediately after monocrotaline injection, or a group that received control-aptamer immediately after monocrotaline injection. All rats survived 21 days after injection of monocrotaline and control-aptamer or RAGE-aptamer. Injection of monocrotaline with continuous subcutaneous delivery of control-aptamer resulted in higher right ventricular systolic pressure compared with controls. This increase was attenuated by continuous subcutaneous delivery of RAGE-aptamer. The proportion of small pulmonary arteries with full muscularization was greater in the monocrotaline and control-aptamer group than in the control group. Continuous subcutaneous delivery of RAGE-aptamer significantly reduced the percentage of small pulmonary arteries with full muscularization. CONCLUSIONS: Continuous subcutaneous delivery of RAGE-aptamer suppresses development of monocrotaline-induced PAH in rats. Inhibition of RAGE ameliorates muscularization of small pulmonary arteries. Treatment with RAGE-aptamer might be a new therapeutic option for PAH.

DOI： 10.1016/j.jjcc.2020.12.009

Cardio-Ankle Vascular Index and Atrial Remodeling for Atrial Fibrillation.

Toru Miyoshi

Journal of atherosclerosis and thrombosis 28 ( 6 ) 584 - 585 2021.6

Efficacy and Safety of Early Intravenous Landiolol on Myocardial Salvage in Patients with ST-segment Elevation Myocardial Infarction before Primary Percutaneous Coronary Intervention: A Randomized Study.

Masakazu Miyamoto, Kazuhiro Osawa, Toru Miyoshi, Atsushi Mori, Masaki Yoshikawa, Takefumi Oka, Keishi Ichikawa, Kazufumi Nakamura, Hiroshi Ito

Acta medica Okayama 75 ( 3 ) 289 - 297 2021.6

Language：English Publishing type：Research paper (scientific journal)

Early treatment with an oral β-blocker is recommended in patients with a ST-segment-elevation myocardial infarction (STEMI). In this multicenter study, we evaluated the effects of a continuous administration of landiolol, an ultrashort-acting β-blocker, before primary percutaneous coronary intervention (PCI) on myocardial salvage and its safety in STEMI patients. A total of 47 Japanese patients with anterior or lateral STEMI undergoing a primary PCI within 12 h of symptom onset were randomized to receive intravenous landiolol (started at 3 μg/min/kg dose and continued to a total of 50 mg; n=23) or not (control; n=24). Patients with Killip class III or more were excluded. The primary outcome was the myocardial salvage index on cardiac magnetic resonance imaging (MRI) performed 5-7 days after the PCI. Cardiac MRI was performed in 35 patients (74%). The myocardial salvage index in the landiolol group was significantly greater than that in the control group (44.4±14.6% vs. 31.7±18.9%, respectively; p=0.04). There were no significant differences in adverse events at 24 h between the landiolol and control groups. A continuous administration of landiolol before a primary PCI may increase the degree of myocardial salvage without additional hemodynamic adverse effects within the first 24 h after STEMI.

DOI： 10.18926/AMO/62220

Fibrosis-4 index reflects right ventricular function and prognosis in heart failure with preserved ejection fraction. International journal

Mitsutaka Nakashima, Satoru Sakuragi, Toru Miyoshi, Shin Takayama, Tatsuto Kawaguchi, Nobuhisa Kodera, Hiroaki Akai, Yuji Koide, Hiroaki Otsuka, Tadashi Wada, Kenji Kawamoto, Machiko Tanakaya, Yusuke Katayama, Hiroshi Ito

ESC heart failure 8 ( 3 ) 2240 - 2247 2021.6

Language：English Publishing type：Research paper (scientific journal)

AIMS: Fibrosis-4 index (FIB-4 index), calculated by age, aspartate aminotransferase, alanine aminotransferase, and platelet count, is a simple marker to evaluate liver fibrosis and is associated with right-sided heart failure. However, the clinical relevance of FIB-4 in patients with heart failure with preserved ejection fraction (HFpEF) remains unclear. We investigated the prognostic implication of the FIB-4 index regarding right ventricular dysfunction in patients with HFpEF. METHODS AND RESULTS: This prospective study included 116 consecutive HFpEF patients (mean age 79 years, 43% male) hospitalized with acute decompensated heart failure. We evaluated the association of the FIB-4 index with right ventricular function determined by tricuspid annular plane systolic excursion (TAPSE) and tricuspid lateral annular systolic velocity (S') before discharge. Cox regression analysis was performed to evaluate the association between the FIB-4 index and major adverse cardiovascular events (MACE) defined as the composite of cardiovascular death, readmission for heart failure, nonfatal myocardial infarction, and nonfatal stroke. FIB-4 index before discharge was significantly lower than that at admission (2.62 [1.92-3.46] and 3.03 [2.05-4.67], median [interquartile range], P < 0.001). Left ventricular ejection fraction, TAPSE, and S' before discharge were 62.7 (55.9-68.6) %, 17.5 ± 4.6 mm (mean ± standard deviation), and 10.0 (8.0-12.0) cm/s, respectively. In multiple linear regression analysis, the FIB-4 index before discharge was inversely correlated with TAPSE (β minus;0.244, P = 0.014) and S' (β -0.266, P = 0.009). During a median follow-up of 736 days, 37 MACE occurred. Multivariate Cox regression analysis revealed that a high FIB-4 index before discharge (per 1 point) was a significant predictor of MACE (hazard ratio 1.270, 95% confidence interval 1.052-1.532) after adjustment for male, serum creatinine, and haemoglobin. Receiver operating characteristic analysis indicated that the optimal cut-off value of FIB-4 index before discharge to predict MACE was 3.11. Kaplan-Meier survival analysis showed that patients with a FIB-4 index before discharge ≥3.11 had a significantly poorer prognosis than patients with FIB-4 index before discharge <3.11 (P = 0.029). Patients with an FIB-4 index ≥3.11 had a 2.202-fold (95% confidence interval 1.110-4.368) increased risk of MACE compared with those with an FIB-4 index <3.11 after adjustment for male, serum creatinine, and haemoglobin. CONCLUSIONS: An increase in the FIB-4 index was associated with right ventricular dysfunction and a higher risk of future MACE in patients with HFpEF.

DOI： 10.1002/ehf2.13317

Fusion imaging of three-dimensional echocardiographic speckle-tracking with cardiac computed tomography for identification of myocardial ischemia. International journal

Yoichi Takaya, Rie Nakayama, Nobuhisa Watanabe, Norihisa Toh, Toru Miyoshi, Hiroshi Ito

Health science reports 4 ( 2 ) e285 2021.6

Clinical Efficacy of High-Intensity Plaques in Kawasaki Disease - Non-Contrast T1-Weighted Magnetic Resonance Imaging.

Toru Miyoshi, Toshio Honda, Masataka Murakami, Fuminori Shinozuka, Kazuhiko Sadamoto, Yusuke Akazawa, Takashi Higaki, Osamu Yamaguchi

Circulation reports 3 ( 6 ) 356 - 357 2021.5

Increased Circulating Malondialdehyde-Modified Low-Density Lipoprotein Level Is Associated with High-Risk Plaque in Coronary Computed Tomography Angiography in Patients Receiving Statin Therapy. International journal

Keishi Ichikawa, Toru Miyoshi, Kazuhiro Osawa, Takashi Miki, Hiroshi Ito

Journal of clinical medicine 10 ( 7 ) 2021.4

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: To evaluate the association of serum malondialdehyde low-density lipoprotein (MDA-LDL), an oxidatively modified LDL, with the prevalence of high-risk plaques (HRP) determined with coronary computed tomography angiography (CTA) in statin-treated patients. METHODS: This study was a single-center retrospective cohort comprising 268 patients (mean age 67 years, 58% men) with statin therapy and who underwent coronary CTA for suspected stable coronary artery disease. Patients were classified into two groups according to median MDA-LDL level or median LDL-C level. Coronary CTA-verified HRP was defined when two or more characteristics, including positive remodeling, low-density plaques, and spotty calcification, were present. RESULTS: Patients with HRP had higher MDA-LDL (p = 0.011), but not LDL-C (p = 0.867) than those without HRP. High MDA-LDL was independently associated with HRP (odds ratio 1.883, 95% confidential interval 1.082-3.279) after adjustment for traditional risk factors. Regarding incremental value of MDA-LDL for predicting CTA-verified HRP, addition of serum MDA-LDL levels to the baseline model significantly increased global chi-square score from 26.1 to 32.8 (p = 0.010). CONCLUSIONS: A high serum MDA-LDL level is an independent predictor of CTA-verified HRP, which can lead to cardiovascular events in statin-treated patients.

DOI： 10.3390/jcm10071480

Higher oxidized high-density lipoprotein to apolipoprotein A-I ratio is associated with high-risk coronary plaque characteristics determined by CT angiography. International journal

Kazuki Suruga, Toru Miyoshi, Kazuhiko Kotani, Keishi Ichikawa, Takashi Miki, Kazuhiro Osawa, Kentaro Ejiri, Hironobu Toda, Kazufumi Nakamura, Hiroshi Morita, Hiroshi Ito

International journal of cardiology 324 193 - 198 2021.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Oxidized high-density lipoprotein (oxHDL), unlike native HDL, is characterized by reduced cholesterol efflux capability and anti-inflammatory properties. The ratio of oxHDL to apolipoprotein A-I (oxHDL/apoAI) is a possible marker of dysfunctional HDL. The aim of this study was to evaluate the association between oxHDL/apoAI and coronary plaque characteristics that increase the likelihood of cardiovascular events as determined by coronary computed tomography (CT) angiography. METHODS: A total of 297 patients (mean age; 67 years, men; 63%) who underwent coronary CT angiography for suspected stable coronary artery disease (CAD) were included. High-risk plaques (HRP) were defined by three characteristics: positive remodeling; low-density plaques; and spotty calcification. Significant stenosis was defined as a luminal narrowing of >70%. Serum concentrations of oxHDL were measured using an enzyme-linked immunosorbent assay. RESULTS: Patients with higher oxHDL/ApoAI showed significantly greater prevalence of HRP (p = 0.03) and significant stenosis (p < 0.01) compared with patients with low oxHDL/ ApoAI. The multivariate logistic analysis demonstrated that oxHDL/ApoAI significantly associated with the presence of HRP and significant coronary stenosis (p = 0.01 and < 0.01). In the follow-up study including 243 patients for a median period of 1.8 years, univariate cox regression analysis showed that oxHDL/ApoAI, HRP and significant stenosis were significant predictors of cardiovascular events. CONCLUSIONS: A high oxHDL/apoAI was associated with the presence of HRP and significant stenosis determined by coronary CT angiography, which can lead to cardiovascular events in patients with suspected stable CAD.

DOI： 10.1016/j.ijcard.2020.09.060

Possible Protective Effect of Remote Ischemic Preconditioning on Acute Kidney Injury Following Elective Percutaneous Coronary Intervention: Secondary Analysis of a Multicenter, Randomized Study.

Hiroaki Otsuka, Toru Miyoshi, Kentaro Ejiri, Kunihisa Kohno, Makoto Nakahama, Masayuki Doi, Mitsuru Munemasa, Masaaki Murakami, Kazufumi Nakamura, Hiroshi Ito

Acta medica Okayama 75 ( 1 ) 45 - 53 2021.2

Language：English Publishing type：Research paper (scientific journal)

Remote ischemic preconditioning (RIPC) is a promising strategy for protecting against ischemic reperfusion injury. This study is a secondary analysis of a randomized study that aimed to evaluate the effect of RIPC on the early increase in serum creatinine (SCr) following percutaneous coronary intervention (PCI), which is associ-ated with contrast-induced acute kidney injury. Patients with stable angina undergoing elective PCI were assigned to control, RIPC, and continuous infusion of nicorandil (nicorandil) groups. The endpoint of this study was the incidence of the early increase in SCr, a predictor of contrast-induced acute kidney injury, which was defined as either a > 20% or absolute increase by 0.3 mg/dl of SCr levels after 24 h of PCI. This study included 220 patients for whom a dataset of SCr values was available. The incidence of the early increase in SCr was significantly lower in the RIPC than in the control (1.3% vs 10.8%, p = 0.03) group, but was not significantly different between the nicorandil and control groups. In multivariate analysis, RIPC remained a significant fac-tor associated with a reduction in the incidence of early increase in SCr. RIPC reduces the incidence of early increase in SCr in patients with stable angina following elective PCI.

DOI： 10.18926/AMO/61433

High Plasma Docosahexaenoic Acid Associated to Better Prognoses of Patients with Acute Decompensated Heart Failure with Preserved Ejection Fraction. International journal

Naoaki Matsuo, Toru Miyoshi, Atsushi Takaishi, Takao Kishinoue, Kentaro Yasuhara, Masafumi Tanimoto, Yukari Nakano, Nobuhiko Onishi, Masayuki Ueeda, Hiroshi Ito

Nutrients 13 ( 2 ) 2021.1

Language：English Publishing type：Research paper (scientific journal)

The clinical relevance of polyunsaturated fatty acids (PUFAs) in heart failure remains unclear. The aim of this study was to investigate the association between PUFA levels and the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). This retrospective study included 140 hospitalized patients with acute decompensated HFpEF (median age 84.0 years, 42.9% men). The patients' nutritional status was assessed, using the geriatric nutritional risk index (GNRI), and their plasma levels of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-gamma-linolenic acid (DGLA) were measured before discharge. The primary outcome was all-cause mortality. During a median follow-up of 23.3 months, the primary outcome occurred in 37 patients (26.4%). A Kaplan-Meier analysis showed that lower DHA and DGLA levels, but not EPA or AA levels, were significantly associated with an increase in all-cause death (log-rank; p < 0.001 and p = 0.040, respectively). A multivariate Cox regression analysis also revealed that DHA levels were significantly associated with the incidence of all-cause death (HR: 0.16, 95% CI: 0.06-0.44, p = 0.001), independent of the GNRI. Our results suggest that low plasma DHA levels may be a useful predictor of all-cause mortality and potential therapeutic target in patients with acute decompensated HFpEF.

DOI： 10.3390/nu13020371

Secular Decreasing Trend in Plasma Eicosapentaenoic and Docosahexaenoic Acids among Patients with Acute Coronary Syndrome from 2011 to 2019: A Single Center Descriptive Study. International journal

Tomoaki Okada, Toru Miyoshi, Masayuki Doi, Kosuke Seiyama, Wataru Takagi, Masahiro Sogo, Kazumasa Nosaka, Masahiko Takahashi, Keisuke Okawa, Hiroshi Ito

Nutrients 13 ( 1 ) 2021.1

Language：English Publishing type：Research paper (scientific journal)

Despite intensive lipid-lowering interventions, patients treated with statins develop atherosclerotic cardiovascular disease (ASCVD), and these patients have an increased risk of developing recurrent cardiovascular events during follow-up. Therefore, there is a need to focus on the residual risks in patients in statin therapy to further reduce ASCVD. The aim of this study was to retrospectively investigate the 10-year trend (2011-2019) regarding changes in polyunsaturated fatty acids (PUFAs) in patients with acute coronary syndrome (ACS) in a single center. We included 686 men and 203 women with ACS admitted to Kagawa Prefectural Central Hospital. Plasma PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-γ-linolenic acid (DGLA), were measured at admission for suspected ACS. A secular decreasing trend in the levels of EPA and DHA and the EPA/AA ratio, but not of AA and DGLA, was observed. The analyses based on age (>70 or <70 years) and sex showed that the decreasing trend in the levels of EPA and DHA did not depend on age and remained significant only in men. Further studies are needed to obtain robust evidence to justify that the administration of n-3 PUFA contributes to the secondary prevention of ACS.

DOI： 10.3390/nu13010253

Prognostic value of non-alcoholic fatty liver disease for predicting cardiovascular events in patients with diabetes mellitus with suspected coronary artery disease: a prospective cohort study. International journal

Keishi Ichikawa, Toru Miyoshi, Kazuhiro Osawa, Takashi Miki, Hironobu Toda, Kentaro Ejiri, Masatoki Yoshida, Yusuke Nanba, Masashi Yoshida, Kazufumi Nakamura, Hiroshi Morita, Hiroshi Ito

Cardiovascular diabetology 20 ( 1 ) 8 - 8 2021.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Risk stratification of cardiovascular events in patients with type 2 diabetes mellitus (T2DM) has not been established. Coronary artery calcium score (CACS) and non-alcoholic fatty liver disease (NAFLD) are independently associated with cardiovascular events in T2DM patients. This study examined the incremental prognostic value of NAFLD assessed by non-enhanced computed tomography (CT) in addition to CACS and Framingham risk score (FRS) for cardiovascular events in T2DM patients. METHODS: This prospective pilot study included 529 T2DM outpatients with no history of cardiovascular disease who underwent CACS measurement because of suspected coronary artery disease. NAFLD was defined on CT images as a liver:spleen attenuation ratio < 1.0. Cardiovascular events were defined as cardiovascular death, nonfatal myocardial infarction, late coronary revascularization, nonfatal stroke, or hospitalization for heart failure. RESULTS: Among 529 patients (61% men, mean age 65 years), NAFLD was identified in 143 (27%). Forty-four cardiovascular events were documented during a median follow-up of 4.4 years. In multivariate Cox regression analysis, NAFLD, CACS, and FRS were associated with cardiovascular events (hazard ratios and 95% confidence intervals 5.43, 2.82-10.44, p < 0.001; 1.56, 1.32-1.86, p < 0.001; 1.23, 1.08-1.39, p = 0.001, respectively). The global χ2 score for predicting cardiovascular events increased significantly from 27.0 to 49.7 by adding NAFLD to CACS and FRS (p < 0.001). The addition of NAFLD to a model including CACS and FRS significantly increased the C-statistic from 0.71 to 0.80 (p = 0.005). The net reclassification achieved by adding CACS and FRS was 0.551 (p < 0.001). CONCLUSIONS: NAFLD assessed by CT, in addition to CACS and FRS, could be useful for identifying T2DM patients at higher risk of cardiovascular events.

DOI： 10.1186/s12933-020-01192-4

Lack of collagen α6(IV) chain in mice does not cause severe-to-profound hearing loss or cochlear malformation, a distinct phenotype from nonsyndromic hearing loss with COL4A6 missense mutation. International journal

Shaoying Tang, Tomoko Yonezawa, Yukihide Maeda, Mitsuaki Ono, Takahiro Maeba, Toru Miyoshi, Ryusuke Momota, Yasuko Tomono, Toshitaka Oohashi

PloS one 16 ( 4 ) e0249909 2021

Language：English Publishing type：Research paper (scientific journal)

Congenital hearing loss affects 1 in every 1000 births, with genetic mutations contributing to more than 50% of all cases. X-linked nonsyndromic hereditary hearing loss is associated with six loci (DFNX1-6) and five genes. Recently, the missense mutation (c.1771G>A, p.Gly591Ser) in COL4A6, encoding the basement membrane (BM) collagen α6(IV) chain, was shown to be associated with X-linked congenital nonsyndromic hearing loss with cochlear malformation. However, the mechanism by which the COL4A6 mutation impacts hereditary hearing loss has not yet been elucidated. Herein, we investigated Col4a6 knockout (KO) effects on hearing function and cochlear formation in mice. Immunohistochemistry showed that the collagen α6(IV) chain was distributed throughout the mouse cochlea within subepithelial BMs underlying the interdental cells, inner sulcus cells, basilar membrane, outer sulcus cells, root cells, Reissner's membrane, and perivascular BMs in the spiral limbus, spiral ligament, and stria vascularis. However, the click-evoked auditory brainstem response analysis did not show significant changes in the hearing threshold of Col4a6 KO mice compared with wild-type (WT) mice with the same genetic background. In addition, the cochlear structures of Col4a6 KO mice did not exhibit morphological alterations, according to the results of high-resolution micro-computed tomography and histology. Hence, loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation, which differs from humans with the COL4A6 missense mutation c.1771G>A, p.Gly591Ser. Therefore, the deleterious effects in the auditory system caused by the missense mutation in COL4A6 are likely due to the dominant-negative effects of the α6(IV) chain and/or α5α6α5(IV) heterotrimer with an aberrant structure that would not occur in cases with loss of gene expression.

DOI： 10.1371/journal.pone.0249909

Early Initiation of Evolocumab Markedly Reduces Low-Density Lipoprotein Cholesterol Levels After Myocardial Infarction. International journal

Tomoaki Okada, Masayuki Doi, Toru Miyoshi, Kazumasa Nosaka, Satoshi Taya, Keisuke Yamamoto, Ai Sakamoto, Satoko Ugawa, Ryu Tsushima, Hiroshi Ito

JACC. Cardiovascular interventions 13 ( 24 ) 2944 - 2946 2020.12

Correction to: Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet. International journal

Masatoki Yoshida, Kazufumi Nakamura, Toru Miyoshi, Masashi Yoshida, Megumi Kondo, Kaoru Akazawa, Tomonari Kimura, Hiroaki Ohtsuka, Yuko Ohno, Daiji Miura, Hiroshi Ito

Cardiovascular diabetology 19 ( 1 ) 213 - 213 2020.12

Improvement in renal and endothelial function after catheter ablation in patients with persistent atrial fibrillation Reviewed

Okawa K, Miyoshi T, Sogo M, Hara S, Sudo Y, Ugawa S, Takahashi M, Doi M, Morita H, Ito H

J Cardiol 76 ( 6 ) 610 - 617 2020.12

Improvement in renal and endothelial function after catheter ablation in patients with persistent atrial fibrillation. International journal

Keisuke Okawa, Toru Miyoshi, Masahiro Sogo, Shohei Hara, Yuya Sudo, Satoko Ugawa, Masahiko Takahashi, Masayuki Doi, Hiroshi Morita, Hiroshi Ito

Journal of cardiology 76 ( 6 ) 610 - 617 2020.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Cardiovascular events in patients with atrial fibrillation (AF) can be lowered by catheter ablation. We hypothesized the underlying mechanism was improvement in renal and endothelial function corresponding to AF burden, and investigated whether restoration of sinus rhythm (SR) after ablation affected these functions according to AF type. METHODS AND RESULTS: We prospectively measured estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and reactive hyperemia index (RHI) in 358 consecutive patients with AF before and 6 and 12 months after the ablation. For each AF type [paroxysmal AF (PAF), n = 229, and persistent AF (PeAF), n = 129], we evaluated changes in these markers and influence of chronic kidney disease (CKD). The eGFR and natural logarithm-transformed (ln) UACR improved at 6 months in the PeAF group (68.7 ± 18.7-71.8 ± 18.9 mL/min/1.73 m2, p = 0.003 and 3.1±1.6 to 2.8±1.5, p < 0.001, respectively) and remained unchanged in the PAF group. Among the PeAF patients, recurrent AF was identified in 41, but only transiently in 38 patients. PeAF at baseline independently predicted increased eGFR [odds ratio (OR)=2.13, 95 % confidence interval (CI) 1.35-3.40, p = 0.001] and decreased UACR (OR=1.94, 95 % CI 1.05-3.58, p = 0.033). In the PeAF patients with CKD, ln-RHI significantly increased at 6 months after the ablation, and the change (Δ) in ln-RHI was significantly correlated with the ΔeGFR (r=0.35, p = 0.03). CONCLUSIONS: SR restoration after ablation was associated with an improved eGFR and UACR in PeAF patients, but not PAF patients. In PeAF patients with CKD, an improved endothelial function after ablation was associated with an improved renal function.

DOI： 10.1016/j.jjcc.2020.07.002

Cardio-Ankle Vascular Index and Atrial Remodeling for Atrial Fibrillation Reviewed

Miyoshi T

J Atheroscler Thromb 2020.11

Chemoradiation therapy for non-small cell lung cancer exacerbates thoracic aortic calcification determined by computed tomography Reviewed

Miki T, Miyauchi S, Miyoshi T, Yoshida M, Ichikawa K, Soh J, Nakamura K, Kiura K, Kanazawa S, Toyooka S, Ito H

Heart Vessels 35 ( 10 ) 1401 - 1408 2020.10

Ischemic Myocardial Burden Subtended by Computed Tomography-Derived Fractional Flow Reserve (APPROACHFFRCT): An Exploratory Analysis on Diagnostic Performance Reviewed

Ihdayhid AR, Norgaard BL, Achenbach S, Khav N, Gaur S, Leipsic J, Nerlekar N, Osawa K, Miyoshi T, Jensen JM, Kimura T, Shiomi H, Erglis A, Oldroyd KG, Botker HE, Narula J, Ko BS

JACC Cardiovasc Imaging 13 ( 10 ) 2264 - 2267 2020.10

Ischemic Myocardial Burden Subtended by Computed Tomography-Derived Fractional Flow Reserve (APPROACHFFRCT): An Exploratory Analysis on Diagnostic Performance. International journal

Abdul Rahman Ihdayhid, Bjarne L Norgaard, Stephan Achenbach, Nancy Khav, Sara Gaur, Jonathan Leipsic, Nitesh Nerlekar, Kazuhiro Osawa, Toru Miyoshi, Jesper M Jensen, Takeshi Kimura, Hiroki Shiomi, Andrejs Erglis, Keith G Oldroyd, Hans Erik Botker, Jagat Narula, Brian S Ko

JACC. Cardiovascular imaging 13 ( 10 ) 2264 - 2267 2020.10

Chemoradiation therapy for non-small cell lung cancer exacerbates thoracic aortic calcification determined by computed tomography.

Takashi Miki, Shunsaku Miyauchi, Toru Miyoshi, Masashi Yoshida, Keishi Ichikawa, Junichi Soh, Kazufumi Nakamura, Katsuyuki Kiura, Susumu Kanazawa, Shinichi Toyooka, Hiroshi Ito

Heart and vessels 35 ( 10 ) 1401 - 1408 2020.10

Language：English Publishing type：Research paper (scientific journal)

Preoperative chemoradiation therapy (CRT) has been considered as an effective treatment for non-small cell lung cancer. However, there is concern that CRT progresses atherosclerosis in cancer survivors. This study sought to determine if preoperative CRT exacerbated thoracic aortic calcification (TAC) detected by computed tomography (CT) in patients with lung cancer. Among 473 patients who underwent surgery for lung cancer at Okayama University Hospital between 2011 and 2015, 34 patients undergoing preoperative CRT and surgery (CRT group) and 33 matched patients undergoing initial surgery (non-CRT group) were analyzed and compared. The volume of TAC between the 2nd and 12th thoracic vertebrae was quantitatively measured by CT at baseline and 1-year follow-up. Patients in the CRT group (62 ± 7 years old, 74% male) received cisplatin chemotherapy with docetaxel or vinorelbine and radiation therapy (mean 47.3 ± 4.0 Gy). The percent change in TAC volume was significantly greater in the CRT compared with the non-CRT group (58.7%, 95% confidence interval [CI] 41.7-75.7% vs. 27.2%, 95% CI 9.9-44.4%; p = 0.01). Multivariate logistic regression analysis identified CRT as an independent factor associated with greater TAC progression (> the median value) (odds ratio 3.63, 95% CI 1.19-11.08; p = 0.02). In conclusion, preoperative CRT for lung cancer exacerbates TAC. Follow-up of such patients should thus include careful longitudinal assessment for cardiovascular disease.

DOI： 10.1007/s00380-020-01611-2

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet Reviewed

Yoshida M, Nakamura K, Miyoshi T, Yoshida M, Kondo M, Akazawa K, Kimura T, Ohtsuka H, Ohno Y, Miura D, Ito H

Cardiovasc Diabetol 19 ( 1 ) 149 2020.9

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet. International journal

Masatoki Yoshida, Kazufumi Nakamura, Toru Miyoshi, Masashi Yoshida, Megumi Kondo, Kaoru Akazawa, Tomonari Kimura, Hiroaki Ohtsuka, Yuko Ohno, Daiji Miura, Hiroshi Ito

Cardiovascular diabetology 19 ( 1 ) 149 - 149 2020.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. METHODS: Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated. RESULTS: After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone. CONCLUSIONS: Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.

DOI： 10.1186/s12933-020-01132-2

Effect of Luseogliflozin on Heart Failure With Preserved Ejection Fraction in Patients With Diabetes Mellitus Reviewed

Ejiri K, Miyoshi T, Kihara H, Hata Y, Nagano T, Takaishi A, Toda H, Nanba S, Nakamura Y, Akagi S, Sakuragi S, Minagawa T, Kawai Y, Nishii N, Fuke S, Yoshikawa M, Nakamura K, Ito H; MUSCAT‐HF Study Investigators

J Am Heart Assoc 9 ( 16 ) e015103 2020.8

Effect of Luseogliflozin on Heart Failure With Preserved Ejection Fraction in Patients With Diabetes Mellitus. International journal

Kentaro Ejiri, Toru Miyoshi, Hajime Kihara, Yoshiki Hata, Toshihiko Nagano, Atsushi Takaishi, Hironobu Toda, Seiji Nanba, Yoichi Nakamura, Satoshi Akagi, Satoru Sakuragi, Taro Minagawa, Yusuke Kawai, Nobuhiro Nishii, Soichiro Fuke, Masaki Yoshikawa, Kazufumi Nakamura, Hiroshi Ito

Journal of the American Heart Association 9 ( 16 ) e015103 2020.8

Language：English Publishing type：Research paper (scientific journal)

Background Effects of sodium-glucose cotransporter 2 inhibitors on reducing hospitalization for heart failure have been reported in randomized controlled trials, but their effects on patients with heart failure with preserved ejection fraction (HFpEF) are unknown. This study aimed to evaluate the drug efficacy of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 2 diabetes mellitus and HFpEF. Methods and Results We performed a multicenter, open-label, randomized, controlled trial for comparing luseogliflozin 2.5 mg once daily with voglibose 0.2 mg 3 times daily in patients with type 2 diabetes mellitus suffering from HFpEF (left ventricular ejection fraction >45% and BNP [B-type natriuretic peptide] concentrations ≥35 pg/mL) in a 1:1 randomization fashion. The primary outcome was the difference from baseline in BNP levels after 12 weeks of treatment between the 2 drugs. A total of 173 patients with diabetes mellitus and HFpEF were included. Of these, 83 patients were assigned to receive luseogliflozin and 82 to receive voglibose. There was no significant difference in the reduction in BNP concentrations after 12 weeks from baseline between the 2 groups. The ratio of the mean BNP value at week 12 to the baseline value was 0.79 in the luseogliflozin group and 0.87 in the voglibose group (percent change, -9.0% versus -1.9%; ratio of change with luseogliflozin versus voglibose, 0.93; 95% CI, 0.78-1.10; P=0.26). Conclusion In patients with type 2 diabetes mellitus and HFpEF, there is no significant difference in the degree of reduction in BNP concentrations after 12 weeks between luseogliflozin and voglibose. Registration URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000018395.

DOI： 10.1161/JAHA.119.015103

Prognostic Value of Coronary Computed Tomographic Angiography in Patients With Nonalcoholic Fatty Liver Disease Reviewed

Ichikawa K, Miyoshi T, Osawa K, Miki T, Nakamura K, Ito H

JACC Cardiovasc Imaging 13 ( 7 ) 1628 - 1630 2020.7

Prognostic Value of Coronary Computed Tomographic Angiography in Patients With Nonalcoholic Fatty Liver Disease. International journal

Keishi Ichikawa, Toru Miyoshi, Kazuhiro Osawa, Takashi Miki, Kazufumi Nakamura, Hiroshi Ito

JACC. Cardiovascular imaging 13 ( 7 ) 1628 - 1630 2020.7

【臨床医が知っていほしい循環器基礎研究最新の成果】心不全　酸化ストレスは心不全の原因か?

中村一文、網岡尚史、三好　亨、伊藤　浩

循環器内科 87 ( 5 ) 597 - 600 2020.5

Automated interpretation of the coronary angioscopy with deep convolutional neural networks. International journal

Toru Miyoshi, Akinori Higaki, Hideo Kawakami, Osamu Yamaguchi

Open heart 7 ( 1 ) 2020.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Coronary angioscopy (CAS) is a useful modality to assess atherosclerotic changes, but interpretation of the images requires expert knowledge. Deep convolutional neural networks (DCNN) can be used for diagnostic prediction and image synthesis. METHODS: 107 images from 47 patients, who underwent CAS in our hospital between 2014 and 2017, and 864 images, selected from 142 MEDLINE-indexed articles published between 2000 and 2019, were analysed. First, we developed a prediction model for the angioscopic findings. Next, we made a generative adversarial networks (GAN) model to simulate the CAS images. Finally, we tried to control the output images according to the angioscopic findings with conditional GAN architecture. RESULTS: For both yellow colour (YC) grade and neointimal coverage (NC) grade, we could observe strong correlations between the true grades and the predicted values (YC grade, average r=0.80±0.02, p<0.001; NC grade, average r=0.73±0.02, p<0.001). The binary classification model for the red thrombus yielded 0.71±0.03 F1-score and the area under the receiver operator characteristic curve was 0.91±0.02. The standard GAN model could generate realistic CAS images (average Inception score=3.57±0.06). GAN-based data augmentation improved the performance of the prediction models. In the conditional GAN model, there were significant correlations between given values and the expert's diagnosis in YC grade but not in NC grade. CONCLUSION: DCNN is useful in both predictive and generative modelling that can help develop the diagnostic support system for CAS.

DOI： 10.1136/openhrt-2019-001177

Deficiency of CD44 prevents thoracic aortic dissection in a murine model Reviewed

Hatipoglu OF, Miyoshi T, Yonezawa T, Kondo M, Amioka N, Yoshida M, Akagi S, Nakamura K, Hirohata S, Ito H

Sci Rep 10 ( 1 ) 6869 2020.4

Deficiency of CD44 prevents thoracic aortic dissection in a murine model. International journal

Omer F Hatipoglu, Toru Miyoshi, Tomoko Yonezawa, Megumi Kondo, Naofumi Amioka, Masashi Yoshida, Satoshi Akagi, Kazufumi Nakamura, Satoshi Hirohata, Hiroshi Ito

Scientific reports 10 ( 1 ) 6869 - 6869 2020.4

Language：English Publishing type：Research paper (scientific journal)

Thoracic aortic dissection (TAD) is a life-threatening vascular disease. We showed that CD44, a widely distributed cell surface adhesion molecule, has an important role in inflammation. In this study, we examined the role of CD44 in the development of TAD. TAD was induced by the continuous infusion of β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, and angiotensin II (AngII) for 7 days in wild type (WT) mice and CD44 deficient (CD44-/-) mice. The incidence of TAD in CD44-/- mice was significantly reduced compared with WT mice (44% and 6%, p < 0.01). Next, to evaluate the initial changes, aortic tissues at 24 hours after BAPN/AngII infusion were examined. Neutrophil accumulation into thoracic aortic adventitia in CD44-/- mice was significantly decreased compared with that in WT mice (5.7 ± 0.3% and 1.6 ± 0.4%, p < 0.01). In addition, BAPN/AngII induced interleukin-6, interleukin-1β, matrix metalloproteinase-2 and matrix metalloproteinase-9 in WT mice, all of which were significantly reduced in CD44-/- mice (all p < 0.01). In vitro transmigration of neutrophils from CD44-/- mice through an endothelial monolayer was significantly decreased by 18% compared with WT mice (p < 0.01). Our findings indicate that CD44 has a critical role in TAD development in association with neutrophil infiltration into adventitia.

DOI： 10.1038/s41598-020-63824-9

Clinical Utility of Diffusion-weighted Whole-body Magnetic Resonance Imaging with Background Body Signal Suppression for Assessing and Monitoring IgG4-related Disease.

Akira Oshita, Yusuke Kono, Toru Miyoshi, Moeko Suzuki, Takuro Kazatani, Hiroshi Matsuoka, Hideo Kawakami

Internal medicine (Tokyo, Japan) 59 ( 7 ) 951 - 955 2020.4

Language：English Publishing type：Research paper (scientific journal)

A 77-year-old man with symptoms of chest pain was diagnosed with immunoglobulin G4 (IgG4)-related disease. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) revealed an intense uptake in the submandibular gland, lymph nodes and abdominal aortic wall. Diffusion-weighted imaging with background body signal suppression (DWIBS) revealed signal enhancements at the same location as those of the FDG-PET/CT findings. The DWIBS signal intensity decreased after steroid treatment, so we decreased the steroid dosage. Relapse did not occur. DWIBS makes it possible to adjust the medicine dosage while confirming the therapeutic effects and will likely be a useful method for monitoring IgG4-related disease.

DOI： 10.2169/internalmedicine.3712-19

Effects of Bisoprolol Transdermal Patches for Prevention of Perioperative Myocardial Injury in High-Risk Patients Undergoing Non-Cardiac Surgery　- Multicenter Randomized Controlled Study Reviewed

Toda H, Nakamura K, Shimizu K, Ejiri K, Iwano T, Miyoshi T, Nakagawa K, Yoshida M, Watanabe A, Nishii N, Hikasa Y, Hayashi M, Morita H, Morimatsu H, Ito H; MAMACARI Investigators

Circ J 84 ( 4 ) 642 - 649 2020.3

Effects of Bisoprolol Transdermal Patches for Prevention of Perioperative Myocardial Injury in High-Risk Patients Undergoing Non-Cardiac Surgery - Multicenter Randomized Controlled Study.

Hironobu Toda, Kazufumi Nakamura, Kazuyoshi Shimizu, Kentaro Ejiri, Takayuki Iwano, Toru Miyoshi, Koji Nakagawa, Masashi Yoshida, Atsuyuki Watanabe, Nobuhiro Nishii, Yukiko Hikasa, Masao Hayashi, Hiroshi Morita, Hiroshi Morimatsu, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society 84 ( 4 ) 642 - 649 2020.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of transdermal β-blocker patches, which offer stable blood concentration and easy availability during operation, for prevention of perioperative myocardial injury (PMI) in high-risk patients.Methods and Results:In this randomized controlled trial, patients aged >60 years with hypertension and high revised cardiac risk index (≥2) undergoing non-cardiac surgery were randomly assigned to a bisoprolol patch or control group. Primary efficacy outcome was incidence of PMI, defined as postoperative high-sensitivity cardiac troponin T (hs-cTnT) >0.014ng/mL and relative hs-cTnT change ≥20%. Secondary efficacy outcomes were number of cardiovascular events and 30-day mortality. From November 2014 to February 2019, 240 patients from 5 hospitals were enrolled in this study. The incidence of PMI was 35.7% in the bisoprolol patch group and 44.5% in the control group (P=0.18). Incidence of major adverse cardiac events including non-critical myocardial infarction, strokes, decompensated heart failure and tachyarrhythmia was similar between the 2 groups. Tachyarrhythmia tended to be higher in the control group. There were no significant differences in safety outcomes including significant hypotension and bradycardia requiring any treatment between the 2 groups. CONCLUSIONS: Bisoprolol patches do not influence the incidence of PMI and cardiovascular events in high-risk patients undergoing non-cardiac surgery, but perioperative use of these patches is safe.

DOI： 10.1253/circj.CJ-19-0871

New Appearance of Fragmented QRS as a Predictor of Ventricular Arrhythmic Events in Patients With Hypertrophic Cardiomyopathy Reviewed

Ogura S, Nakamura K, Morita H, Toh N, Nakagawa K, Yoshida M, Watanabe A, Nishii N, Miyoshi T, Ito H

Circ J 84 ( 3 ) 487 - 494 2020.2

New Appearance of Fragmented QRS as a Predictor of Ventricular Arrhythmic Events in Patients With Hypertrophic Cardiomyopathy.

Soichiro Ogura, Kazufumi Nakamura, Hiroshi Morita, Norihisa Toh, Koji Nakagawa, Masashi Yoshida, Atsuyuki Watanabe, Nobuhiro Nishii, Toru Miyoshi, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society 84 ( 3 ) 487 - 494 2020.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Multiple spikes in the QRS complex (fragmented QRS [fQRS]) on 12-lead electrocardiography have been associated with ventricular arrhythmic events (VAEs) in patients with hypertrophic cardiomyopathy (HCM). The aim of this study was to assess the association between new appearances of fQRS and cardiac events in patients with HCM.Methods and Results:The association between baseline fQRS and cardiac events, namely VAEs, heart failure-related hospitalization, and all-cause death, was evaluated retrospectively in 146 HCM patients (46 patients with fQRS, 100 without fQRS). The median follow-up was 5.3 years. Cardiac events occurred in 29 patients with baseline fQRS and 32 patients without baseline fQRS (63% vs. 32%; P<0.001). VAEs occurred in a significantly larger percentage of patients with than without baseline fQRS (54% vs. 23%, respectively; P<0.001). Of the 100 patients without baseline fQRS, 33 had a new appearance of fQRS during the 4.6-year follow-up, whereas 67 did not. VAEs occurred more frequently in the 33 patients with the appearance of fQRS than in those without (42% vs. 13%, respectively; P=0.001). Multivariable analysis showed that the new appearance of fQRS documented before VAEs was associated with VAEs (hazard ratio 4.29, 95% confidence interval 1.81-10.2; P=0.001). CONCLUSIONS: The new appearance of fQRS was associated with an increased risk of VAEs in HCM patients.

DOI： 10.1253/circj.CJ-19-0968

大動脈疾患の最新トピックス　接着分子CD44の機能制御と大動脈瘤・大動脈解離における役割

Hatipoglu Omer F., 三好　亨

血管 43 ( 1 ) 28 2020.1

Pathology of Coronary Artery Embolism Derived From Mural Thrombus of Left Ventricle.

Toru Miyoshi, Hiroyuki Hao, Akira Oshita, Hideo Kawakami, Toshiharu Maeda, Hiroshi Matsuoka

Circulation journal : official journal of the Japanese Circulation Society 84 ( 1 ) 129 - 129 2019.12

Low Consultation Rate of General Population with Atrial Fibrillation.

Hiroaki Matsumi, Kazufumi Nakamura, Eri Eguchi, Toru Miyoshi, Koji Nakagawa, Nobuhiro Nishii, Atsuyuki Watanabe, Akira Ueoka, Masashi Yoshida, Naoto Tokunaga, Naofumi Amioka, Nobuyuki Yamada, Daiji Saito, Hiroshi Morita, Keiki Ogino, Hiroshi Ito

International heart journal 60 ( 6 ) 1303 - 1307 2019.11

Language：English Publishing type：Research paper (scientific journal)

In order to prevent ischemic stroke, it is important to identify and treat patients with atrial fibrillation (AF) who do not consult a doctor in a medical institution. The aim of this study was to determine the consultation rate at medical institutions for patients with AF in group medical examinations conducted in a city in western Japan. Of 6101 examinees of group medical examinations (40 years of age or older) conducted in Ibara City, Okayama Prefecture, Japan, from 2012 to 2014, 4338 participants (71.1%) who were evaluated by electrocardiogram (ECG) gave written informed consent and responded to surveys in the form of questionnaires through a personal interview conducted by nurses were included in the Ibara-AF study. A cumulative total of 82 subjects were diagnosed as having AF by ECG (prevalence of AF = 1.89%), and 51 individuals had AF during the three-year period.15 (29.4%) of the 51 patients with AF did not regularly visit medical institutions. Among them, 46.7% (n = 7) and 53.3% (n = 8) of the patients were symptomatic and asymptomatic, respectively, and 73.3% of the patients had a CHADS2 score of more than one point. There were no significant differences in patients' characteristics between regular and non-regular visit groups. In conclusion, about one-third of the patients with AF did not regularly see a doctor in a medical institution and most of them had a CHADS2 score of more than one point in a Japanese rural area. Educating the public about the risks of AF is required.

DOI： 10.1536/ihj.19-062

Current Treatment Strategies and Nanoparticle-Mediated Drug Delivery Systems for Pulmonary Arterial Hypertension. International journal

Kazufumi Nakamura, Satoshi Akagi, Kentaro Ejiri, Masashi Yoshida, Toru Miyoshi, Norihisa Toh, Koji Nakagawa, Yoichi Takaya, Hiromi Matsubara, Hiroshi Ito

International journal of molecular sciences 20 ( 23 ) 2019.11

Language：English Publishing type：Research paper (scientific journal)

There are three critical pathways for the pathogenesis and progression of pulmonary arterial hypertension (PAH): the prostacyclin (prostaglandin I2) (PGI2), nitric oxide (NO), and endothelin pathways. The current approved drugs targeting these three pathways, including prostacyclin (PGI2), phosphodiesterase type-5 (PDE5) inhibitors, and endothelin receptor antagonists (ERAs), have been shown to be effective, however, PAH remains a severe clinical condition and the long-term survival of patients with PAH is still suboptimal. The full therapeutic abilities of available drugs are reduced by medication, patient non-compliance, and side effects. Nanoparticles are expected to address these problems by providing a novel drug delivery approach for the treatment of PAH. Drug-loaded nanoparticles for local delivery can optimize the efficacy and minimize the adverse effects of drugs. Prostacyclin (PGI2) analogue, PDE5 inhibitors, ERA, pitavastatin, imatinib, rapamycin, fasudil, and oligonucleotides-loaded nanoparticles have been reported to be effective in animal PAH models and in vitro studies. However, the efficacy and safety of nanoparticle mediated-drug delivery systems for PAH treatment in humans are unknown and further clinical studies are required to clarify these points.

DOI： 10.3390/ijms20235885

Serum malondialdehyde-modified low-density lipoprotein levels on admission predict prognosis in patients with acute coronary syndrome undergoing percutaneous coronary intervention. International journal

Naofumi Amioka, Toru Miyoshi, Hiroaki Otsuka, Daisuke Yamada, Atsushi Takaishi, Masayuki Ueeda, Satoshi Hirohata, Hiroshi Ito

Journal of cardiology 74 ( 3 ) 258 - 266 2019.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is a predictive marker of cardiovascular events in patients with stable angina pectoris. However, little is known about this marker in patients with acute coronary syndrome (ACS). We investigated the prognostic relevance of MDA-LDL to cardiovascular outcomes in patients with ACS. METHODS: A total of 370 consecutive patients with ACS who underwent primary percutaneous coronary intervention (PCI) were enrolled from October 2009 to September 2014 at Mitoyo General Hospital. Serum MDA-LDL levels were measured at admission. The patients were divided into three tertile groups according to serum MDA-LDL levels. The primary outcomes were cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization, and heart failure requiring hospital admission. RESULTS: MDA-LDL levels in patients with acute myocardial infarction were significantly greater than those in patients with unstable angina pectoris (mean±standard deviation: 133±48U/L vs. 157±69U/L, p=0.001). During follow-up [472 (195-920) days], 82 (22%) events occurred. Kaplan-Meier analysis showed that patients in the highest MDA-LDL tertile had the worst prognosis (log-rank, p<0.001). Cox regression analysis showed that serum MDA-LDL levels were an independent predictor of cardiovascular events after PCI in patients with ACS, even after adjustment for age, sex, body mass index, conventional cardiovascular risk factors, other lipid biomarkers, statin use on admission, cardiac biomarkers, and presence or absence of multivessel disease (hazard ratio: 1.80 per 1 standard deviation U/L increase, 95% confidence interval: 1.07-3.16, p=0.027). CONCLUSION: Serum MDA-LDL levels on admission are a significant prognostic marker in patients with ACS who undergo successful PCI.

DOI： 10.1016/j.jjcc.2019.02.012

Brachial intima-media thickness is associated with coronary artery atherosclerosis in patients with diabetes mellitus.

Tamaki Ono, Toru Miyoshi, Yuko Ohno, Kazuhiro Osawa, Yoichi Takaya, Takashi Miki, Keishi Ichikawa, Hiroshi Ito

Heart and vessels 34 ( 9 ) 1405 - 1411 2019.9

Language：English Publishing type：Research paper (scientific journal)

Coronary artery calcification (CAC) as measured by computed tomography is a strong predictor of coronary artery disease. The brachial intima-media thickness (IMT) was recently reported to be associated with cardiovascular risk factors. This study investigated the association of brachial IMT with CAC, which is a marker of coronary artery atherosclerosis, in patients with diabetes. We enrolled 292 patients with diabetes (mean age, 65 ± 12 years; 59% men) who underwent both endothelial function testing and computed tomography for risk assessment of coronary artery disease. Flow-mediated dilation (FMD) and IMT in the brachial artery were measured with a specialized machine. FMD was lower and brachial IMT was thicker in patients with than without CAC. The CAC score was significantly correlated with both brachial IMT and FMD, while the multivariate logistic analysis demonstrated that brachial IMT (> 0.32 mm) but not FMD (< 5.1%) was significantly associated with the presence of CAC (odds ratio, 2.03; 95% confidence interval, 1.10-3.77; p = 0.02). The receiver operating characteristic curve analysis showed that the area under the curve for discriminating patients with CAC was 0.67 for IMT (p < 0.001) and 0.62 for FMD (p < 0.001). When patients were classified into four groups based on brachial IMT and FMD, the CAC score was higher in patients with thicker brachial IMT and lower FMD than in patients of the other groups (p < 0.001). Measurement of brachial IMT could be useful for the risk assessment of patients with diabetes.

DOI： 10.1007/s00380-019-01371-8

遺残坐骨動脈瘤に対しステントグラフト(VIABAHN)を用いて治療した一例 Reviewed

大塚寛昭, 戸田洋伸, 江尻健太郎, 杜徳尚, 三好亨, 中村一文, 伊藤浩

日本心血管インターベンション治療学会抄録集 28回 [MP34 - 006] 2019.9

Prognostic Value and Risk Continuum of Noninvasive Fractional Flow Reserve Derived from Coronary CT Angiography. International journal

Abdul Rahman Ihdayhid, Bjarne L Norgaard, Sara Gaur, Jonathan Leipsic, Nitesh Nerlekar, Kazuhiro Osawa, Toru Miyoshi, Jesper M Jensen, Takeshi Kimura, Hiroki Shiomi, Andrejs Erglis, Sanda Jegere, Keith G Oldroyd, Hans Erik Botker, Sujith K Seneviratne, Stephan Achenbach, Brian S Ko

Radiology 292 ( 2 ) 343 - 351 2019.8

Language：English Publishing type：Research paper (scientific journal)

Background Coronary CT angiography with noninvasive fractional flow reserve (FFR) predicts lesion-specific ischemia when compared with invasive FFR. The longer term prognostic value of CT-derived FFR (FFRCT) is unknown. Purpose To determine the prognostic value of FFRCT when compared with coronary CT angiography and describe the relationship of the numeric value of FFRCT with outcomes. Materials and Methods This prospective subanalysis of the NXT study (Clinicaltrials.gov: NCT01757678) evaluated participants suspected of having stable coronary artery disease who were referred for invasive angiography and who underwent FFR, coronary CT angiography, and FFRCT. The incidence of the composite primary end point of death, myocardial infarction, and any revascularization and the composite secondary end point of major adverse cardiac events (MACE: cardiac death, myocardial infarction, unplanned revascularization) were compared for an FFRCT of 0.8 or less versus stenosis of 50% or greater on coronary CT angiograms, with treating physicians blinded to the FFRCT result. Results Long-term outcomes were obtained in 206 individuals (age, 64 years ± 9.5), including 64% men. At median follow-up of 4.7 years, there were no cardiac deaths or myocardial infarctions in participants with normal FFRCT. The incidence of the primary end point was more frequent in participants with positive FFRCT compared with clinically significant stenosis at coronary CT angiography (73.4% [80 of 109] vs 48.7% [91 of 187], respectively; P < .001), with the majority of outcomes being planned revascularization. Corresponding hazard ratios (HRs) were 9.2 (95% confidence interval [CI]: 5.1, 17; P < .001) for FFRCT and 5.9 (95% CI: 1.5, 24; P = .01) for coronary CT angiography. FFRCT was a superior predictor compared with coronary CT angiography for primary end point (C-index FFRCT, 0.76 vs coronary CT angiography, 0.54; P < .001) and MACE (FFRCT, 0.71 vs coronary CT angiography, 0.52; P = .001). Frequency of MACE was higher in participants with positive FFRCT compared with coronary CT angiography (15.6% [17 of 109] vs 10.2% [19 of 187], respectively; P = .02), driven by unplanned revascularization. MACE HR was 5.5 (95% CI: 1.6, 19; P = .006) for FFRCT and 2.0 (95% CI: 0.3, 14; P = .46) for coronary CT angiography. Each 0.05-unit FFRCT reduction was independently associated with greater incidence of primary end point (HR, 1.7; 95% CI: 1.4, 1.9; P < .001) and MACE (HR, 1.4; 95% CI: 1.1, 1.8; P < .001). Conclusion In stable patients referred for invasive angiography, a CT-derived fractional flow reserve (FFRCT) value of 0.8 or less was a predictor of long-term outcomes driven by planned and unplanned revascularization and was superior to clinically significant stenosis on coronary CT angiograms. Additionally, the numeric value of FFRCT was an independent predictor of outcomes. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Dennie and Rubens in this issue.

DOI： 10.1148/radiol.2019182264

Combination of Renal Angioplasty and Angiotensin-converting-enzyme Inhibitor Can Reduce Proteinuria in Patients with Bilateral Renal Artery Disease.

Hironobu Toda, Haruhito Uchida, Kazufumi Nakamura, Hidemi Takeuchi, Masaru Kinomura, Koji Nakagawa, Atsuyuki Watanabe, Toru Miyoshi, Nobuhiro Nishii, Hiroshi Morita, Jun Wada, Hiroshi Ito

Internal medicine (Tokyo, Japan) 58 ( 13 ) 1917 - 1922 2019.7

Language：English Publishing type：Research paper (scientific journal)

Recent large clinical trials failed to show clear benefits of percutaneous transluminal renal angioplasty (PTRA) as compared with medical therapy on patients with renal artery stenosis. It was also reported that proteinuria is an adverse prognostic factor after PTRA, and PTRA is less effective in patients with overt proteinuria. From the renoprotective point of view, to reduce proteinuria after PTRA is an important therapeutic goal in patients with renal artery stenosis with overt proteinuria. We hereby describe two patients successfully treated by combination therapy with PTRA and administration of angiotensin-converting enzyme (ACE) inhibitor for bilateral renal artery disease with overt proteinuria.

DOI： 10.2169/internalmedicine.2076-18

Emerging Role of Coronary Computed Tomography Angiography in Lipid-Lowering Therapy: a Bridge to Image-Guided Personalized Medicine. International journal

Toru Miyoshi, Kazuhiro Osawa, Keishi Ichikawa, Kazuki Suruga, Takashi Miki, Masashi Yoshida, Koji Nakagawa, Hironobu Toda, Kazufumi Nakamura, Hiroshi Morita, Hiroshi Ito

Current cardiology reports 21 ( 8 ) 72 - 72 2019.6

Language：English Publishing type：Research paper (scientific journal)

PURPOSE OF REVIEW: To summarize the current status of coronary computed tomography angiography (CTA) in the assessment of coronary plaques and discuss the ability of serial coronary CTA to quantitatively measure changes in the plaque burden in response to lipid-lowering therapy. RECENT FINDINGS: Recent advances in coronary CTA have allowed identification of high-risk coronary features in acute coronary syndrome and measurement of changes in the coronary plaque burden with good reproducibility. Statin therapy may delay plaque progression and change some plaque features. However, the clinical relevance of quantitative changes in coronary plaques and the optimal methods to reduce the plaque burden remain unclear. Despite guideline-directed lipid-lowering therapy, adverse events still occur in substantial numbers of patients receiving statins. Coronary CTA is noninvasive and has high diagnostic performance in patients with coronary artery disease, making change in the plaque burden an applicable biomarker for individualized assessment of future risk.

DOI： 10.1007/s11886-019-1170-4

Massive pulmonary embolism with cardiac arrest in pregnancy: A case report.

Toru Miyoshi, Hideo Kawakami, Reiko Hori, Kazuo Nakanishi, Takehisa Kusumoto, Yusuke Kono, Shinsuke Kido, Akira Oshita, Hiroshi Matsuoka

Journal of cardiology cases 19 ( 6 ) 186 - 189 2019.6

Language：English

A 39-year-old woman developed a pulmonary embolism at 28 weeks of gestation, after a 4-week period of bedrest, and required emergencycesarean section due to a decrease in fetal heart rate. Pulseless electrical activity (PEA) developed after intravenous anesthesia. The fetus was delivered 5 min after PEA onset, during cardiopulmonary resuscitation of the mother. Intravenous recombinant tissue-plasminogen activator injection, percutaneous cardiopulmonary support, and 24-h hypothermia therapy were administered to the mother, followed by inferior vena cava filter insertion, combined with catheter thrombus fragmentation and percutaneous thrombectomy. Both the patient and her baby survived. <Learning objective: Massive pulmonary embolism with pregnancy may result in death of both mother and child. In this case, after maternal cardiac arrest due to massive pulmonary embolism, the fetus was delivered by cesarean section, followed by thrombolysis treatment using recombinant tissue-plasminogen activator and percutaneous cardiac pulmonary support, pulmonary thrombectomy which was performed on day 3 was effective. Both the patient and her baby survived.>.

DOI： 10.1016/j.jccase.2019.01.004

Correlation of Arterial Stiffness With Left Atrial Volume Index and Left Ventricular Mass Index in Young Adults: Evaluation by Coronary Computed Tomography Angiography. International journal

Kazuhiro Osawa, Rine Nakanishi, Toru Miyoshi, Sina Rahmani, Indre Ceponiene, Negin Nezarat, Mitsuru Kanisawa, Hong Qi, Eranthi Jayawardena, Nicholas Kim, Hiroshi Ito, Matthew J Budoff

Heart, lung & circulation 28 ( 6 ) 932 - 938 2019.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Increased arterial stiffness is reportedly associated with cardiac remodelling, including the left atrium and left ventricle, in middle-aged and older adults. However, little is known about this association in young adults. METHODS: In total, 73 patients (44 (60%) men) aged 25 to 45 years with suspected coronary artery disease were included in the analysis. The left atrial volume index (LAVI), left ventricular volume index (LVVI), and left ventricular mass index (LVMI) were measured using coronary computed tomography angiography (CCTA). Arterial stiffness was assessed with the cardio-ankle vascular index (CAVI). An abnormally high CAVI was defined as that above the age- and sex-specific cut-off points of the CAVI. RESULTS: Compared with patients with a normal CAVI, those with an abnormally high CAVI were older and had a greater prevalence of diabetes mellitus, higher diastolic blood pressure, greater coronary artery calcification score, and a greater LAVI (33.5±10.3 vs. 43.0±10.3mL/m2, p <0.01). In contrast, there were no significant differences in the LVVI or LVMI between the subgroups with a normal CAVI and an abnormally high CAVI. Multivariate linear regression analysis showed that the LAVI was significantly associated with an abnormally high CAVI (standardised regression coefficient=0.283, p=0.03). CONCLUSIONS: The present study demonstrated that increased arterial stiffness is associated with the LAVI, which reflects the early stages of cardiac remodelling, independent of various comorbidity factors in young adults with suspected coronary artery disease.

DOI： 10.1016/j.hlc.2018.04.286

Inhibitory Effects of Tofogliflozin on Cardiac Hypertrophy in Dahl Salt-Sensitive and Salt-Resistant Rats Fed a High-Fat Diet.

Tomonari Kimura, Kazufumi Nakamura, Toru Miyoshi, Masashi Yoshida, Kaoru Akazawa, Yukihiro Saito, Satoshi Akagi, Yuko Ohno, Megumi Kondo, Daiji Miura, Jun Wada, Hiroshi Ito

International heart journal 60 ( 3 ) 728 - 735 2019.5

Language：English Publishing type：Research paper (scientific journal)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are drugs for diabetes and might prevent heart failure. In this study, we investigated the effects of tofogliflozin, an SGLT2 inhibitor, on cardiac hypertrophy and metabolism in hypertensive rats fed a high-fat diet. Dahl salt-sensitive (DS) rats, hypertensive model rats, and Dahl salt-resistant (DR) rats, non-hypertensive model rats, were fed a high-salt and high-fat diet containing tofogliflozin (0.005%) for 9 weeks to examine the effects of this drug on cardiac hypertrophy and metabolism. Tofogliflozin tended to suppress a rise of the systolic blood pressure, relative to the control, throughout the treatment period in both DR and DS rats, and significantly suppress a rise of the systolic blood pressure, relative to the control, at the 9th week in DS rats. Tofogliflozin reduced cardiac hypertrophy (heart weight/body weight) not only in DS rats but also in DR rats. Histological analysis showed that tofogliflozin significantly decreased cardiomyocyte hypertrophy and perivascular fibrosis in both DS and DR rats. Tofogliflozin significantly decreased the expression levels of genes related to cardiac hypertrophy (encoding for natriuretic peptides A and B and interleukin-6), and to cardiac fibrosis (encoding for transforming growth factor-β1 and collagen type IV), in DS rats. Recent studies have shown that hypertrophied and failing hearts shift to oxidizing ketone bodies as a significant fuel source. We also performed metabolome analysis for ventricular myocardial tissue. Tofogliflozin reduced 3-hydroxybutyrate, a ketone body, and significantly decreased the expression levels of β-hydroxybutyrate dehydrogenase 1 and 3-oxoacid CoA-transferase, which are related to ketone oxidization. In conclusion, tofogliflozin ameliorated cardiac hypertrophy and fibrosis along with reduction of ketone usage in myocardial tissue.

DOI： 10.1536/ihj.18-392

The optimal amount of salt intake. International journal

Kazufumi Nakamura, Toru Miyoshi

Hypertension research : official journal of the Japanese Society of Hypertension 42 ( 5 ) 752 - 753 2019.5

Percutaneous Coronary Intervention for Chronic Total Occlusion in Patients With Chronic Kidney Disease: Should Imaging Surveillance Be Mandatory? International journal

Kazuhiro Dan, Toru Miyoshi, Makoto Nakahama, Hiroshi Ito, Hector M Garcia-Garcia

The Canadian journal of cardiology 35 ( 4 ) 545.e9 2019.4

Decrease in oxidized high-density lipoprotein is associated with slowed progression of coronary artery calcification: Subanalysis of a prospective multicenter study. International journal

Takashi Miki, Toru Miyoshi, Kazuhiko Kotani, Kunihisa Kohno, Hirohiko Asonuma, Satoru Sakuragi, Yasushi Koyama, Kazufumi Nakamura, Hiroshi Ito

Atherosclerosis 283 1 - 6 2019.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIMS: Oxidized high-density lipoprotein (oxHDL) is characterized by reduced anti-inflammatory properties compared with HDL. However, the role of oxHDL in the pathogenesis of coronary artery calcification (CAC), a marker of subclinical atherosclerosis, remains unclear. We prospectively investigated the association between the change in oxHDL and progression of CAC in a substudy of a multicenter study. METHODS: In the principal study, patients with a CAC score of 1-999 were treated with pitavastatin with/without eicosapentaenoic acid. Measurement of CAC with multidetector-row computed tomography and a blood test were performed at baseline and at the 1-year follow-up. In the principal study, the increase in CAC did not differ among treatment groups. In this substudy, patients were divided into two groups: CAC progression (change in Agatston score of >0) and no CAC progression. RESULTS: In total, 140 patients were analyzed. The oxHDL level significantly decreased from 167 (132-246) at baseline to 122 (103-149) after treatment (median [25th-75th percentile], U/ml) (p < 0.001). The annual change in CAC was significantly positively associated with changes in oxHDL (r = 0.17, p = 0.04), triglycerides (r = 0.17, p = 0.04), and high-sensitivity C-reactive protein (r = 0.22, p = 0.01) but was not associated with changes in low-density lipoprotein cholesterol or HDL-cholesterol. Multiple logistic analysis demonstrated that the decrease in oxHDL per 10 U/ml was independently associated with CAC progression (odds ratio, 0.95; 95% confidence interval, 0.90-0.99; p = 0.04). CONCLUSIONS: The decrease in oxHDL is associated with the attenuation of CAC progression, suggesting that oxHDL is a potential target for atherosclerosis prevention.

DOI： 10.1016/j.atherosclerosis.2019.01.032

CLI診療(循環器内科医に求められる役割について) Reviewed

大塚寛昭, 戸田洋伸, 江尻健太郎, 三好亨, 中村一文, 森田宏, 伊藤浩

日本下肢救済・足病学会誌 11 ( 1 ) 58 - 58 2019.4

The effect of luseogliflozin and alpha-glucosidase inhibitor on heart failure with preserved ejection fraction in diabetic patients: rationale and design of the MUSCAT-HF randomised controlled trial. International journal

Kentaro Ejiri, Toru Miyoshi, Kazufumi Nakamura, Satoru Sakuragi, Mitsuru Munemasa, Seiji Namba, Atsushi Takaishi, Hiroshi Ito

BMJ open 9 ( 3 ) e026590 2019.3

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a strong risk factor for coronary artery disease and heart failure, particularly heart failure with preserved ejection fraction (HFpEF). The aim of the ongoing MUSCAT-HF (It stands for Prospective Comparison of Luseogliflozin and Alpha-glucosidase on the Management of Diabetic Patients with Chronic Heart Failure and Preserved Ejection Fraction) trial is to evaluate the efficacy of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, versus voglibose, an alpha-glucosidase inhibitor, using brain natriuretic peptide (BNP) as the index of therapeutic effect in T2DM patients with HFpEF. METHODS AND ANALYSIS: A total of 190 patients with T2DM and HFpEF (ejection fraction >45%) who are drug-naïve or taking any anti-diabetic agents will be randomised (1:1) to receive luseogliflozin 2.5 mg one time per day or voglibose 0.2 mg three times per day. The patients will be stratified by age (<65 years, ≥65 years), baseline haemoglobin A1c (<8.0%, ≥8.0%), baseline BNP (<100 pg/mL, ≥100 pg/mL), baseline renal function (estimated glomerular filtration rate ≥60 mL/min/1.73 m2, <60 mL/min/1.73 m2), use of thiazolidine or not and presence or absence of atrial fibrillation and flutter at screening. After randomisation, participants will receive the study drug for 12 weeks in addition to their background therapy. The primary endpoint is the proportional change in baseline BNP after 12 weeks of treatment. The key secondary endpoints are the change from baseline in the ratio of early mitral inflow velocity to mitral annular early diastolic velocity, body weight and glycaemic control after 12 weeks of treatment. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee and the patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: UMIN000018395.

DOI： 10.1136/bmjopen-2018-026590

Neoatherosclerosis in Sirolimus-Eluting Stents After Paclitaxel-Coated Ballooning Cannot Be Stabilized Despite PCSK9 Inhibitor Therapy.

Toru Miyoshi, Hideo Kawakami, Yusuke Kono, Akira Oshita, Hiroshi Matsuoka

Circulation reports 1 ( 4 ) 196 - 196 2019.3

Tobacco smoking protective effect via remote ischemic preconditioning on myocardial damage after elective percutaneous coronary intervention: Subanalysis of a randomized controlled trial. International journal

Kentaro Ejiri, Toru Miyoshi, Kunihisa Kohno, Makoto Nakahama, Masayuki Doi, Mitsuru Munemasa, Masaaki Murakami, Atsushi Takaishi, Kazufumi Nakamura, Hiroshi Ito

International journal of cardiology. Heart & vasculature 22 55 - 60 2019.3

Language：English Publishing type：Research paper (scientific journal)

Background: Remote ischemic preconditioning (RIPC) is promising for preventing periprocedural myocardial damage (pMD) in patients undergoing percutaneous coronary intervention (PCI). However, the impact of RIPC on pMD on smokers is not well elucidated. The aim of this study was to investigate an association between tobacco smoking and RIPC on pMD in patients planning to undergo PCI. Methods: This study used data from a multicenter randomized controlled trial involving patients with stable angina who planned to undergo elective PCI. We analyzed data for 262 patients in the control (n = 133) and upper-limb RIPC (n = 129) groups, including 166 current or former smokers. The major outcome was the pMD incidence following PCI, with pMD defined as an elevated level of highly sensitive cardiac troponin T or a creatine kinase myocardial band 12 or 24 h after PCI. Results: The incidence of pMD was significantly lower in the upper-limb RIPC group than in the control group (28/83 patients [33.8%] vs. 43/83 patients [51.8%], respectively; p = 0.018). In a multiple logistic regression model, tobacco smoking was an independent predictor of interacting with and enhancing the effect of RIPC on reducing the incidence of pMD after PCI (regression coefficient, -0.4 [95% confidence interval, -0.74 to -0.082]; p = 0.015). Conclusions: Tobacco smoking may have a beneficial effect on RIPC against pMD after PCI.

DOI： 10.1016/j.ijcha.2018.12.005

Effect of Switching to Azilsartan From Fixed-Dose Combination of an Angiotensin II Receptor Blocker and Calcium Channel Blocker or a Thiazide in Patients With Hypertension. International journal

Toru Miyoshi, Go Onoue, Hiroshi Ito

Journal of clinical medicine research 11 ( 3 ) 202 - 207 2019.3

Language：English Publishing type：Research paper (scientific journal)

Background: Despite the availability of antihypertensive treatments, fewer than half of patients who receive treatment successfully achieve blood pressure (BP) goals. The purpose of this study was to evaluate the effect of switching to azilsartan 40 mg from a fixed-dose combination tablet of an angiotensin II receptor blocker (ARB) and amlodipine at 5 mg or azelnidipine at 16 mg (ARB/CCB) or an ARB and hydrochlorothiazide (HCT) at 6.25 mg or 12.5 mg (ARB/HCT) on BP. Methods: This prospective, multicenter, open-labeled, single-arm study included 40 patients treated with a fixed-dose combination tablet of an ARB/CCB or an ARB/HCT, which was switched to azilsartan 40 mg after enrollment. The primary outcome was the change in BP from baseline to the 24-week follow-up. Results: Of the 40 patients who completed this study, 33 did not require changes in their antihypertensive medications after switching to azilsartan, and their BP did not change from baseline to follow-up. However, the systolic BP in seven patients was elevated at 12 weeks, and amlodipine at 5 mg was therefore added; these patients' baseline medications were an ARB/CCB (n = 6) and an ARB/HCT (n = 1). In all patients, the serum potassium level was slightly increased after switching to azilsartan at 6 months, while the serum creatinine, hemoblobinA1c, and lipid profile did not change. Conclusions: Azilsartan at 40 mg did not result in a greater decrease in BP than a fixed-dose combination tablet of an ARB/CCB or an ARB/HCT. However, our findings suggest a substantial BP-lowering effect of azilsartan at 40 mg in patients with hypertension.

DOI： 10.14740/jocmr3723

Association between changes in platelet reactivity during elective percutaneous coronary intervention and periprocedural myocardial infarction: A pilot study. International journal

Yusuke Kawai, Toru Miyoshi, Kazufumi Nakamura, Gentaro Shokoku, Keisuke Yamamoto, Tamaki Ono, Kouji Tokioka, Tohru Ohe, Hiroshi Ito

Journal of cardiology 73 ( 2 ) 134 - 141 2019.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: High platelet reactivity before percutaneous coronary intervention (PCI) reportedly increases the risk of PCI-related myocardial infarction (PMI) following elective PCI. We conducted a pilot study to evaluate changes in platelet reactivity during PCI and their association with the incidence of PMI. METHODS: In total, 133 consecutive patients undergoing elective PCI after pretreatment with dual antiplatelet therapy for at least 7 days were prospectively enrolled. Platelet reactivity was measured by the VerifyNow® assay (International Technidyne Corporation, Edison, NJ, USA) immediately before and after PCI. RESULTS: Platelet reactivity significantly increased from 177.3 ± 53.4 P2Y12 reaction units (PRU) before PCI to 203.4 ± 52.8 PRU immediately after PCI (p < 0.001). Absolute changes in platelet reactivity were significantly greater in patients with than without PMI (32.4 ± 29.0 vs. 21.2 ± 24.8 PRU, respectively; p = 0.021). In the multivariable logistic regression analysis, the absolute change in PRU was an independent predictor of the incidence of PMI. Receiver operating characteristic curve analysis of the change in PRU during PCI for discriminating PMI showed a sensitivity, specificity, and the cut-off value of 46%, 76%, and 37 PRU, respectively (area under the curve = 0.607, p = 0.0235). When the patients were divided into two groups, namely a greater (change in PRU ≥ 37) and smaller (change in PRU < 37) increase group, the incidence rate of PMI was significantly higher in the greater than smaller increase group (59.1% vs. 34.8%, respectively; p = 0.008). Additional exploratory analyses by intracoronary imaging demonstrated that the proximal reference lumen area in the greater increase group was significantly smaller than that in the smaller increase group (6.5 ± 2.4 vs. 7.7 ± 3.1 mm2, respectively; p = 0.032). CONCLUSION: An increase in platelet reactivity after elective PCI is possibly associated with PMI. This finding should be validated by a larger-scale study.

DOI： 10.1016/j.jjcc.2018.07.006

Cardio-ankle vascular index and cardiovascular disease: Systematic review and meta-analysis of prospective and cross-sectional studies. International journal

Kunihiro Matsushita, Ning Ding, Esther D Kim, Matthew Budoff, Julio A Chirinos, Bo Fernhall, Naomi M Hamburg, Kazuomi Kario, Toru Miyoshi, Hirofumi Tanaka, Raymond Townsend

Journal of clinical hypertension (Greenwich, Conn.) 21 ( 1 ) 16 - 24 2019.1

Language：English Publishing type：Research paper (scientific journal)

The cardio-ankle vascular index (CAVI) is a new measure of arterial stiffness that reflects the stiffness from the ascending aorta to the ankle arteries, and demonstrates little dependence on blood pressure during the evaluation. However, a comprehensive assessment of the association of CAVI with cardiovascular disease (CVD) has not been reported. We performed a systematic review to assess the association between CAVI and CVD. We searched for both prospective and cross-sectional studies using MEDLINE, Embase, and Cochrane from inception until April 11, 2017. We pooled the results using random-effects models. Among 1519 records, we identified nine prospective studies (n = 5214) and 17 cross-sectional eligible studies (n = 7309), with most enrolling high CVD risk populations in Asia. All nine prospective studies investigated composite CVD events as an outcome (498 cases including coronary events and stroke) but modeled CAVI inconsistently. The pooled adjusted hazard ratio for CVD events per 1 standard deviation increment of CAVI in four studies was 1.20 (95% CI: 1.05-1.36, P = 0.006). Of the 17 cross-sectional studies, 13 studies compared CAVI values between patients with and without CVD and all reported significantly higher values in those with CVD (pooled mean difference in CAVI values 1.28 [0.86-1.70], P < 0.001). This systematic review suggests a modest association between CAVI and incident CVD risk, and highlights the need for studies assessing CAVI as a predictor of CVD in the general population and non-Asian countries.

DOI： 10.1111/jch.13425

Effect of LCZ696, a dual angiotensin receptor neprilysin inhibitor, on isoproterenol-induced cardiac hypertrophy, fibrosis, and hemodynamic change in rats. International journal

Toru Miyoshi, Kazufumi Nakamura, Daiji Miura, Masashi Yoshida, Yukihiro Saito, Satoshi Akagi, Yuko Ohno, Megumi Kondo, Hiroshi Ito

Cardiology journal 26 ( 5 ) 575 - 583 2019

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Recent clinical studies have shown that treatment with LCZ696, a complex containing the angiotensin receptor blocker valsartan and neprilysin inhibitor sacubitril, improves the prognosis of heart failure patients with a reduced ejection fraction. This study evaluated whether LCZ696 affects left ventricular hypertrophy, fibrosis, and hemodynamics in isoproterenol (ISO)-treated rats compared with valsartan alone. METHODS: Male Wistar rats received subcutaneous saline (n = 10), subcutaneous ISO (2.4 mg/kg/day; n = 10), subcutaneous ISO + oral LCZ696 (60 mg/kg/day; n = 20) (ISO-LCZ), or subcutaneous ISO + oral valsartan (30 mg/kg/day; n = 20) (ISO-VAL) for 7 days. RESULTS: LCZ696 and valsartan did not significantly reduce the increased heart weight/body weight ratio in rats treated with ISO. Echocardiography showed that the deceleration time shortened by ISO was restored by LCZ696 but not valsartan alone (p = 0.01 vs. the ISO group). Histological analysis showed that cardiac interstitial fibrosis increased by ISO was decreased significantly by LCZ696 but not valsartan alone (control: 0.10 ± 0.14%; ISO: 0.41 ± 0.32%; ISO-LCZ: 0.19 ± 0.23% [p < 0.01 vs. the ISO group]; ISO-VAL: 0.34 ± 0.23% [p = 0.34 vs. the ISO group]). Quantitative polymerase chain reaction showed that mRNA expression of Tgfb1, Col1a1, Ccl2, and Anp increased by ISO was significantly attenuated by LCZ696 but not valsartan alone (p < 0.05 vs. the ISO group). CONCLUSIONS: LCZ696 improves cardiac fibrosis, but not hypertrophy, caused by continuous exposure to ISO in rats.

DOI： 10.5603/CJ.a2018.0048

Physiological Diagnostic Criteria for Vascular Failure. International journal

Atsushi Tanaka, Hirofumi Tomiyama, Tatsuya Maruhashi, Yasushi Matsuzawa, Toru Miyoshi, Tomoyuki Kabutoya, Kazuomi Kario, Seigo Sugiyama, Masanori Munakata, Hiroshi Ito, Shinichiro Ueda, Charalambos Vlachopoulos, Yukihito Higashi, Teruo Inoue, Koichi Node

Hypertension (Dallas, Tex. : 1979) 72 ( 5 ) 1060 - 1071 2018.11

Potential benefit of a simultaneous, side-by-side display of contrast MDCT and echocardiography over routine sequential imaging for assessment of adult congenital heart disease: A preliminary study. International journal

Hiroki Oe, Nobuhisa Watanabe, Toru Miyoshi, Kazuhiro Osawa, Teiji Akagi, Susumu Kanazawa, Hiroshi Ito

Journal of cardiology 72 ( 5 ) 395 - 402 2018.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Management of adult congenital heart disease (ACHD) patients requires understanding of its complex morphology and functional features. An innovative imaging technique has been developed to display a virtual multi-planar reconstruction obtained from contrast-enhanced multidetector-computed tomography (MDCT) corresponding to the same cross-sectional image from transthoracic echocardiography (TTE). The aim of this study is to assess the usefulness of this imaging technology in ACHD patients. METHODS: This study consisted of 46 consecutive patients (30 women; mean age, 52±18 years old) with ACHD who had undergone contrast MDCT. All patients underwent TTE within a week of MDCT. An experienced sonographer who did not know the results of MDCT conducted a diagnosis using TTE and, then, using the new imaging technology. We studied whether this imaging technology provided additional or unexpected findings or makes more accurate diagnosis. RESULTS: In this imaging technology, MDCT cross-section provides higher-resolution image to the deep compared to corresponding TTE image. Depending on the MDCT section which can be arbitrarily set under the echo guide, we can diagnose unexpected or incremental lesions or more accurately assess the severity of the lesion in 27 patients (59%) compared to TTE study alone. This imaging technology was useful in the following situations: CONCLUSIONS: This integrated imaging technology provides incremental role over TTE in complex anatomy, and allows functional information in ACHD patients.

DOI： 10.1016/j.jjcc.2018.04.015

Impact of Serum Malondialdehyde-Modified Low-Density Lipoprotein Levels on Admission for Predicting Prognosis in Patients With Acute Coronary Syndrome Who Received Successful Percutaneous Coronary Intervention.

Naofumi Amioka, Toru Miyoshi, Hiroaki Otsuka, Atsushi Takaishi, Masayuki Ueeda, Satoshi Hirohata, Hiroshi Ito

CIRCULATION 138 2018.11

Corrigendum to "Serum cystatin C levels are associated with coronary artery calcification in women without chronic kidney disease" [J. Cardiol. 70 (2017) 559-564]. International journal

Hiroyasu Sugiyama, Toru Miyoshi, Kazuhiro Osawa, Takashi Miki, Yuji Koide, Kazufumi Nakamura, Hiroshi Morita, Hiroshi Ito

Journal of cardiology 72 ( 3 ) 267 - 268 2018.9

To what extent can 3D model replicate dimensions of individual mitral valve prolapse?

Takashi Shirakawa, Masao Yoshitatsu, Yasushi Koyama, Akira Kurata, Toru Miyoshi, Hiroki Mizoguchi, Takafumi Masai, Koichi Toda, Yoshiki Sawa

Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs 21 ( 3 ) 348 - 355 2018.9

Language：English Publishing type：Research paper (scientific journal)

Determining the complex geometry of mitral valve prolapse is often difficult. We constructed 3D models of six prolapsed mitral valves for surgical assessment, and evaluated how accurately the models could replicate individual valve dimensions. 3D polygon data were constructed based on an original segmentation method for computed tomography images. The model's replication performance was confirmed via dimensional comparison between the actual hearts during surgery and those models. The results revealed that the prolapsed segments matched in all cases; however, torn chordae were replicated in four cases. The mean height differences were 0.0 mm (SD 1.6, range - 2 to + 2 mm) for the anterolateral side, 0.0 mm (SD 1.7, range - 2 to + 2 mm) for the prolapsed leaflet center, and - 1.5 mm (SD 0.6, range - 1 to - 2 mm) for the posteromedial side. Regression analysis showed a strong and positive correlation, and Bland-Altman plots indicated quantitative similarity of the models to the actual hearts. We concluded that our 3D valve models could replicate the actual mitral valve prolapses within acceptable dimensional differences. Our concepts are useful for better 3D valve creation and better surgical planning with reliable 3D valve models.

DOI： 10.1007/s10047-018-1033-6

Coral reef aorta一連の病変と考えられた移植腎動脈狭窄に対する血管内治療の1例 Reviewed

戸田洋伸, 大塚寛昭, 江尻健太郎, 内田治仁, 杜徳尚, 中川晃志, 渡邊敦之, 三好亨, 西井伸洋, 中村一文, 森田宏, 伊藤浩

脈管学 58 ( Suppl. ) S206 - S206 2018.9

Anomalous aortic origin of the right coronary artery with functional ischemia determined with fractional flow reserve derived from computed tomography. International journal

Takashi Miki, Toru Miyoshi, Atsuyuki Watanabe, Kazuhiro Osawa, Naofumi Amioka, Hiroshi Ito

Clinical case reports 6 ( 7 ) 1371 - 1372 2018.7

Language：English Publishing type：Research paper (scientific journal)

A right coronary artery of anomalous origin is rare congenital anatomy that can be fatal. CT angiography is an excellent tool for its anatomical assessment. Noninvasive CT-based fractional flow reserve measurement can additionally evaluate the functional severity of coronary stenosis and is potentially useful for evaluating coronary anomalies.

DOI： 10.1002/ccr3.1582

Protective Effect of Remote Ischemic Preconditioning on Myocardial Damage After Percutaneous Coronary Intervention in Stable Angina Patients With Complex Coronary Lesions - Subanalysis of a Randomized Controlled Trial.

Kentaro Ejiri, Toru Miyoshi, Kunihisa Kohno, Makoto Nakahama, Masayuki Doi, Mitsuru Munemasa, Masaaki Murakami, Atsushi Takaishi, Kazufumi Nakamura, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society 82 ( 7 ) 1788 - 1796 2018.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The effect of remote ischemic preconditioning (RIPC) on periprocedural myocardial damage (pMD) in patients undergoing percutaneous coronary intervention (PCI) is controversial. The aim of this study was to investigate the effect of RIPC or intravenous nicorandil on pMD following elective PCI in a subgroup of patients with complex coronary lesions from a multicenter randomized controlled trial.Methods and Results:Patients with stable angina who underwent elective PCI were assigned to 3 groups: control, upper-limb RIPC or intravenous nicorandil. The major outcome was pMD incidence following PCI, with pMD defined as an elevated level of high-sensitivity cardiac troponin T or creatine kinase myocardial band at 12 or 24 h after PCI. A total of 171 patients with complex coronary lesions (ACC-AHA coronary classification type B2 or C) were analyzed. The incidence of pMD following PCI was significantly lower in the RIPC group than in the control group (44.4% vs. 66.1%; P=0.023). The adjusted odds ratio (95% confidence interval) for pMD in the RIPC vs. the controls was 0.41 (0.18-0.94). The incidence of pMD in the nicorandil group was not significantly reduced compared with the control groups. CONCLUSIONS: This substudy suggested that RIPC prior to PCI prevented pMD in patients with complex coronary lesions. Further investigation in a multicenter prospective study is needed to confirm these results.

DOI： 10.1253/circj.CJ-17-1000

Assessment of Second- and Third-Generation Drug-Eluting Stents on Chronic Coronary Angioscopy - Multicenter Study on Intra-Coronary AngioScopy After Stent (MICASA) Prospective Data Analysis.

Toru Miyoshi, Hiroshi Matsuoka, Hideo Kawakami, Kazuoki Dai, Tetsuya Sato, Kouki Watanabe, Masaharu Ishihara

Circulation journal : official journal of the Japanese Circulation Society 82 ( 7 ) 1830 - 1835 2018.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The vascular response, in terms of quality and quantity, of the second- and third-generation drug-eluting stents (2G- and 3G-DES, respectively) was assessed prospectively on coronary angioscopy (CAS).Methods and Results:The Multicenter study on Intra-Coronary AngioScopy After Stent (MICASA) is a multicenter CAS registry. A total of 107 DES (71 2G- and 36 3G-DES) were prospectively observed on CAS 8.7±2.7 months after percutaneous coronary intervention. Neointimal coverage (NC) grade was evaluated using a 4-point grading scale, from 0 (no coverage) to 3 (complete coverage). Plaque yellow color (YC) was also assessed using a 4-point grading system, from 0 (white) to 3 (bright yellow). Max-NC (2G-DES vs. 3G-DES: 2.14±0.68 vs. 2.44±0.73, P=0.023); min-NC (1.07±0.48 vs. 1.39±0.60, P=0.002), and dominant-NC (1.57±0.69 vs. 2.08±0.84, P=0.002) were significantly higher and the YC grade (1.23±0.82 vs. 0.86±0.76, P=0.031) significantly lower in the 3G-DES group than in the 2G-DES group. There was no significant difference in the presence of thrombus (28.2% vs. 22.2%, P=0.51) between the 2G- and 3G-DES groups. CONCLUSIONS: The higher NC grade and lower YC grade in 3G-DES than in 2G-DES might be associated with better long-term clinical outcome, which remains to be determined in future studies.

DOI： 10.1253/circj.CJ-17-1396

High Baseline Lipoprotein(a) Level as a Risk Factor for Coronary Artery Calcification Progression: Sub-analysis of a Prospective Multicenter Trial.

Jun Ida, Kazuhiko Kotani, Toru Miyoshi, Kazufumi Nakamura, Kunihisa Kohno, Hirohiko Asonuma, Satoru Sakuragi, Masayuki Doi, Takashi Miki, Yasushi Koyama, Hiroshi Ito

Acta medica Okayama 72 ( 3 ) 223 - 230 2018.6

Language：English Publishing type：Research paper (scientific journal)

Lipoprotein(a), or Lp(a), is a low-density lipoprotein-like particle largely independent of known risk factors for, and predictive of, cardiovascular disease (CVD). We investigated the association between baseline Lp(a) levels and the progression of coronary artery calcification (CAC) in patients with hypercholesterolemia undergoing statin therapy. This study was a sub-analysis of a multicenter prospective study that evaluated the annual progression of CAC under intensive and standard pitavastatin treatment with or without eicosapentaenoic acid in patients with an Agatston score of 1 to 999, and hypercholesterolemia treated with statins. We classified the patients into 3 groups according to CAC progression. A total of 147 patients (mean age, 67 years; men, 54%) were analyzed. The proportion of patients with Lp(a) > 30 mg/dL significantly increased as CAC progressed (non-progression; 5.4%, 0<CAC progression ≦100; 7.7%, and CAC progression >100; 23.6%). Logistic regression analysis showed that Lp(a) > 30 mg/dL was an independent predictor of the annual change in Agatston score > 100 (OR: 5.51; 95% CI: 1.28-23.68; p=0.02), even after adjusting for age, sex, hypertension, diabetes mellitus, current smoking, body mass index, and lipid-lowering medications. Baseline Lp(a) >30 mg/dL was a predictor of CAC progression in this population of patients with hypercholesterolemia undergoing statin therapy.

DOI： 10.18926/AMO/56067

血行再建後の末梢動脈疾患患者に対する非監視下運動療法の効果

木元朗, 中山理絵, 原賀泰誠, 戸田洋伸, 三好亨

日本下肢救済・足病学会誌 10 ( 1 ) 77 - 77 2018.6

重度低心機能患者に発症した重症下肢虚血、糖尿病性壊疽に対し集学的治療を行った一例 Reviewed

大塚寛昭, 戸田洋伸, 江尻健太郎, 奥山倫弘, 大澤晋, 山田潔, 三好亨, 中村一文, 伊藤浩

日本下肢救済・足病学会誌 10 ( 1 ) 83 - 83 2018.6

TRPM4 Mutation in Patients With Ventricular Noncompaction and Cardiac Conduction Disease. International journal

Yukihiro Saito, Kazufumi Nakamura, Nobuhiro Nishi, Osamu Igawa, Masashi Yoshida, Toru Miyoshi, Atsuyuki Watanabe, Hiroshi Morita, Hiroshi Ito

Circulation. Genomic and precision medicine 11 ( 5 ) e002103 2018.5

Diastolic Dysfunction Is a Risk of Perioperative Myocardial Injury Assessed by High-Sensitivity Cardiac Troponin T in Elderly Patients Undergoing Non-Cardiac Surgery.

Hironobu Toda, Kazufumi Nakamura, Koji Nakagawa, Atsuyuki Watanabe, Toru Miyoshi, Nobuhiro Nishii, Kazuyoshi Shimizu, Masao Hayashi, Hiroshi Morita, Hiroshi Morimatsu, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society 82 ( 3 ) 775 - 782 2018.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) is useful for detecting myocardial injury and is expected to become a prognostic marker in patients undergoing non-cardiac surgery. The aim of this pilot study evaluating the efficacy of β-blocker therapy in a perioperative setting (MAMACARI study) was to assess perioperative myocardial injury (PMI) in elderly patients with preserved ejection fraction (EF) undergoing non-cardiac surgery.Methods and Results:In this prospective observational cohort study of 151 consecutive patients with preserved EF and aged >60 years who underwent non-cardiac surgery, serum levels of hs-cTnT were measured before and on postoperative days 1 and 3 after surgery. PMI was defined as postoperative hs-cTnT >0.014 ng/mL and relative hs-cTnT change ≥20%. A total of 36 (23.8%) of the patients were diagnosed as having PMI. The incidence of a composite of cardiovascular events within 30 days after surgery, including myocardial infarction, stroke, worsening heart failure, atrial fibrillation and pulmonary embolism, was significantly higher in patients with PMI than in patients without PMI (odds ratio (OR) 9.25, P<0.001, 95% confidence interval (CI) 2.65-32.3). Multivariate analysis revealed that left ventricular diastolic dysfunction defined by echocardiography was independently associated with PMI (OR: 3.029, 95% CI: 1.341-6.84, P=0.008). CONCLUSIONS: PMI is frequently observed in elderly patients undergoing non-cardiac surgery. Diastolic dysfunction is an independent predictor of PMI.

DOI： 10.1253/circj.CJ-17-0747

Angioscopic Findings of Acute Myocardial Infarction After Kawasaki Disease.

Toru Miyoshi, Fumiyasu Seike, Hideo Kawakami, Akira Oshita, Hiroshi Matsuoka

Circulation journal : official journal of the Japanese Circulation Society 82 ( 3 ) 925 - 927 2018.2

Effect of Intensive and Standard Pitavastatin Treatment With or Without Eicosapentaenoic Acid on Progression of Coronary Artery Calcification Over 12 Months - Prospective Multicenter Study.

Toru Miyoshi, Kunihisa Kohno, Hirohiko Asonuma, Satoru Sakuragi, Makoto Nakahama, Yusuke Kawai, Tadahisa Uesugi, Takefumi Oka, Mitsuru Munemasa, Natsuki Takahashi, Naoki Mukohara, Seiji Habara, Yasushi Koyama, Kazufumi Nakamura, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society 82 ( 2 ) 532 - 540 2018.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The effect of lipid-lowering agents on progression of coronary artery calcification (CAC) remains unclear. We evaluated the effects of pitavastatin 2 mg/day (PIT2), pitavastatin 4 mg/day (PIT4), and PIT2 combined with eicosapentaenoic acid (PIT2+EPA) on CAC progression.Methods and Results:This prospective multicenter study in Japan included patients with an Agatston score of 1-999, hypercholesterolemia, and no evidence of cardiovascular disease. Patients were allocated into PIT2, PIT4, or PIT2+EPA groups. The primary outcome was the annual percent change in Agatston score in all patients. In total, 156 patients who had multi-detector row computed tomography without any artifacts were included in the primary analysis. Pitavastatin did not significantly reduce the annual progression rate of the Agatston score (40%; 95% CI: 19-61%). The annual progression rate of Agatston score in the PIT2 group was not significantly different from that in the PIT4 group (34% vs. 42%, respectively; P=0.88) or the PIT2+EPA group (34% vs. 44%, respectively; P=0.80). On post-hoc analysis the baseline ratio of low- to high-density lipoprotein cholesterol was a significant predictor of non-progression of Agatston score by pitavastatin (OR, 2.17; 95% CI: 1.10-44.12; P=0.02). CONCLUSIONS: Pitavastatin does not attenuate progression of CAC. Intensive pitavastatin treatment and standard treatment with EPA does not reduce progression of CAC compared with standard treatment.

DOI： 10.1253/circj.CJ-17-0419

Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension. International journal

Kazufumi Nakamura, Masakiyo Sakaguchi, Hiromi Matsubara, Satoshi Akagi, Toshihiro Sarashina, Kentaro Ejiri, Kaoru Akazawa, Megumi Kondo, Koji Nakagawa, Masashi Yoshida, Toru Miyoshi, Takeshi Ogo, Takahiro Oto, Shinichi Toyooka, Yuichiro Higashimoto, Kei Fukami, Hiroshi Ito

PloS one 13 ( 9 ) e0203046 2018

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Pulmonary vascular remodeling of pulmonary arterial hypertension (PAH) is characterized by an inappropriate increase of vascular cells. The receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of hyperproliferative diseases. RAGE is also implicated in the etiology of PAH and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in patients with PAH. METHODS AND RESULTS: PASMCs were obtained from 12 patients with PAH including 9 patients with idiopathic PAH (IPAH) and 3 patients with heritable PAH (HPAH) (2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining revealed that RAGE and S100A8 and A9, ligands of RAGE, were overexpressed in IPAH and HPAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE in IPAH and HPAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by 3H-thymidine incorporation. This result indicates overgrowth characterized by continued growth under a condition of no growth stimulation in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under a condition of no growth stimulation in IPAH and HPAH-PASMCs (P<0.0001). Furthermore, AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH and HPAH-PASMCs (P<0.0001). CONCLUSIONS: RAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH.

DOI： 10.1371/journal.pone.0203046

Protective effect of nicorandil on myocardial injury following percutaneous coronary intervention in older patients with stable coronary artery disease: Secondary analysis of a randomized, controlled trial (RINC). International journal

Norifumi Kawakita, Kentaro Ejiri, Toru Miyoshi, Kunihisa Kohno, Makoto Nakahama, Masayuki Doi, Mitsuru Munemasa, Masaaki Murakami, Kazufumi Nakamura, Hiroshi Ito

PloS one 13 ( 4 ) e0194623 2018

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Our previous study examined an effect of remote ischemic preconditioning (RIPC) or intravenous nicorandil on reduction of periprocedural myocardial injury (pMI) following percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD). We further investigated the effect of RIPC or nicorandil on pMI in older patients. METHODS: Patients with stable CAD who planned to undergo PCI were assigned to a 1:1:1 ratio to control, intravenous nicorandil, or upper-limb RIPC groups. This substudy analyzed patients aged >65 years (n = 282) from the principal cohort. The primary outcome was the incidence of pMI following PCI. We defined pMI as an elevated level of high-sensitive cardiac troponin T or creatine kinase myocardial band 12 or 24 hours after PCI. RESULTS: We found that pMI following PCI was significantly reduced in the nicorandil group compared with the control group (37.2% vs. 53.7%, multiplicity-adjusted p = 0.046), but not in the RIPC group compared with the control group (43.0% vs. 53.7%, multiplicity-adjusted p = 0.245). The adjusted odds ratios (95% confidence interval) for pMI in the RIPC and nicorandil groups versus the control group were 0.63 (0.34 to 1.16) and 0.51 (0.27 to 0.96), respectively. CONCLUSION: Intravenous nicorandil significantly reduces pMI following PCI in a subgroup of older patients with stable CAD. Phase 3 trials are required to validate our results. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000005607.

DOI： 10.1371/journal.pone.0194623

Impact of Chronic Kidney Disease on Cardiovascular and Renal Events in Patients Undergoing Percutaneous Coronary Intervention with Everolimus-Eluting Stent: Risk Stratification with C-Reactive Protein. International journal

Kazuhiro Dan, Toru Miyoshi, Makoto Nakahama, Tomofumi Mizuno, Kenzo Kagawa, Yoichiro Naito, Satoshi Kawada, Hiroshi Ito

Cardiorenal medicine 8 ( 2 ) 151 - 159 2018

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Chronic kidney disease (CKD) and inflammation play critical roles in atherosclerosis. There is limited evidence regarding the relationship between CKD and patients receiving second-generation drug-eluting stents for coronary artery disease. OBJECTIVE: This study aimed to investigate the effect of CKD on cardiovascular and renal events in patients undergoing percutaneous coronary intervention (PCI) with everolimus-eluting stents (EES). METHODS: We analyzed 504 consecutive patients with stable angina pectoris and significant coronary artery stenosis treated with EES. CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 before coronary angiography. The primary outcome was the occurrence of major adverse renal and cardiovascular events (MARCE) including cardiac death, revascularization, heart failure, cerebral infarction, worsening renal function > 25% from baseline, and renal replacement therapy at 1 year. RESULTS: Patients were divided into the a MARCE (n = 126) and a non-MARCE (n = 378) group. The incidence of CKD was 51% in all subjects (including those on hemodialysis) and was significantly higher in the MARCE group than in the non-MARCE group (p = 0.00001). Multivariate logistic regression analysis identified that CKD was independently associated with MARCE (adjusted odds ratio 2.03, 95% confidence interval 1.21-3.39, p = 0.007). Patients were divided into four groups based on CKD and C-reactive protein (CRP) level prior to initial coronary angiography. Cox proportional hazards analysis revealed that patients with CKD and high CRP (≥0.3 mg/dL) had the worst prognosis (hazard ratio 4.371, 95% confidence interval 2.634-7.252, p = 0.00001) compared to patients without CKD and with low CRP. CONCLUSION: CKD combined with CRP predicted more clinical events in patients undergoing PCI with EES.

DOI： 10.1159/000486971

Serum cystatin C levels are associated with coronary artery calcification in women without chronic kidney disease. International journal

Hiroyasu Sugiyama, Toru Miyoshi, Kazuhiro Osawa, Takashi Miki, Yuji Koide, Kazufumi Nakamura, Hiroshi Morita, Hiroshi Ito

Journal of cardiology 70 ( 6 ) 559 - 564 2017.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Chronic renal disease (CKD) is a determinant of coronary artery calcification (CAC), which is a predictor of cardiovascular events. However, in a population without CKD, the association between CAC and renal function is unclear. CAC is affected by sex. This study aimed to determine whether serum cystatin C, a sensitive marker of kidney function, or sex differences are associated with CAC in patients without CKD. METHODS: We evaluated 456 consecutive patients (61±13 years, 42% women) without CKD and evidence of coronary artery disease. The CAC (Agatston) score was examined by multidetector computed tomography. RESULTS: When patients were categorized into three CAC groups based on the Agatston score, mild (<10), moderate (11-399), and severe (≥400) in each sex, serum cystatin C levels gradually increased by severity of CAC in women, but not men. Receiver operating characteristic curve analysis showed that, in women, a cut-off value of 0.97mg/l for cystatin C discriminated patients with severe CAC with a sensitivity of 71% and specificity of 77% (area under the curve, 0.74; 95% CI: 0.62-0.86; p<0.01). Multivariate logistic analysis showed that serum cystatin C was not associated with severe CAC in all patients and men, but this association was observed in women (OR: 7.80 for cystatin C≥0.97mg/l, 95% CI: 1.76-34.6, p<0.01). CONCLUSION: Higher serum cystatin C levels are associated with greater CAC in women without CKD. Measurement of cystatin C may be useful for identifying women who are at high risk for cardiovascular disease.

DOI： 10.1016/j.jjcc.2017.05.001

Characterization of high-intensity plaques on noncontrast T1-weighted magnetic resonance imaging by coronary angioscopy. International journal

Akira Oshita, Hideo Kawakami, Toru Miyoshi, Fumiyasu Seike, Hiroshi Matsuoka

Journal of cardiology 70 ( 6 ) 520 - 523 2017.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: A recent study showed that coronary high-intensity plaques (HIPs) visualized by noncontrast T1-weighted imaging (T1WI) in cardiac magnetic resonance were associated with coronary events. We used coronary angioscopy to analyze HIP plaque morphology. METHODS AND RESULTS: A total 17 lesions from 17 patients with stable or unstable angina pectoris were evaluated at the culprit lesion by noncontrast T1WI using 1.5-T magnetic resonance; of them, nine (53%) were HIPs and eight (47%) were non-HIPs, and all were analyzed by coronary angioscopy. We assessed the existence of thrombus and plaque yellow color grade (YG). YG was assessed visually according to a four-grade scale: 0, white; 1, light yellow; 2, yellow; 3, intense yellow. The frequency of thrombus was significantly higher in HIPs than in non-HIPs (89% vs. 25%, respectively; p=0.007). YG was significantly more frequent in HIPs than in non-HIPs (2.2±0.4 vs. 0.7±0.7, respectively; p=0.01). CONCLUSIONS: These data indicated that HIPs on noncontrast T1WI were associated with the presence of high-grade yellow plaque with thrombus.

DOI： 10.1016/j.jjcc.2017.04.009

Circulating adipocyte fatty acid-binding protein is a predictor of cardiovascular events in patients with stable angina undergoing percutaneous coronary intervention. International journal

Wataru Takagi, Toru Miyoshi, Masayuki Doi, Keisuke Okawa, Kazumasa Nosaka, Tomoyuki Nishibe, Naoaki Matsuo, Satoshi Hirohata, Hiroshi Ito

BMC cardiovascular disorders 17 ( 1 ) 258 - 258 2017.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Adipocyte fatty acid-binding protein (A-FABP) is expressed in both adipocytes and macrophages. Recent studies have shown that A-FABP is secreted by adipocytes and that the A-FABP concentration is associated with obesity, insulin resistance, and atherosclerosis. We have reported that the coronary atherosclerotic burden is associated with the serum A-FABP concentration. In the present study, we investigated whether the serum A-FABP concentration is associated with prognosis in patients with stable angina pectoris who have undergone percutaneous coronary intervention (PCI). METHODS: This was a prospective single-center trial. In total, 130 patients with stable angina pectoris undergoing their first PCI were enrolled from August 2008 to July 2010 at Kagawa Prefectural Central Hospital. The primary endpoints were cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, revascularization, and hospitalization for heart failure. RESULTS: During the follow-up (median, 50 months; interquartile range, 23-66 months), 49 cardiovascular events occurred. Kaplan-Meier analysis showed that the cumulative incidence of the primary endpoints in the high A-FABP group (median A-FABP concentration of ≥ 18.6 ng/ml) was greater than that in the low A-FABP group. Cox analysis showed that the A-FABP concentration was an independent predictor of cardiovascular events adjusted for age and the presence of multi-vessel disease (hazard ratio, 1.03; 95% confidence interval, 1.01-1.04; p = 0.01). CONCLUSION: The serum A-FABP concentration is associated with prognosis in patients with stable angina undergoing PCI, suggesting that the serum A-FABP concentration could be useful for risk assessment of secondary prevention. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000029283 (registration date: September 25, 2017), retrospectively registered.

DOI： 10.1186/s12872-017-0691-2

Differences in endothelial dysfunction induced by paroxysmal and persistent atrial fibrillation: Insights from restoration of sinus rhythm by catheter ablation. International journal

Keisuke Okawa, Toru Miyoshi, Saori Tsukuda, Syouhei Hara, Naoaki Matsuo, Noriyuki Nishibe, Masahiro Sogo, Tomoaki Okada, Kazumasa Nosaka, Kousuke Sakane, Masayuki Doi, Hiroshi Morita, Hiroshi Ito

International journal of cardiology 244 180 - 185 2017.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Atrial fibrillation (AF) is associated with endothelial dysfunction. Studies have shown the incidence of cardiovascular events to be greater in patients with persistent AF (PeAF) than paroxysmal AF (PAF). OBJECTIVE: The aim of this study was to investigate whether endothelial dysfunction and the impact of catheter ablation on the endothelial function differs between PAF and PeAF. METHODS: We prospectively measured the endothelial function by reactive hyperemia peripheral arterial tonometry (RH-PAT) in 103 PAF, 75 PeAF, and 51 control patients at baseline, with follow-up in the AF patients at 6 and 12months after the catheter ablation. RESULTS: The log-transformed RH-PAT index (ln RHI) was the highest in the control group, followed by the PAF and PeAF (0.67±0.23, 0.57±0.29, and 0.45±0.3, respectively, p<0.001) groups. PeAF was determined to be an independent factor of endothelial dysfunction (ln RHI <0.55) even after adjustment for the conventional cardiovascular risk factors. For 12months after the catheter ablation, 102 (99%) PAF and 72 (96%) PeAF patients maintained sinus rhythm. On average, the ln RHI in the PAF group did not change during the follow-up, but it significantly increased in the PeAF group to a level comparable to that of the PAF patients 6months after the catheter ablation (0.53±0.28, p=0.034), and maintained the same level at 12months after the catheter ablation. CONCLUSIONS: The persistent form of AF may independently contribute to endothelial dysfunction. In addition, by catheter ablation, the maintenance of sinus rhythm may protect against exacerbations of endothelial dysfunction.

DOI： 10.1016/j.ijcard.2017.06.038

Relationship between yellow plaque grade and tissue protrusion after stent implantation: A coronary angioscopy study. International journal

Toru Miyoshi, Hideo Kawakami, Fumiyasu Seike, Akira Oshita, Hiroshi Matsuoka

Journal of cardiology 70 ( 4 ) 342 - 345 2017.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Tissue protrusion detected with optical coherence tomography after percutaneous coronary intervention using stents is one of the risk factors for early stent thrombosis. However, tissue protrusion features have not been described. The aim of this study was to compare tissue morphology at stented sites with or without tissue protrusion by using coronary angioscopy. METHODS: Using optical coherence tomography and coronary angioscopy, we assessed 42 patients [31 men, 11 women; age, 70.7±7.4years; acute coronary syndrome (ACS), n=19; effort angina pectoris (EAP), n=23] after stenting. RESULTS: Twenty patients had tissue protrusion. ACS patients had a higher incidence of tissue protrusion than EAP patients (70.0% vs 29.4%; p=0.002). The plaque at the protrusion site had higher-grade yellow plaque with thrombus than those without protrusion (2.35±0.67 vs 1.40±0.67; p<0.001). The plaque at protrusion sites developed more thrombi (60.0% vs 22.7%; p=0.041). CONCLUSIONS: Tissue protrusion after stent implantation was associated with high-grade yellow plaque with thrombi.

DOI： 10.1016/j.jjcc.2016.12.007

顕性蛋白尿をきたした腎動脈狭窄症に対するPTRAの腎保護効果についての検討 Reviewed

戸田洋伸, 内田治仁, 竹内英実, 江尻健太郎, 大塚寛昭, 中川晃志, 渡邊敦之, 西井伸洋, 三好亨, 中村一文, 森田宏, 和田淳, 伊藤浩

脈管学 57 ( Suppl. ) S138 - S138 2017.10

Reply to letter to the Editor: "Myocardial protection by remote ischemic preconditioning in elective PCI: Effect of aging". International journal

Kentaro Ejiri, Toru Miyoshi, Hiroshi Ito

International journal of cardiology 243 106 - 107 2017.9

Suppression of Wnt Signaling and Osteogenic Changes in Vascular Smooth Muscle Cells by Eicosapentaenoic Acid. International journal

Yukihiro Saito, Kazufumi Nakamura, Daiji Miura, Kei Yunoki, Toru Miyoshi, Masashi Yoshida, Norifumi Kawakita, Tomonari Kimura, Megumi Kondo, Toshihiro Sarashina, Satoshi Akagi, Atsuyuki Watanabe, Nobuhiro Nishii, Hiroshi Morita, Hiroshi Ito

Nutrients 9 ( 8 ) 2017.8

Language：English Publishing type：Research paper (scientific journal)

Vascular medial calcification is often observed in patients with arteriosclerosis. It is also associated with systolic hypertension, wide pulse pressure, and fluctuation of blood pressure, which results in cardiovascular events. Eicosapentaenoic acid (EPA) has been shown to suppress vascular calcification in previous animal experiments. We investigated the inhibitory effects of EPA on Wnt signaling, which is one of the important signaling pathways involved in vascular calcification. Intake of food containing 5% EPA resulted in upregulation of the mRNA expression of Klotho, an intrinsic inhibitor of Wnt signaling, in the kidneys of wild-type mice. Expression levels of β-catenin, an intracellular signal transducer in the Wnt signaling pathway, were increased in the aortas of Klotho mutant (kl/kl) mice compared to the levels in the aortas of wild-type mice. Wnt3a or BIO, a GSK-3 inhibitor that activates β-catenin signaling, upregulated mRNA levels of AXIN2 and LEF1, Wnt signaling marker genes, and RUNX2 and BMP4, early osteogenic genes, in human aorta smooth muscle cells. EPA suppressed the upregulation of AXIN2 and BMP4. The effect of EPA was cancelled by T0070907, a PPARγ inhibitor. The results suggested that EPA could suppress vascular calcification via the inhibition of Wnt signaling in osteogenic vascular smooth muscle cells via PPARγ activation.

DOI： 10.3390/nu9080858

Differences of plaque characterization of high-intensity and non high-intensity plaques on non-contrast T1-weighted magnetic resonance imaging using angioscopy and optical coherence tomography.

Akira Oshita, Hideo Kawakami, Shinsuke Kido, Toru Miyoshi, Hiroshi Matsuoka

Journal of cardiology cases 16 ( 2 ) 35 - 37 2017.8

Language：English

Coronary high-intensity plaques (HIPs) visualized by non-contrast T1-weighted imaging (T1WI) in cardiac magnetic resonance (CMR) were associated with coronary events. We report a case of a 68-year-old man with an old myocardial infarction. He had undergone CMR to exclude new coronary artery disease, because he sometimes had an atypical chest symptom. The moderate stenosis in the right coronary artery (RCA) showed non HIP on non-contrast T1WI. We observed HIP in the proximal left anterior descending artery (LAD) without significant stenosis. Non HIP lesion in the RCA showed fibrous and calcified plaque without thrombus by optical coherence tomography (OCT) and angioscopy. On the other hand, the HIP lesion in the LAD showed lipid plaque with thrombus by OCT, and yellow plaque with mobile mixed thrombus by angioscopy. <Learning objective: These intracoronary modalities suggested that the HIP lesion is correlated with vulnerable plaques. Invasive coronary angiography (CAG) is considered the gold standard for the diagnosis of coronary disease, but CAG is thought not to be able to predict future events. Non-contrast T1WI on CMR may be able to use for screening of vulnerable plaques.>.

DOI： 10.1016/j.jccase.2017.04.001

Effect of Azilsartan on Day-to-Day Variability in Home Blood Pressure: A Prospective Multicenter Clinical Trial. International journal

Toru Miyoshi, Ryoji Suetsuna, Naoto Tokunaga, Masayasu Kusaka, Ryuichiro Tsuzaki, Kazuya Koten, Kohno Kunihisa, Hiroshi Ito

Journal of clinical medicine research 9 ( 7 ) 618 - 623 2017.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The blood pressure variability (BPV) such as visit-to-visit, day-by-day, and ambulatory BPV has been also shown to be a risk of future cardiovascular events. However, the effects of antihypertensive therapy on BPV remain unclear. The purpose of this study was to evaluate the effect of azilsartan after switching from another angiotensin II receptor blocker (ARB) on day-to-day BPV in home BP monitoring. METHODS: This prospective, multicenter, open-labeled, single-arm study included 28 patients undergoing treatment with an ARB, which was switched to azilsartan after enrollment. The primary outcome was the change in the mean of the standard deviation and the coefficient of variation of morning home BP for 5 consecutive days from baseline to the 24-week follow-up. The secondary outcome was the change in arterial stiffness measured by the cardio-ankle vascular index. RESULTS: The mean BPs in the morning and evening for 5 days did not statistically differ between baseline and 24 weeks. For the morning BP, the means of the standard deviations and coefficient of variation of the systolic BP were significantly decreased from 7.4 ± 3.6 mm Hg to 6.1 ± 3.2 mm Hg and from 5.4±2.7% to 4.6±2.3% (mean ± standard deviation, P = 0.04 and P = 0.04, respectively). For the evening BP, no significant change was observed in the systolic or diastolic BPV. The cardio-ankle vascular index significantly decreased from 8.3 ± 0.8 to 8.1 ± 0.8 (P = 0.03). CONCLUSIONS: Switching from another ARB to azilsartan reduced day-to-day BPV in the morning and improved arterial stiffness.

DOI： 10.14740/jocmr3050w

Effect of remote ischemia or nicorandil on myocardial injury following percutaneous coronary intervention in patients with stable coronary artery disease: A randomized controlled trial. International journal

Toru Miyoshi, Kentaro Ejiri, Kunihisa Kohno, Makoto Nakahama, Masayuki Doi, Mitsuru Munemasa, Masaaki Murakami, Atsushi Takaishi, Yusuke Kawai, Tetsuya Sato, Katsumasa Sato, Takefumi Oka, Natsuki Takahashi, Satoru Sakuragi, Atsushi Mima, Kenki Enko, Shingo Hosogi, Seiji Nanba, Ryoichi Hirami, Kazufumi Nakamura, Hiroshi Ito

International journal of cardiology 236 36 - 42 2017.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The effect of remote ischemic preconditioning (RIPC) and nicorandil on periprocedural myocardial injury (pMI) in patients with planned percutaneous coronary intervention (PCI) remains controversial. The aim of this randomized trial was to evaluate the effect of RIPC or nicorandil on pMI following PCI in patients with stable coronary artery disease (CAD) compared with a control group. METHODS: Patients with stable CAD who planned to undergo PCI were assigned to a 1:1:1 ratio to control, RIPC, or intravenous nicorandil (6mg/h). Automated RIPC was performed by a device, which performs intermittent arm ischemia through three cycles of 5min of inflation and 5min of deflation of a pressure cuff. The primary outcome was the incidence of pMI, determined by an elevation in high-sensitive troponin T or creatine kinase myocardial band at 12 or 24h after PCI. The secondary outcomes were ischemic events during PCI and adverse clinical events at 8months after PCI. RESULTS: A total of 391 patients were enrolled. The incidence of pMI following PCI was not significantly different between the control group (48.9%) and RIPC group (39.5%; p=0.14), or between the control group and nicorandil group (40.3%; p=0.17). There were no significant differences in ischemic events during PCI or adverse clinical events within 8months after PCI among the three groups. CONCLUSIONS: This study demonstrated moderate reductions in biomarker release and pMI by RIPC or intravenous nicorandil prior to the PCI consistently, but may have failed to achieve statistical significance because the study was underpowered.

DOI： 10.1016/j.ijcard.2017.02.028

Reply to letter to the editor: "Left ventricular ejection fraction in the prognosis of acute coronary syndromes". International journal

Kazumasa Nosaka, Toru Miyoshi, Masayuki Doi

International journal of cardiology 234 138 - 138 2017.5

A case of in-stent restenosis with pathologically proven chronic inflammation seven years after sirolimus-eluting stent implantation.

Toru Miyoshi, Hideo Kawakami, Akira Oshita, Hiroshi Matsuoka

Journal of cardiology cases 15 ( 5 ) 176 - 179 2017.5

Language：English

A 67-year-old man was admitted to our hospital due to chest pain at rest. Seven years previously, the patient underwent percutaneous coronary intervention (PCI) of the left ascending artery and implanted sirolimus-eluting stent (SES). Coronary angioscopy (CAS) performed at that time showed a white plaque at the SES site. Two years after the first PCI, repeat CAS demonstrated light yellow plaques at the SES site. At the time of his presentation to our hospital, coronary angiography showed in-stent restenosis at the SES site, and CAS demonstrated the plaque rupture with presence of dense yellow plaque and various thrombi. After distal protection, drug-eluting balloon treatment was performed. Collected specimens from culprit sites included foamy macrophages, cholesterin crystals, neutrophils, and fibrin, suggesting that progressive neoatherosclerosis at the SES site triggered the acute coronary syndrome. This study highlights the importance of ensuring careful patient follow-up after SES implantation. <Learning objective: After 1st generation drug-eluting stent implantation, careful follow up is warranted, as the process of neoatherosclerosis can be ongoing and contribute to in-stent restenosis.>.

DOI： 10.1016/j.jccase.2017.01.002

Nanoparticle-Mediated Drug Delivery System for Pulmonary Arterial Hypertension. International journal

Kazufumi Nakamura, Hiromi Matsubara, Satoshi Akagi, Toshihiro Sarashina, Kentaro Ejiri, Norifumi Kawakita, Masashi Yoshida, Toru Miyoshi, Atsuyuki Watanabe, Nobuhiro Nishii, Hiroshi Ito

Journal of clinical medicine 6 ( 5 ) 2017.4

Language：English Publishing type：Research paper (scientific journal)

Nanoparticles have been used as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. The efficacy and safety of intratracheal administration of prostacyclin analog (beraprost) -incorporated nanoparticles and imatinib (a PDGF-receptor tyrosine kinase inhibitor) -incorporated nanoparticles in Sugen-hypoxia-normoxia or monocrotaline rat models of pulmonary arterial hypertension (PAH) and in human PAH-pulmonary arterial smooth muscle cells have been reported. The use of inhaled drug-incorporated nanoparticles might be a novel approach for the treatment of PAH.

DOI： 10.3390/jcm6050048

Coronary lesion characteristics with mismatch between fractional flow reserve derived from CT and invasive catheterization in clinical practice.

Kazuhiro Osawa, Toru Miyoshi, Takashi Miki, Yuji Koide, Yusuke Kawai, Kentaro Ejiri, Masatoki Yoshida, Shuhei Sato, Susumu Kanazawa, Hiroshi Ito

Heart and vessels 32 ( 4 ) 390 - 398 2017.4

Language：English Publishing type：Research paper (scientific journal)

High diagnostic performance of noninvasive fractional flow reserve computed from CT (FFR-CT) was recently reported in prospective multicenter trials. The aims of this study were to evaluate the diagnostic accuracy of FFR-CT in clinical practice and to examine the lesion characteristics showing a mismatch between FFR-CT and invasive FFR. A total of 20 patients (29 vessels) with suspected coronary artery disease were included. All patients underwent invasive coronary angiography and invasive FFR according to coronary artery CT angiography (CCTA) findings. The same raw data used for CCTA were used to evaluate FFR-CT. Results from FFR-CT were compared with invasively measured FFR. A positive ischemia was defined as FFR <0.80. Analyses from three vessels in two patients were not evaluated because of severe calcification or motion artifacts. The diagnostic accuracy, sensitivity, and specificity of FFR-CT per-vessel basis were 81, 100, and 69 %, respectively. To find the reason for mismatch in positive ischemia, lesion characteristics determined with CCTA were compared between the matched group and the mismatched group. A significant difference in bifurcation lesions with positive remodeling was observed between the matched group and the mismatched group (p < 0.01). The high sensitivity of FFR-CT may provide an additional support to the use of CCTA, although particular attention should be paid when using FFR-CT in bifurcation lesions with positive remodeling.

DOI： 10.1007/s00380-016-0892-0

Unstable Saphenous Vein Graft Atheroma in Patients With Stable Angina Pectoris. International journal

Fumiyasu Seike, Shuntaro Ikeda, Hideo Kawakami, Toru Miyoshi, Akira Oshita, Shinji Inaba, Takafumi Okura, Jitsuo Higaki, Hiroshi Matsuoka

Circulation. Cardiovascular interventions 10 ( 3 ) 2017.3

Early initiation of eicosapentaenoic acid and statin treatment is associated with better clinical outcomes than statin alone in patients with acute coronary syndromes: 1-year outcomes of a randomized controlled study. International journal

Kazumasa Nosaka, Toru Miyoshi, Mutsumi Iwamoto, Masahito Kajiya, Keisuke Okawa, Saori Tsukuda, Fumi Yokohama, Masahiro Sogo, Tomoyuki Nishibe, Naoaki Matsuo, Satoshi Hirohata, Hiroshi Ito, Masayuki Doi

International journal of cardiology 228 173 - 179 2017.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Early initiation of EPA treatment in combination with a statin within 24h after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (MI) reduces inflammation and ventricular arrhythmia compared with statin monotherapy; however, the impact of early initiation of EPA treatment on cardiovascular events is unclear. We determined whether early eicosapentaenoic acid (EPA) treatment in patients with acute coronary syndrome (ACS) reduces adverse cardiovascular events. METHODS: This prospective, open-label, blind end point-randomized trial consisted of 241 patients with ACS. Patients were randomly assigned to receive pitavastatin (2mg/day) with or without 1800mg/day of EPA initiated within 24h after PCI. The primary endpoint was defined as cardiovascular events occurring within 1year, including death from a cardiovascular cause, nonfatal stroke, nonfatal MI and revascularization. RESULTS: The mean EPA/arachidonic acid ratio at follow-up was 0.40 in the control group and 1.15 in the EPA group. A primary endpoint event occurred in 11 patients (9.2%) in the EPA group and 24 patients (20.2%) in the control group (absolute risk reduction, 11.0%; hazard ratio, 0.42; 95% confidence interval, 0.21 to 0.87; P=0.02). Notably, death from a cardiovascular cause at 1year was significantly lower in the EPA group than in the control group (0.8% vs. 4.2%, P=0.04). CONCLUSIONS: Early initiation of treatment with EPA combined with statin after successful primary PCI reduced cardiovascular events after ACS. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR); Registry Number, UMIN000016723; URL, http://www.umin.ac.jp/ctr/index-j.htm.

DOI： 10.1016/j.ijcard.2016.11.105

Protocol for Evaluating the Cardio-Ankle Vascular Index to Predict Cardiovascular Events in Japan: A Prospective Multicenter Cohort Study. International journal

Toru Miyoshi, Hiroshi Ito, Shigeo Horinaka, Kohji Shirai, Jitsuo Higaki, Hajime Orimo

Pulse (Basel, Switzerland) 4 ( Suppl 1 ) 11 - 16 2017.1

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: The cardio-ankle vascular index (CAVI) was developed in Japan and is a blood pressure-independent index of arterial stiffness from the origin of the aorta to the ankle. In recent years, it has been studied by many researchers worldwide, and it is strongly anticipated that it will play a role as a predictive factor for arteriosclerotic diseases. The objective of this study was to examine the benefits of using CAVI as a predictor of cardiovascular events in high-risk patients. METHODS AND DESIGN: This prospective multicenter study to evaluate the usefulness of the CAVI to predict cardiovascular events in Japan (CAVI-J) is a cohort study with central registration. Participants (n = 3,000) will be scheduled to enroll and data will be collected for up to 5 years from entry of participants into the study. To be eligible to participate in the CAVI-J study, individuals have to be aged between 40 and 74 years and have at least one of the following risk factors for arteriosclerosis: (1) type 2 diabetes mellitus; (2) high-risk hypertension; (3) metabolic syndrome; (4) chronic kidney disease (stage 3), or (5) history of coronary artery disease or noncardiogenic cerebral infarction. The primary endpoints of this study are cardiovascular death, nonfatal myocardial infarction, and stroke. The secondary endpoints are composite cardiovascular events including all cause death, angina pectoris with revascularization, new incidence of peripheral artery disease, abdominal aortic aneurysm, aortic dissection, heart failure requiring hospitalization, and deterioration in renal function. The cutoff for CAVI against the incidence of cardiovascular events will be determined.

DOI： 10.1159/000448464

Eicosapentaenoic acid prevents arterial calcification in klotho mutant mice. International journal

Kazufumi Nakamura, Daiji Miura, Yukihiro Saito, Kei Yunoki, Yasushi Koyama, Minoru Satoh, Megumi Kondo, Kazuhiro Osawa, Omer F Hatipoglu, Toru Miyoshi, Masashi Yoshida, Hiroshi Morita, Hiroshi Ito

PloS one 12 ( 8 ) e0181009 2017

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The klotho gene was identified as an "aging-suppressor" gene that accelerates arterial calcification when disrupted. Serum and vascular klotho levels are reduced in patients with chronic kidney disease, and the reduced levels are associated with arterial calcification. Intake of eicosapentaenoic acid (EPA), an n-3 fatty acid, reduces the risk of fatal coronary artery disease. However, the effects of EPA on arterial calcification have not been fully elucidated. The aim of this study was to determine the effect of EPA on arterial calcification in klotho mutant mice. METHODS AND RESULTS: Four-week-old klotho mutant mice and wild-type (WT) mice were given a diet containing 5% EPA (EPA food, klotho and WT: n = 12, each) or not containing EPA (control food, klotho and WT: n = 12, each) for 4 weeks. Calcium volume scores of thoracic and abdominal aortas assessed by computed tomography were significantly elevated in klotho mice after 4 weeks of control food, but they were not elevated in klotho mice after EPA food or in WT mice. Serum levels of EPA and resolvin E1, an active metabolite of EPA, in EPA food-fed mice were significantly increased compared to those in control food-fed mice. An oxidative stress PCR array followed by quantitative PCR revealed that NADPH oxidase-4 (NOX4), an enzyme that generates superoxide, gene expression was up-regulated in arterial smooth muscle cells (SMCs) of klotho mice. Activity of NOX was also significantly higher in SMCs of klotho mice than in those of WT mice. EPA decreased expression levels of the NOX4 gene and NOX activity. GPR120, a receptor of n-3 fatty acids, gene knockdown by siRNA canceled effects of EPA on NOX4 gene expression and NOX activity in arterial SMCs of klotho mice. CONCLUSIONS: EPA prevents arterial calcification together with reduction of NOX gene expression and activity via GPR120 in klotho mutant mice.

DOI： 10.1371/journal.pone.0181009

Comparable effect of aliskiren or a diuretic added on an angiotensin II receptor blocker on augmentation index in hypertension: a multicentre, prospective, randomised study. Reviewed International journal

Toru Miyoshi, Takashi Murakami, Satoru Sakuragi, Masayuki Doi, Seiji Nanba, Atsushi Mima, Youkou Tominaga, Takafumi Oka, Yutaka Kajikawa, Kazufumi Nakamura, Hiroshi Ito

Open heart 4 ( 1 ) e000591 2017

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The effects of antihypertensive drug combination therapy on central blood pressure (BP) and augmentation index (AI) have not been fully elucidated. We investigated the effects of the direct renin inhibitor, aliskiren, or a diuretic added to an angiotensin II receptor blocker on AI in patients with essential hypertension. METHODS: A 24-week, prospective, multicentre, randomised, open-label study enrolled 103 patients already treated with valsartan. Participants were randomly allocated to receive either valsartan with aliskiren (V+A), or valsartan with trichlormethiazide (V+T). The primary outcome was the change in AI derived from radial artery tonometry. Secondary outcome measures included systolic and diastolic BP, cardio-ankle vascular index (CAVI, which reflects arterial stiffness) and urinary 8-hydroxydeoxyguanosine concentration. RESULTS: After 24 weeks, systolic and diastolic BP were significantly reduced in both groups to a broadly comparable extent. There was no significant difference in AI at the end of the study between the V+A group and the V+T group (between-group difference: -2.3%, 95% CI -6.9% to 2.2%, p=0.31). Central BP at the end of the study also did not differ between the two groups (p=0.62). There was no significant difference in the CAVI between the groups at the end of the study. Urinary 8-hydroxydeoxyguanosine concentration was significantly lower in the V+A group than in the V+T group (p<0.01), suggesting that V+A attenuated oxidative stress more than V+T. CONCLUSION: The combination of valsartan and aliskiren had an effect on AI comparable with that of the combination of valsartan and trichlormethiazide. UMIN CLINICAL TRIAL REGISTRATION NUMBER: UMIN000005726.

DOI： 10.1136/openhrt-2017-000591

Measurement of epicardial fat thickness by transthoracic echocardiography for predicting high-risk coronary artery plaques.

Motomi Tachibana, Toru Miyoshi, Kazuhiro Osawa, Norihisa Toh, Hiroki Oe, Kazufumi Nakamura, Takanori Naito, Shuhei Sato, Susumu Kanazawa, Hiroshi Ito

Heart and vessels 31 ( 11 ) 1758 - 1766 2016.11

Language：English Publishing type：Research paper (scientific journal)

Epicardial adipose tissue (EAT) volume is reported to be associated with coronary plaques. We evaluated whether non-invasive measurement of EAT thickness by echocardiography can predict high-risk coronary plaque characteristics determined independently by coronary computed tomography (CT) angiography. We enrolled 406 patients (mean age 63 years, 57 % male) referred for 64-slice CT. EAT was measured on the right ventricle free wall from a parasternal long-axis view at the end of systole. High-risk coronary plaques were defined as low-density plaques (<30 Hounsfield units) with positive remodeling (remodeling index >1.05). Patients were divided into thin or thick EAT groups using a cutoff value derived from receiver operator characteristic curve analysis for discriminating high-risk plaques. The receiver operator characteristic cutoff value was 5.8 mm with a sensitivity of 83 % and specificity of 64 % (area under the curve 0.77, 95 % confidence interval 0.70-0.83, p < 0.01). Compared with the thin EAT group, the thick EAT group had a high prevalence of low-density plaques (4 vs. 24 %, p < 0.01), positive remodeling (39 vs. 60 %, p < 0.01), and high-risk plaques (3 vs. 17 %, p < 0.01). Multiple logistic analysis revealed that thick EAT was a significant predictor of high-risk plaques (odds ratio 7.98, 95 % confidence interval 2.77-22.98, p < 0.01) after adjustment for covariates, including conventional risk factors, visceral adipose tissue area, and medications. The measurement of EAT thickness by echocardiography may provide a non-invasive option for predicting high-risk coronary plaques.

A patient with acute coronary syndrome and shock due to occlusion of both native coronaries and bypass grafts who was rescued by revascularization.

Toru Miyoshi, Hideo Kawakami, Fumiyasu Seike, Akira Oshita, Hiroshi Matsuoka

Journal of cardiology cases 14 ( 5 ) 149 - 152 2016.11

Language：English Publishing type：Research paper (scientific journal)

A 72-year-old male was admitted to our hospital because of chest pain in a pre-shock condition. He underwent coronary artery bypass grafting (CABG) 25 years prior. The most recent coronary angiography revealed total occlusion of both native coronaries and the saphenous vein graft (SVG) that was anastomosed to the right coronary artery. Emergency coronary angiography revealed that his SVG anastomosed to the left circumflex artery (LCX) and the distal left anterior descending artery (LAD) were also occluded. Emergency revascularization of the SVG anastomosed to the LCX and distal LAD restored blood flow and hemodynamic function. Subsequently, he received reoperative CABG to the LCX and LAD, and his angina and chronic heart failure improved. Careful follow-up is needed in patients having an old and deteriorated SVG. <Learning objective: We treated a patient with acute coronary syndrome in a pre-shock condition. His native coronary arteries and bypass graft were totally occluded. Due to the pre-shock condition, we selected emergency revascularization, and he recovered.>.

DOI： 10.1016/j.jccase.2016.07.003

Approximately half of patients with coronary spastic angina had pathologic exercise tests. International journal

Shozo Sueda, Toru Miyoshi, Yasuhiro Sasaki, Tomoki Sakaue, Hirokazu Habara, Hiroaki Kohno

Journal of cardiology 68 ( 1 ) 13 - 9 2016.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: We examined the clinical usefulness of treadmill exercise tests (TETs) in diagnosing coronary spastic angina (CSA). METHODS: We performed the TETs and 24-h Holter monitoring in 300 CSA patients consisting of 152 patients with rest angina, 77 patients with effort angina, and 71 patients with rest and effort angina. Organic stenosis (>75%) was observed in 44 patients. Multiple spasms were recognized in 204 patients (68%). RESULTS: Positive TETs were recognized in 113 patients (38%) and borderline was observed in 30 patients (10%). Positive response was significantly higher in patients with organic stenosis than those without fixed stenosis (63.6% vs. 33.2%, p<0.001). Moreover, ST elevation was more frequent in patients with organic stenosis than those without fixed stenosis (27.3% vs. 1.2%, p<0.001). Positive response in patients with effort angina (46.8%) was higher than those in patients with rest angina (33.6%) and rest and effort angina (36.6%), but not significant. Positive response was not different between single spasm and multiple spasms. In all 300 patients, ST segment elevation was observed in only four patients (1.3%) on the 24-h Holter monitoring. CONCLUSIONS: TET was useful in documenting ischemia in patients with CSA. More than a third of patients with CSA had positive TETs. Moreover, we obtained the pathologic TET response in approximately half of patients with CSA.

DOI： 10.1016/j.jjcc.2016.01.009

Assessment of Arterial Stiffness Using the Cardio-Ankle Vascular Index. International journal

Toru Miyoshi, Hiroshi Ito

Pulse (Basel, Switzerland) 4 ( 1 ) 11 - 23 2016.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Arterial stiffness is an independent predictor of outcomes for patients with cardiovascular disease. Although measurement of pulse wave velocity is a widely accepted, noninvasive approach for the assessment of arterial stiffness, its accuracy is affected by changes in blood pressure. SUMMARY: The cardio-ankle vascular index (CAVI) is an index of the overall stiffness of the artery from the origin of the aorta to the ankle and is theoretically independent of blood pressure at the time of measurement. CAVI increases linearly with age and is elevated even in mild arteriosclerotic disease. It can identify differences in the degree of arteriosclerosis among patients with severe arteriosclerotic disease and better reflects the severity of disease of the coronary artery than does brachial-ankle pulse wave velocity. Patients with higher CAVI values show a poor prognosis compared with those with lower CAVI values. Furthermore, CAVI can be lowered by controlling diabetes mellitus and hypertension. KEY MESSAGES: The primary aims of assessing arterial stiffness using CAVI are to assist in the early detection of arteriosclerosis, allowing timely treatment and lifestyle modification, and to quantitatively evaluate the progression of disease and the effectiveness of treatment. Whether CAVI-guided therapy can improve prognosis in high-risk patients needs to be further examined to confirm the clinical usefulness of this measure.

DOI： 10.1159/000445214

Intraprocedural Stent Thrombosis Detected on Coronary Angioscopy.

Toru Miyoshi, Hideo Kawakami, Akira Oshita, Hiroshi Matsuoka

Circulation journal : official journal of the Japanese Circulation Society 80 ( 6 ) 1484 - 5 2016.5

Postprandial hyperlipidemia as a potential residual risk factor. International journal

Kazufumi Nakamura, Toru Miyoshi, Kei Yunoki, Hiroshi Ito

Journal of cardiology 67 ( 4 ) 335 - 9 2016.4

Language：English Publishing type：Research paper (scientific journal)

Statin therapy targeting reduction of low-density lipoprotein cholesterol (LDL-C) decreases the risk of coronary heart disease (CHD) and all-cause mortality. However, a substantial number of cases of CHD are not prevented and residual risk factors remain unsettled. A high triglyceride (TG) level is considered to be an important and residual risk factor. Postprandial hyperlipidemia is a condition in which TG-rich chylomicron remnants are increased during the postprandial period and hypertriglycedemia is protracted. Postprandial hyperlipidemia evokes atherogenesis during the postprandial period. Several prospective studies have revealed that nonfasting serum TG levels predict the incidence of CHD. Values of TG, remnant lipoprotein cholesterol, and remnant lipoprotein TG after fat loading were significantly higher in diabetes patients with insulin resistance than in diabetes patients without insulin resistance. Endothelial dysfunction is an initial process of atherogenesis and it contributes to the pathogenesis of CHD. Postprandial hyperlipidemia (postprandial hypertriglyceridemia) is involved in the production of proinflammatory cytokines, recruitment of neutrophils, and generation of oxidative stress, resulting in endothelial dysfunction in healthy subjects, hypertriglyceridemic patients, or type 2 diabetic patients. Effective treatment has not been established till date. Ezetimibe or omega-3 fatty acids significantly decrease postprandial TG elevation and postprandial endothelial dysfunction. Ezetimibe or omega-3 fatty acids added to statin therapy reduce serum TG levels and result in good outcomes in patients with CHD. In conclusion, postprandial hyperlipidemia is an important and residual risk factor especially in patients with insulin resistance syndrome (metabolic syndrome) and diabetes mellitus. Further studies are needed to establish effective treatment.

DOI： 10.1016/j.jjcc.2015.12.001

Association between coronary artery calcification and left ventricular diastolic dysfunction in elderly people.

Kazuhiro Osawa, Toru Miyoshi, Hiroki Oe, Shuhei Sato, Kazufumi Nakamura, Kunihisa Kohno, Hiroshi Morita, Susumu Kanazawa, Hiroshi Ito

Heart and vessels 31 ( 4 ) 499 - 507 2016.4

Language：English Publishing type：Research paper (scientific journal)

Coronary artery calcification (CAC) is associated with the incidence of congestive heart failure. We evaluated the association between CAC and left ventricular diastolic dysfunction (LVDD) in elderly patients without coronary artery disease. Coronary computed tomography was performed in 1,021 consecutive patients >55 years of age who were suspected of having coronary artery disease. A total of 530 patients (age, 70 ± 8 years; 56 % men) with a LV ejection fraction >50 % and without obstructive coronary artery disease and a history of coronary artery disease were included in the analysis. LVDD was defined according to a standard algorithm by echocardiography (septal e' <8, lateral e' <10, and left atrial volume index ≥34 mL/m(2)). A total of 224 of 530 patients had LVDD. CAC scores in patients with LVDD were higher than those in patients without LVDD (p < 0.01). The prevalence of LVDD in patients with CAC scores ≥400 was greater than that in patients with CAC scores of 0-9 (58 vs. 34 %, p < 0.01). After adjustment for confounding factors, the CAC score was associated with LVDD, with an odds ratio of 1.96 (95 % confidence interval: 1.11-3.43, p = 0.02) for a CAC score ≥400 compared with a CAC score of 0-9. A CAC score ≥400 was associated with LVDD in elderly patients without CAD in this population. Further prospective studies are needed to evaluate the clinical relevance of CAC as a risk of heart failure with preserved ejection fraction.

DOI： 10.1007/s00380-015-0645-5

Gender differences in sensitivity of acetylcholine and ergonovine to coronary spasm provocation test.

Shozo Sueda, Toru Miyoshi, Ysuhiro Sasaki, Tomoki Sakaue, Hirokazu Habara, Hiroaki Kohno

Heart and vessels 31 ( 3 ) 322 - 9 2016.3

Language：English Publishing type：Research paper (scientific journal)

We examined the sex difference concerning the coronary artery response between ACh and ER in this study. We already reported the difference of coronary response between acetylcholine (ACh) and ergonovine (ER). We performed both ACh and ER tests of 461 patients (male 294 patients, female 167 patients, mean age 64.4 ± 11.3 years) during 23 years. Positive coronary spasm was defined as >99 % transient luminal narrowing with usual chest pain and/or ischemic ECG changes. Firstly, ACh was administered in incremental doses of 20/50/(80) μg into the RCA and 20/50/100/(200) μg into the LCA over 20 s. Secondly, ER was administered in a total dose of 40 μg into the RCA and of 64 μg into the LCA over 2-4 min. Intracoronary injection of ACh and ER provoked spasm in 221 patients consisting of 160 male patients and 61 female patients. In female patients, the spasm provoked by ACh was almost perfect except in two patients (59 patients, 96.7 %), while ER provoked spasm in only 20 patients (32.8 %). In male patients, provoked spasm by ACh (129 patients, 80.6 %) was significantly higher than ER (97 patients, 60.6 %). As a spasm provocation test, ACh is more sensitive than ER in both sexes and especially in females. We may select two pharmacological agents by sex differences to provoke coronary artery spasm in the cardiac catheterization laboratory in the future.

DOI： 10.1007/s00380-014-0614-4

Clinical characteristics of responders to treatment with tolvaptan in patients with acute decompensated heart failure: Importance of preserved kidney size. International journal

Hironobu Toda, Kazufumi Nakamura, Makoto Nakahama, Tadashi Wada, Atsuyuki Watanabe, Katsushi Hashimoto, Ritsuko Terasaka, Koji Tokioka, Nobuhiro Nishii, Toru Miyoshi, Kunihisa Kohno, Yusuke Kawai, Kohei Miyaji, Yuji Koide, Motomi Tachibana, Ryo Yoshioka, Hiroshi Ito

Journal of cardiology 67 ( 2 ) 177 - 83 2016.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Recent clinical trials have demonstrated the efficacy of short-term treatment with tolvaptan, an oral vasopressin V2 receptor antagonist, in patients with heart failure. However, the response to tolvaptan varies among patients. The aim of this study was to determine factors associated with response to tolvaptan in patients with acute decompensated heart failure (ADHF). METHODS: The Tolvaptan Registry, a prospective, observational, multicenter cohort study performed in Japan, aims to determine factors affecting the responsiveness of tolvaptan in patients with ADHF. We enrolled ADHF patients treated with tolvaptan and they were divided into two groups: responders and non-responders. Responders were defined as subjects who met all of the following three conditions: (1) increasing urine volume during a 24-hour period after the start of tolvaptan treatment; (2) improvement in New York Heart Association functional class; and (3) decrease in cardiothoracic ratio assessed by chest X-ray on day 3 of tolvaptan administration. RESULTS: Among the 114 patients, treatment with tolvaptan improved three conditions of heart failure in more than half of all the cohorts (71 patients, 62%). As for baseline characteristics, estimated glomerular filtration rate, urine osmolality, and kidney size were significantly greater in responders than in non-responders. Multivariate logistic analysis revealed that kidney size was independently associated with responders (odds ratio: 1.083, p=0.001, 95% confidence interval 1.031-1.137). CONCLUSIONS: The main clinical characteristic of responders to treatment with tolvaptan is that kidney size is preserved.

DOI： 10.1016/j.jjcc.2015.04.017

Complete definite positive spasm on acetylcholine spasm provocation tests: comparison of clinical positive spasm.

Shozo Sueda, Toru Miyoshi, Yasuhiro Sasaki, Kousei Ohshima, Tomoki Sakaue, Hirokazu Habara, Hiroaki Kohno

Heart and vessels 31 ( 2 ) 143 - 51 2016.2

Language：English Publishing type：Research paper (scientific journal)

In the clinical grounds, patients with ≥90 % luminal narrowing during acetylcholine (ACh) testing had variable response. We investigated ischemic findings and chest symptoms in patients with ≥90 % luminal narrowing when performing ACh tests, retrospectively. We performed 763 ACh tests over 13 years (2001-2013). We analyzed chest symptoms and positive ischemic ECG changes during ACh tests. More than 90 % luminal narrowing was found in 441 patients (57.8 %) including 355 patients in the right coronary artery (RCA) and 363 patients in the left coronary artery (LCA). Chest symptom was observed in 386 patients (87.5 %) including 293 patients in the RCA and 304 patients in the LCA. ST elevation was found in 161 patients including 110 in the RCA and 85 patients in the LCA, while ST depression was recognized in 146 patients including 119 patients in the RCA and 117 patients in the LCA. Three quarter of patients with ≥90 % luminal narrowing had significant ischemic ECG changes, whereas two-third of patients with ≥90 % luminal narrowing complained usual chest pain accompanied with significant ischemic ECG changes. Unusual chest symptom was complained in 7.3 % patients with ≥90 % luminal narrowing. Neither chest symptom nor ECG changes were found in 30 patients (6.8 %) with ≥90 % luminal narrowing. A third of these patients had ischemic findings on non-invasive tests before catheterization and six patients had subtotal or total occlusion. We should realize some limitation to define positive coronary spasm based on the ischemic ECG change and chest symptom during ACh tests.

DOI： 10.1007/s00380-014-0595-3

Safety and optimal protocol of provocation test for diagnosis of multivessel coronary spasm.

Shozo Sueda, Toru Miyoshi, Yasuhiro Sasaki, Tomoki Sakaue, Hirokazu Habara, Hiroaki Kohno

Heart and vessels 31 ( 2 ) 137 - 42 2016.2

Language：English Publishing type：Research paper (scientific journal)

We examined the safety of acetylcholine (ACh) and ergonovine (ER) tests retrospectively and investigated the optimal protocol of provocation test for diagnosis of multivessel coronary spasm. We performed 1546 ACh tests and 1114 ER tests during 23 years. ACh was injected in incremental doses of 20/50/80 μg into the right coronary artery (RCA) and of 20/50/100/200 μg into the left coronary artery (LCA) over 20 s. ER was administered in total doses of 40 μg into the RCA and of 64 μg into the LCA over 2-4 min. When a coronary spasm was induced and did not resolve spontaneously within 3 min after the completion of ACh/ER injection, or when hemodynamic instability due to coronary spasms occurred, 2.5-5.0 mg of nitrate was administered into the responsible vessel. To relive provoked spasm, it is necessary to administer nitrate in 31 cases by ACh and in 76 cases by ER (2.0 vs. 6.8 %, p < 0.01) before another vessel attempts. Multivessel spasms were often observed in LCA testing than in RCA testing on both agents [ACh: 78.6 % (11/14) vs. 11.8 % (2/17), p < 0.001, ER: 37.8 % (14/37) vs. 20.5 % (8/39), ns]. Even after the administration of nitrates, positive coronary spasm was obtained in 21.1 % by ACh and 52.9 % by ER tests on another coronary artery. No irreversible complications were recognized on both tests. We should firstly perform spasm provocation tests in the LCA and we may be able to diagnose another vessel spasm by performing the complete spasm provocation tests after the administration of nitrates to relieve provoked spasm in the first attempt.

DOI： 10.1007/s00380-014-0591-7

Contrast-enhanced ultrasound for the evaluation of acute renal infarction.

Toru Miyoshi, Hideki Okayama, Go Hiasa, Yoshitaka Kawata, Tadakatsu Yamada, Yukio Kazatani

Journal of medical ultrasonics (2001) 43 ( 1 ) 141 - 3 2016.1

Language：English Publishing type：Research paper (scientific journal)

A 65-year-old male in the dilated phase of hypertrophic cardiomyopathy and with persistent atrial fibrillation was admitted to our hospital because of an episode of ventricular fibrillation following an appropriate shock from an implantable cardiac defibrillator (ICD). At admission, electrocardiography showed a normal sinus rhythm. He had complained of back pain 7 days after the ICD shock. Renal infarction was suspected, although computed tomography and magnetic resonance imaging could not be performed because of chronic renal failure and the presence of his ICD. We, therefore, used contrast-enhanced ultrasonography with a contrast agent to evaluate his acute kidney injury. This showed the left kidney contained a wedge-shaped area that was not enhanced by the contrast agent, indicating an area of infarction.

DOI： 10.1007/s10396-015-0655-z

Diagnostic Performance of First-Pass Myocardial Perfusion Imaging without Stress with Computed Tomography (CT) Compared with Coronary CT Angiography Alone, with Fractional Flow Reserve as the Reference Standard. International journal

Kazuhiro Osawa, Toru Miyoshi, Takashi Miki, Yasushi Koyama, Shuhei Sato, Susumu Kanazawa, Hiroshi Ito

PloS one 11 ( 2 ) e0149170 2016

Language：English Publishing type：Research paper (scientific journal)

Coronary computed tomography angiography (CCTA) in combination with first-pass CT myocardial perfusion imaging (MPI) has a better diagnostic performance than CCTA alone, compared with invasive coronary angiography as the reference standard. The aim of this study was to investigate the additional diagnostic value of first-pass CT-MPI without stress for detecting hemodynamic significance of coronary stenosis, compared with invasive fractional flow reserve (FFR). We recruited 53 patients with suspected coronary artery disease undergoing both CCTA and first-pass CT-MPI without stress and invasive FFR, and 75 vessels were analyzed. We used the same raw data for CCTA and CT-MPI. First-pass CT-MPI was reconstructed by examining the diastolic signal densities as a bull's eye map. Invasive FFR <0.8 was considered as positive. On per-vessel analysis, the area under the receiver operating characteristic curve for CCTA plus first-pass CT-MPI and CCTA alone was 0.81 (0.73-0.90) and 0.70 (0.61-0.81), respectively (P = 0.036). CCTA plus first-pass CT-MPI without stress showed 0.73 sensitivity, 0.74 specificity, 0.53 positive predictive value, and 0.87 negative predictive value for detecting hemodynamically significant coronary stenosis. First-pass CT-MPI without stress correctly reclassified 38% of CCTA false-positive vessels as true negative. First-pass CT-MPI without stress combined with CCTA demonstrated excellent diagnostic accuracy, compared with invasive FFR as the reference standard. This technique could complement CCTA for diagnosis of coronary artery disease.

DOI： 10.1371/journal.pone.0149170

A calcified amorphous tumor that developed on both sides of the atrioventricular valve annulus.

Masaki Kinoshita, Hideki Okayama, Go Kawamura, Tatsuya Shigematsu, Tatsunori Takahashi, Toru Miyoshi, Akinori Higaki, Kayo Hara, Yoshitaka Kawata, Go Hiasa, Tadakatsu Yamada, Yukio Kazatani, Yutaka Hayashi

Journal of echocardiography 13 ( 4 ) 148 - 50 2015.12

Language：English Publishing type：Research paper (scientific journal)

We report a rare case of a hemodialysis patient with a calcified amorphous tumor (CAT) on both sides of the atrioventricular valve annulus. A 70-year-old female who had received hemodialysis for 23 years because of chronic glomerulonephritis presented to our hospital with acute heart failure. Echocardiography indicated the presence of mobile cardiac masses on the mitral valve and tricuspid valve annulus. We suspected the presence of a cardiac tumor or vegetation. The patient received 3 g/day sulbactam-ampicillin and 60 mg/day gentamicin. Surgery was performed on the 14th day after hospital admission. The patient underwent mitral valve replacement, tricuspid annuloplasty, and tumor resection. Based on the pathological findings, the cardiac tumor was diagnosed as a CAT.

DOI： 10.1007/s12574-015-0267-z

Maximal acetylcholine dose of 200 μg into the left coronary artery as a spasm provocation test: comparison with 100 μg of acetylcholine.

Shozo Sueda, Hiroaki Kohno, Toru Miyoshi, Tomoki Sakaue, Yasuhiro Sasaki, Hirokazu Habara

Heart and vessels 30 ( 6 ) 771 - 8 2015.11

Language：English Publishing type：Research paper (scientific journal)

As a spasm provocation test of acetylcholine (ACH), incremental dose up (20/50/100 μg) into the left coronary artery (LCA) is recommended in the guidelines established by Japanese Circulation Society. Recently, Ong et al. reported the ACOVA study which maximal ACH dose was 200 μg in the LCA. We compared the angiographic findings between ACH 100 μg and ACH 200 μg in the LCA and also examined the usefulness and safety of ACH 200 μg in Japanese patients without variant angina. As a spasm provocation test, we performed intracoronary injection of ACH 200 μg after ACH 100 μg in 88 patients (55 males, 68.4 ± 11.7 years old) including 59 ischemic heart disease (IHD) patients and 29 non-IHD patients. Positive spasm was defined as >99 % transient stenosis (focal spasm) or 90 % severe diffuse vasoconstriction (diffuse spasm). Positive spasm by ACH 200 μg was significantly higher than that by ACH 100 μg (36 pts: 40.9 % vs. 17 pts: 19.3 %, p < 0.01). Diffuse distal spasm on the left anterior descending artery was more recognized in ACH 200 μg than in ACH 100 μg (30.7 vs. 13.6 %, p < 0.01). In 29 rest angina patients, positive spasm by ACH 200 μg (19 pts) was significantly higher than that by ACH 100 μg (7 pts) (65.5 vs. 24.1 %, p < 0.01). No serious irreversible complications were found during ACH 200 μg. Administration of ACH 200 μg into the LCA was safe and useful. We may reexamine the maximal ACH dose into the LCA.

DOI： 10.1007/s00380-014-0563-y

Prognostic significance of endothelial dysfunction in patients undergoing percutaneous coronary intervention in the era of drug-eluting stents. International journal

Motoki Kubo, Toru Miyoshi, Hiroki Oe, Yuko Ohno, Kazufumi Nakamura, Hiroshi Ito

BMC cardiovascular disorders 15 102 - 102 2015.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Endothelial function is a prognostic predictor in patients undergoing percutaneous coronary intervention (PCI). However, in an era with widespread use of drug-eluting stents, the clinical relevance of endothelial dysfunction on restenosis in patients undergoing PCI has not been fully evaluated. METHODS: This study included 80 patients with stable angina pectoris. Flow-mediated dilation (FMD) of the brachial artery was examined 1 week after PCI. Patients were retrospectively followed-up for an average of 21 months after PCI. The primary endpoints included cardiac death, nonfatal myocardial infarction, stroke, coronary revascularization, and critical limb ischemia. RESULTS: A drug-eluting stent was used in 58 patients and a cardiovascular event was recorded in 34 patients during follow-up. The incidence of all cardiovascular diseases was significantly greater in the low FMD (median FMD <4.2%) than the high FMD (median FMD ≥4.2%) group (60% vs. 25%, p <0.01). Furthermore, the incidence of coronary revascularization was significantly higher in the low than the high FMD group (p = 0.02), while the incidence of in-stent restenosis did not differ between the two groups. Cox regression analysis showed that low FMD was an independent predictor of cardiovascular events (hazard ratio: 2.77, 95% confidence interval: 1.23 to 6.19, p = 0.01). CONCLUSIONS: Impaired brachial artery FMD independently predicts long-term cardiovascular events after PCI in the era of drug-eluting stents.

DOI： 10.1186/s12872-015-0096-z

Influence of Coronary Calcification on the Diagnostic Performance of CT Angiography Derived FFR in Coronary Artery Disease: A Substudy of the NXT Trial. International journal

Bjarne L Nørgaard, Sara Gaur, Jonathon Leipsic, Hiroshi Ito, Toru Miyoshi, Seung-Jung Park, Ligita Zvaigzne, Nikolaos Tzemos, Jesper M Jensen, Nicolaj Hansson, Brian Ko, Hiram Bezerra, Evald H Christiansen, Anne Kaltoft, Jens F Lassen, Hans Erik Bøtker, Stephan Achenbach

JACC. Cardiovascular imaging 8 ( 9 ) 1045 - 1055 2015.9

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: The goal of this study was to examine the diagnostic performance of noninvasive fractional flow reserve (FFR) derived from coronary computed tomography angiography (CTA) (FFRCT) in relation to coronary calcification severity. BACKGROUND: FFRCT has shown promising results in identifying lesion-specific ischemia. The extent to which the severity of coronary calcification affects the diagnostic performance of FFRCT is not known. METHODS: Coronary calcification was assessed by using the Agatston score (AS) in 214 patients suspected of having coronary artery disease who underwent coronary CTA, FFRCT, and FFR (FFR examination was performed in 333 vessels). The diagnostic performance of FFRCT (≤0.80) in identifying vessel-specific ischemia (FFR ≤0.80) was investigated across AS quartiles (Q1 to Q4) and for discrimination of ischemia in patients and vessels with a low-mid AS (Q1 to Q3) versus a high AS (Q4). Coronary CTA stenosis was defined as lumen reduction >50%. RESULTS: Mean ± SD per-patient and per-vessel AS were 302 ± 468 (range 0 to 3,599) and 95 ± 172 (range 0 to 1,703), respectively. There was no statistical difference in diagnostic accuracy, sensitivity, or specificity of FFRCT across AS quartiles. Discrimination of ischemia by FFRCT was high in patients with a high AS (416 to 3,599) and a low-mid AS (0 to 415), with no difference in area under the receiver-operating characteristic curve (AUC) (0.86 [95% confidence interval (CI): 0.76 to 0.96] vs. 0.92 [95% CI: 0.88 to 0.96]) (p = 0.45). Similarly, discrimination of ischemia by FFRCT was high in vessels with a high AS (121 to 1,703) and a low-mid AS (0 to 120) (AUC: 0.91 [95% CI: 0.85 to 0.97] vs. 0.95 [95% CI: 0.91 to 0.98]; p = 0.65). Diagnostic accuracy and specificity of FFRCT were significantly higher than for stenosis assessment in each AS quartile at the per-patient (p < 0.001) and per-vessel (p < 0.05) level with similar sensitivity. In vessels with a high AS, FFRCT exhibited improved discrimination of ischemia compared with coronary CTA alone (AUC: 0.91 vs. 0.71; p = 0.004), whereas on a per-patient level, the difference did not reach statistical significance (AUC: 0.86 vs. 0.72; p = 0.09). CONCLUSIONS: FFRCT provided high and superior diagnostic performance compared with coronary CTA interpretation alone in patients and vessels with a high AS.

DOI： 10.1016/j.jcmg.2015.06.003

Sequential spasm provocation tests might overcome a limitation of the standard spasm provocation tests. International journal

Shozo Sueda, Toru Miyoshi, Yasuhiro Sasaki, Tomoki Sakaue, Hirokazu Habara, Hiroaki Kohno

Coronary artery disease 26 ( 6 ) 490 - 4 2015.9

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: We examined the clinical usefulness of sequential spasm provocation tests as follows: first, acetylcholine (ACh) test, second, ergonovine (ER) test, and finally, the ACh test following the ER test. PATIENTS AND METHODS: We performed the ACh and ER tests in 461 patients (294 men, 64.4±11.3 years of age) during a 23-year period. In addition, we administered an intracoronary injection of ACh after the ER tests in 240 patients. First, ACh [right coronary artery (RCA): 20/50/(80) μg, left coronary artery (LCA): 20/50/100/(200) μg] was administered incrementally over 20 s. Second, ER (RCA: 40 μg, LCA: 64 μg) was administered over 2-4 min. If a provoked spasm did not occur, we administered an intracoronary injection of ACh (50/80 μg into the RCA and 100/200 μg into the LCA) just after the ER tests. A positive spasm was defined as more than 99% transient luminal narrowing. RESULTS: A positive spasm was observed in 221 (47.9%) patients including 181 ACh-positive (39.3%) and 119 ER-positive (25.8%) patients by the ACh or ER tests. In the 240 patients with a negative spasm in the ACh and ER tests, 48 (10.4%) patients developed provoked spasms on adding ACh after the ER test. The distributions of various cardiac disorders and provoked spasm vessels were similar among the three positive groups. Focal spasm was frequently observed in the ER-positive group, whereas diffuse spasm was frequently obtained in the ACh-positive group and by adding ACh after ER in the positive group. No major complications were recognized during the sequential spasm provocation tests. CONCLUSION: Sequential spasm provocation tests might overcome a limitation of standard spasm provocation tests.

DOI： 10.1097/MCA.0000000000000267

Comprehensive assessment of morphology and severity of atrial septal defects in adults by CT

Kazuhiro Osawa, Toru Miyoshi, Yusuke Morimitsu, Teiji Akagi, Hiroki Oe, Koji Nakagawa, Yoichi Takaya, Yasufumi Kijima, Shuhei Sato, Susumu Kanazawa, Hiroshi Ito

Journal of Cardiovascular Computed Tomography 9 ( 4 ) 354 - 361 2015.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Inc.

Background: Cardiac CT is an excellent tool for evaluating the anatomy of a secundum atrial septal defect (ASD). However, a comprehensive assessment of its usefulness, including measurement of the pulmonary to systemic blood flow ratio in secundum ASD patients, has not been performed. Objective: Therefore, this study was designed to evaluate the usefulness of CT for assessing the hemodynamics of secundum ASD in adults compared with transesophageal echocardiography (TEE), transthoracic echocardiography, and invasive catheterization. Methods: Fifty adult patients with secundum ASD were enrolled. Cardiac CT scans (128-slice multidetector CT instrument) were acquired. These were followed by 2-dimensional reconstruction of the secundum ASDs to determine the defect size, the rim length between the outer edge of the defect, and the pulmonary to systemic blood flow (Qp/Qs) ratio. Results: The maximum sizes of the secundum ASDs derived from CT and TEE studies were comparable (21.2 ± 8.0 vs 20.0 ± 7.3 mm
P = .41
r = 0.960
P &lt
.001). The rim lengths for the aortic, mitral, and tricuspid valves
the inferior vena cava
and posterior atrium were also comparable between CT and TEE measurements. The mean Qp/Qs ratio that was derived from CT measurements was comparable with that found by invasive catheterization (2.3 ± 0.7 vs 2.3 ± 0.8
P = .73
r = 0.786
P &lt
.001). Conclusion: Cardiac CT is feasible for assessing pathology and the severity of secundum ASD in adults.

DOI： 10.1016/j.jcct.2015.04.007

Comparison of effects of sitagliptin and voglibose on left ventricular diastolic dysfunction in patients with type 2 diabetes: results of the 3D trial. International journal

Hiroki Oe, Kazufumi Nakamura, Hajime Kihara, Kenei Shimada, Shota Fukuda, Tsutomu Takagi, Toru Miyoshi, Kumiko Hirata, Junichi Yoshikawa, Hiroshi Ito

Cardiovascular diabetology 14 83 - 83 2015.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Left ventricular (LV) diastolic dysfunction is frequently observed in patients with type 2 diabetes. Dipeptidyl peptidase-4 inhibitor (DPP-4i) attenuates postprandial hyperglycemia (PPH) and may have cardio-protective effects. It remains unclear whether DPP-4i improves LV diastolic function in patients with type 2 diabetes, and, if so, it is attributable to the attenuation of PPH or to a direct cardiac effect of DPP-4i. We compared the effects of the DPP-4i, sitagliptin, and the alpha-glucosidase inhibitor, voglibose, on LV diastolic function in patients with type 2 diabetes. METHODS: We conducted a prospective, randomized, open-label, multicenter study of 100 diabetic patients with LV diastolic dysfunction. Patients received sitagliptin (50 mg/day) or voglibose (0.6 mg/day). The primary endpoints were changes in the e' velocity and E/e' ratio from baseline to 24 weeks later. The secondary efficacy measures included HbA1c, GLP-1, lipid profiles, oxidative stress markers and inflammatory markers. RESULTS: The study was completed with 40 patients in the sitagliptin group and 40 patients in the voglibose group. There were no significant changes in the e' velocity and E/e' ratio from baseline to 24 weeks later in both groups. However, analysis of covariance demonstrated that pioglitazone use is an independent factor associated with changes in the e' and E/e' ratio. Among patients not using pioglitazone, e' increased and the E/e' ratio decreased in both the sitagliptin and voglibose groups. GLP-1 level increased from baseline to 24 weeks later only in the sitagliptin group (4.8 ± 4.7 vs. 7.3 ± 5.5 pmol/L, p < 0.05). The reductions in HbA1c and body weight were significantly greater in the sitagliptin group than in the voglibose group (-0.7 ± 0.6 % vs. -0.3 ± 0.4, p < 0.005; -1.3 ± 3.2 kg vs. 0.4 ± 2.8 kg, p < 0.05, respectively). There were no changes in lipid profiles and inflammatory markers in both groups. CONCLUSIONS: Our trial showed that sitagliptin reduces HbA1c levels more greatly than voglibose does, but that neither was associated with improvement in the echocardiographic parameters of LV diastolic function in patients with diabetes. TRIAL REGISTRATION: Registered at http://www.umin.ac.jp under UMIN000003784.

DOI： 10.1186/s12933-015-0242-z

Impact of Ezetimibe Alone or in Addition to a Statin on Plasma PCSK9 Concentrations in Patients with Type 2 Diabetes and Hypercholesterolemia: A Pilot Study. International journal

Toru Miyoshi, Keigo Nakamura, Masayuki Doi, Hiroshi Ito

American journal of cardiovascular drugs : drugs, devices, and other interventions 15 ( 3 ) 213 - 9 2015.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIM: The increase in proprotein convertase subtilisin/kexin type 9 (PCSK9) leads to low-density lipoprotein (LDL) receptor degradation. Statins significantly reduce LDL-cholesterol levels, but upregulate PCSK9. This study evaluated the effect of ezetimibe monotherapy or ezetimibe in combination with a statin on serum levels of PCSK9 in patients with type 2 diabetes and hypercholesterolemia. METHODS: Ezetimibe treatment was given to ten patients with diabetes without statin therapy and ten patients with statin therapy. Plasma levels of PCSK9 were examined at baseline and 24 weeks after treatment. RESULTS: At baseline, PCSK9 concentrations in patients with statin therapy were significantly higher than those in patients without statin use and in control subjects [median (25th-75th percentile) 411 (272-467) and 382 (356-453) ng/mL, respectively, p < 0.01]. After ezetimibe treatment for 24 weeks, LDL-cholesterol, triglyceride and remnant-like lipoprotein cholesterol were significantly decreased in both groups. However, PCSK9 concentration did not change compared with baseline measurements in both groups. The percentage change in LDL-cholesterol after ezetimibe therapy for 24 weeks was not correlated with the percentage change in PCSK9 concentration. CONCLUSION: Ezetimibe may reduce LDL-cholesterol levels without affecting PCSK9 in patients with type 2 diabetes and hypercholesterolemia.

DOI： 10.1007/s40256-015-0119-2

Remote ischemic preconditioning reduces contrast-induced acute kidney injury in patients with ST-elevation myocardial infarction: a randomized controlled trial. International journal

Toshiaki Yamanaka, Yusuke Kawai, Toru Miyoshi, Tsutomu Mima, Kenji Takagaki, Saori Tsukuda, Yukio Kazatani, Kazufumi Nakamura, Hiroshi Ito

International journal of cardiology 178 136 - 41 2015.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Contrast medium-induced acute kidney injury (CI-AKI) is a cardiovascular complication after myocardial infarction treated with emergency percutaneous coronary intervention. The aim of this randomized, sham-controlled trial was to evaluate the impact of remote ischemic preconditioning (RIPC) on CI-AKI in patients with ST-elevation myocardial infarction who received emergency primary percutaneous coronary intervention. METHODS AND RESULTS: Patients with a suspected ST-elevation myocardial infarction were randomly assigned at a 1:1 ratio to receive percutaneous coronary intervention either with (n=63) or without (n=62) RIPC (intermittent arm ischemia through three cycles of 5min of inflation and 5min of deflation of a blood pressure cuff). A total of 47 RIPC patients and 47 control patients met all study criteria. The primary endpoint was the incidence of CI-AKI, which was defined as an increase in serum creatinine >0.5mg/dL or >25% over the baseline value 48-72h after administration of contrast medium. The incidence of CI-AKI was 10% (n=5) in the RIPC group and 36% (n=17) in the control group (p=0.003). The odds ratio of CI-AKI in patients who received RIPC was 0.18 (95% confidence interval: 0.05-0.64; p=0.008). CONCLUSIONS: In patients with ST-elevation myocardial infarction, RIPC before percutaneous coronary intervention reduced the incidence of CI-AKI.

DOI： 10.1016/j.ijcard.2014.10.135

Single administration of vildagliptin attenuates postprandial hypertriglyceridemia and endothelial dysfunction in normoglycemic individuals. International journal

Kaoru Noguchi, Minoru Hirota, Toru Miyoshi, Yoshinori Tani, Yoko Noda, Hiroshi Ito, Seiji Nanba

Experimental and therapeutic medicine 9 ( 1 ) 84 - 88 2015.1

Language：English Publishing type：Research paper (scientific journal)

Postprandial hypertriglyceridemia impairs endothelial function and plays an important role in the development of atherosclerosis. The aim of the present study was to examine the postprandial effects of the dipeptidyl peptidase-4 inhibitor vildagliptin and the α-glucosidase inhibitor voglibose on endothelial dysfunction and lipid profiles following a single administration. A randomized cross-over trial using 11 normoglycemic individuals was performed. The postprandial effects of a single administration of vildagliptin (50 mg) or voglibose (0.3 mg) on endothelial function were analyzed using brachial artery flow-mediated dilation (FMD) and lipid profiles during fasting and 1.5 and 3 h after an oral cookie-loading test. Compared with voglibose, vildagliptin significantly suppressed postprandial endothelial dysfunction, (%FMD, -1.6±0.9 vildagliptin vs. -4.0±0.7 voglibose; P=0.01) and the postprandial incremental increase in the triglyceride level (28±18 vildagliptin vs. 51±26 mg/dl voglibose; P=0.01) 3 h after a cookie-loading test. In addition, vildagliptin significantly increased the levels of glucagon-like peptide-1 compared with voglibose 3 h after a loading cookie test (4.4±0.6 vs. 2.9±0.7 pmol/l, respectively; P=0.04). No significant differences in the levels of glucose, apolipoprotein B-48, glucagon or insulin were observed between vildagliptin and voglibose treatments. In conclusion, a single administration of vildagliptin attenuated postprandial endothelial dysfunction and postprandial hypertriglyceridemia, suggesting that vildagliptin may be a promising antiatherogenic agent.

成人先天性心疾患センター開設と教育体制の確立

赤木禎治, 中川晃志, 高谷陽一, 三好亨, 西井伸洋, 大月審一, 笠原慎吾, 佐野俊二, 伊藤浩

日本成人先天性心疾患学会雑誌 4 ( 1 ) 110 - 110 2015.1

Nonalcoholic Hepatic Steatosis Is a Strong Predictor of High-Risk Coronary-Artery Plaques as Determined by Multidetector CT. International journal

Kazuhiro Osawa, Toru Miyoshi, Kentarou Yamauchi, Yasushi Koyama, Kazufumi Nakamura, Shuhei Sato, Susumu Kanazawa, Hiroshi Ito

PloS one 10 ( 6 ) e0131138 2015

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Nonalcoholic fatty liver disease is associated with a risk of coronary artery disease (e.g., diabetes mellitus, dyslipidemia, metabolic syndrome). We evaluated whether nonalcoholic hepatic steatosis is associated with high-risk plaques as assessed by multidetector computed tomography (CT). METHODS: This retrospective study involved 414 participants suspected of having coronary artery disease. Nonalcoholic hepatic steatosis was defined as a liver-to-spleen fat ratio of <1.0 and the presence and appropriate characteristics of coronary-artery plaques as assessed by coronary CT angiography. High-risk plaques were identified, as were low-density plaques, positive remodeling, and spotty calcification. RESULTS: Compared with patients who did not have nonalcoholic hepatic steatosis, patients with nonalcoholic hepatic steatosis had more low-density plaques (21% vs. 44%, p<0.01), positive remodeling (41% vs. 58%, p = 0.01), and spotty calcification (12% vs. 36%, p<0.01). The number of high-risk plaques in patients with nonalcoholic hepatic steatosis was greater than in those without nonalcoholic hepatic steatosis (p<0.01). Patients with nonalcoholic hepatic steatosis were more likely to have high-risk plaques than were those with only an elevated level of visceral adipose tissue (≥86 cm2; 35% vs. 16%, p<0.01). Multivariate analyses that included nonalcoholic hepatic steatosis, amount of visceral adipose tissue, and the presence/absence of traditional risk factors demonstrated that nonalcoholic hepatic steatosis was an independent predictor of high-risk plaques (odds ratio: 4.60; 95% confidence interval: 1.94-9.07, p<0.01). CONCLUSIONS: Diagnosis of nonalcoholic hepatic steatosis may be of value when assessing the risk of coronary artery disease.

DOI： 10.1371/journal.pone.0131138

Non-invasive computed fractional flow reserve from computed tomography (CT) for diagnosing coronary artery disease – Japanese results from NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps).

Toru Miyoshi, Kazuhiro Osawa, Hiroshi Ito, Susumu Kanazawa, Takeshi Kimura, Hiroki Shiomi, Sachio Kuribayashi, Masahiro Jinzaki, Akio Kawamura, Hiram Bezerra, Stephan Achenbach, Bjarne L Nørgaard

Circulation journal : official journal of the Japanese Circulation Society 79 ( 2 ) 406 - 12 2015

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Recently, a non-invasive method using computational fluid dynamics to calculate vessel-specific fractional flow reserve (FFRCT) from routinely acquired coronary computed tomography angiography (CTA) was described. The Analysis of Coronary Blood Flow Using CT Angiography: Next Steps (NXT) trial, which was a prospective, multicenter trial including 254 patients with suspected coronary artery disease, noted high diagnostic performance of FFRCT compared with invasive FFR. The aim of this post-hoc analysis was to assess the diagnostic performance of non-invasive FFRCT vs. standard stenosis quantification on coronary CTA in the Japanese subset of the NXT trial. METHODS AND RESULTS: A total of 57 Japanese participants were included from Okayama University (n=36), Kyoto University (n=17), and Keio University (n=4) Hospitals. Per-patient diagnostic accuracy of FFRCT(74%; 95% confidence interval [CI]: 60-85%) was higher than for coronary CTA (47%; 95% CI: 34-61%, P<0.001) arising from improved specificity (63% vs. 27%, P<0.001). FFRCT correctly reclassified 53% of patients and 63% of vessels with coronary CTA false positives as true negatives. When patients with Agatston score >1,000 were excluded, per-patient accuracy of FFRCT was 83% with a high specificity of 76%, similar to the overall NXT trial findings. CONCLUSIONS: FFRCT has high diagnostic performance compared with invasive FFR in the Japanese subset of patients in the NXT trial.

DOI： 10.1253/circj.CJ-14-1051

One of six patients with non-ischemic heart disease exhibit provoked coronary spasms: non-ischemic heart disease associated with ischemia?

Shozo Sueda, Toru Miyoshi, Yasuhiro Sasaki, Tomoki Sakaue, Hirokazu Habara, Hiroaki Kohno

Internal medicine (Tokyo, Japan) 54 ( 3 ) 281 - 6 2015

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The majority of cardiologists do not perform spasm provocation tests in patients with non-ischemic heart disease (non-IHD) or non-obstructive coronary artery disease (non-ob-CAD). We herein examined the frequency of provoked spasms in non-IHD and non-ob-CAD patients, including those with atypical chest pain (Aty), valvular heart disease (Val), hypertrophic cardiomyopathy (HCM), congestive heart failure (CHF), and others (Oth). METHODS & RESULTS: We performed acetylcholine (ACh) spasm provocation tests over a period of 22 years (1991-2012) among 1,440 patients, including 981 IHD and 459 non-IHD subjects. A total of 43 patients with significant organic stenosis were excluded, and the remaining 416 patients with non-IHD or non-ob-CAD disease were assessed. ACh was injected in incremental doses of 20/50/80 μg into the right coronary artery (RCA) and 20/50/100/(200) μg into the left coronary artery (LCA). Positive coronary spasms were defined as transient luminal narrowing of >99%. Positive coronary spasms were noted in 17.3% of the non-IHDs patients (72/416), compared to 11.4% (15/132), 19% (8/42), 16.7% (5/30), 23.9% (16/67), and 19.3% (28/145), in the patients in the Aty, Val, HCM, CHF, and Oth groups, respectively. The rate of positive provoked spasms was higher in men than women, although not significantly [20.6% (46/223) vs. 13.4% (26/193), ns], and significantly higher in the late period (2001-2012) than in the early period (1991-2000) (36.8% vs. 7.0%, p<0.001). CONCLUSION: Physicians should perform spasm provocation tests in patients with IHD as well as non-IHD with non-ob-CAD, as one of six non-IHD patients in this study exhibited provoked coronary spasms.

DOI： 10.2169/internalmedicine.54.2660

Aortic vascular graft infection caused by Cardiobacterium valvarum: a case report. International journal

Hideharu Hagiya, Susumu Kokeguchi, Hiroko Ogawa, Tomohiro Terasaka, Kosuke Kimura, Koichi Waseda, Yoshihisa Hanayama, Kaori Oda, Hisatoshi Mori, Toru Miyoshi, Fumio Otsuka

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 20 ( 12 ) 804 - 9 2014.12

Language：English Publishing type：Research paper (scientific journal)

A 53-year-old man with a past medical history of total arch replacement surgery and severe aortic regurgitation presented with a 1-month history of persistent general malaise, anorexia, body weight loss and night sweats. His recent history included gingival hyperplasia for 6 years, gingivitis after tooth extraction 3 years before, prolonged inflammatory status for 4 months, fundal hemorrhage and leg tenderness for 2 months. A pathogen was detected from blood culture, but conventional microbiological examination failed to identify the pathogen. The organism was eventually identified as Cardiobacterium valvarum by 16S rRNA analysis, and the patient was diagnosed with infective endocarditis and prosthetic vascular graft infection. The patient received intravenous antibiotic therapy using a combination of ceftriaxone and levofloxacin for 5 weeks and was discharged with a good clinical course. C. valvarum is a rare human pathogen in clinical settings. Only 10 cases have been reported to date worldwide, and therefore, the clinical characteristics of C. valvarum infection are not fully known. This is a first well-described case of C. valvarum infection in Japan, and further, a first report of aortic prosthetic vascular graft infection worldwide. Identification of C. valvarum is usually difficult due to its phenotypic characteristics, and molecular approaches would be required for both clinicians and microbiologists to facilitate more reliable diagnosis and uncover its clinical picture more clearly.

DOI： 10.1016/j.jiac.2014.07.008

Early eicosapentaenoic acid treatment after percutaneous coronary intervention reduces acute inflammatory responses and ventricular arrhythmias in patients with acute myocardial infarction: a randomized, controlled study. International journal

Masayuki Doi, Kazumasa Nosaka, Toru Miyoshi, Mutsumi Iwamoto, Masahito Kajiya, Keisuke Okawa, Rie Nakayama, Wataru Takagi, Ko Takeda, Satoshi Hirohata, Hiroshi Ito

International journal of cardiology 176 ( 3 ) 577 - 82 2014.10

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: We examined whether early loading of eicosapentaenoic acid (EPA) reduces clinical adverse events by 1 month, accompanied by a decrease in C-reactive protein (CRP) values in patients with acute myocardial infarction (MI). BACKGROUND: Acute MI triggers an inflammatory reaction, which plays an important role in myocardial injury. EPA could attenuate the inflammatory response. METHODS: This prospective, open-label, blinded endpoint, randomized trial consisted of 115 patients with acute MI. They were randomly assigned to the EPA group (57 patients) and the control group (58 patients). After percutaneous coronary intervention (PCI), 1800 mg/day of EPA was initiated within 24h. The primary endpoint was composite events, including cardiac death, stroke, re-infarction, ventricular arrhythmias, and paroxysmal atrial fibrillation within 1 month. RESULTS: Administration of EPA significantly reduced the primary endpoint within 1 month (10.5 vs 29.3%, p=0.01), especially the incidence of ventricular arrhythmias (7.0 vs 20.6%, p=0.03). Peak CRP values after PCI in the EPA group were significantly lower than those in the control group (median [interquartile range], 8.2 [5.6-10.2] mg/dl vs 9.7 [7.6-13.9] mg/dl, p<0.01). Logistic regression analysis showed that EPA use was an independent factor related to ventricular arrhythmia until 1 month, with an odds ratio of 0.29 (95% confidence interval, 0.09 to 0.96, p=0.04). CONCLUSIONS: Early EPA treatment after PCI in the acute stage of MI reduces the incidence of ventricular arrhythmias, and lowers CRP values.

DOI： 10.1016/j.ijcard.2014.08.055

Add-on ezetimibe reduces small dense low-density lipoprotein cholesterol levels without affecting absorption of eicosapentaenoic acid in patients with coronary artery disease: a pilot study. International journal

Motoki Kubo, Toru Miyoshi, Tomonari Kimura, Yoko Noda, Kunihisa Kohno, Kazufumi Nakamura, Hiroshi Morita, Hiroshi Ito

American journal of cardiovascular drugs : drugs, devices, and other interventions 14 ( 5 ) 387 - 92 2014.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Residual risk of cardiovascular disease from increased small dense low-density lipoprotein (sdLDL)-cholesterol levels and low n-3 polyunsaturated fatty acid (PUFA) levels is a considerable therapeutic issue. The purpose of this study was to evaluate the effect of ezetimibe as an add-on to statins and supplemental eicosapentaenoic acid (EPA) on sdLDL cholesterol and absorption of EPA in patients with coronary artery disease. METHODS: The study population consisted of ten male patients who were concurrently receiving statins and EPA 1,800 mg/day. Serum lipids and PUFAs, including EPA and arachidonic acid, were measured in blood samples collected before ezetimibe (baseline), 4 weeks after starting 10-mg/day ezetimibe, and 4 weeks after discontinuing ezetimibe. RESULTS: Ezetimibe significantly decreased sdLDL-cholesterol levels after 4 weeks of treatment (baseline 35 ± 13 mg/dl; treatment 27 ± 9 mg/dl), but the levels returned to baseline after discontinuation of ezetimibe (37 ± 13 mg/dl). The concentration of EPA did not significantly change during the study. CONCLUSION: Ezetimibe shows great promise as an add-on therapy to statins to reduce sdLDL-cholesterol-related residual risk of cardiovascular disease without affecting absorption of supplemental EPA in patients with coronary artery disease.

DOI： 10.1007/s40256-014-0082-3

Pioglitazone prevents the endothelial dysfunction induced by ischemia and reperfusion in healthy subjects. International journal

Yuka Sakatani, Toru Miyoshi, Hiroki Oe, Yoko Noda, Yuko Ohno, Kazufumi Nakamura, Yukihiro Saito, Kazuhiro Osawa, Hiroshi Morita, Kunihisa Kohno, Hiroshi Ito

Journal of cardiovascular pharmacology 64 ( 4 ) 326 - 31 2014.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: No study has investigated whether pioglitazone (an agonist of peroxisome proliferator-activated receptor gamma) protects against ischemia and reperfusion (IR)-induced endothelial dysfunction in humans. METHODS AND RESULTS: In the first crossover study, 20 volunteers were randomized to 1 week of pioglitazone (30 mg/d, postoperatively) or control (no treatment). In the second single-arm study, 15 volunteers received pioglitazone and the cyclooxygenase-2 inhibitor meloxicam for 1 week. On day 7, endothelium-dependent flow-mediated dilation (FMD) of the distal brachial artery was measured before and after IR (15 minutes of ischemia followed by 15 minutes of reperfusion in the proximal upper arm). Pre-IR brachial-artery diameter and FMD were similar across the 2 sessions (control, pioglitazone) in protocol 1 and between the 2 protocols. IR significantly blunted FMD after no treatment (pre-IR FMD: 10.2% ± 2.6%; post-IR FMD: 3.5% ± 1.9%, P < 0.01) but not after pioglitazone administration (pre-IR FMD: 9.7% ± 2.5%; post-IR FMD: 8.8% ± 2.9%, P = 0.11). This protective effect was accompanied by an increase in serum levels of the antioxidant enzyme extracellular superoxide dismutase and was not affected by concomitant administration of the cyclooxygenase-2 inhibitor meloxicam (P = 0.10). CONCLUSIONS: In humans, pioglitazone provides potent protection against IR-induced endothelial dysfunction.

DOI： 10.1097/FJC.0000000000000124

Omega-3 fatty acids improve postprandial lipemia and associated endothelial dysfunction in healthy individuals - a randomized cross-over trial. International journal

Toru Miyoshi, Yoko Noda, Yuko Ohno, Hiroki Sugiyama, Hiroki Oe, Kazufumi Nakamura, Kunihisa Kohno, Hiroshi Ito

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 68 ( 8 ) 1071 - 7 2014.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Postprandial elevation of triglycerides impairs endothelial function and contributes to the development of atherosclerosis. We investigated the effects of omega-3 fatty acids on postprandial endothelial function and lipid profiles. METHODS: Healthy volunteers [10] were given supplementation at 4g/day omega-3 fatty acids (or were not treated) for 4 weeks in a randomised crossover study. Postprandial levels of various lipids were monitored and endothelial function assessed by brachial artery flow-mediated dilation during fasting and after a standard cookie test. RESULTS: Omega-3 fatty acids reduced postprandial endothelial dysfunction compared with the control diet (flow-mediated dilation at 4h=-0.5±1.2 vs. -2.0±1.6%, P=0.03). Postprandial levels of triglycerides, apolipoprotein B-48, and remnant lipoprotein-cholesterol increased in untreated subjects, peaked at 2-4h, and returned to baseline at 8h, whereas low-density lipoprotein-cholesterol levels did not change. Supplementation with omega-3 fatty acids significantly suppressed postprandial elevation of triglycerides (incremental area under the curve=220±209 vs. 374±216mg/h/dL, P=0.04) and remnant lipoprotein-cholesterol (incremental area under the curve=21.7±13.8 vs. 13.3±12.9mg/h/dL, P=0.04). Supplementation with omega-3 fatty acids significantly suppressed the increase in triglyceride content in chylomicrons as well as in very-low-density lipoproteins from baseline to 4h after the cookie test. CONCLUSION: Omega-3 fatty acids significantly decreased postprandial triglyceride elevation and postprandial endothelial dysfunction, suggesting that omega-3 fatty acids may have vascular protective effects in postprandial state.

DOI： 10.1016/j.biopha.2014.10.008

DPP-4 inhibitor and alpha-glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes: EDGE study. International journal

Kazufumi Nakamura, Hiroki Oe, Hajime Kihara, Kenei Shimada, Shota Fukuda, Kyoko Watanabe, Tsutomu Takagi, Kei Yunoki, Toru Miyoshi, Kumiko Hirata, Junichi Yoshikawa, Hiroshi Ito

Cardiovascular diabetology 13 110 - 110 2014.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Alpha glucosidase inhibitor (GI) attenuates postprandial hyperglycemia (PPH) and reduces the risk of cardiovascular events in patients with impaired glucose tolerance or type 2 diabetes. Dipeptidyl peptidase 4 (DPP-4) inhibitors also attenuate PPH. PPH is one of the factors leading to endothelial dysfunction which is an early event in the pathogenesis of atherosclerosis. Furthermore, DPP-4 inhibitors protect endothelial function through a GLP-1-dependent mechanism. However, the impact of these two types of drugs on endothelial dysfunction in patients with type 2 diabetes has not been fully elucidated. We compared the effects of sitagliptin, a DPP-4 inhibitor, and voglibose, an alpha GI, on endothelial function in patients with diabetes. METHODS: We conducted a randomized prospective multicenter study in 66 patients with type 2 diabetes who did not achieve the treatment goal with sulfonylurea, metformin or pioglitazone treatment; 31 patients received sitagliptin treatment and 35 patients, voglibose treatment. The flow-mediated dilatation (FMD) of the brachial artery was measured in the fasting state at baseline and after 12 weeks of treatment. The primary endpoint was a change in FMD (ΔFMD) from the baseline to the end of follow-up. The effects of sitagliptin and voglibose on FMD were assessed by ANCOVA after adjustment for the baseline FMD, age, sex, current smoking, diabetes duration and body mass index. Secondary efficacy measures included changes in HbA1c, GIP, GLP-1, C-peptide, CD34, lipid profile, oxidative stress markers, inflammatory markers and eGFR and any adverse events. RESULTS: ΔFMD was significantly improved after 12 weeks of treatment in both groups, and there was no significant difference in ΔFMD between the two groups. There were no significant differences in changes in HbA1c, GIP, GLP-1, C-peptide, lipid profile, oxidative stress marker, inflammatory marker and eGFR between the two groups. Compared with voglibose, sitagliptin significantly increased the circulating CD34, a marker of endothelial progenitor cells. Adverse events were observed in 5 patients in only the voglibose group (diarrhea 1, nausea 1, edema 2 and abdominal fullness 1). CONCLUSIONS: Sitagliptin improved endothelial dysfunction just as well as voglibose in patients with type 2 diabetes. Sitagliptin had protective effects on endothelial function without adverse events. TRIAL REGISTRATION: registered at http://www.umin.ac.jp/ctrj/ under UMIN000003951.

DOI： 10.1186/s12933-014-0110-2

Additional diagnostic value of first-pass myocardial perfusion imaging without stress when combined with 64-row detector coronary CT angiography in patients with coronary artery disease. International journal

Kazuhiro Osawa, Toru Miyoshi, Yasushi Koyama, Katsushi Hashimoto, Shuhei Sato, Kazufumi Nakamura, Nobuhiro Nishii, Kunihisa Kohno, Hiroshi Morita, Susumu Kanazawa, Hiroshi Ito

Heart (British Cardiac Society) 100 ( 13 ) 1008 - 15 2014.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Multi-detector coronary CT angiography (CCTA) can detect coronary stenosis, but it has a limited ability to evaluate myocardial perfusion. We evaluated the usefulness of first-pass CT-myocardial perfusion imaging (MPI) in combination with CCTA for diagnosing coronary artery disease (CAD). METHODS: A total of 145 patients with suspected CAD were enrolled. We used 64-row multi-detector CT (Definition Flash, Siemens). The same coronary CCTA data were used for first-pass CT-MPI without drug loading. Images were reconstructed by examining the signal densities at diastole as colour maps. Diagnostic accuracy was assessed by comparison with invasive coronary angiography. RESULTS: First-pass CT-MPI in combination with CCTA significantly improved diagnostic performance compared with CCTA alone. With per-vessel analysis, the sensitivity, specificity, positive predictive value and negative predictive value increased from 81% to 85%, 87% to 94%, 63% to 79% and 95% to 96%, respectively. The area under the receiver operating characteristic curve for detecting CAD also increased from 0.84 to 0.89 (p=0.02). First-pass CT-MPI was particularly useful for assessing segments that could not be directly evaluated due to severe calcification and motion artefacts. CONCLUSIONS: First-pass CT-MPI has an additional diagnostic value for detecting coronary stenosis, in particular in patients with severe calcification.

DOI： 10.1136/heartjnl-2013-305468

Bezafibrate improves postprandial hypertriglyceridemia and associated endothelial dysfunction in patients with metabolic syndrome: a randomized crossover study. International journal

Yuko Ohno, Toru Miyoshi, Yoko Noda, Hiroki Oe, Norihisa Toh, Kazufumi Nakamura, Kunihisa Kohno, Hiroshi Morita, Hiroshi Ito

Cardiovascular diabetology 13 71 - 71 2014.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Postprandial elevation of triglyceride-rich lipoproteins impairs endothelial function, which can initiate atherosclerosis. We investigated the effects of bezafibrate on postprandial endothelial dysfunction and lipid profiles in patients with metabolic syndrome. METHODS: Ten patients with metabolic syndrome were treated with 400 mg/day bezafibrate or untreated for 4 weeks in a randomized crossover study. Brachial artery flow-mediated dilation (FMD) and lipid profiles were assessed during fasting and after consumption of a standardized snack. Serum triglyceride and cholesterol contents of lipoprotein fractions were analyzed by high-performance liquid chromatography. RESULTS: Postprandial FMD decreased significantly and reached its lowest value 4 h after the cookie test in both the bezafibrate and control groups, but the relative change in FMD from baseline to minimum in the bezafibrate group was significantly smaller than that in the control group (-29.0 ± 5.9 vs. -42.9 ± 6.2%, p = 0.04). Bezafibrate significantly suppressed postprandial elevation of triglyceride (incremental area under the curve (AUC): 544 ± 65 vs. 1158 ± 283 mg h/dl, p = 0.02) and remnant lipoprotein cholesterol (incremental AUC: 27.9 ± 3.5 vs. 72.3 ± 14.1 mg h/dl, p < 0.01). High-performance liquid chromatography analysis revealed that postprandial triglyceride content of the chylomicron and very low-density lipoprotein fractions was significantly lower in the bezafibrate group than in the control group (p < 0.05). CONCLUSION: Bezafibrate significantly decreased postprandial endothelial dysfunction, and elevations of both exogenous and endogenous triglycerides in patients with metabolic syndrome, suggesting that bezafibrate may have vascular protective effects in these patients. CLINICAL TRIAL REGISTRATION: Unique Identifiers: UMIN000012557.

DOI： 10.1186/1475-2840-13-71

Low serum level of secreted frizzled-related protein 5, an anti-inflammatory adipokine, is associated with coronary artery disease. International journal

Toru Miyoshi, Masayuki Doi, Shinichi Usui, Mutsumi Iwamoto, Masahito Kajiya, Ko Takeda, Kazumasa Nosaka, Rie Nakayama, Keisuke Okawa, Wataru Takagi, Kazufumi Nakamura, Satoshi Hirohata, Hiroshi Ito

Atherosclerosis 233 ( 2 ) 454 - 459 2014.4

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipokine that is associated with insulin resistance in animals. To extend these observations to humans, we investigated the association of serum SFRP5 levels in subjects with and without coronary artery disease (CAD). METHODS: Subjects (n=185, 68±11 years, 79% male) suspected of having CAD were enrolled in the study and were divided into two groups, CAD and non-CAD subjects, according to the results of their coronary angiographies. Serum SFRP5 levels of the subjects were measured by an enzyme-linked immunosorbent assay. RESULTS: The serum SFRP5 levels in the subjects with CAD were significantly lower than those in the non-CAD subjects (median [interquartile range]: 47.7 [26.6] vs. 52.4 [29.6] ng/mL, respectively; p=0.02). The serum SFRP5 levels significantly correlated with body mass index, the homeostasis model of assessment of insulin resistance, adiponectin levels, and CAD severity. Multivariate logistic regression analysis revealed that a decreased serum SFRP5 level (log transformed) was independently associated with CAD for all subjects (adjusted odds ratio, 0.36; 95% confidence interval, 0.14-0.94; p=0.03). CONCLUSION: Serum SFRP5 levels are significantly associated with CAD in humans, suggesting that low SFRP5 levels may contribute to CAD.

DOI： 10.1016/j.atherosclerosis.2014.01.019

Differential association of visceral adipose tissue with coronary plaque characteristics in patients with and without diabetes mellitus. International journal

Kazuhiro Osawa, Toru Miyoshi, Yasushi Koyama, Shuhei Sato, Noriaki Akagi, Yusuke Morimitsu, Motoki Kubo, Hiroki Sugiyama, Kazufumi Nakamura, Hiroshi Morita, Susumu Kanazawa, Hiroshi Ito

Cardiovascular diabetology 13 61 - 61 2014.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Excess visceral adipose tissue (VAT) is closely associated with the presence of coronary artery plaques that are vulnerable to rupture. Patients with diabetes mellitus (DM) have more VAT than patients without DM, but the extent to which VAT contributes to the characteristics of coronary plaques before and after the development of DM is not fully understood. METHODS: We retrospectively evaluated 456 patients (60% male, age 64 ± 16 years) who were suspected to have cardiovascular disease and underwent 64-slice computed tomography angiography (CTA). Seventy-one (16%) patients had vulnerable plaques (CT density < 50 Hounsfield Units, positive remodeling index > 1.05, and adjacent spotty areas of calcification). RESULTS: Patients were divided into tertiles according to the VAT area. There were stepwise increases in noncalcified and vulnerable plaques with increasing tertiles of VAT area in patients without DM, but not in patients with DM. Multivariate analysis showed that a larger VAT area was significantly associated with a higher risk of vulnerable plaque in patients without DM (odds ratio 3.17, 95% confidence interval 1.08-9.31, p = 0.04), but not in patients with DM. CONCLUSIONS: The VAT area is associated with the characteristics of coronary plaques on CTA in patients without DM, but not in patients with DM. VAT may be a significant cardiometabolic risk factor that is associated with plaque vulnerability before the development of DM. CTA findings may help to improve risk stratification in such patients.

DOI： 10.1186/1475-2840-13-61

Olmesartan reduces inflammatory biomarkers in patients with stable coronary artery disease undergoing percutaneous coronary intervention: results from the OLIVUS trial.

Toru Miyoshi, Atsushi Hirohata, Shinichi Usui, Keizo Yamamoto, Takashi Murakami, Issei Komatsubara, Shozo Kusachi, Tohru Ohe, Kazufumi Nakamura, Hiroshi Ito

Heart and vessels 29 ( 2 ) 178 - 85 2014.3

Language：English Publishing type：Research paper (scientific journal)

The OLmesartan on the progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound (OLIVUS) trial demonstrated that an angiotensin II receptor blocker, olmesartan, reduces the rate of coronary atheroma progression as evaluated by intravascular ultrasound in patients with stable angina pectoris undergoing percutaneous coronary intervention. This substudy examined the impact of olmesartan on serum biomarkers and the relationship between biomarker changes and atheroma progression. Patients in the OLIVUS trial (n = 247) were randomly assigned to a control group or the olmesartan group. A subgroup of these patients (n = 135, 55 %) was analyzed at baseline and at 14 months. Patients' characteristics and blood-pressure control were identical between the control group (n = 65) and the olmesartan group (n = 70), and also between the subpopulation and total population. The change in the level of high-sensitivity C-reactive protein (hs-CRP) (mg/l) and adiponectin (μg/ml) was significantly greater in the olmesartan group than in the control group (between-group differences: 0.5 and -0.7; 95 % confidence interval: 0.2-0.8 and -1.3 to -0.1; P = 0.001 and 0.02, respectively). Multiple regression analysis revealed that the nominal changes in total atheroma volume and percent atheroma volume were significantly associated with the nominal change in hs-CRP in the olmesartan group but not in the control group. Olmesartan reduced hs-CRP in patients with stable angina, and this correlated with the change in coronary atheroma.

DOI： 10.1007/s00380-013-0343-0

Effect of vildagliptin, a dipeptidyl peptidase 4 inhibitor, on cardiac hypertrophy induced by chronic beta-adrenergic stimulation in rats. International journal

Toru Miyoshi, Kazufumi Nakamura, Masashi Yoshida, Daiji Miura, Hiroki Oe, Satoshi Akagi, Hiroki Sugiyama, Kaoru Akazawa, Tomoko Yonezawa, Jun Wada, Hiroshi Ito

Cardiovascular diabetology 13 43 - 43 2014.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Heart failure with left ventricular (LV) hypertrophy is often associated with insulin resistance and inflammation. Recent studies have shown that dipeptidyl peptidase 4 (DPP4) inhibitors improve glucose metabolism and inflammatory status. We therefore evaluated whether vildagliptin, a DPP4 inhibitor, prevents LV hypertrophy and improves diastolic function in isoproterenol-treated rats. METHODS: Male Wistar rats received vehicle (n = 20), subcutaneous isoproterenol (2.4 mg/kg/day, n = 20) (ISO), subcutaneous isoproterenol (2.4 mg/kg/day + oral vildagliptin (30 mg/kg/day, n = 20) (ISO-VL), or vehicle + oral vildagliptin (30 mg/kg/day, n = 20) (vehicle-VL) for 7 days. RESULTS: Blood pressure was similar among the four groups, whereas LV hypertrophy was significantly decreased in the ISO-VL group compared with the ISO group (heart weight/body weight, vehicle: 3.2 ± 0.40, ISO: 4.43 ± 0.39, ISO-VL: 4.14 ± 0.29, vehicle-VL: 3.16 ± 0.16, p < 0.05). Cardiac catheterization revealed that vildagliptin lowered the elevated LV end-diastolic pressure observed in the ISO group, but other parameters regarding LV diastolic function such as the decreased minimum dp/dt were not ameliorated in the ISO-VL group. Histological analysis showed that vildagliptin attenuated the increased cardiomyocyte hypertrophy and perivascular fibrosis, but it did not affect angiogenesis in cardiac tissue. In the ISO-VL group, quantitative PCR showed attenuation of increased mRNA expression of tumor necrosis factor-α, interleukin-6, insulin-like growth factor-l, and restoration of decreased mRNA expression of glucose transporter type 4. CONCLUSIONS: Vildagliptin may prevent LV hypertrophy caused by continuous exposure to isoproterenol in rats.

DOI： 10.1186/1475-2840-13-43

Spasm provocation tests performed under medical therapy: a new approach for treating patients with refractory coronary spastic angina on emergency admission.

Shozo Sueda, Hiroaki Kohno, Toru Miyoshi, Yasuhiro Sasaki, Tomoki Sakaue, Hirokazu Habara

Internal medicine (Tokyo, Japan) 53 ( 16 ) 1739 - 47 2014

Language：English Publishing type：Research paper (scientific journal)

Objective There are no objective methods for evaluating the severity of vasospasms in patients with refractory coronary spastic angina (R-CSA) under adequate medical therapy. We examined whether spasm provocation tests performed under adequate medication are useful for evaluating the severity of disease in R-CSA patients on emergency admission. Methods and Results We performed spasm provocation tests before and after the administration of medical therapy in eight R-CSA patients, including one ventricular fibrillation survivor (VF-S) and seven patients with unstable angina (UAP) on emergency readmission. We also performed these tests only after medical therapy on urgent admission in four R-CSA patients, including two patients with UAP, one patient with VF-S and one patient with acute coronary syndrome. All 12 R-CSA patients had been medicated with ≥ 2 vasodilator drugs. Positive coronary spasms were defined as >99% transient narrowing. The coronary artery spasms disappeared in three patients under medication, and mitigation of vasospasticity was observed in three patients. In these six cases we continued the same medications. Meanwhile in two patients, we recommended a consultation for psychosomatic medicine. In contrast, the remaining six R-CSA patients exhibited higher levels of vasospasticity, irrespective of the administration of aggressive medical therapy, in which the doses of vasoactive drugs were increased in order to suppress coronary artery spasms. Conclusion In some R-CSA patients on emergency admission, performing spasm provocation tests under medical therapy is useful for determining the subsequent treatment strategy. Therefore, this test may become a new tool in the treatment of R-CSA.

Arterial stiffness determined according to the cardio-ankle vascular index is associated with paroxysmal atrial fibrillation: a cross-sectional study. International journal

Toru Miyoshi, Masayuki Doi, Yoko Noda, Yuko Ohno, Kosuke Sakane, Shigeshi Kamikawa, Youko Noguchi, Hiroshi Ito

Heart Asia 6 ( 1 ) 59 - 63 2014

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Several lines of evidence suggest that atrial fibrillation (AF) may be a consequence of vascular disease. We investigated the relationship between cardio-ankle vascular index (CAVI), a new index of arterial stiffness, and the presence of paroxysmal AF (PAF). METHODS AND RESULTS: 181 outpatients (91 patients with PAF and 90 age- and gender-matched subjects without PAF) were analysed for their sinus rhythm. The CAVI was significantly higher in patients with PAF than in subjects without PAF (9.0±1.0 vs 8.7±0.8, p<0.01). In all subjects, the CAVI was significantly correlated with the left ventricular mass index (r=0.30, p<0.01), left atrial diameter (r=0.22, p<0.01), and augmentation index, a parameter of wave reflection (r=0.32, p<0.01), in addition to age, systolic blood pressure and pulse pressure. Logistic analysis demonstrated that the CAVI was independently associated with PAF even after adjustment for confounding factors. The adjusted OR of PAF was 1.8 for each unit increase in the CAVI (p=0.01). CONCLUSIONS: Our finding suggests that increased arterial stiffness may be involved in the maintenance of AF.

DOI： 10.1136/heartasia-2014-010503

Serum adipocyte fatty acid-binding protein is independently associated with complex coronary lesions in patients with stable coronary artery disease.

Masahito Kajiya, Toru Miyoshi, Masayuki Doi, Shinichi Usui, Mutsumi Iwamoto, Ko Takeda, Kazumasa Nosaka, Rie Nakayama, Satoshi Hirohata, Shozo Kusachi, Kazufumi Nakamura, Hiroshi Ito

Heart and vessels 28 ( 6 ) 696 - 703 2013.11

Language：English Publishing type：Research paper (scientific journal)

The association between circulating adipocyte fatty acid-binding protein (A-FABP) levels and coronary artery disease (CAD) is reported. We assessed whether plasma A-FABP levels are associated with angiographic coronary lesion morphology in patients with stable CAD. Serum A-FABP levels were analyzed in 115 patients with stable CAD (mean age 69 ± 10 years; 80 % men). These patients were angiographically studied and divided into two groups: simple lesions (n = 34) and complex lesions (n = 81). We also compared 50 age- and gender-matched controls with no evidence of CAD. Serum A-FABP levels in patients with stable CAD were significantly higher than those in controls. In patients with stable CAD, serum A-FABP levels were significantly higher in patients with complex lesions than in those with simple lesions: median (25th-75th percentile), 23.4 (17.7-30.8) vs 18.2 (12.2-24.7) ng/ml, P < 0.01. Serum A-FABP levels were also significantly associated with angiographic scores of extent of coronary lesion (r = 0.21, P = 0.02). Multiple logistic analysis that included dyslipidemia, statin therapy, and extent score demonstrated that serum A-FABP was independently associated with complex lesions. The multiple adjusted odds ratio for a complex lesion with a serum A-FABP level (per doubling) was 2.38 (95 % confidence interval, 1.03-6.41; P = 0.03). High serum A-FABP levels were significantly associated with complex coronary lesions in patients with stable CAD, suggesting that high A-FABP levels may be involved in coronary plaque vulnerability.

DOI： 10.1007/s00380-012-0310-1

[Treatment of hypertriglyceridemia with omega-3 fatty acids].

Toru Miyoshi, Hiroshi Ito

Nihon rinsho. Japanese journal of clinical medicine 71 ( 9 ) 1650 - 4 2013.9

Language：Japanese Publishing type：Research paper (scientific journal)

Omega-3 fatty acids such as eicosapentaenoic acid(EPA) and docosahexaenoic acid(DHA) have important biologic functions, including effects on membranes, eicosanoid metabolism, and gene transcription. Studies indicate that the use of EPA and DHA lowered triglyceride levels, which is accomplished by decreasing the production of hepatic triglycerides and increasing the clearance of plasma triglycerides. Recent clinical studies showed that intake of omega-3 fatty acids reduced cardiovascular events. In addition, combination therapy with omega-3 fatty acids and a statin is a safe and effective way to improve lipid levels and cardiovascular prognosis beyond the benefits provided by statin therapy alone. Our focus is to review the potential mechanisms by which these fatty acids reduce cardiovascular disease risk.

Serum cystatin C as a biomarker of cardiac diastolic dysfunction in patients with cardiac disease and preserved ejection fraction

Nosaka Kazumasa, Nakamura Kazufumi, Kusano Kengo, Toh Norihisa, Tada Takeshi, Miyoshi Toru, Doi Masayuki, Kohno Kunihisa, Morita Hiroshi, Ito Hiroshi

Congestive Heart Failure 19 ( 4 ) E35 - E39 2013.8

Reduced diurnal variation of heart rate is associated with increased plasma B-type natriuretic peptide level in patients with atrial fibrillation. International journal

Shigeshi Kamikawa, Toru Miyoshi, Masayuki Doi, Naoko Orita, Mutsuko Sangawa, Takaaki Nakatsu, Youko Noguchi, Satoshi Hirohata, Shozo Kusachi, Kazufumi Nakamura, Hiroshi Ito

Clinical cardiology 36 ( 7 ) 394 - 400 2013.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The plasma B-type natriuretic peptide (BNP) level has been shown to be increased in patients with chronic atrial fibrillation (AF) independent of left ventricular ejection fraction (LVEF). The purpose of this study is to evaluate the relationship between the plasma BNP level and heart rate variation in patients with AF. HYPOTHESIS: The plasma BNP level is associated with heart rate variation in patients with AF. METHODS: A total of 102 patients with AF and preserved LVEF were included from 2 hospitals. The ambulatory electrocardiographic recording and measurement of plasma BNP levels were performed simultaneously. Echo-Doppler parameters were measured as the average of 10 consecutive cardiac cycles. RESULTS: A difference in the mean heart rate between night and day (DIFF) and the standard deviation of the 5-miniute mean R-R interval (SDARR) were significantly associated with log-transformed BNP levels (r = -0.411, P < 0.001 and r = -0.243, P = 0.049, respectively). In echocardiography, the ratio of E velocity to early diastolic velocity, which reflects left ventricular (LV) filling pressure, was significantly correlated with the DIFF and SDARR, along with the log-transformed BNP level. Stepwise multiple linear regression analysis revealed that the DIFF and age were independent factors related with the BNP level (P < 0.01). CONCLUSIONS: The reduced diurnal variation of heart rate was significantly associated with increased BNP, which is linked to LV diastolic dysfunction in patients with AF.

DOI： 10.1002/clc.22128

Alogliptin ameliorates postprandial lipemia and postprandial endothelial dysfunction in non-diabetic subjects: a preliminary report. International journal

Yoko Noda, Toru Miyoshi, Hiroki Oe, Yuko Ohno, Kazufumi Nakamura, Norihisa Toh, Kunihisa Kohno, Hiroshi Morita, Kengo Kusano, Hiroshi Ito

Cardiovascular diabetology 12 8 - 8 2013.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Postprandial hyperlipidemia impairs endothelial function and participates in the development of atherosclerosis. We investigated the postprandial effects of a dipeptidyl peptidase IV inhibitor, alogliptin, on endothelial dysfunction and the lipid profile. METHODS: A randomized cross-over trial design in 10 healthy volunteers (8 males and 2 females, 35 ± 10 years) was performed. The postprandial effects before and after a 1-week treatment of 25 mg/day alogliptin on endothelial function were assessed with brachial artery flow-mediated dilation (FMD) and changing levels of lipids, apolipoprotein B48 (apoB-48), glucose, glucagon, insulin, and glucagon-like peptide-1 (GLP-1) during fasting and at 2, 4, 6, and 8 h after a standard meal loading test. RESULTS: Alogliptin treatment significantly suppressed the postprandial elevation in serum triglyceride (incremental area under the curve [AUC]; 279 ± 31 vs. 182 ± 32 mg h/dl, p = 0.01), apoB-48 (incremental AUC; 15.4 ± 1.7 vs. 11.7 ± 1.1 μg h/ml, p = 0.04), and remnant lipoprotein cholesterol (RLP-C) (incremental AUC: 29.3 ± 3.2 vs. 17.6 ± 3.3 mg h/dl, p = 0.01). GLP-1 secretion was significantly increased after alogliptin treatment. Postprandial endothelial dysfunction (maximum decrease in%FMD, from -4.2 ± 0.5% to -2.6 ± 0.4%, p = 0.03) was significantly associated with the maximum change in apoB-48 (r = -0.46, p = 0.03) and RLP-C (r = -0.45, p = 0.04). CONCLUSION: Alogliptin significantly improved postprandial endothelial dysfunction and postprandial lipemia, suggesting that alogliptin may be a promising anti-atherogenic agent.

DOI： 10.1186/1475-2840-12-8

Vasoprotective effect of incretins

Toru Miyoshi, Hiroshi Ito

Respiration and Circulation 61 ( 1 ) 34 - 38 2013.1

Safety and efficacy of a bolus injection of landiolol hydrochloride as a premedication for multidetector-row computed tomography coronary angiography.

Kazuhiro Osawa, Toru Miyoshi, Shuhei Sato, Noriaki Akagi, Yusuke Morimitsu, Kazufumi Nakamura, Kunihisa Kohno, Kengo Kusano, Susumu Kanazawa, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society 77 ( 1 ) 146 - 52 2013

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: We evaluated the safety and efficacy of a bolus injection of landiolol hydrochloride, an ultrashort-acting β1-selective antagonist, as an additional treatment after premedication with an oral β-blocker to reduce heart rate prior to multidetector-row computed tomography (MDCT) coronary angiography (CAG). METHODS AND RESULTS: A total of 458 patients who underwent MDCT CAG were retrospectively enrolled. Image quality and hemodynamic parameters were compared in patients before and after approval of landiolol hydrochloride. If heart rate reduction was insufficient after premedication with an oral β-blocker, a bolus injection of landiolol hydrochloride (n=66) or other drugs (n=30) was used. The percentage of evaluable images per segment in patients after approval of landiolol (99.3%) was greater than that in patients before approval of landiolol (97.4%, P<0.01). Heart rates before scanning in patients receiving landiolol hydrochloride were similar to those receiving other drugs. Heart rate was significantly reduced approximately 5 min after injection of landiolol hydrochloride and increased shortly. No decrease in systolic blood pressure or other adverse effects was observed. CONCLUSIONS: Bolus injection of landiolol hydrochloride sufficiently reduced heart rate without significantly reducing systolic blood pressure and produced a high percentage of evaluable images, suggesting that bolus injection of landiolol hydrochloride as an additional pretreatment is feasible in MDCT CAG.

Increased passive stiffness of cardiomyocytes in the transverse direction and residual actin and myosin cross-bridge formation in hypertrophied rat hearts induced by chronic β-adrenergic stimulation.

Wakako Sumita Yoshikawa, Kazufumi Nakamura, Daiji Miura, Juichiro Shimizu, Ken Hashimoto, Noriyuki Kataoka, Hiroko Toyota, Hiroshi Okuyama, Toru Miyoshi, Hiroshi Morita, Kengo Fukushima Kusano, Tatsuhito Matsuo, Miyako Takaki, Fumihiko Kajiya, Naoto Yagi, Tohru Ohe, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society 77 ( 3 ) 741 - 8 2013

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Left ventricular (LV) hypertrophy is often present in patients with diastolic heart failure. However, stiffness of hypertrophied cardiomyocytes in the transverse direction has not been fully elucidated. The aim of this study was to assess passive cardiomyocyte stiffness of hypertrophied hearts in the transverse direction and the influence of actin-myosin cross-bridge formation on the stiffness. METHODS AND RESULTS: Wistar rats received a vehicle (control) or isoproterenol (ISO) subcutaneously. After 7 days, compared with the controls, ISO administration had significantly increased heart weight and LV wall thickness and had decreased peak early annular relaxation velocity (e') assessed by echocardiography. Elastic modulus of living cardiomyocytes in the transverse direction assessed by an atomic force microscope was significantly higher in the ISO group than in controls. We added butanedione monoxime (BDM), an inhibitor of actin-myosin interaction, and blebbistatin, a specific myosin II inhibitor, to the medium. BDM and blebbistatin significantly reduced the elastic modulus of cardiomyocytes in the ISO group. X-ray diffraction analysis showed that the reflection intensity ratio (I((1,0))/I((1,1))) at diastole was not different before and after treatment with BDM, which induces complete relaxation, in control hearts, but that I((1,0))/I((1,1)) was significantly increased after BDM treatment in the ISO group, indicating residual cross-bridge formation in hypertrophied hearts. CONCLUSIONS: Passive cardiomyocyte stiffness in the transverse direction is increased in hearts with ISO-induced hypertrophy and this is caused by residual actin-myosin cross-bridge formation.

PDGF-BB Activates Inflammatory Signaling in Pulmonary Arterial Smooth Muscle Cells from Patients with Idiopathic Pulmonary Arterial Hypertension Reviewed

Kazufumi Nakamura, Satoshi Akagi, Hiromi Matsubara, Aiko Ogawa, Aya Miura, Daiji Miura, Toru Miyoshi, Satoshi Nagase, Hiroshi Morita, Kunihisa Kohno, Kengo F. Kusano, Hiroshi Ito

CIRCULATION 126 ( 21 ) 2012.11

Tumor growth inhibitory effect of ADAMTS1 is accompanied by the inhibition of tumor angiogenesis. International journal

Masanari Obika, Hiroko Ogawa, Katsuyuki Takahashi, Jiayi Li, Omer Faruk Hatipoglu, Mehmet Zeynel Cilek, Toru Miyoshi, Junko Inagaki, Takashi Ohtsuki, Shozo Kusachi, Yoshifumi Ninomiya, Satoshi Hirohata

Cancer science 103 ( 10 ) 1889 - 97 2012.10

Language：English Publishing type：Research paper (scientific journal)

Angiogenesis plays an important role in tumor progression. Several reports have demonstrated that a disintegrin and metalloproteinase with thrombospondin motifs1 (ADAMTS1) inhibited angiogenesis via multiple mechanisms. The aim of this study was to investigate the effect of ADAMTS1 on endothelial cells in vitro and on tumor growth with regard to angiogenesis in vivo. We examined the effects of the transfection of ADAMTS1 using two constructs, full-length ADAMTS1 (full ADAMTS1) and catalytic domain-deleted ADAMTS1 (delta ADAMTS1). Transfection of both the full ADAMTS1 and delta ADAMTS1 gene constructs demonstrated the secretion of tagged-ADAMTS1 protein into the conditioned medium, so we examined the effects of ADAMTS1-containing conditioned medium on endothelial cells. Both types of conditioned media inhibited endothelial tube formation, and this effect was completely abolished after immunoprecipitation of the secreted protein from the medium. Both types of conditioned media also inhibited endothelial cell migration and proliferation. We then examined the impact of ADAMTS1 on endothelial cell apoptosis. Both conditioned media increased the number of Annexin V-positive endothelial cells and caspase-3 activity and this effect was attenuated when z-vad was added. These results indicated that ADAMTS1 induced endothelial cell apoptosis. We next examined the effects of ADAMTS1 gene transfer into tumor-bearing mice. Both full ADAMTS1 and delta ADAMTS1 significantly inhibited the subcutaneous tumor growth. Collectively, our results demonstrated that ADAMTS1 gene transfer inhibited angiogenesis in vitro and in vivo, likely as a result of the induction of endothelial cell apoptosis by ADAMTS1 that occurs independent of the protease activity.

DOI： 10.1111/j.1349-7006.2012.02381.x

Brugada症候群におけるspontaneous type1波形を呈さないハイリスク群の検討

和田匡史, 森田宏, 三好亨, 西井伸洋, 橋本克史, 永瀬聡, 中村一文, 河野晋久, 草野研吾, 伊藤浩

心電図 32 ( Suppl.5 ) S - 156 2012.9

Elevated serum adipocyte fatty acid-binding protein concentrations are independently associated with renal dysfunction in patients with stable angina pectoris. International journal

Mutsumi Iwamoto, Toru Miyoshi, Masayuki Doi, Ko Takeda, Masahito Kajiya, Kazumasa Nosaka, Rie Nakayama, Satoshi Hirohata, Shinichi Usui, Shozo Kusachi, Kosuke Sakane, Kazuhfumi Nakamura, Hiroshi Ito

Cardiovascular diabetology 11 26 - 26 2012.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Chronic kidney disease (CKD) is associated with cardiovascular events. Adipocyte fatty acid-binding protein (A-FABP) plays an important role in atherosclerosis. We investigated whether plasma A-FABP is involved in renal function in patients with stable angina pectoris. METHODS: A total of 221 patients with significant coronary artery stenosis were enrolled after coronary angiography. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. The severity of coronary stenosis was assessed using a modified Gensini score and coronary angiography. Serum A-FABP levels were determined by enzyme-linked immunosorbent assay. RESULTS: Serum A-FABP levels were significantly correlated with both eGFR (r = -0.41, p < 0.01) and the severity of coronary artery stenosis (r = 0.16, p = 0.02), and these relationships remained significant after adjusting for confounding factors. The prevalence of CKD and multi-vessel disease was significantly higher among patients with serum A-FABP levels above the median value of 20.3 ng/ml than among patients with serum A-FABP levels below the median value (57% vs. 27%, p < 0.01 and 64% vs. 48%, p = 0.02, respectively). Multivariate analysis revealed that the presence of three-vessel disease in comparison with single-vessel disease was independently associated with the higher A-FABP (per doubling) (odds ratio; 2.26, 95% confidential interval; 1.28-3.98, p < 0.01) and tended to be associated with the lower eGFR (p = 0.06). CONCLUSION: Serum A-FABP may have a significant role in the interplay between renal dysfunction and coronary atherosclerosis.

DOI： 10.1186/1475-2840-11-26

Four-year clinical outcomes of the OLIVUS-Ex (impact of Olmesartan on progression of coronary atherosclerosis: evaluation by intravascular ultrasound) extension trial. International journal

Atsushi Hirohata, Keizo Yamamoto, Toru Miyoshi, Kunihiko Hatanaka, Satoshi Hirohata, Hitoshi Yamawaki, Issei Komatsubara, Eiki Hirose, Yuhei Kobayashi, Keisuke Ohkawa, Minako Ohara, Hiroya Takafuji, Fumihiko Sano, Yuko Toyama, Shozo Kusachi, Tohru Ohe, Hiroshi Ito

Atherosclerosis 220 ( 1 ) 134 - 8 2012.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The previous OLIVUS trial reported a positive role in achieving a lower rate of coronary atheroma progression through the administration of olmesartan, an angiotension-II receptor blocking agent (ARB), for stable angina pectoris (SAP) patients requiring percutaneous coronary intervention (PCI). However, the benefits between ARB administration on long-term clinical outcomes and serial atheroma changes by IVUS remain unclear. Thus, we examined the 4-year clinical outcomes from OLIVUS according to treatment strategy with olmesartan. METHODS: Serial volumetric IVUS examinations (baseline and 14 months) were performed in 247 patients with hypertension and SAP. When these patients underwent PCI for culprit lesions, IVUS was performed in their non-culprit vessels. Patients were randomly assigned to receive 20-40mg of olmesartan or control, and treated with a combination of β-blockers, calcium channel blockers, glycemic control agents and/or statins per physician's guidance. Four-year clinical outcomes and annual progression rate of atherosclerosis, assessed by serial IVUS, were compared with major adverse cardio- and cerebrovascular events (MACCE). RESULTS: Cumulative event-free survival was significantly higher in the olmesartan group than in the control group (p=0.04; log-rank test). By adjusting for validated prognosticators, olmesartan administration was identified as a good predictor of MACCE (p=0.041). On the other hand, patients with adverse events (n=31) had larger annual atheroma progression than the rest of the population (23.8% vs. 2.1%, p<0.001). CONCLUSIONS: Olmesartan therapy appears to confer improved long-term clinical outcomes. Atheroma volume changes, assessed by IVUS, seem to be a reliable surrogate for future major adverse cardio- and cerebrovascular events in this study cohort.

DOI： 10.1016/j.atherosclerosis.2011.10.013

Impact of chronic kidney disease on left main coronary artery disease and prognosis in Japanese patients.

Kazuhiro Dan, Toru Miyoshi, Masayuki Ueeda, Hiroaki Ohtsuka, Satoko Ugawa, Nobuhiko Ohnishi, Atsushi Takaishi, Kazufumi Nakamura, Kengo Kusano, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society 76 ( 9 ) 2266 - 72 2012

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Renal insufficiency plays a critical role in the pathogenesis of ischemic heart disease. The aim of the present study was to investigate the prevalence of renal dysfunction and its impact on prognosis in patients with left main coronary artery disease (LMCAD) and stable angina pectoris. METHODS AND RESULTS: A total of 626 consecutive patients with significant coronary artery stenosis were enrolled. Renal insufficiency was graded using estimated glomerular filtration rate (eGFR) before coronary angiography. Chronic kidney disease (CKD) was defined as eGFR <60 ml·min(-1)·1.73 m(-2) and/or proteinuria. Patients with LMCAD (n=95) had a significantly higher prevalence of CKD than those without LMCAD (P=0.02). Multiple logistic regression analysis showed that CKD was independently associated with LMCAD (adjusted odds ratio, 1.74; 95% confidence interval [CI]: 1.09-2.76, P=0.01). A 1-year follow-up of patients with LMCAD showed that the cumulative incidence of major adverse cardiovascular events among patients with eGFR <30 ml·min(-1)·1.73 m(-2) was higher than that among patients with eGFR ≥60 ml·min(-1)·1.73 m(-2) (P=0.03). The hazard ratio for a cardiovascular event was 9.54 (95% CI: 3.15-28.89, P<0.01) when comparing patients with LMCAD and eGFR <30 ml·min(-1)·1.73 m(-2) vs. patients without LMCAD and eGFR ≥60 ml·min(-1)·1.73 m(-2). CONCLUSIONS: Renal insufficiency is a risk factor for LMCAD and predicts poor prognosis in Japanese patients.

An adult patient with acute infection with hepatitis B virus genotype C that progressed to chronic infection.

Toru Miyoshi, Atsushi Hiraoka, Satoshi Hidaka, Yuko Shimizu, Keiko Ninomiya, Hiroki Utsunomiya, Nayu Tazuya, Tetsuya Tanihira, Aki Hasebe, Yasunao Miyamoto, Tomoyuki Ninomiya, Masanori Abe, Yoichi Hiasa, Morikazu Onji, Kojiro Michitaka

Internal medicine (Tokyo, Japan) 51 ( 2 ) 173 - 6 2012

Language：English Publishing type：Research paper (scientific journal)

In 2008, a 28-year-old woman consulted our hospital due to general fatigue. Her ALT level was within normal range but she was positive for hepatitis B surface antigen (HBsAg). Her ALT level was nearly within normal range thereafter and she was consistently positive for HBeAg. Later, it was proven that she was negative for HBsAg in 1999. She had been a sex worker in 2007-2008. Complete genome sequencing revealed that her HBV was genotype C. The present case may indicate that it is possible for acute infection with HBV genotype C to progress to chronic infection in adults.

Intermittent arm ischemia induces vasodilatation of the contralateral upper limb.

Kenki Enko, Kazufumi Nakamura, Kei Yunoki, Toru Miyoshi, Satoshi Akagi, Masashi Yoshida, Norihisa Toh, Mutsuko Sangawa, Nobuhiro Nishii, Satoshi Nagase, Kunihisa Kohno, Hiroshi Morita, Kengo F Kusano, Hiroshi Ito

The journal of physiological sciences : JPS 61 ( 6 ) 507 - 13 2011.11

Language：English Publishing type：Research paper (scientific journal)

Intermittent arm ischemia before percutaneous coronary intervention induces remote ischemic preconditioning (RIPC) and attenuates myocardial injury in patients with myocardial infarction. Several studies have shown that intermittent arm ischemia increases coronary flow and is related to autonomic nerve system. The aim of this study was to determine whether intermittent arm ischemia induces vasodilatation of other arteries and to assess changes in the autonomic nerve system during intermittent arm ischemia in humans. We measured change in the right brachial artery diameter during intermittent left arm ischemia through three cycles of 5-min inflation (200 mmHg) and 5-min deflation of a blood-pressure cuff using a 10-MHz linear array transducer probe in 20 healthy volunteers. We simultaneously performed power spectral analysis of heart rate. Ischemia-reperfusion of the left arm significantly dilated the right brachial artery time-dependently, resulting in a 3.2 ± 0.4% increase after the 3rd cycle. In the power spectral analysis of heart rate, the high-frequency domain (HF), which is a marker of parasympathetic activity, was significantly higher after the 3rd cycle of ischemia-reperfusion than baseline HF (P = 0.02). Intermittent arm ischemia was accompanied by vasodilatation of another artery and enhancement of parasympathetic activity. Those effects may play an important role in the mechanism of RIPC.

DOI： 10.1007/s12576-011-0172-9

Residual Diastolic Cross-Bridge and Decreased Expression of Energy Metabolism Genes in Hypertrophied Rat Hearts Induced by Chronic beta-Adrenergic Stimulation

Kazufumi Nakamura, Daiji Miura, Juichiro Shimizu, Toru Miyoshi, Hiroko Toyota, Hiroshi Okuyama, Wakako Yoshikawa, Satoshi Akagi, Kunihisa Kohno, Masahi Yoshida, Hiroshi Morita, Satoshi Hirohata, Kengo Kusano, Tatsuhito Matsuo, Naoto Yagi, Hirhoshi Ito

CIRCULATION 124 ( 21 ) 2011.11

ARB内服中高血圧患者に対するカルシウム拮抗薬もしくは利尿剤の追加がAugmentation indexへ与える影響

三好亨, 土井正行, 小川弘子, 廣畑聡, 草地省蔵, 小出典男, 伊藤浩

臨床病理 59 ( 補冊 ) 219 - 219 2011.10

Beta-Blockers and Oxidative Stress in Patients with Heart Failure. International journal

Kazufumi Nakamura, Masato Murakami, Daiji Miura, Kei Yunoki, Kenki Enko, Masamichi Tanaka, Yukihiro Saito, Nobuhiro Nishii, Toru Miyoshi, Masashi Yoshida, Hiroki Oe, Norihisa Toh, Satoshi Nagase, Kunihisa Kohno, Hiroshi Morita, Hiromi Matsubara, Kengo F Kusano, Tohru Ohe, Hiroshi Ito

Pharmaceuticals (Basel, Switzerland) 4 ( 8 ) 1088 - 100 2011.8

Language：English Publishing type：Research paper (scientific journal)

Oxidative stress has been implicated in the pathogenesis of heart failure. Reactive oxygen species (ROS) are produced in the failing myocardium, and ROS cause hypertrophy, apoptosis/cell death and intracellular Ca(2+) overload in cardiac myocytes. ROS also cause damage to lipid cell membranes in the process of lipid peroxidation. In this process, several aldehydes, including 4-hydroxy-2-nonenal (HNE), are generated and the amount of HNE is increased in the human failing myocardium. HNE exacerbates the formation of ROS, especially H₂O₂ and ·OH, in cardiomyocytes and subsequently ROS cause intracellular Ca(2+) overload. Treatment with beta-blockers such as metoprolol, carvedilol and bisoprolol reduces the levels of oxidative stress, together with amelioration of heart failure. This reduction could be caused by several possible mechanisms. First, the beta-blocking effect is important, because catecholamines such as isoproterenol and norepinephrine induce oxidative stress in the myocardium. Second, anti-ischemic effects and negative chronotropic effects are also important. Furthermore, direct antioxidative effects of carvedilol contribute to the reduction of oxidative stress. Carvedilol inhibited HNE-induced intracellular Ca(2+) overload. Beta-blocker therapy is a useful antioxidative therapy in patients with heart failure.

DOI： 10.3390/ph4081088

Impact of hypertriglyceridemia on endothelial dysfunction during statin ± ezetimibe therapy in patients with coronary heart disease. International journal

Kei Yunoki, Kazufumi Nakamura, Toru Miyoshi, Kenki Enko, Motoki Kubo, Masato Murakami, Yoshiki Hata, Kunihisa Kohno, Hiroshi Morita, Kengo F Kusano, Hiroshi Ito

The American journal of cardiology 108 ( 3 ) 333 - 9 2011.8

Language：English Publishing type：Research paper (scientific journal)

Despite the use of statin therapy and achieving the target for low-density lipoprotein cholesterol, a substantial number of coronary events are not prevented, and residual risk factors remain unsettled. Recently, ezetimibe has been shown to reduce not only low-density lipoprotein cholesterol but also triglyceride (TG) levels. The aim of this study was to investigate the associations of residual risk factors, mainly hypertriglyceridemia, with endothelial function during statin therapy in patients with coronary heart disease and examine the effect of ezetimibe add-on therapy. A total of 109 consecutive patients with coronary heart disease during statin therapy were enrolled. Lipid profile was measured and endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery in a fasting state. Next, 32 patients with high TG levels (≥150 mg/dl) were prospectively assigned to the ezetimibe add-on group or the no-ezetimibe group, and endothelial function was assessed after 3 months. Multivariate linear regression analysis demonstrated that serum TG and high-density lipoprotein cholesterol levels were independent determinants of percentage FMD (β = -0.210 and 0.208, respectively, p <0.05). In patients with high TG levels, ezetimibe add-on therapy significantly improved percentage FMD (from 3.3 ± 1.1% to 4.0 ± 1.1%, p <0.005), whereas no significant change was observed in the no-ezetimibe group. Moreover, the improvement in percentage FMD was significantly associated with reduction in serum TG levels (β = -0.387, p <0.05) independent of the change in serum low-density lipoprotein cholesterol levels. In conclusion, hypertriglyceridemia is independently associated with endothelial dysfunction in patients with coronary heart disease during statin therapy. Ezetimibe add-on therapy improves endothelial function in these high-risk populations.

DOI： 10.1016/j.amjcard.2011.03.049

Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction. International journal

Kei Yunoki, Kazufumi Nakamura, Toru Miyoshi, Kenki Enko, Kunihisa Kohno, Hiroshi Morita, Kengo F Kusano, Hiroshi Ito

Atherosclerosis 217 ( 2 ) 486 - 91 2011.8

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Postprandial hyperlipemia has been shown to impair endothelial function and contribute to the development of atherosclerosis. We investigated the association between postprandial lipid profiles and endothelial function, and we examined the effects of ezetimibe on postprandial hyperlipemia and lipemia-induced endothelial dysfunction. METHODS: A randomized prospective trial in which 10 mg/day of ezetimibe was administered to 10 subjects for 4 weeks and not administered to 10 subjects (control group) was performed. Lipid profiles and endothelial function, assessed by brachial artery flow-mediated dilation (FMD) during a fasting state and at 2, 4, 6 and 8 h after an oral cookie loading test, were determined before and after treatment for 4 weeks. RESULTS: In all subjects before treatment, the maximum reduction in postprandial %FMD was significantly correlated with the maximum increases in postprandial triglyceride (TG) (r=-0.499, P<0.05) and apolipoprotein B-48 (apoB-48) concentrations (r=-0.551, P<0.05). Ezetimibe treatment for 4 weeks significantly suppressed postprandial elevation in TG (area under the incremental curve, from 1419±594 to 968±32 1 mg h/dl, P<0.05), remnant lipoprotein cholesterol (from 66.9±27.6 to 38.9±15.4 mg h/dl, P<0.01) and apoB-48 (from 58.8±27.5 to 36.2±17.0 μg h/ml, P<0.05) concentrations, and postprandial endothelial dysfunction assessed by %FMD (maximum reduction in %FMD, from -2.6±1.1% to -1.2±0.8%, P<0.05), whereas no significant changes were observed in the control group. CONCLUSION: Postprandial hyperlipemia is closely correlated with transient endothelial dysfunction. Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction.

DOI： 10.1016/j.atherosclerosis.2011.04.019

Olmesartan reduces arterial stiffness and serum adipocyte fatty acid-binding protein in hypertensive patients.

Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Shigeshi Kamikawa, Shinichi Usui, Hiroko Ogawa, Kosuke Sakane, Reishi Izumi, Yoshifumi Ninomiya, Shozo Kusachi

Heart and vessels 26 ( 4 ) 408 - 13 2011.7

Language：English Publishing type：Research paper (scientific journal)

Adipocyte fatty acid binding protein (A-FABP) has been reported to be involved in insulin resistance, lipid metabolism, and atherosclerosis; however, little is known about the effect of medication on the change in circulating A-FABP in human subjects. We evaluated the effects of angiotensin II type 1 receptor blocker (ARB) on arterial stiffness and its association with serum A-FABP in patients with hypertension. Thirty patients newly diagnosed with essential hypertension were treated with olmesartan (20 mg/day), an ARB, for 6 months. Serum levels of A-FABP and high-sensitivity C-reactive protein (hsCRP) were examined and the cardio-ankle vascular index (CAVI), which is a marker of arterial stiffness, was also determined. Serum A-FABP at baseline was significantly correlated with the body mass index (r = 0.45, P = 0.01), homeostasis model assessment as a marker of insulin resistance (r = 0.53, P < 0.01), and systolic blood pressure (r = 0.37, P = 0.047), and tended to be correlated with low-density lipoprotein cholesterol, triglyceride, and CAVI. Olmesartan treatment resulted in a significant decrease in CAVI, serum A-FABP levels, and hsCRP, besides a significant reduction of blood pressure. Multiple regression analysis revealed that the change in CAVI was independently correlated with the change in serum A-FABP. Olmesartan ameliorated arterial stiffness in patients with hypertension, which may be involved in the reduction of serum A-FABP.

DOI： 10.1007/s00380-010-0060-x

Association of increased plasma adipocyte fatty acid-binding protein with coronary artery disease in non-elderly men. International journal

Masayuki Doi, Toru Miyoshi, Satoshi Hirohata, Kazufumi Nakamura, Shinichi Usui, Ko Takeda, Mutsumi Iwamoto, Shozo Kusachi, Kengo Kusano, Hiroshi Ito

Cardiovascular diabetology 10 44 - 44 2011.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Adipocyte fatty acid-binding protein (A-FABP) has been reported to play critical roles in the development of atherosclerosis. We investigated whether an increased in plasma A-FABP level can be independently associated with the presence of coronary artery disease (CAD). METHODS: Two hundred eleven consecutive male patients (mean age: 66 years, range: 33-87 years) were enrolled from inpatients who underwent coronary angiography. Age-matched male subjects (n = 211) having no evidence of CAD served as controls. Plasma A-FABP levels were measured by enzyme-linked immunosorbent assays. RESULTS: Plasma A-FABP levels in CAD patients were significantly higher than in control subjects (median [IQR], 20.6 [15.7-27.8] ng/mL vs. 15.1 [11.7-19.9] ng/mL, p < 0.01). Multivariate logistic regression analysis revealed that an increased plasma A-FABP level was independently associated with the presence of CAD in all subjects (adjusted odds ratio: 1.76, 95% confidence interval: 1.14 to 2.70, p = 0.01). Furthermore, sub-analysis based on age showed that this association remained significant in subjects aged < 65 years (adjusted odds ratio: 3.06, 95% confidence interval: 1.34 to 6.98, p < 0.01), but not in subjects aged ≥65 years. CONCLUSIONS: Increased plasma A-FABP in non-elderly men had a significant association with the presence of CAD, independent of established CAD risk factors.

DOI： 10.1186/1475-2840-10-44

ANTI-INFLAMMATORY EFFECT OF OLMESARTAN ON CORONARY PLAQUE PROGRESSION, FINDING FROM THE IMPACT OF OLMESARTAN ON PROGRESSION OF CORONARY ATHEROSCLEROSIS: EVALUATION BY INTRAVASCULAR ULTRASOUND (OLIVUS) TRIAL

Toru Miyoshi, Atsushi Hirohata, Shozo Kusachi, Satoshi Hirohata, Kazufumi Nakamura, Hiroshi Morita, Kengo Kusano, Hiroshi Ito

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 57 ( 14 ) E604 - E604 2011.4

IMPACT OF INCREASED ARTERIAL STIFFNESS AND WAVE REFLECTION ON THE PREVALENCE OF PAROXYSMAL ATRIAL FIBRILLATION

Toru Miyoshi, Msayuki Doi, Satoshi Hirohata, Shozo Kusachi, Kazufumi Nakamura, Satoshi Nagase, Kunihisa Kono, Hiroshi Morita, Kengo Kusano, Hiroshi Ito

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 57 ( 14 ) E563 - E563 2011.4

Association of serum levels of arachidonic acid and eicosapentaenoic acid with prevalence of major adverse cardiac events after acute myocardial infarction.

Masayuki Ueeda, Takenori Doumei, Yoichi Takaya, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Toru Miyoshi, Ryoko Shinohata, Shinichi Usui, Shozo Kusachi

Heart and vessels 26 ( 2 ) 145 - 52 2011.3

Language：English Publishing type：Research paper (scientific journal)

We studied the association of serum levels of arachidonic acid (AA) and eicosapentaenoic acid (EPA) with the prevalence of major adverse cardiac events (MACE) after acute myocardial infarction (AMI). We measured serum AA and EPA on admission in 146 consecutive AMI patients. The primary clinical endpoint was occurrence of MACE, defined as cardiac death, occurrence of heart failure, reinfarction, recurrent angina pectoris, and requirement of coronary intervention. Common logarithmic transformed serum levels of AA (logAA) and EPA (logEPA) were used in the analyses. The optimum cutoff point of each fatty acid used to distribute patients into two groups for Kaplan-Meier analysis was determined by receiver operating characteristic curves analysis. MACE occurred in 40 patients (27.4%). Kaplan-Meier analysis disclosed that the group with a logAA above the cutoff point [145.3 μg/mL (logAA 2.162)] showed a higher prevalence of MACE than those with a logAA below the cutoff point (P < 0.01). Conversely, the prevalence of MACE was significantly higher in the group with a logEPA below the cutoff point [52.3 μg/mL (logEPA 1.719)] compared to the group with a logEPA above it (P < 0.01). Similar to logAA, logAA/logEPA showed significant differences in the MACE-free curve between the two groups (cutoff 1.301, P < 0.001). Cox proportional hazards regression analysis suggested that logAA, logEPA, and logAA/logEPA were independently associated with the prevalence of MACE. Although the present study included a limited number of patients with single-time point measurement, the results suggested an association of logAA, logEPA, and logAA/logEPA with the prevalence of MACE after AMI. The present study warrants further studies involving a large number of patients to confirm that the serum levels of these fatty acids and their ratios are predictors of MACE after AMI.

DOI： 10.1007/s00380-010-0038-8

AHR, a novel acute hypoxia-response sequence, drives reporter gene expression under hypoxia in vitro and in vivo. International journal

Mehmet Zeynel Cilek, Satoshi Hirohata, Omer Faruk Hatipoglu, Hiroko Ogawa, Toru Miyoshi, Junko Inagaki, Takashi Ohtsuki, Hiroshi Harada, Shigeshi Kamikawa, Shozo Kusachi, Yoshifumi Ninomiya

Cell biology international 35 ( 1 ) 1 - 8 2011.1

Language：English Publishing type：Research paper (scientific journal)

ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is an early immediate gene. We have previously reported that ADAMTS1 was strongly induced by hypoxia. In this study, we investigated whether ADAMTS1 promoter-driven reporter signal is detectable by acute hypoxia. We constructed the GFP (green fluorescent protein) expression vector [AHR (acute hypoxia-response sequence)-GFP] under the control of ADAMTS1 promoter and compared it with the constitutive GFP-expressing vector under the control of CMV (cytomegalovirus promoter-GFP). We transduced AHR-GFP and examined whether GFP signals can be detected under the acute hypoxia. When the human umbilical vein [HUVEC (human umbilical vein endothelial cells)] was transduced under normoxia, there were few GFP signals, while CMV-GFP showed considerable GFP signals. When HUVEC was stimulated with hypoxia, GFP signals from AHR-GFP gene were induced under hypoxic conditions. Notably, the GFP signals peaked at 3 h under hypoxia. In ischaemic hind limb model, transduced AHR-GFP showed hypoxic induction of GFP signals. In summary, we have demonstrated that the AHR system induced the reporter gene expression by acute hypoxia, and its induction is transient. This is the first report showing the unique acute hypoxia-activated gene expression system.

DOI： 10.1042/CBI20100290

Circulating KCNH2 current-activating factor in patients with heart failure and ventricular tachyarrhythmia. International journal

Hiroki Sugiyama, Kazufumi Nakamura, Hiroshi Morita, Satoshi Akagi, Yoshinori Tani, Yusuke Katayama, Nobuhiro Nishii, Toru Miyoshi, Satoshi Nagase, Kunihisa Kohno, Kengo Fukushima Kusano, Tohru Ohe, Junko Kurokawa, Tetsushi Furukawa, Hiroshi Ito

PloS one 6 ( 5 ) e19897 2011

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: It is estimated that approximately half of the deaths in patients with HF are sudden and that the most likely causes of sudden death are lethal ventricular tachyarrhythmias such as ventricular tachycardia (VT) or fibrillation (VF). However, the precise mechanism of ventricular tachyarrhythmias remains unknown. The KCNH2 channel conducting the delayed rectifier K(+) current (I(Kr)) is recognized as the most susceptible channel in acquired long QT syndrome. Recent findings have revealed that not only suppression but also enhancement of I(Kr) increase vulnerability to major arrhythmic events, as seen in short QT syndrome. Therefore, we investigated the existence of a circulating KCNH2 current-modifying factor in patients with HF. METHODOLOGY/PRINCIPAL FINDINGS: We examined the effects of serum of HF patients on recombinant I(Kr) recorded from HEK 293 cells stably expressing KCNH2 by using the whole-cell patch-clamp technique. Study subjects were 14 patients with non-ischemic HF and 6 normal controls. Seven patients had a history of documented ventricular tachyarrhythmias (VT: 7 and VF: 1). Overnight treatment with 2% serum obtained from HF patients with ventricular arrhythmia resulted in a significant enhancement in the peaks of I(Kr) tail currents compared to the serum from normal controls and HF patients without ventricular arrhythmia. CONCLUSIONS/SIGNIFICANCE: Here we provide the first evidence for the presence of a circulating KCNH2 channel activator in patients with HF and ventricular tachyarrhythmias. This factor may be responsible for arhythmogenesis in patients with HF.

DOI： 10.1371/journal.pone.0019897

Identification of Soat1 as a quantitative trait locus gene on mouse chromosome 1 contributing to hyperlipidemia. International journal

Zongji Lu, Zuobiao Yuan, Toru Miyoshi, Qian Wang, Zhiguang Su, Catherine C Chang, Weibin Shi

PloS one 6 ( 10 ) e25344 2011

Language：English Publishing type：Research paper (scientific journal)

We previously identified two closely linked quantitative trait loci (QTL) on distal chromosome 1 contributing to major variations in plasma cholesterol and triglyceride levels in an intercross derived from C57BL/6 (B6) and C3H/HeJ (C3H) apolipoprotein E-deficient (apoE(-/-)) mice. Soat1, encoding sterol o-acyltransferase 1, is a functional candidate gene located underneath the proximal linkage peak. We sequenced the coding region of Soat1 and identified four single nucleotide polymorphisms (SNPs) between B6 and C3H mice. Two of the SNPs resulted in amino-acid substitutions (Ile147Val and His205Tyr). Functional assay revealed an increased enzyme activity of Soat1 in peritoneal macrophages of C3H mice relative to those of B6 mice despite comparable protein expression levels. Allelic variants of Soat1 were associated with variations in plasma cholesterol and triglyceride levels in an intercross between B6.apoE(-/-) and C3H.apoE(-/-) mice. Inheritance of the C3H allele resulted in significantly higher plasma lipid levels than inheritance of the B6 allele. Soat1 variants were also significantly linked to major variations in plasma esterified cholesterol levels but not with free cholesterol levels. Trangenic expression of C3H Soat1 in B6.apoE(-/-) mice resulted in elevations of plasma cholesterol and triglyceride levels. These results indicate that Soat1 is a QTL gene contributing to hyperlipidemia.

DOI： 10.1371/journal.pone.0025344

Fragmented QRS is associated with torsades de pointes in patients with acquired long QT syndrome. International journal

Kayo Haraoka, Hiroshi Morita, Yukihiro Saito, Norihisa Toh, Toru Miyoshi, Nobuhiro Nishii, Satoshi Nagase, Kazufumi Nakamura, Kunihisa Kohno, Kengo F Kusano, Kenji Kawaguchi, Tohru Ohe, Hiroshi Ito

Heart rhythm 7 ( 12 ) 1808 - 14 2010.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Acquired long QT syndrome (LQTS) is a disease due to a secondary repolarization abnormality induced by various predisposing factors. In contrast to congenital LQTS, risk factors that produce acquired LQTS include organic heart diseases that often exhibit depolarization abnormality. Although various repolarization parameters have been evaluated in acquired LQTS, the existence of depolarization abnormality in association with torsades de pointes (TdP) has not been reported. OBJECTIVE: The purpose of this study was to evaluate both repolarization (QT components) and depolarization parameters (fragmented QRS [fQRS]) in acquired LQTS patients with markedly prolonged QT interval. METHODS: Seventy patients with acquired severe QT prolongation (QTc ≥ 550 ms) were studied. Thirty-two patients had syncope or TdP (syncope group). Thirty-eight patients did not have any symptoms (asymptomatic group). The existence of fQRS and QT components (QT, QTc, Tpe [interval between peak and end of T wave] intervals, and U-wave voltage) was analyzed. RESULTS: The syncope group had more frequent fQRS (81%) than did the asymptomatic group (21%, P < .01) and the incidence of fQRS was not different before and after removal of predisposing factors. The incidence of organic heart disease was not different between the two groups. No differences in QTc interval were noted between the syncope and asymptomatic groups, although the syncope group had longer QT and Tpe intervals and higher U wave than the asymptomatic group (P < .01). CONCLUSION: Acquired predisposing factors promoted repolarization abnormality (especially prolongation of QT and Tpe intervals), and the existence of fQRS had an important role in the development of TdP in patients with acquired LQTS.

DOI： 10.1016/j.hrthm.2010.09.008

Connective tissue growth factor induction in a pressure-overloaded heart ameliorated by the angiotensin II type 1 receptor blocker olmesartan. International journal

Mutsumi Iwamoto, Satoshi Hirohata, Hiroko Ogawa, Takashi Ohtsuki, Ryoko Shinohata, Toru Miyoshi, Faruk O Hatipoglu, Shozo Kusachi, Kazuhide Yamamoto, Yoshifumi Ninomiya

Hypertension research : official journal of the Japanese Society of Hypertension 33 ( 12 ) 1305 - 11 2010.12

Language：English Publishing type：Research paper (scientific journal)

Connective tissue growth factor (CTGF) is a secreted protein that regulates fibrosis. We hypothesized that CTGF is induced in a pressure-overloaded (PO) heart and that blocking the angiotensin II type 1 receptor would reduce CTGF expression. Accordingly, we administered olmesartan and compared its effects with other antihypertensive drugs in a PO heart. CTGF induction was determined in a rat PO model, and olmesartan, hydralazine or saline was continuously administered. The effects of olmesartan on CTGF induction, myocyte hypertrophy and fibrosis were evaluated. The effect of olmesartan on cardiac function was also examined in CTGF- and transforming growth factor-beta 1 (TGF-β1)-infused rats. CTGF was increased in the PO heart 3 days after aortic banding and was markedly distributed around the perivascular fibrotic area. After 28 days, blood pressure was not significantly different in the olmesartan and hydralazine groups, but olmesartan treatment reduced CTGF distribution in PO hearts. Olmesartan was associated with a significantly reduced myocyte hypertrophy index (4.77±0.48 for olmesartan and 6.05±1.45 for saline, P<0.01), fibrosis area (32.0±15.5% compared with the saline group, P<0.05) and serum TGF-β1 level (62.6±10.6 ng ml⁻¹ for olmesartan and 84.4±7.2 ng ml⁻¹ for hydralazine, P<0.05). In addition, cardiac function was significantly preserved in the olmesartan group compared with the saline group. Finally, olmesartan ameliorated the cardiac dysfunction in CTGF- and TGF-β1-infused rats. Olmesartan attenuated CTGF induction, reduced perivascular fibrosis and ameliorated cardiac dysfunction in a PO heart. Our results provide insight into the beneficial effects of olmesartan on PO hearts, independent of blood-pressure lowering.

DOI： 10.1038/hr.2010.189

Significant relationship between changes in brachial-ankle pulse wave velocity relative to blood pressure elevation and coronary artery disease. International journal

Issei Komatsubara, Shinichi Inoue, Rie Koumoto, Shigeru Matano, Tomoki Kitawaki, Satoshi Hirohata, Toru Miyoshi, Hiroko Ogawa, Ryoko Shinohata, Shozo Kusachi

Coronary artery disease 21 ( 7 ) 407 - 13 2010.11

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Based on well-established physiological theories, we studied correlations between changes in brachial-ankle pulse wave velocity (baPWV) relative to blood pressure (BP) elevation (elasticity of large-to-medium-sized arteries), and coronary artery disease (CAD). METHODS: The baPWV (in centimeters/second) and BP (in millimeters of mercury) were determined in 101 patients before, during, and/or after a cold pressor test using a volume-plethysmographic system. RESULTS: Significantly higher rates of increase in PWV relative to changes in BP were observed in the CAD(+) group than in the CAD(-) group when mean BP [median (25th-75th percentiles): 14.8 (8.3-24.9) vs. 8.6 (5.7-11.4) cm/s/mmHg, P<0.0001], and systolic [10.1 (6.0-17.5) vs. 6.4 (4.4-10.6) cm/s/mmHg, P=0.0023] and diastolic BP [21.0 (14.0-34.4) vs. 10.8 (6.8-16.1) cm/s/mmHg, P<0.0001] were used as BP indices. Similarly, the rates of increase in baPWV showed a significant correlation with the extent of CAD. The rate of increase in baPWV obtained using the mean, systolic and diastolic BP as indices showed an area under the receiver operating characteristic curve of 0.68-0.76, sensitivity of 65-75%, and specificity of 65-75% for the detection of CAD. The area under the receiver operating characteristic curve, sensitivity, and specificity for the rate of increase were slightly higher than those for baseline baPWV and baseline baPWV/baseline BP ratio, but not to a significant degree. CONCLUSION: The rate of increase in baPWV relative to BP elevation determined by cold pressor test is significantly and moderately correlated with CAD. To identify patients with CAD, the rate of increase in baPWV relative to changes in BP can provide considerable, but limited, information.

DOI： 10.1097/MCA.0b013e32833e1c19

Serum Adipocyte Fatty Acid-Binding Protein is Associated With Coronary Lesion Complexity in Patients With Coronary Artery Disease

Masayuki Doi, Toru Miyoshi, Mutsumi Iwamoto, Kunio Nogami, Kajiya Masashi, Ko Takeda, Satoshi Hirohata, Shozo Kusachi, Hiroshi Ito

CIRCULATION 122 ( 21 ) 2010.11

Remote ischemic preconditioning(RIPC)により血管弛緩反応が惹起される

圓光賢希, 中村一文, 柚木佳, 杜徳尚, 三好亨, 西井伸洋, 永瀬聡, 河野晋久, 森田宏, 草野研吾, 伊藤浩, 寒川睦子

日本心臓病学会誌 5 ( Suppl.I ) 257 - 257 2010.8

Serum adipocyte fatty acid-binding protein is independently associated with coronary atherosclerotic burden measured by intravascular ultrasound. International journal

Toru Miyoshi, Go Onoue, Atsushi Hirohata, Satoshi Hirohata, Shinichi Usui, Kazuyoshi Hina, Hiroshi Kawamura, Masayuki Doi, Kengo Fukushima Kusano, Shozo Kusachi, Yoshifumi Ninomiya

Atherosclerosis 211 ( 1 ) 164 - 9 2010.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Adipocyte fatty acid-binding protein (A-FABP) has been shown to have an effect on insulin resistance, lipid metabolism, and atherosclerosis in animals. We therefore investigated the association between the serum A-FABP level and coronary atherosclerosis. METHODS: One hundred twenty-five consecutive patients with coronary artery disease (CAD) were enrolled after coronary angiography. Plaque volume in non-culprit coronary arteries was determined using intravascular ultrasound and expressed as percent plaque volume (%PV). Voluntary blood donors (n=120), matched for age and gender, served as controls. Serum levels of A-FABP, adiponectin, and inflammatory markers were measured by enzyme-linked immunosorbent assay. RESULTS: The serum A-FABP level in CAD patients was significantly higher than in control subjects (median [25th-75th percentiles], 27.2 [20.5-37.1] ng/mL vs. 18.9 [14.6-24.5] ng/mL) (p<0.01). Serum A-FABP showed 0.74 of the area under the curve in the receiver operating characteristic curve for the detection of CAD, with 76% specificity and 65% sensitivity with a cut-off value of 20.1 ng/mL. Further, in CAD patients, serum A-FABP had a significant correlation with %PV in all subjects (r=0.33, p<0.01). Serum A-FABP was positively correlated with the body mass index, serum interleukin-6 and high-sensitive CRP, and negatively correlated with HDL-cholesterol and serum adiponectin in CAD patients. Stepwise regression analysis revealed that serum A-FABP was independently associated with %PV. CONCLUSION: Increased serum A-FABP was significantly associated with a greater coronary plaque burden. Our findings revealed that the measurement of serum A-FABP could be utilized for the evaluation of the extent of coronary atherosclerosis.

DOI： 10.1016/j.atherosclerosis.2010.01.032

Combination therapy of calcium channel blocker and angiotensin II receptor blocker reduces augmentation index in hypertensive patients. International journal

Masayuki Doi, Toru Miyoshi, Satoshi Hirohata, Shigeshi Kamikawa, Shinichi Usui, Youko Kaji, Kosuke Sakane, Hiroko Ogawa, Yoshifumi Ninomiya, Shozo Kusachi

The American journal of the medical sciences 339 ( 5 ) 433 - 9 2010.5

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: The optimal combination treatment for hypertension has not been established. We investigated the effect of a calcium channel blocker or a diuretic added to angiotensin II receptor blockers (ARBs) on the augmentation index (AI), as a marker of arterial stiffness and wave reflection, in hypertensive patients. METHODS: Thirty-seven patients treated with ARBs were randomly allocated to either of the 2 groups receiving an ARB plus azelnidipine (AZ group) or trichlormethiazide (TCM group). Changes in brachial blood pressure (BP), AI, high-sensitive C-reactive protein (hsCRP), and serum asymmetric dimethylarginine, as an endogenous nitric oxide synthase inhibitor, were determined. RESULTS: Systolic and diastolic blood pressure after 6 months were significantly reduced in both the groups similarly; however, after adjustment for baseline covariates, the extent of the reduction in AI (%) in the AZ group was significantly greater than in the TCM group (between-group difference was 3.2; 95%CI: 0.2-6.3; P = 0.03). The reduction of high-sensitive C-reactive protein (mg/L) and serum asymmetric dimethylarginine (micromol/L) was significantly greater in the AZ group than in the TCM group (between-group difference was 0.18 and 0.05; 95%CI: -0.01 to 0.36 and -0.01 to 0.11; P = 0.04 and 0.02, respectively). Further, when patients were analyzed according to age younger than 60 years or older than 60 years, the reduction in AI in the AZ group aged older than 60 years was significantly greater than in the TCM group. CONCLUSION: The results suggest that azelnidipine has a more beneficial effect on vascular properties in combination therapy with ARB than trichlormethiazide.

DOI： 10.1097/MAJ.0b013e3181d658c4

Type IV collagen induces expression of thrombospondin-1 that is mediated by integrin alpha1beta1 in astrocytes. International journal

Tomoko Yonezawa, Shunji Hattori, Junko Inagaki, Masae Kurosaki, Tomoyuki Takigawa, Satoshi Hirohata, Toru Miyoshi, Yoshifumi Ninomiya

Glia 58 ( 7 ) 755 - 67 2010.5

Language：English Publishing type：Research paper (scientific journal)

Following brain injury, thrombospondin-1 (TSP-1) is involved in angiogenesis and synaptic recovery. In this study, we used a cold injury-model and found that TSP-1 mRNA was markedly upregulated after brain injury. Immunohistochemistry showed that TSP-1 was upregulated in both the core of the lesion and in the perilesional area of injured brain tissue. Numerous astrocytes immunopositive for glial fibrillary acidic protein (GFAP) were found in the perilesional area, and TSP-1 was also expressed in almost all astrocytes surrounding blood vessels at 4 days after injury. Next, we examined the influence of vascular basement membrane components on TSP-1 expression. When astrocytes were cultured on type IV collagen, TSP-1 was significantly upregulated compared with the expression when cells were grown on laminin, fibronectin, or poly-L-lysine. This increase occurred exclusively when astrocytes were grown on the native form of type IV collagen but not on the heat-denatured form or the non-collagenous 1 domain. Further, integrin alpha1 and beta1 mRNAs were upregulated concomitantly with GFAP mRNA, and integrin alpha1 protein was localized to the endfeet of astrocytes that surrounded blood vessels in the injured brain. Using function-blocking antibodies, we found that the effect of type IV collagen was attributed to integrin alpha1beta1 in primary astrocytes. Collectively, our results suggest that vascular basement membrane components substantially impact gene expression in astrocytes during brain tissue repair.

DOI： 10.1002/glia.20959

Cardio-ankle vascular index is independently associated with the severity of coronary atherosclerosis and left ventricular function in patients with ischemic heart disease.

Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Kosuke Sakane, Shigeshi Kamikawa, Tomoki Kitawaki, Youko Kaji, Kengo Fukushima Kusano, Yoshifumi Ninomiya, Shozo Kusachi

Journal of atherosclerosis and thrombosis 17 ( 3 ) 249 - 58 2010.3

Language：English Publishing type：Research paper (scientific journal)

AIM: The cardio-ankle vascular index (CAVI) has been proposed as a new noninvasive marker of arterial stiffness independent of blood pressure. We investigated the association of the CAVI with coronary atherosclerosis and left ventricular (LV) systolic and diastolic function in patients with ischemic heart disease (IHD). METHODS: A total of 206 consecutive subjects undergoing coronary angiography were enrolled. CAVI measurement and echocardiography were performed simultaneously. Patients having significant coronary stenosis were classified into the IHD group. RESULTS: CAVI in the IHD group (n=133) was significantly higher than in the non-IHD group(n=73)(9.1+/-1.3 vs. 8.7+/-1.2, p=0.02). In all IHD patients, CAVI was negatively correlated with LV ejection fraction (LVEF)(r=-0.31, p<0.01), LV mass index (r=0.24, p<0.01) and angiographic scores of coronary atherosclerosis. Stepwise regression analysis revealed that CAVI was independently associated with LVEF, along with a history of myocardial infarction, LV mass index, and left atrial diameter in all IHD patients (p<0.01). In the sub-analysis of IHD patients with preserved LVEF, CAVI was correlated with echocardiographic parameters regarding LV diastolic function. Multivariate analysis demonstrated that the increased CAVI was significantly associated with LV diastolic dysfunction in patients with preserved LVEF. CONCLUSION: CAVI, a new parameter of aortic stiffness, was independently associated with LV systolic and diastolic function as well as coronary artery disease in IHD patients.

Impact of olmesartan on progression of coronary atherosclerosis a serial volumetric intravascular ultrasound analysis from the OLIVUS (impact of OLmesarten on progression of coronary atherosclerosis: evaluation by intravascular ultrasound) trial. International journal

Atsushi Hirohata, Keizo Yamamoto, Toru Miyoshi, Kunihiko Hatanaka, Satoshi Hirohata, Hitoshi Yamawaki, Issei Komatsubara, Masaaki Murakami, Eiki Hirose, Shinji Sato, Keisuke Ohkawa, Makoto Ishizawa, Hirosuke Yamaji, Hiroshi Kawamura, Shozo Kusachi, Takashi Murakami, Kazuyoshi Hina, Tohru Ohe

Journal of the American College of Cardiology 55 ( 10 ) 976 - 82 2010.3

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: The aim of this study was to evaluate the impact of olmesartan on progression of coronary atherosclerosis. BACKGROUND: Prior intravascular ultrasound (IVUS) trial results suggest slowing of coronary atheroma progression with some medicines but have not shown convincing evidence of regression with angiotension-II receptor blocking agents. METHODS: A prospective, randomized, multicenter trial-OLIVUS (Impact of OLmesartan on progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound)-was performed in 247 stable angina pectoris patients with native coronary artery disease. When these patients underwent percutaneous coronary intervention for culprit lesions, IVUS was performed in their nonculprit vessels (without angiographically documented coronary stenosis [<50%]). Patients were randomly assigned to receive 10 to 40 mg of olmesartan or control and treated with a combination of beta-blockers, calcium channel blockers, diuretics, nitrates, glycemic control agents, and/or statins per physician's guidance. Serial IVUS examinations (baseline and 14-month follow-up) were performed to assess coronary atheroma volume. Volumetric IVUS analyses included lumen, plaque, vessel volume, percent atheroma volume (PAV), percent change in total atheroma volume (TAV) and PAV. RESULTS: Patient characteristics and blood pressure control were identical between the 2 groups. However, follow-up IVUS showed significantly decreased TAV and percent change in PAV in the olmesartan group (5.4% vs. 0.6 % for TAV and 3.1% vs. -0.7% for percent change in PAV, control vs. olmesartan, p < 0.05 for all). CONCLUSIONS: These observations suggest a positive role in a potentially lower rate of coronary atheroma progression through the administration of olmesartan, an angiotension-II receptor blocking agent, for patients with stable angina pectoris.

DOI： 10.1016/j.jacc.2009.09.062

Effect of cilnidipine on normal to marginally elevated urine albumin-creatinine ratio in asymptomatic non-diabetic hypertensive patients: an exponential decay curve analysis. International journal

Takaaki Nakatsu, Shinji Toyonaga, Keiichi Mashima, Yoko Yuki, Aya Nishitani, Hiroko Ogawa, Toru Miyoshi, Satoshi Hirohata, Reishi Izumi, Shozo Kusachi

Clinical drug investigation 30 ( 10 ) 699 - 706 2010

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: High-normal urinary albumin excretion has been reported to have clinical significance with respect to progression of proteinuria and hypertension. OBJECTIVE: We analysed the effect of cilnidipine (10 mg/day) on morning systolic blood pressure (SBP) and urine albumin-creatinine ratio (UACR) in 16 non-diabetic hypertensive patients with a normal to marginally elevated UACR (mean +/- SD 29.4 +/- 21.7; range 7.5-72.9 mg/g creatinine). METHODS: Sequential home BP and UACR data were fitted to a simple exponential function as follows: where y is SBP (mmHg) or UACR (mg/g creatinine); alpha is the extent of the SBP (mmHg)- or UACR (mg/g creatinine)-lowering effect; beta (days) is the time-constant for SBP or UACR decrease; t is the number of days after the start of cilnidipine administration; and gamma is the finally stabilized SBP (mmHg) or UACR (mg/g creatinine). RESULTS: Mean +/- SD morning SBP and UACR decreased by 20.4 +/- 11.4 mmHg and 15.2 +/- 13.1 mg/g creatinine, respectively, as determined by coefficient alpha. The mean +/- SD time-constant for UACR decrease was significantly longer than that for BP decrease (43.5 +/- 22.9 vs 15.4 +/- 7.1 days). UACR reduction correlated with pre-treatment UACR values (correlation coefficient [R] = 0.88, p < 0.01) but not with BP decrease. CONCLUSIONS: The present study demonstrated that cilnidipine reduced UACR in hypertensive patients with normal to marginally elevated UACR independent of its BP-lowering effect.

DOI： 10.2165/11538510-000000000-00000

ADAMTS-1 is an Endothelial Cell-specific Hypoxia-inducible Gene

Satoshi Hirohata, Faruk O. Hatipoglu, Toru Miyoshi, Hiroko Ogawa, Masanari Obika, Shigeshi Kamikawa, Shozo Kusachi, Hiroshi Itoh, Yoshifumi Ninomiya

CIRCULATION 120 ( 18 ) S1172 - S1172 2009.11

A Novel Cationic Protein Reduced Infracted Size and Protected Myocytes From Oxidative Stress Through Modification of Akt Signaling

Shigeshi Kamikawa, Satoshi Hirohata, Syougo Watanabe, Takashi Ohtsuki, Toru Miyoshi, Hiroko Ogawa, Shozo Kusachi, Masaharu Senoo, Yoshifumi Ninomiya, Hiroshi Itoh

CIRCULATION 120 ( 18 ) S888 - S889 2009.11

Association of Increased Plasma Adipocyte Fatty Acid-binding Protein With Coronary Artery Disease in Men

Shunichi Higashiya, Masayuki Doi, Kunio Nogami, Mutsumi Iwamoto, Akihisa Yumoto, Kou Takeda, Masayuki Ueeda, Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi, Yoshifumi Ninomiya, Hiroshi Ito

CIRCULATION 120 ( 18 ) S397 - S398 2009.11

Augmentation index is associated with B-type natriuretic peptide in patients with paroxysmal atrial fibrillation. International journal

Youko Kaji, Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Shigeshi Kamikawa, Kosuke Sakane, Tomoki Kitawaki, Shozo Kusachi, Kengo Fukushima Kusano, Hiroshi Ito

Hypertension research : official journal of the Japanese Society of Hypertension 32 ( 7 ) 611 - 6 2009.7

Language：English Publishing type：Research paper (scientific journal)

B-type natriuretic peptide (BNP) levels have been shown to be elevated in patients with paroxysmal atrial fibrillation (PAF); however, the underlying mechanisms have not been fully elucidated. Earlier, we reported that an increase in the augmentation index (AI), which is an index of wave reflection and arterial stiffness, is associated with PAF. In this study, we investigate the relationship between the BNP level and AI in patients with PAF. We enrolled 92 patients with a history of PAF and 90 age- and gender-matched individuals without PAF. AI was calculated using applanation tonometry of the radial artery when all patients were on sinus rhythm. Plasma BNP levels were measured simultaneously. An arterial stiffness parameter, the cardio-ankle vascular index (CAVI), was also evaluated. The increased AI in patients with PAF correlated with the elevation of the BNP level (r=0.47, P<0.01). When PAF patients were classified into tertiles on the basis of the BNP level, the left atrial volume index, left ventricular mass index, AI and CAVI increased, and mitral annular e' velocity (e'), as an index of left ventricular diastolic pressure, decreased with BNP tertiles. AI was also associated with e' and left ventricular mass index. Multiple regression analysis showed that the AI in PAF patients independently correlated with BNP levels. This study showed that AI was an independent correlate of the BNP level in PAF patients. Left ventricular diastolic dysfunction, which linked to an increase in arterial stiffness, may be involved in the elevated BNP level.

DOI： 10.1038/hr.2009.62

ADAMTS1 is a unique hypoxic early response gene expressed by endothelial cells. International journal

Omer F Hatipoglu, Satoshi Hirohata, M Zeynel Cilek, Hiroko Ogawa, Toru Miyoshi, Masanari Obika, Kadir Demircan, Ryoko Shinohata, Shozo Kusachi, Yoshifumi Ninomiya

The Journal of biological chemistry 284 ( 24 ) 16325 - 16333 2009.6

Language：English Publishing type：Research paper (scientific journal)

ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is a member of the matrix metalloproteinase family. We have previously reported that ADAMTS1 was strongly expressed in myocardial infarction. In this study, we investigated whether hypoxia induced ADAMTS1 and investigated its regulatory mechanism. In hypoxia, the expression level of ADAMTS1 mRNA and protein rapidly increased in endothelial cells, but not in other cell types. Interestingly, the induction of ADAMTS1 by hypoxia was transient, whereas vascular endothelial growth factor induction by hypoxia in human umbilical vein endothelial cells (HUVEC) increased in a time-dependent manner. CoCl2, a transition metal that mimics hypoxia, induced ADAMTS1 in HUVEC. The phosphatidylinositol 3-kinase inhibitor LY294002 dose-dependently inhibited the increase of ADAMTS1 mRNA expression in hypoxia. We characterized the promoter region of ADAMTS1, and the secreted luciferase assay system demonstrated that hypoxia induced luciferase secretion in the culture medium 4.6-fold in HUVEC. In the promoter region of ADAMTS1, we found at least three putative hypoxia-inducible factor (HIF) binding sites, and the chromatin immunoprecipitation assay revealed HIF-1 binding to HIF binding sites in the promoter region of ADAMTS1 under hypoxia. Recombinant ADAMTS1 protein promoted the migration of HUVEC under hypoxic conditions. In summary, we found that ADAMTS1 is transiently induced by hypoxia in endothelial cells, and its transcription is mediated by HIF-1 binding. Our data indicate that ADAMTS1 is a novel acute hypoxia-inducible gene.

DOI： 10.1074/jbc.M109.001313

Microarray analysis of gene expression in mouse aorta reveals role of the calcium signaling pathway in control of atherosclerosis susceptibility. International journal

Zuobiao Yuan, Toru Miyoshi, Yongde Bao, Jason P Sheehan, Alan H Matsumoto, Weibin Shi

American journal of physiology. Heart and circulatory physiology 296 ( 5 ) H1336-43 2009.5

Language：English Publishing type：Research paper (scientific journal)

Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit a marked difference in atherosclerotic lesion formation when deficient in apolipoprotein E (apoE(-/-)), and the arterial wall has been identified as a source of the difference in atherosclerosis susceptibility. In the present study, differences in gene expression in aortic walls of the two strains were analyzed by microarrays. Total RNA was extracted from the aorta of 6-wk-old female B6 and C3H apoE(-/-) mice fed a chow or Western diet. There were 1,514 genes in chow fed mice and 590 genes in Western fed mice that were found to be differentially expressed between the two strains. Pathway analysis of differentially expressed genes suggested a role for the calcium signaling pathway in regulating atherosclerosis susceptibility. Oxidized LDL (oxLDL) induced a dose-dependent rise in cytosolic calcium levels in B6 endothelial cells. oxLDL-induced monocyte chemoattractant protein-1 production was inhibited by pretreatment with calcium chelator EGTA or intracellular calcium trapping compound BAPTA, indicating that calcium ions mediate the effect of oxLDL on monocyte chemoattractant protein-1 induction. The present findings demonstrate involvement of the calcium signaling pathway in the inflammatory process of atherogenesis.

DOI： 10.1152/ajpheart.01095.2008

Relationship between activin A level and infarct size in patients with acute myocardial infarction undergoing successful primary coronary intervention. International journal

Toru Miyoshi, Satoshi Hirohata, Tadahisa Uesugi, Minoru Hirota, Hiromichi Ohnishi, Kunio Nogami, Kunihiko Hatanaka, Hiroko Ogawa, Shinichi Usui, Shozo Kusachi

Clinica chimica acta; international journal of clinical chemistry 401 ( 1-2 ) 3 - 7 2009.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Activin A, a member of the transforming growth factor-beta cytokine family, has been suggested to have a role in inflammation. We examined the serum level of activin A in patients with acute myocardial infarction (AMI) undergoing successful primary percutaneous coronary intervention (PCI). METHODS: The subjects were 30 AMI patients, 20 stable angina pectoris (AP) patients and 20 normal subjects. The serum levels of activin A in AMI patients were measured before PCI and on days 1, 2, 7, and 14. RESULTS: Activin A levels before PCI in AMI patients (557+/-255 pg/ml) showed a significantly higher value than those in AP patients (364+/-159 pg/ml) and control subjects (316+/-144 pg/ml). Increased serum activin A level before PCI was decreased on day 2, and then gradually re-elevated on days 7 and 14. The serum activin A level before PCI was correlated with log-transformed peak creatine kinase (CK) as a surrogate of infarct size (r=0.48, p=0.008). Stepwise multiple regression analysis demonstrated that the serum activin A level before PCI was an independent predictor of peak CK. CONCLUSIONS: The serum activin A level, increased in AMI, was positively correlated with peak CK and CK-MB levels which are measures of infarction size.

DOI： 10.1016/j.cca.2008.10.027

Hyaluronan receptors involved in cytokine induction in monocytes. International journal

Hitoshi Yamawaki, Satoshi Hirohata, Toru Miyoshi, Katsuyuki Takahashi, Hiroko Ogawa, Ryoko Shinohata, Kadir Demircan, Shozo Kusachi, Kazuhide Yamamoto, Yoshifumi Ninomiya

Glycobiology 19 ( 1 ) 83 - 92 2009.1

Language：English Publishing type：Research paper (scientific journal)

During inflammation, lower molecular weight fragments of hyaluronan accumulate, and this is known to be inflammatory and immune-stimulatory. In diseases such as inflammatory bowel disease, inflammatory cells bind to hyaluronan; however, the cellular response and molecular mechanism of hyaluronan-hyaluronan receptor interactions in mononuclear cells are not well understood. The expression of hyaluronan receptors in peripheral blood mononuclear cells (PBMC) was examined. PBMC were stimulated with lower and higher molecular weight hyaluronan (molecular weight 100-150 kDa and 2700 kDa) and the induction of proinflammatory cytokines (interleukin-6 (IL-6) and monocyte chemoattractant protein (MCP-1)) was compared by enzyme-linked immunoabsorbant assay (ELISA). Cells were coincubated with various signaling pathway inhibitors. In addition, neutralizing antibodies against CD44 and TLR4 were added and the effects on PBMC were investigated. Finally, mononuclear cells from CD44-null and toll-like receptor 4 (TLR4) mutant mice were both stimulated with lower molecular weight hyaluronan. Among the hyaluronan receptors, TLR4 and CD44 were markedly expressed on PBMC. Hyaluronan-stimulated PBMC enhanced the attachment to the extracellular matrix. Lower molecular weight hyaluronan induced IL-6 and MCP-1 production in PBMC, but high-molecular-weight hyaluronan did not induce IL-6 and MCP-1 production. An anti-CD44 antibody attenuated the induction of both IL-6 and MCP-1 in lower molecular weight hyaluronan-stimulated PBMC. In both TLR4 mutant and CD44-null mice, the induction of IL-6 by lower molecular weight hyaluronan stimulation was decreased. SB203580 completely abolished IL-6 production in both TLR4 mutant and CD44-null mononuclear cells, while PD98059 abolished IL-6 production in CD44-null mononuclear cells. Hyaluronan receptors, CD44 and TLR4, play distinct roles in cytokine induction in hyaluronan-stimulated mononuclear cells.

DOI： 10.1093/glycob/cwn109

Increased augmentation index of the radial pressure waveform in patients with paroxysmal atrial fibrillation. International journal

Masayuki Doi, Toru Miyoshi, Satoshi Hirohata, Akihiro Iwabu, Youkou Tominaga, Youko Kaji, Shigeshi Kamikawa, Kosuke Sakane, Tomoki Kitawaki, Kengo F Kusano, Shozo Kusachi

Cardiology 113 ( 2 ) 138 - 45 2009

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The augmentation index, a marker of wave reflection, has been reported to reflect vascular properties and to determine left ventricular (LV) characteristics. We investigated the relationship between the augmentation index and paroxysmal atrial fibrillation (AF). METHODS: A total of 244 outpatients (122 patients with paroxysmal AF and 122 age-, and gender-matched controls without paroxysmal AF) were examined during sinus rhythm. The augmentation index was calculated from the radial arterial waveform using applanation tonometry methods. RESULTS: After adjusting for age, gender, heart rate, and medications, the augmentation index was significantly higher in patients with paroxysmal AF than in subjects without paroxysmal AF (means +/- SE: 88.9 +/- 1.0 and 81.8 +/- 1.0%, respectively; p < 0.001). In all subjects, an increase in the augmentation index was significantly correlated with LV hypertrophy and left atrial enlargement. Multiple logistic analysis revealed that an increase in the augmentation index was significantly related with paroxysmal AF, and the adjusted odds ratio of paroxysmal AF was approximately 1.8 for each 10% augmentation index increase (p < 0.01). CONCLUSION: An increase in the augmentation index was independently associated with paroxysmal AF. This result suggests that enhanced wave reflection may be related to the development of AF.

DOI： 10.1159/000177951

Serum N-3 polyunsaturated fatty acid levels correlate with the extent of coronary plaques and calcifications in patients with acute myocardial infarction.

Masayuki Ueeda, Takenori Doumei, Yoichi Takaya, Ryoko Shinohata, Yusuke Katayama, Nobuhiko Ohnishi, Atsushi Takaishi, Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi

Circulation journal : official journal of the Japanese Circulation Society 72 ( 11 ) 1836 - 43 2008.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The relationship between serum fatty acid levels and the extent of coronary plaques and calcification was examined in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: The serum levels of the n-3 polyunsaturated fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) and the n-6 polyunsaturated fatty acids (arachidonic acid (AA) and dihomo-gamma-linolenic acid (DGLA)) were determined using gas chromatography on admission of 95 consecutive patients with their first AMI and 17 controls. Using multidetector-row computed tomography, soft plaques and calcification lesions were scored according to the extent of coronary involvement. Serum logarithmic transformed (log) EPA and logDHA levels were inversely correlated with soft plaque scores (r=-0.546, p<0.0001 and r=-0.377, p<0.0001, respectively). Serum logAA and logDGLA levels were not significantly correlated with soft plaque scores. Serum logEPA and logDHA levels were significantly, but weakly, correlated with calcification scores. Multivariate analysis with clinical characteristics and risk factors selected serum n-3 polyunsaturated fatty acid levels as independent factors associated with the extent of coronary soft plaques. CONCLUSION: The present study demonstrates a significant correlation between serum n-3 polyunsaturated fatty acid levels and the extent of coronary soft plaques and calcification in AMI patients.

Quantitative trait locus analysis of circulating adhesion molecules in hyperlipidemic apolipoprotein E-deficient mice. International journal

Zuobiao Yuan, Zhiguang Su, Toru Miyoshi, Jessica S Rowlan, Weibin Shi

Molecular genetics and genomics : MGG 280 ( 5 ) 375 - 83 2008.11

Language：English Publishing type：Research paper (scientific journal)

Circulating soluble adhesion molecules have been suggested as useful markers to predict several clinical conditions such as atherosclerosis, type 2 diabetes, obesity, and hypertension. To determine genetic factors influencing plasma levels of soluble vascular cell adhesion molecule-1 (VCAM-1) and P-selectin, quantitative trait locus (QTL) analysis was performed on an intercross between C57BL/6J (B6) and C3H/HeJ (C3H) mouse strains deficient in apolipoprotein E-deficient (apoE-/-). Female F2 mice were fed a western diet for 12 weeks. One significant QTL, named sVcam1 (71 cM, LOD 3.9), on chromosome 9 and three suggestive QTLs on chromosomes 5, 13 and 15 were identified to affect soluble VCAM-1 levels. Soluble P-selectin levels were controlled by one significant QTL, named sSelp1 (8.5 cM, LOD 3.4), on chromosome 16 and two suggestive QTLs on chromosomes 10 and 13. Both adhesion molecules showed significant or an apparent trend of correlations with body weight, total cholesterol, and LDL/VLDL cholesterol levels in the F2 population. These results indicate that plasma VCAM-1 and P-selectin levels are complex traits regulated by multiple genes, and this regulation is conferred, at least partially, by acting on body weight and lipid metabolism in hyperlipidemic apoE-/- mice.

DOI： 10.1007/s00438-008-0371-0

Association of new arterial stiffness parameter, the cardio-ankle vascular index, with left ventricular diastolic function.

Kosuke Sakane, Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Youko Kaji, Shigeshi Kamikawa, Hiroko Ogawa, Kunihiko Hatanaka, Tomoki Kitawaki, Shozo Kusachi, Kazuhide Yamamoto

Journal of atherosclerosis and thrombosis 15 ( 5 ) 261 - 8 2008.10

Language：English Publishing type：Research paper (scientific journal)

AIM: Pulse wave velocity has been used as an index of aortic stiffness. Recently, the cardio-ankle vascular index (CAVI), which reflects the stiffness of the aorta independently of blood pressure, has been developed. In this study, we analyzed the relationship between CAVI and left ventricular (LV) diastolic dysfunction. METHODS: A total of 119 patients were referred for echocardiography to evaluate ventricular function. Patients with reduced systolic function were excluded. Patients were divided on the basis of normal or reduced LV diastolic function determined by echocardiography. CAVI was measured using an automatic waveform analyzer. RESULTS: CAVI was significantly higher in patients with reduced LV diastolic function than those with normal LV diastolic function (9.0+/-1.1 and 8.5+/-1.1, p=0.009). Multiple linear regression analysis revealed that CAVI was independently associated with the ratio of peak early diastolic velocity to peak atrial diastolic velocity and left atrial diameter. When patients were classified on the basis of CAVI quartiles, multiple logistic regression analysis demonstrated that the highest quartile of CAVI showed an increased odds ratio for the presence of LV diastolic dysfunction. CONCLUSION: The present study revealed that an increased CAVI was independently associated with LV diastolic dysfunction in patients with preserved systolic function.

The Impact of Increased Augmentation Index of Radial Pressure Waveform on Paroxysmal Atrial Fibrillation

Youko Kaji, Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Tadahisa Uesugi, Shigeshi Kamikawa, Kosuke Sakane, Shozo Kusachi, Kengo F. Kusano

CIRCULATION 118 ( 18 ) S730 - S730 2008.10

Serum Adipocyte Fatty Acid-Binding Protein Levels are Independently Associated with Coronary Atherosclerosis

Toru Miyoshi, Atsushi Hirohata, Shinichi Usui, Keizo Yamamoto, Kazuyoshi Hina, Satoshi Hirohata, Shozo Kusachi, Yoshifumi Ninomiya, Kengo F. Kusano

CIRCULATION 118 ( 18 ) S470 - S470 2008.10

Prone position is essential for detection of pulmonary vein pseudostenosis by enhanced multidetector computed tomography in patients who undergo pulmonary vein isolation.

Hirosuke Yamaji, Kazuyoshi Hina, Hiroshi Kawamura, Takashi Murakami, Masaaki Murakami, Keizo Yamamoto, Atsushi Hirohata, Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi

Circulation journal : official journal of the Japanese Circulation Society 72 ( 9 ) 1460 - 4 2008.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Pulmonary vein (PV) stenosis is a major complication of PV isolation (PVI) by catheter ablation, so in the present study the optimal position for detecting PV stenosis on enhanced multidetector computed tomography (MDCT) image acquisition was determined. METHODS AND RESULTS: The 64-slice enhanced MDCT was carried out before and after PVI in 116 consecutive patients with atrial fibrillation while they were in the prone position, as well as while supine. The supine position MDCT image showed >50% diameter stenosis of the PV in 11 (9%) patients before PVI (% diameter stenosis: mean 55+/-4%, range 51-65%). Greater than 50% diameter stenosis was seen in the left inferior PV in all 11 patients. The prone position attenuated the PV stenosis findings in the MDCT images in all 11 patients (mean 9+/-6%, range 2-18%). Stenosis visualized on images acquired in the supine position was, therefore, concluded to be pseudostenosis caused by descending aorta compression. At 3 months after PVI, no significant changes in PV diameter were observed in these 11 patients. CONCLUSION: The present study demonstrated that the prone position is essential for eliminating PV pseudostenosis observed on supine-position enhanced MDCT images. The results also indicate that preexisting PV organic stenosis is rare.

siRNA silencing reveals role of vascular cell adhesion molecule-1 in vascular smooth muscle cell migration. International journal

Erik J Petersen, Toru Miyoshi, Zuobiao Yuan, Satoshi Hirohata, Jin Zhong Li, Weibin Shi, John F Angle

Atherosclerosis 198 ( 2 ) 301 - 6 2008.6

Language：English Publishing type：Research paper (scientific journal)

Vascular cell adhesion molecule-1 (VCAM-1) is an adhesion molecule expressed by endothelial cells for recruitment of leukocytes during inflammation. It is also abundantly expressed by smooth muscle cells in atherosclerotic lesions and in injured arteries. In this study, we examined the role of VCAM-1 in smooth muscle cell migration. Smooth muscle cells were isolated from the aorta of C57BL/6 mice and transfected with short interfering RNAs (siRNAs) targeting VCAM-1. Inhibition on VCAM-1 expression by siRNAs was assessed by Western blot analysis, RT-PCR and by measuring soluble VCAM-1 concentrations in the incubation medium. One siRNA that showed greater suppression on VCAM-1 expression was used for migration assay. A single scratch wound was made on 70% confluent cells and cells migrated from wounded monolayer were counted 24 and 48h after injury. Treatment with VCAM-1 siRNA resulted in a significant reduction in the number of migrated cells. This siRNA also exhibited a minor effect on smooth muscle cell proliferation. Thus, our findings indicate that VCAM-1 is necessary for the migration of smooth muscle cells and interfering VCAM-1 expression could be an effective approach to prevention and treatment of atherosclerosis and restenosis.

Increased augmentation index of radial pulse wave in patients with paroxysmal atrial fibrillation

Toru Miyoshi, Masayuki Doi, Youko Kaji, Satoshi Hirohata, Shigeshi Kamikawa, Shozo Kusachi, Tohru Ohe

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 51 ( 10 ) A304 - A304 2008.3

Association of a Vcam1 mutation with atherosclerosis susceptibility in diet-induced models of atherosclerosis. International journal

Toru Miyoshi, Zuobiao Yuan, Weibin Shi

Atherosclerosis 196 ( 1 ) 234 - 239 2008.1

Language：English Publishing type：Research paper (scientific journal)

We previously identified a G>A single nucleotide polymorphism (SNP) between C57BL/6J (B6) and C3H/HeJ (C3H) mouse strains at position 2077 in the coding region of Vcam1 that leads to substitution of an amino acid from aspartic acid (D) to asparagine (N) in the protein product. In the present study, we investigated the association of this SNP with atherosclerosis susceptibility using a panel of inbred mouse strains, a set of recombinant inbred (RI) strains derived from B6 and C3H mice, and a cohort of F2 mice derived from B6 and C3H apolipoprotein E-deficient (apoE(-/-)) mice. Inbred strain analysis revealed that mouse strains with the B6 Vcam1 genotype developed significantly larger atherosclerotic lesions than strains with the C3H genotype (4622+/-2816 microm(2)/section versus 362+/-697 microm(2)/section; P=0.029). BXH RI strains with the B6 Vcam1 genotype also developed larger atherosclerotic lesions than those with the C3H genotype (8305+/-9031 microm(2)/section versus 2139+/-2931 microm(2)/section) although the difference was not statistically significant (P=0.13). In contrast, no association was detected between Vcam1 and atherosclerotic lesion size in F2 mice. The present data indicate that the G>A mutation of Vcam1 is associated with atherosclerotic lesion formation in the dietary but not apoE(-/-) models of atherosclerosis and this association suggests a role for the Vcam1 gene in influencing atherosclerosis susceptibility.

DOI： 10.1016/j.atherosclerosis.2007.05.004

Serum interferon-gamma-inducible protein 10 level was increased in myocardial infarction patients, and negatively correlated with infarct size. International journal

Kazuya Koten, Satoshi Hirohata, Toru Miyoshi, Hiroko Ogawa, Shinichi Usui, Ryoko Shinohata, Mutsumi Iwamoto, Tomoki Kitawaki, Shozo Kusachi, Kosaku Sakaguchi, Tohru Ohe

Clinical biochemistry 41 ( 1-2 ) 30 - 7 2008.1

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: We examined the serum levels of interferon-gamma-inducible protein 10 (IP-10), an inflammation-induced chemokine, in acute myocardial infarction (AMI). DESIGN AND METHODS: The subjects were 33 AMI patients, 20 stable angina pectoris patients (AP) and 20 normal subjects. In AMI patients, blood samples were collected before percutaneous coronary intervention (PCI) and on days 3, 7 and 28. RESULTS: Patients with AMI showed significantly higher serum IP-10 levels (137.5+/-79.8 pg/mL) than control subjects (91.2+/-40.1 pg/mL) and patients with AP (93.3+/-41.1 pg/mL). The serum IP-10 level before PCI was negatively correlated with infarct size, as indicated by cumulative release of creatine kinase (CK) and peak CK and its isoenzyme CK-MB. Stepwise multiple regression analysis revealed that the serum IP-10 level before PCI was an independent predictor of cumulative CK release. CONCLUSIONS: The serum IP-10 level was increased in AMI, and a higher level of serum IP-10 before PCI may be informative regarding infarct size.

Serum activin a level is associated with infarct size in patients with acute myocardial infarction who undergo successful primary percutaneous coronary intervention

Toru Miyoshi, Satoshi Hirohata, Tadahisa Uesugi, Minoru Hirota, Hiromichi Ohnishi, Kunio Nogami, Shozo Kusachi, Tohru Ohe

CIRCULATION 116 ( 16 ) 711 - 711 2007.10

Paradoxical increase in LDL oxidation by endothelial cells from an atherosclerosis-resistant mouse strain. International journal

Toru Miyoshi, Alan H Matsumoto, Weibin Shi

Atherosclerosis 192 ( 2 ) 259 - 65 2007.6

Language：English Publishing type：Research paper (scientific journal)

Oxidative modification of LDL accumulated in the subendothelial space is a critical step in atherogenesis. Mouse strains C57BL/6 (B6) and BALB/c differ markedly in atherosclerosis susceptibility. We sought to determine whether variation of endothelial cells in the capacity to oxidize LDL or in response to minimally modified LDL (MM-LDL) constitutes a genetic component in atherosclerosis. LDL oxidation was assessed by measuring thiobarbituric acid-reactive substance (TBARS) production. Responses to MM-LDL were evaluated by examining induction of monocyte chemotactic protein-1, macrophage-colony stimulating factor, and vascular cell adhesion molecule-1. Both strains exhibited comparable endothelial responses to MM-LDL, whereas BALB/c mice had an increased rate of oxidizing LDL compared with B6 mice. To examine whether endothelial nitric oxide synthase (eNOS) contributed to the difference in LDL oxidation, cells were incubated with native LDL in the presence or absence of N(Omega)-nitro-l-arginine methyl ester (l-NAME), a specific NOS inhibitor. Although l-NAME significantly inhibited endothelial cell-mediated LDL oxidation, it failed to abolish the difference between the strains. In contrast, Baicalein, a specific 12/15 lipoxygenase inhibitor, abolished the difference in LDL oxidation. Thus, the paradoxical increase in LDL oxidation by endothelial cells is attributable to higher oxidant activity of 12/15-lipoxygenase in BALB/c mice and endothelial cells appear unlikely to be a source of the resistance to atherosclerosis.

ADAMTS1は内皮細胞特異的に細胞浸潤を抑制する

廣畑聡, 小比賀真就, 小川弘子, 三好亨, Cilek Mehmet Zeynel, Demircan Kadir, Hatipoglu Omer Faruk, 草地省蔵, 二宮善文

日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集 39回・54回 134 - 134 2007.5

Direct evidence for a crucial role of the arterial wall in control of atherosclerosis susceptibility. International journal

Hong Pei, Yinong Wang, Toru Miyoshi, Zhimin Zhang, Alan H Matsumoto, Gregory A Helm, George Tellides, Weibin Shi

Circulation 114 ( 22 ) 2382 - 9 2006.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit marked differences in atherosclerosis susceptibility. We sought to determine whether the difference in atherosclerosis susceptibility resides at the level of arterial walls. METHODS AND RESULTS: Thoracic aortic segments from 8-week-old female B6 and C3H apolipoprotein E-deficient mice were transplanted into the infrarenal aorta of 10-week-old female F1 mice. After transplantation, recipients were maintained on a chow diet for 16 weeks. The donor aortic segments of B6 mice developed significantly larger atherosclerotic lesions than those of C3H (44,983+/-11,702 versus 5600+/-4885 microm2 per section; P=0.011). Expression of vascular cell adhesion molecule (VCAM)-1 by endothelial cells was examined both in vitro and in vivo. B6 mice expressed significantly more VCAM-1 than their C3H counterparts. Sequence analysis of VCAM-1 cDNA revealed a nucleotide difference in the coding region that resulted in substitution of an amino acid in the protein product. CONCLUSIONS: These data provide direct proof that factors operating in the vessel wall, particularly endothelial cells, can serve as atherosclerosis modifiers and suggest a possibility for the contribution of VCAM-1 to atherosclerosis susceptibility.

Differential response of vascular smooth muscle cells to oxidized LDL in mouse strains with different atherosclerosis susceptibility. International journal

Toru Miyoshi, Jing Tian, Alan H Matsumoto, Weibin Shi

Atherosclerosis 189 ( 1 ) 99 - 105 2006.11

Language：English Publishing type：Research paper (scientific journal)

Oxidized low-density lipoprotein (LDL) has numerous atherogenic properties, including induction of inflammatory genes, and vascular smooth muscle cells (VSMC) are involved in the development of atherosclerosis. In this study, we examined whether variations of VSMC in the capacity to oxidize LDL or in response to minimally modified LDL (MM-LDL) constitute a genetic component in atherosclerosis. VSMC were isolated from the aorta of two inbred mouse strains C57BL/6J (B6) and C3H, which differ markedly in susceptibility to atherosclerosis. LDL oxidation was assessed by measuring thiobarbituric acid-reactive substance (TBARS) production. Responses to MM-LDL were evaluated by examining the expression of inflammatory genes involved atherosclerosis, including monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1), and an oxidant stress gene, heme oxygenase-1 (HO-1). VSMC from the two strains exhibited a comparable ability to transform native LDL to oxidized LDL, whereas their response to MM-LDL differed markedly. MM-LDL resulted in dramatic induction of MCP-1, VCAM-1, and HO-1 mRNAs in the cells from B6 mice but exerted little effect in cells from C3H mice. MCP-1 and soluble VCAM-1 protein levels in conditioned media were measured by ELISA. B6 cells produced significantly more MCP-1 and VCAM-1 proteins in response to MM-LDL than C3H cells. These data suggest that variation in the response of VSMC to oxidized LDL may contribute to the difference between B6 and C3H mice in atherosclerosis susceptibility.

Tumor-specific expression of the RGD-alpha3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice. International journal

Toru Miyoshi, Satoshi Hirohata, Hiroko Ogawa, Masayuki Doi, Masanari Obika, Tomoko Yonezawa, Yoshikazu Sado, Shozo Kusachi, Satoru Kyo, Seiji Kondo, Yasushi Shiratori, Billy G Hudson, Yoshifumi Ninomiya

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20 ( 11 ) 1904 - 6 2006.9

Language：English Publishing type：Research paper (scientific journal)

Angiogenesis plays an essential role in tumor growth. This study investigated expression of the noncollagenous domain of alpha3(IV) collagen (alpha3(IV)NC1) transduced into tumors and its inhibition of tumor growth. We hypothesized that if a human telomerase reverse transcriptase (hTERT) promoter-driven RGD motif containing alpha3(IV)NC1 (hTERT/RGD-alpha3(IV)NC1) were expressed in telomerase-expressing tumor cells, it would inhibit tumor growth by its anti-angiogenic property. Adenoviral transduction of hTERT/RGD-alpha3(IV)NC1 expressed RGD-alpha3(IV)NC1 in hTERT-positive tumor cell lines. However, hTERT/RGD-alpha3(IV)NC1 did not express RGD-alpha3(IV)NC1 in hTERT-negative cells such as keratinocytes and fibroblasts. The secreted RGD-alpha3(IV)NC1 in the conditioned medium from tumor cells inhibited cell proliferation as well as tube formation in cultured endothelial cells, but had no effect on other types of cells. In an in vivo model, adenoviral hTERT/RGD-alpha3(IV)NC1 gene therapy showed limited expression of RGD-alpha3(IV)NC1 in tumors and resulted in a significant decrease of vessel density in tumors. The growth of subcutaneous (s.c.) tumors in nude mice was significantly suppressed by treatment with hTERT/RGD-alpha3(IV)NC1. In addition, long-term inhibition of tumor growth was achieved by intermittent administration of hTERT/RGD-alpha3(IV)NC1. In conclusion, our findings demonstrate that tumor-specific anti-angiogenic gene therapy utilizing RGD-alpha3(IV)NC1 under the hTERT promoter inhibited angiogenesis in tumors, resulting in an antitumor effect.

Deficiency of inducible NO synthase reduces advanced but not early atherosclerosis in apolipoprotein E-deficient mice. International journal

Toru Miyoshi, Yuhua Li, Diana M Shih, Xuping Wang, Victor E Laubach, Alan H Matsumoto, Gregory A Helm, Aldons J Lusis, Weibin Shi

Life sciences 79 ( 6 ) 525 - 31 2006.7

Language：English Publishing type：Research paper (scientific journal)

The inducible nitric oxide synthase (iNOS) is abundantly expressed by smooth muscle cells and macrophages in atherosclerotic lesions. Apolipoprotein E-deficient (apoE(-/-)) mice develop early and advanced atherosclerotic lesions. The role of iNOS in both early and advanced atherosclerotic formation was determined in apoE(-/-) mice. Mice were fed chow or a Western diet containing 42% fat, 0.15% cholesterol, and 19.5% casein. At 12 weeks of age on chow diet, iNOS(-/-)/apoE(-/-) mice developed comparable sizes of early atherosclerotic lesions in the aortic root as did iNOS(+/+)/apoE(-/-) mice (30,993+/-4746 vs. 26,648+/-6815 microm(2)/section; P=0.608). After being fed the Western diet for 12 weeks, iNOS(-/-)/apoE(-/-) mice developed significantly smaller advanced lesions than iNOS(+/+)/apoE(-/-) mice (458,734+/-14,942 vs. 519,570+/-22,098 microm(2)/section; P=0.029). This reduction in lesion formation could not be explained by differences in plasma lipid levels. To examine whether iNOS contributed to LDL oxidation, smooth muscle cells were isolated from the aorta, activated with TNF-alpha, and then incubated with native LDL in the absence or presence of N-Omega-nitro-L-arginine methyl ester (L-NAME), a specific NOS inhibitor. L-NAME significantly inhibited LDL oxidation by smooth muscle cells from iNOS(+/+)/apoE(-/-) mice (P=0.048), but it had no effect on LDL oxidation by cells from iNOS(-/-)/apoE(-/-) mice. iNOS(-/-)/apoE(-/-) mice had a significantly lower plasma lipoperoxide level on the Western diet (2.74+/-0.23 vs. 3.89+/-0.41 microM MDA; P=0.021) but not on chow diet (1.02+/-0.07 vs. 1.51+/-0.29 microM MDA; P=0.11). Thus, the absence of iNOS-mediated LDL oxidation may contribute to the reduction in advanced lesion formation of iNOS(-/-)/apoE(-/-) mice.

Thrombospondin-1 is induced in rat myocardial infarction and its induction is accelerated by ischemia/reperfusion. International journal

Satoshi Sezaki, Satoshi Hirohata, Akihiro Iwabu, Keigo Nakamura, Kenichi Toeda, Toru Miyoshi, Hitoshi Yamawaki, Kadir Demircan, Shozo Kusachi, Yasushi Shiratori, Yoshifumi Ninomiya

Experimental biology and medicine (Maywood, N.J.) 230 ( 9 ) 621 - 30 2005.10

Language：English Publishing type：Research paper (scientific journal)

Thrombospondin-1 (TSP-1) is a multifunctional, rapid-turnover matricellular protein. Recent studies demonstrated that TSP-1 has a role in regulating inflammatory reactions. Myocardial infarction (MI) is associated with an inflammatory response, ultimately leading to healing and scar formation. In particular, an enhanced inflammatory reaction and a massive accumulation of monocytes/macrophages is seen with reperfusion after MI. To examine the role of TSP-1 in MI, we isolated rat TSP-1 complementary DNA (cDNA) and analyzed the level and distribution of the mRNA expression. In infarcted rat hearts, TSP-1 mRNA increased markedly at 6 and 12 hrs after coronary artery ligation (27.97 +/- 3.40-fold and 22.77 +/- 1.83-fold, respectively, compared with sham-operated hearts). Western blot analysis revealed that TSP-1 protein was transiently induced in the infarcted heart. Using in situ hybridization analysis, TSP-1 mRNA signals were observed in the infiltrating cells at the border area of infarction. We then examined the effect of ischemia/reperfusion (I/R) on TSP-1 mRNA induction in the rats with infarcted hearts. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) demonstrated that I/R enhanced the TSP-1 mRNA expression approximately 4-fold, as compared with the level in the permanently ligated heart. Finally, we examined the effect of TSP-1 on proinflammatory cytokine release in mononuclear cells. The releases of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) from human mononuclear cells were enhanced by TSP-1 in a dose-dependent manner. Thus, the immediate and marked increase of TSP-1 expression suggests that TSP-1 has an inflammatory-associated role in MI.

Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status. International journal

Hideaki Ito, Takao Kanzawa, Toru Miyoshi, Satoshi Hirohata, Satoru Kyo, Arifumi Iwamaru, Hiroshi Aoki, Yasuko Kondo, Seiji Kondo

Human gene therapy 16 ( 6 ) 685 - 98 2005.6

Language：English Publishing type：Research paper (scientific journal)

Replacement of the p53 tumor suppressor gene is a rational approach to the management of malignant gliomas because p53 is frequently mutated or inactivated in these cancers. Major weaknesses of this approach are that malignant gliomas are mixtures of cells with wild-type and mutant p53, and that tumor cells exhibiting wildtype p53 are resistant to p53 gene transfer. An effective alternative is needed to overcome these difficulties. p53-upregulated modulator of apoptosis (PUMA) was identified as a p53-inducible proapoptotic molecule. Our purpose was to elucidate a role for PUMA in p53 gene therapy and to investigate whether PUMA is an efficient substitute for p53 in cancer therapy. We demonstrated that PUMA was upregulated in mutant p53 malignant glioma cells (U373-MG and T98G) undergoing apoptosis but was not upregulated in apoptosis-resistant wild-type p53 malignant glioma cells (U87-MG and D54) after adenoviral transfer of p53. Overexpression of PUMA resulted in massive apoptosis associated with mitochondrial damage and caspase-3 activation in all tumor cells tested. Use of the human telomerase reverse transcriptase (hTERT) promoter system induced apoptosis only in malignant glioma cells with telomerase activity, while sparing normal cells lacking telomerase. The ability of PUMA to induce apoptosis was greater than that of caspase-6 or caspase-8 transfer, using the same system. Moreover, exogenous expression of PUMA under the hTERT promoter system significantly suppressed the growth of subcutaneous U87-MG tumors in nude mice and did not induce apoptosis in surrounding nontumor tissues. These results indicate that PUMA, which is regulated under a tumor-specific expression system such as the hTERT promoter, may be better than p53 as a therapeutic tool for malignant gliomas.

Time-dependent changes in plasma osteopontin levels in patients with anterior-wall acute myocardial infarction after successful reperfusion: correlation with left-ventricular volume and function. International journal

Chisato Suezawa, Shozo Kusachi, Takashi Murakami, Kenichi Toeda, Satoshi Hirohata, Keigo Nakamura, Keizo Yamamoto, Kazuya Koten, Toru Miyoshi, Yasushi Shiratori

The Journal of laboratory and clinical medicine 145 ( 1 ) 33 - 40 2005.1

Language：English Publishing type：Research paper (scientific journal)

Osteopontin is a secreted extracellular-matrix glycoprotein that plays a role in the healing of remodeling tissue. We examined the relationship of plasma osteopontin levels with left-ventricular (LV) volume and function in 18 consecutive patients who underwent successful reperfusion after anterior-wall acute myocardial infarction (AMI). The plasma osteopontin level was within the control range at admission (mean +/- SD 420 +/- 195 ng/mL), began to increase on day 2 (935 +/- 464 ng/mL), and reached a maximum around day 3 (1139 +/- 482 ng/mL). The level remained high on days 4, 5, and 7 ( approximately 1000 ng/mL) and then decreased on day 14. Maximal plasma osteopontin levels and the difference between maximal and minimal levels were positively correlated with LV end-systolic volume index (r = .58, P < .05; and r = .65, P < .01, respectively) and negatively correlated with LV ejection fraction (r = -.52, P < .05; and r = -.60, P < .01, respectively). The area under the curve of plasma osteopontin levels for 14 days after AMI was significantly correlated with LV end-systolic volume index (r = .66, P < .01), LV end-diastolic volume index (r = .50, P < .05), and LV ejection fraction (r = -.55, P < .05). In subgroup patients with the same area of risk for myocardial infarction (ie, responsible lesions located at the same proximal left anterior descending coronary artery), essentially the same or a closer relationship between plasma osteopontin level and LV volume and function was noted. Plasma osteopontin levels were correlated substantially with plasma levels of high-sensitivity C-reactive protein (hsCRP) and weakly with serum creatine kinase release. In conclusion, the plasma level of osteopontin changes in a time-dependent fashion and is correlated with LV volumes and function and associated substantially with the extent of the inflammatory response indicated by the plasma hsCRP level and weakly with infarct size estimated on the basis of cardiac-enzyme release.

Dynamic induction of ADAMTS1 gene in the early phase of acute myocardial infarction. International journal

Keigo Nakamura, Satoshi Hirohata, Takashi Murakami, Toru Miyoshi, Kadir Demircan, Toshitaka Oohashi, Hiroko Ogawa, Kazuya Koten, Kenichi Toeda, Shozo Kusachi, Yoshifumi Ninomiya, Yasushi Shiratori

Journal of biochemistry 136 ( 4 ) 439 - 46 2004.10

Language：English Publishing type：Research paper (scientific journal)

Extracellular matrix (ECM)-degrading enzymes such as matrix metalloproteases (MMPs) play an essential role in the repair of infarcted tissue, which affects ventricular remodeling after myocardial infarction. ADAMTS1 (A disintegrin and metalloprotease with thrombospondin motifs), a newly discovered metalloprotease, was originally cloned from a cancer cell line, but little is known about its contribution to disease. To test the hypothesis that ADAMTS1 appears in infarcted myocardial tissue, we examined ADAMTS1 mRNA expression in a rat myocardial infarction model by Northern blotting, real-time RT-PCR and in situ hybridization. Normal endothelium expressed little ADAMTS1 mRNA, while normal myocardium expressed no detectable ADAMTS1 mRNA. Up-regulation of ADAMTS1 was demonstrated by Northern blot analysis and real-time RT-PCR at 3 h after coronary artery ligation. In situ hybridization revealed strong ADAMTS1 mRNA signals in the endothelium and myocardium in the infarcted heart, mainly in the infarct zone, at 3 h after myocardial infarction. The rapid and transient up-regulation of the ADAMTS1 gene in the ischemic heart was distinct from the regulatory patterns of other MMPs. Our study demonstrated that the ADAMTS1 gene is a new early immediate gene expressed in the ischemic endothelium and myocardium.

Circulating white blood cell count correlates with left ventricular indices independently of the extent of risk area for myocardial infarction after successful reperfusion. International journal

Tadahisa Uesugi, Kohichiro Iwasaki, Masaaki Murakami, Keizo Yamamoto, Shozo Kusachi, Takashi Murakami, Masanari Obika, Shigeshi Kamikawa, Toru Miyoshi, Yasushi Shiratori

Acta cardiologica 59 ( 5 ) 533 - 9 2004.10

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: To test the hypothesis that the circulating white blood cell (WBC) and neutrophil counts are related to left ventricular (LV) indices in patients with the same risk area for acute myocardial infarction (AMI), we examined 100 consecutive AMI patients who had the culprit lesion at segment 6 according to the American Heart Association classification and who underwent successful direct coronary angioplasty. METHODS AND RESULTS: The LV ejection fraction (LVEF), end-systolic volume (LVESVI) and end-diastolic volume index (LVEDVI) were obtained by left ventriculography performed 4 weeks after AMI onset. Univariate analysis disclosed that the counts of WBC and neutrophils on admission, and the maximal WBC count correlated negatively with LVEF (r = -0.46, p < 0.001; r = -0.54, p < 0.001 and r = -0.40, p < 0.001, respectively) and positively with LVESVI (r = 0.43, p < 0.001; r = 0.55, p < 0.001, and r = 0.30, p < 0.01, respectively). The counts of WBC and neutrophils on admission also correlated with LVEDVI (r = 0.28, p < 0.01 and r = 0.41, p < 0.001, respectively). Multivariate analysis with other clinical and angiographic factors revealed that the counts of WBC and neutrophils on admission correlated with LVEF (partial correlation coefficient, r = -0.37, p < 0.001 and r = -0.52, p < 0.001, respectively), with LVESVI (r = 0.34, p < 0.01 and r = 0.56, p < 0.001, respectively) and with LVEDVI (r = 0.28, p < 0.01 and r = 0.44, p < 0.001, respectively). The maximal WBC count also correlated with LVEF and LVESVI (r = -0.40, p < 0.001 and r = 0.21, p < 0.05, respectively). CONCLUSION: The present study revealed that the circulating WBC count correlated with function and volume of the successfully reperfused LV after AMI in patients with the same risk area for AMI, indicating that the WBC count needs to be taken into consideration as an independent factor affecting the LV indices.

新規ラットlink protein geneの同定と特性 Lp3/Hapln3(Identification and Characterization of a novel rat link protein gene: Lp3/Hapln3)

小川弘子, 廣畑聡, 三好亨, 村上充, 白鳥康史, 大橋俊孝, 二宮善文, 草地省蔵, 佐田政隆

Circulation Journal 68 ( Suppl.III ) 938 - 938 2004.10

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