掲載種別：研究論文（学術雑誌）  

In the published article, an author name was incorrectly written as Madoka Sawai. The correct spelling is Madoka Sawada. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

DOI： 10.3389/fcvm.2024.1369831

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12928-023-00956-5

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1001/jamacardio.2023.1650

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 34-year-old woman with pulmonary arterial hypertension (PAH) was admitted to the hospital. She had been diagnosed with PAH three years earlier and treated with triple vasodilator therapy. She was positive for anti-U1 ribonucleoprotein antibodies but did not show any other symptoms associated with autoimmune diseases. Corticosteroid and cyclophosphamide therapy was administered, suspecting the involvement of immunological pathophysiology. After 3 weeks, the mean pulmonary artery pressure decreased from 50 to 38 mmHg without any change in the vasodilators. Immunosuppressive therapy was effective in this patient with PAH with an anti-U1 ribonucleoprotein-antibody-positive response and might be an option for patients with these specific features.

DOI： 10.2169/internalmedicine.1407-22

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記述言語：英語  

BACKGROUND: Impella 5.0 is currently used as a temporary mechanical circulatory support device in cardiogenic shock (CS). However, Impella 5.0 implantation for the systemic right ventricle (sRV) has not been well documented. CASE SUMMARY: A 50-year-old man with atrial switch for dextro-transposition of the great arteries was transferred to our hospital for the treatment of embolic acute myocardial infarction of the left main trunk lesion with CS. To stabilize haemodynamics, we implanted Impella 5.0 via the left subclavian artery in the sRV. After optimal medical therapy initiation and gradual weaning of Impella 5.0, Impella 5.0 was successfully explanted. An electrocardiogram was obtained, which showed complete right branch block with a QRS duration of 172 ms. Acute invasive haemodynamic evaluation of cardiac resynchronization therapy (CRT) pacing showed that dP/dt increased from 497 to 605 mmHg/s (21.7% improvement), and hybrid cardiac resynchronization therapy defibrillator (CRTD) with a sRV epicardial lead was subsequently implanted. The patient was discharged without inotropic support. DISCUSSION: Coronary artery embolism is a rare but serious complication of dextro-transposition of the great arteries after atrial switch operations. Impella 5.0 implantation is a feasible bridge strategy for refractory CS due to sRV failure. Although CRT implantation in patients with sRV is controversial, an acute invasive haemodynamic evaluation can help assess its potential benefits.

DOI： 10.1093/ehjcr/ytad214

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記述言語：英語  

UNLABELLED: A 46-year-old woman with a history of repeated thromboembolic stroke and anti-phospholipid antibody syndrome was referred to our hospital. Saline contrast transthoracic echocardiography showed that microbubbles appeared in the left atrium within 4 heartbeats. Thus, she was initially suspected as having a patent foramen ovale with associated paradoxical embolism. However, no evidence of patent foramen ovale or atrial septal defect could be found using transesophageal echocardiography. Saline contrast transesophageal echocardiography showed that microbubbles flowed into the left atrium through the left superior pulmonary vein. Ultimately, she was diagnosed as having a pulmonary arteriovenous malformation located at the upper left pulmonary lobe using contrast computed tomography and pulmonary artery angiography. Pulmonary arteriovenous malformations are typically located in the lower lobe of either lung and, in bubble studies, contrast appears in the left atrium after 4 heartbeats. Here, the pulmonary arteriovenous malformation was in the upper lobe, and contrast appeared in the left atrium at an earlier time point: one associated with patent foramen ovale. These findings made it difficult to differentiate the two diseases initially. This case suggests that pulmonary arteriovenous malformation should be carefully considered, even if microbubbles appear in the left atrium early on a saline contrast transthoracic echocardiograph. LEARNING OBJECTIVE: Pulmonary arteriovenous malformation occasionally appears in the upper lobe. In these cases, microbubbles may appear in the left atrium after detection in the right atrium with a time-course that is suggestive of a patent foramen ovale. Therefore, diagnosis should be carefully confirmed by using other multimodal imaging tests, such as transesophageal echocardiography, contrast computed tomography, or pulmonary artery angiography.

DOI： 10.1016/j.jccase.2022.11.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Limited data exist on risk factors for the long-term outcome of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). We focused on the index of pulmonary vascular disease (IPVD), an assessment system for pulmonary artery pathology specimens. The IPVD classifies pulmonary vascular lesions into four categories based on severity: (1) no intimal thickening, (2) cellular thickening of the intima, (3) fibrous thickening of the intima, and (4) destruction of the tunica media, with the overall grade expressed as an additive mean of these scores. This study aimed to investigate the relationship between IPVD and the long-term outcome of CHD-PAH. METHODS: This retrospective study examined lung pathology images of 764 patients with CHD-PAH aged <20 years whose lung specimens were submitted to the Japanese Research Institute of Pulmonary Vasculature for pulmonary pathological review between 2001 and 2020. Clinical information was collected retrospectively by each attending physician. The primary endpoint was cardiovascular death. RESULTS: The 5-year, 10-year, 15-year, and 20-year cardiovascular death-free survival rates for all patients were 92.0%, 90.4%, 87.3%, and 86.1%, respectively. The group with an IPVD of ≥2.0 had significantly poorer survival than the group with an IPVD <2.0 (P = .037). The Cox proportional hazards model adjusted for the presence of congenital anomaly syndromes associated with pulmonary hypertension, and age at lung biopsy showed similar results (hazard ratio 4.46; 95% confidence interval: 1.45-13.73; P = .009). CONCLUSIONS: The IPVD scoring system is useful for predicting the long-term outcome of CHD-PAH. For patients with an IPVD of ≥2.0, treatment strategies, including choosing palliative procedures such as pulmonary artery banding to restrict pulmonary blood flow and postponement of intracardiac repair, should be more carefully considered.

DOI： 10.3389/fcvm.2023.1212882

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 59-year-old man with a high level of antinuclear antibody received nivolumab and ipilimumab plus chemotherapy for lung cancer. Two weeks after the second course, he was admitted with a fever and severe fatigue. Laboratory studies showed elevated markers of myocardial damage, and a myocardial biopsy showed inflammatory cell infiltration, damaged myocardial fibers. Myocarditis was diagnosed as an immune-related adverse event (irAE), and high-dose corticosteroids were initiated. However, his cardiac function rapidly worsened, and he died on the fifth day after admission. There is no established treatment strategy for fulminant myocarditis as an irAE, and the further exploration of viable treatment strategies is required.

DOI： 10.2169/internalmedicine.0505-22

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dual-energy computed tomography (DECT) is a promising technique for the assessment of the lung perfused blood volume (LPBV) in the lung parenchyma. This study was performed to compare the LPBV by DECT of patients with pulmonary hypertension (PH) and controls and to evaluate the association between the LPBV and the perfusion ratio derived by lung perfusion scintigraphy. This study involved 45 patients who underwent DECT (25 patients with PH and 20 controls). We measured the total LPBV and distribution of the LPBV in each lung. The total LPBV was significantly lower in the PH group than the control group (38 ± 9 vs. 45 ± 8 HU, p = 0.024). Significant differences were observed between the LPBV of the upper lung of the PH and control groups (34 ± 10 vs. 47 ± 10, p = 0.021 and 37 ± 10 vs. 47 ± 8, p &lt; 0.001). A significant correlation was observed between the LPBV and the lung perfusion scintigraphy. A lower total LPBV and lower LPBV of the upper lung as detected by DECT might be specific findings of PH.

DOI： 10.3390/life12050684

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語  

We report a case of ventricular septal defect (VSD) in which we attempted to treat pulmonary arterial hypertension (PAH) with the goal of VSD closure in an adult with suspected Eisenmenger syndrome in childhood. Four years previously (age 41 years), she was referred to our department due to repeated hemoptysis requiring further treatment of PAH. We started combination therapy with several pulmonary vasodilators. Two years later, her pulmonary vascular resistance (PVR) was improved but still not at the level where VSD closure was possible. To control the increased PA flow resulting from intensive PAH treatment and to reduce the risk of hemoptysis, we performed pulmonary artery banding (PAB). As the risk of hemoptysis decreased, a prostacyclin analog was introduced, and the dose was increased. More than 1 year after PAB, active vasoactivity testing became positive, suggesting that the pulmonary vascular lesion was now "reversible". We performed VSD closure and atrial septal defect creation even though her PVR was still high. After the operation, her exercise capacity was remarkably improved. We suggest that stepwise surgical repair with pulmonary vasodilators is an important treatment option for select patients with VSD with severe PAH. <Learning objective: Advances in pulmonary arterial hypertension (PAH) treatment have led to the use of a "treat-and-repair" strategy to close the intracardiac shunt after PAH treatment in select patients with adult congenital heart disease. In our case, ventricular septal defect (VSD) closure was achieved with stepwise surgical repair and a combination of pulmonary vasodilators, even though long-standing severe PAH with persistent hemoptysis remained. Even after a long period of exposure to high blood flow, this strategy may reduce pulmonary vascular resistance and permit eventual closure of the VSD.>.

DOI： 10.1016/j.jccase.2021.02.013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Previous studies have suggested an association between uric acid (UA) and the severity of pulmonary arterial hypertension (PAH), but it is unknown whether UA contributes to disease pathogenesis.The aim of this study was to determine the prognostic value of circulating UA in the era of current management of PAH and to investigate the role of UA in pulmonary vascular remodelling.Serum UA levels were determined in idiopathic, heritable or anorexigen PAH at baseline and first re-evaluation in the French Pulmonary Hypertension Network. We studied protein levels of xanthine oxidase (XO) and the voltage-driven urate transporter 1 (URATv1) in lungs of control and PAH patients and of monocrotaline (MCT) and Sugen/hypoxia (SuHx) rats. Functional studies were performed using human pulmonary artery smooth muscle cells (PA-SMCs) and two animal models of pulmonary hypertension (PH).High serum UA levels at first follow-up, but not at baseline, were associated with a poor prognosis. Both the generating enzyme XO and URATv1 were upregulated in the wall of remodelled pulmonary arteries in idiopathic PAH patients and MCT and SuHx rats. High UA concentrations promoted a mild increase in cell growth in idiopathic PAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, oxonic acid-induced hyperuricaemia did not aggravate MCT-induced PH in rats. Finally, chronic treatment of MCT and SuHx rats with benzbromarone mildly attenuated pulmonary vascular remodelling.UA levels in idiopathic PAH patients were associated with an impaired clinical and haemodynamic profile and might be used as a non-invasive indicator of clinical prognosis during follow-up. Our findings also indicate that UA metabolism is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH.

DOI： 10.1183/13993003.00332-2020

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The latest guideline from the European Society of Cardiology and European Respiratory Society recommends initial combination therapy with oral pulmonary arterial hypertension (PAH)-specific drugs in PAH patients with World Health Organization functional class (WHO-FC) II or III. However, whether this initial combination therapy improves hemodynamics and clinical failure events regardless of the combination of PAH-specific drugs remains unknown. This study was designed to evaluate whether the initial combination therapy with macitentan plus riociguat or macitentan plus selexipag showed equal efficacy in reducing pulmonary vascular resistance (PVR) 8 months after administration. Methods and Results: This study is a multicenter randomized control trial. PAH subjects with WHO-FC II or III will be randomized (1 : 1) into initial combination therapy with either macitentan plus riociguat or macitentan plus selexipag, and will be observed 8 months after the initiation of treatment. The primary endpoint will be the difference in the change ratio of PVR from baseline to after 8 months of treatment. Conclusions: The SETOUCHI-PH study will clarify whether initial combination therapy with macitentan plus riociguat or macitentan plus selexipag results in equal reductions in PVR 8 months after administration.

DOI： 10.1253/circrep.CR-20-0133

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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担当区分：筆頭著者   記述言語：英語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Transition to pulmonary arterial hypertension (PAH)-specific drugs is considered in patients with PAH and chronic thromboembolic pulmonary hypertension who do not respond to combination therapy or who experience side effects to the combination drugs. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide. Therefore, transition from a phosphodiesterase type 5 inhibitor (PDE5i), which requires nitric oxide to exert its effects, to riociguat might be effective. The length of time of washout periods for transition is important because haemodynamic instability sometimes occurs during these periods or during transition with no washout period. METHOD: We investigated the feasibility of transitioning from a PDE5i to riociguat without washout periods by monitoring haemodynamics under right heart catheterisation in six patients with PAH and one with chronic thromboembolic pulmonary hypertension who had already received dual- or triple-combination therapy. RESULTS: Reasons for transition were headache caused by a PDE5i in three patients, and an inadequate response to combination therapy in four. Transition was successful in all patients, with no haemodynamic instability observed. Pulmonary vascular resistance (from 797 ± 241 to 518 ± 230 dyne/s/cm-5) and systemic blood pressure (from 121 ± 13 to 100 ± 15 mmHg) were significantly reduced immediately after transition. There were no significant differences in the tricuspid regurgitation pressure gradient or systemic blood pressure during the post-transition and follow-up periods. Headaches caused by a PDE5i were diminished after transition to riociguat. CONCLUSIONS: Transition from a PDE5i to riociguat without a washout period is safe. This transition may be a viable option for patients with headaches caused by a PDE5i, or who have an inadequate response to combination therapy that includes a PDE5i.

DOI： 10.1016/j.hlc.2019.01.013

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic-active Epstein-Barr virus infection (CAEBV) is a rare disease that can lead to pulmonary arterial hypertension (PAH). However, the treatment for CAEBV-associated PAH has not been established. We discuss a case of improved pulmonary hypertension after chemotherapy in a patient with CAEBV-associated PAH. A 44-year old man was admitted to our hospital because of an abnormal electrocardiogram and liver dysfunction detected by annual medical examination. Echocardiography showed a dilated right ventricle and an estimated right ventricular systolic pressure of 92 mmHg. Right heart catheterization revealed a mean pulmonary arterial pressure of 45 mmHg and pulmonary vascular resistance of 9.8 Wood units. Laboratory examination showed granular lymphocytes and 91% natural killer cells in lymphocyte subsets in peripheral blood. We diagnosed the patient as having CAEBV-associated PAH. After two cycles of chemotherapy without PAH-specific drugs, echocardiography showed improvement in the dilated right ventricle and an estimated right ventricular systolic pressure of 59 mmHg. Right heart catheterization revealed a mean pulmonary arterial pressure of 27 mmHg and pulmonary vascular resistance of 2.4 Wood units. Chemotherapy may improve pulmonary hypertension in patients with CAEBV-associated PAH.

DOI： 10.1536/ihj.19-419

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The waiting period for lung transplantation (LT) is approximately 3 years in Japan. The prognosis of patients with pulmonary arterial hypertension (PAH) awaiting LT is poor without LT. Patients at the present center often survive in the long term after registration for LT. The aim of this study was to elucidate why some patients survive in the long term by investigating changes in pulmonary artery pressure (PAP) after registration, and medication used.Methods and Results:This study involved 57 patients with PAH who were enrolled in a registry for LT at Okayama University Hospital. We divided patients into 3 groups according to outcome: LT (n=27); death without LT (n=21); and survival without LT (n=9). The median interval from PAH diagnosis to epoprostenol treatment was shorter in the survival group (58 days) than in the LT group (378 days) and death group (545 days). Eight patients in the survival group, 13 in the LT group, and 13 in the death group underwent right heart catheterization after registration. Percent change in mean PAP after registration was significantly greater in the survival group (-32%) than in the LT group (-13%) and death group (1%; P<0.01). CONCLUSIONS: Even after LT registration, patients who received epoprostenol infusion soon after diagnosis of PAH often had marked reduction in PAP and long-term survival without LT.

DOI： 10.1253/circj.CJ-19-0784

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Treatment goals in pulmonary arterial hypertension (PAH) include improved quality of life and exercise capacity as well as improved life prognosis. In our experience, only remarkable reductions in pulmonary arterial pressure (PAP) improve long-term survival. Lowering PAP could contribute to reverse remodeling by reducing hemodynamic stress. Proper and prompt use of PAH-specific drugs lowers PAP in patients with PAH. Upfront combination therapy with different PAH-specific drugs and quickly establishing high-dose epoprostenol lowers PAP sufficiently to improve prognosis in patients with PAH. PAH is often a comorbidity with other diseases including congenital heart defect, connective tissue diseases, and pulmonary arterial aneurysm. It is essential in these conditions to lower PAP to allow the next treatment strategy. In this report, we review modern treatments to lower PAP in patients with PAH.

DOI： 10.1016/j.jjcc.2018.04.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/ehjci/jey033

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Recent advances in pulmonary arterial hypertension (PAH)-specific drugs have dramatically changed the therapeutic strategy for PAH. A strategy that includes 'treatment' with PAH-specific drugs initially and then 'repair' by closure of the cardiac defect (i.e. 'treat and repair') was devised, and has been attempted, in patients with PAH associated with a cardiac defect. Case presentation: We present three cases of severe PAH associated with a ventricular septal defect (VSD) in adult patients who were initially treated with PAH-specific drugs followed by VSD closure. Two of the patients were treated with a combination of an endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor, and intravenous prostacyclin before VSD closure. The third patient was treated with an ERA and pulmonary artery banding before VSD closure. After 12 months of anti-PAH treatment, the pulmonary vascular resistance index and the ratio of the pulmonary vascular index to the systemic vascular resistance index decreased to levels that allowed VSD closure. At the mid- and long-term follow-up measurements after surgical closure of the VSD, the mean pulmonary artery pressure had markedly decreased. Discussion: Our case series suggests that the treat-and-repair strategy is a promising approach for adult patients with severe PAH associated with VSD.

DOI： 10.1093/ehjcr/yty033

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pulmonary artery (PA) dilatation is usually observed in patients with pulmonary hypertension (PH), but a PA aneurysm (PA diameter > 40mm) is rare. The difference between characteristics of patients with and those without progression of PA diameter remains poorly understood. We assessed the changes in PA diameter in patients with PH coexisting with and without a PA aneurysm. METHODS: We investigated the changes in PA diameter by multi-detector computed tomography performed twice with an interval of more than one year in 44 patients with PH. Seventeen patients had a PA aneurysm and 27 patients did not have a PA aneurysm at baseline. RESULTS: The median follow-up period was 3.6 years. All patients received medical or invasive treatment for PH. At baseline, main PA diameters were 52±15mm in patients with a PA aneurysm and 33±3mm in patients without a PA aneurysm. Mean PA pressure was higher in patients with a PA aneurysm than in those without a PA aneurysm (61±15mmHg vs. 51±16mmHg, p=0.04). At follow-up, mean PA pressure significantly decreased in both patients with a PA aneurysm (44±11mmHg) and patients without a PA aneurysm (41±18mmHg). Main PA diameter significantly increased in patients with a PA aneurysm (65±28mm, change ratio: 23.3%), while it did not increase in patients without a PA aneurysm (32±3mm, change ratio: -3.1%). CONCLUSIONS: PA dilatation progressed in patients with a PA aneurysm despite treatment of PH. The progression of PA dilatation is independent of reduction of PA pressure by PH treatment.

DOI： 10.1016/j.jjcc.2017.11.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Adverse cardiovascular events after lung transplantation (LT) increase the mortality in patients with pulmonary arterial hypertension (PAH). Long-term intravenous prostacyclin is the usual treatment in severe patients with PAH, but it may increase the risk of hemorrhage due to its antiplatelet aggregation effect or thrombocytopenia. We investigated the impact of length of intravenous prostacyclin therapy on acute adverse cardiovascular events including hemorrhagic complication after LT. We retrospectively compared the incidence of adverse events (death, intrathoracic hematoma and bleeding, cardiac congestion or shock, cerebral infarction and pulmonary embolism) within 30 days after LT between no/short-term (median 0.6 years, n = 13) and long-term (median 3.7 years, n = 15) intravenous prostacyclin groups. There were no differences in the dose of intravenous prostacyclin and pulmonary artery pressure between the two groups. Among 22 adverse events (0.8 ± 1.1 events/patient), 4 events occurred in the no/short-term intravenous prostacyclin group and 18 occurred in the long-term intravenous prostacyclin group. The event rate per patient in the long-term intravenous prostacyclin group (1.2 ± 1.3 events/patient) was significantly higher than that in the no/short-term intravenous prostacyclin group (0.3 ± 0.5 events/patient) (P < 0.05). Intrathoracic hematoma and bleeding was the most frequent adverse event (9 events, 41%). Preoperative long-term intravenous prostacyclin therapy increases acute adverse cardiovascular events after LT in patients with PAH.

DOI： 10.1536/ihj.16-389

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1536/ihj.17-282

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jjcc.2017.02.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) are currently treated with combination therapy of PAH-targeted drugs. Reverse right ventricular (RV) remodeling after lung transplantation (LTx) in patients with end-stage PAH despite combination therapy of PAH-targeted drugs has not been fully elucidated.Methods and Results:A total of 136 patients, including 32 with PAH, underwent LTx from 1998 to 2014. We enrolled 12 consecutive patients with PAH treated with combination therapy of PAH-targeted drugs who underwent LTx and retrospectively analyzed the temporal and serial changes in hemodynamics and echocardiography before LTx and at 3 and 12 months after LTx. Before LTx, the RV was markedly dilated with substantially reduced RV fractional area change (RVFAC). At 3 months after LTx, pulmonary artery pressure, pulmonary vascular resistance and RV stroke work index were significantly decreased, while left ventricular stroke work index was increased. RV size assessed by echocardiography also significantly decreased and RVFAC improved. At 12 months after LTx, RVFAC was further increased and RV wall thickness was decreased significantly. CONCLUSIONS: Although severe RV dysfunction and dilation were observed in patients with end-stage PAH despite combination therapy of PAH-targeted drugs, RV function and morphology were improved after reduction of RV pressure load by LTx.

DOI： 10.1253/circj.CJ-16-0838

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/CIRCIMAGING.116.005839

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A treatment strategy for patients with pulmonary hypertension (PH) and atrial septal defect (ASD) remains unclear. This study was designed to evaluate the effects of initial repair of ASD followed by treatment with PH-specific drugs in patients with PH and ASD. Eligible patients receive transcatheter ASD closure followed by treatment with bosentan and sildenafil. Right heart catheterization is performed at baseline and at 12, 24 and 48 weeks. The primary endpoint is change in pulmonary artery pressure and pulmonary vascular resistance from baseline to follow-up. This study should provide valuable information to establish a therapeutic strategy for PH and ASD.

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs.

DOI： 10.1097/FJC.0000000000000352

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A therapeutic strategy in patients with atrial septal defect (ASD) and significant pulmonary arterial hypertension (PAH) remains controversial. This study aimed to assess the effect of PAH-specific medications and subsequent transcatheter shunt closure (ie, a treat and repair strategy) in these patients. METHODS AND RESULTS: Among 646 patients with ASD, 22 patients (mean age of 56±20 years) who had PAH [mean pulmonary artery pressure ≥25 mmHg and pulmonary vascular resistance (PVR) ≥3 Wood units] underwent successful transcatheter ASD closure. Prior to the procedure, 8 patients received PAH-specific medications (PHM group) and 14 patients did not (non-PHM group). Initially, the PHM group had higher PVR compared with non-PHM group (9.6±3.8 vs. 4.2±1.0 Wood units, P<0.01). After treatment with PAH-specific medications, PVR in this group decreased to 4.0±0.8 Wood units (P<0.01). No adverse events were observed in either the PHM or non-PHM group during or after the transcatheter procedure. In the PHM group, during a treatment period of 52±48 months, the World Health Organization Functional Classification significantly improved (3.0±0.5 to 2.0±0.0, P<0.01), as well as in the non-PHM group (2.1±0.6 to 1.5±0.5, P<0.01). CONCLUSIONS: Treat and repair strategy provided substantial improvement and no worsening of the WHO-FC, even in patients with ASD and significant PAH. Long-term hemodynamic follow-up is mandatory to evaluate the ultimate efficacy and safety of this new strategy.

DOI： 10.1253/circj.CJ-15-0599

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pulmonary arterial hypertension (PAH) is characterized by elevation of pulmonary artery pressure caused by pulmonary vasoconstriction and vascular remodeling, which leads to right heart failure and death. Epoprostenol (prostaglandin I2) has a potent short-acting vasodilator property, and intravenous continuous epoprostenol is therefore used for treatment of PAH. Here we review evidence for the usefulness of intravenous continuous epoprostenol therapy in patients with PAH. Epoprostenol therapy is effective in idiopathic PAH patients and in patients with PAH associated with connective tissue disease, portal hypertension or congenital heart diseases, but it is not effective in patients with pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. High-dose epoprostenol therapy markedly improved hemodynamics in some patients with PAH, possibly due to reverse remodeling of pulmonary arteries. This therapy has several side effects and complications such as headache, hypotension and catheter-related infections. Intravenous continuous epoprostenol is an effective treatment, but there are still some problems to be resolved.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The release of endogenous prostacyclin (PGI2) is depressed in patients with pulmonary arterial hypertension (PAH). PGI2 replacement therapy by epoprostenol infusion is one of the best treatments available for PAH. Here, we provide an overview of the current clinical data for epoprostenol. Epoprostenol treatment improves symptoms, exercise capacity, and hemodynamics, and is the only treatment that has been shown to reduce mortality in patients with idiopathic PAH (IPAH) in randomized clinical trials. We have reported that high-dose epoprostenol therapy (>40 ng/kg/min) also results in marked hemodynamic improvement in some patients with IPAH. High-dose epoprostenol has a pro-apoptotic effect on PAH-PASMCs via the IP receptor and upregulation of Fas ligand (FasL) in vitro. However, long-term intravenous administration of epoprostenol is sometimes associated with catheter-related infections and leads to considerable inconvenience for the patient. In the future, the development of new routes of administration or the development of powerful PGI2 analogs, IP-receptor agonists, and gene and cell-based therapy enhancing PGI2 production with new routes of administration is required.

DOI： 10.2147/VHRM.S50368

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Platelet-derived growth factor (PDGF) is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Imatinib, a PDGF-receptor tyrosine kinase inhibitor, improved hemodynamics, but serious side effects and drug discontinuation are common when treating PAH. A drug delivery system using nanoparticles (NPs) enables the reduction of side effects while maintaining the effects of the drug. We examined the efficacy of imatinib-incorporated NPs (Ima-NPs) in a rat model and in human PAH-pulmonary arterial smooth muscle cells (PASMCs). Rats received a single intratracheal administration of PBS, FITC-NPs, or Ima-NPs immediately after monocrotaline injection. Three weeks after monocrotaline injection, intratracheal administration of Ima-NPs suppressed the development of pulmonary hypertension, small pulmonary artery remodeling, and right ventricular hypertrophy in the rat model of monocrotaline-induced PAH. We also examined the effects of imatinib and Ima-NPs on PDGF-induced proliferation of human PAH-PASMCs by (3)H-thymidine incorporation. Imatinib and Ima-NPs significantly inhibited proliferation after 24 hours of treatment. Ima-NPs significantly inhibited proliferation compared with imatinib at 24 hours after removal of these drugs. Delivery of Ima-NPs into lungs suppressed the development of MCT-induced PAH by sustained antiproliferative effects on PAS-MCs.

DOI： 10.1536/ihj.14-338

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

RATIONALE: Epoprostenol is a first-line therapy for patients with pulmonary arterial hypertension (PAH) in World Health Organization functional class IV who often have low cardiac output and hypotension. However, initiation of epoprostenol can cause hemodynamic collapse in these vulnerable patients. Inotropic agent support may prevent the hemodynamic instability caused by initiation of epoprostenol; however, a protocol for supportive therapy has not been established. OBJECTIVES: To assess the reliability and prognostic effects of dobutamine and dopamine support at the initiation of epoprostenol therapy in patients with PAH. METHODS: We initiated epoprostenol therapy in 71 patients with PAH. Hemodynamics at the initiation of epoprostenol were measured by right heart catheterization. We initiated dobutamine when a patient's mixed venous oxygen saturation was less than 60% or cardiac index was less than 2.0 L/min/m(2) or when right ventricular failure was clinically suspected. We initiated dopamine when a patient's systolic blood pressure was less than 90 mm Hg or urine volume was less than 20 ml/h. MEASUREMENTS AND MAIN RESULTS: At the initiation of epoprostenol, dobutamine and/or dopamine were required to support 46 patients according to protocol. Eight patients died during the hospitalization and one patient received a living-donor lobar lung transplant after the initiation of epoprostenol therapy. Neither inotropic agent was an independent risk factor for short-term mortality (dobutamine: hazard ratio, 1.63; 95% confidence interval, 0.33-8.11; dopamine: hazard ratio, 0.22; 95% confidence interval, 0.03-1.70). Sixty-two patients were discharged for home infusion of epoprostenol. Transplant-free survival rates at 5 years were 80.0% for patients who did not require inotropic support at the start of epoprostenol and 76.6% for patients with who did require dopamine and/or dobutamine support (P = 0.45). CONCLUSIONS: Temporary use of dobutamine and dopamine appears to be safe for hemodynamic support at the initiation of epoprostenol therapy for selected patients with PAH with low cardiac output and hypotension. The protocol presented here requires validation at other centers.

DOI： 10.1513/AnnalsATS.201308-268OC

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Idiopathic pulmonary arterial hypertension (IPAH) is characterized by pulmonary vascular remodeling. We have reported that high-dose prostaglandin I2 (PGI2) therapy markedly improved hemodynamics in IPAH patients and that PGI2 induced apoptosis of pulmonary artery smooth muscle cells obtained from IPAH patients. PGI2 is thought to have reverse remodeling effects, although it has not been histologically confirmed. In a case series, we examined the reverse pulmonary vascular remodeling effects of PGI2 in lung tissues obtained from an IPAH patient treated with high-dose PGI2 and an IPAH patient not treated with PGI2. Apoptotic cells were detected in small pulmonary arteries of the IPAH patient treated with high-dose PGI2 but not in those from the IPAH patient not treated with PGI2. Media of peripheral pulmonary arteries were thick in the IPAH patient not treated with PGI2. On the other hand, media of peripheral pulmonary arteries were thin in the IPAH patient treated with high-dose PGI2. The single case report suggested that high-dose PGI2 therapy has the potential for reverse pulmonary vascular remodeling by induction of apoptosis and reduction of medial hypertrophy. Accumulation of cases is needed for the application to generalized effect of high-dose PGI2. <Learning objective: Reverse pulmonary vascular remodeling would provide further improvement in patients with IPAH. High-dose PGI2 therapy has the potential for reverse pulmonary vascular remodeling in patients with IPAH.>.

DOI： 10.1016/j.jccase.2013.12.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pulmonary vascular remodeling with idiopathic pulmonary arterial hypertension (IPAH) is associated with impaired apoptosis of pulmonary artery smooth muscle cells (PASMCs). We have reported that high-dose prostaglandin I2 (PGI2) therapy markedly improved hemodynamics in IPAH patients. The therapy is thought to reverse vascular remodeling, though the mechanism is unclear. The aim of this study is to assess proapoptotic effects of PGI2 on PASMCs obtained from IPAH patients. METHODS: We investigated proapoptotic effects of PGI2 in PAH-PASMCs by TUNEL assays, caspase-3,-7 assays and transmission electron microscopy. We examined the expression of Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, in PAH-PASMCs. We measured the serum FasL levels in IPAH patients treated with PGI2. RESULTS: TUNEL-positive, caspase-3, 7-active cells and fragmentation of the nucleus were detected in PAH-PASMCs treated with PGI2. The percentage of apoptotic cells induced by PGI2 at a high concentration was higher than that induced by PGI2 at a low concentration. PCR-array analysis revealed that PGI2 upregulated the FasL gene in PAH-PASMCs, and we measured the FasL expression by quantitative RT-PCR and Western blotting. PGI2 significantly increased the mRNA level of FasL by 3.98 fold and the protein level of FasL by 1.70 fold. An IP receptor antagonist inhibited the induction of apoptosis, elevation of cyclic AMP and upregulation of FasL by PGI2. Serum FasL level had a significant positive correlation with PGI2 dose in IPAH patients treated with PGI2. CONCLUSIONS: PGI2 has proapoptotic effects on PAH-PASMCs via the IP receptor and upregulation of FasL.

DOI： 10.1016/j.ijcard.2011.09.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.carpath.2012.12.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Acute vasoreactivity testing for patients with pulmonary arterial hypertension (PAH) has been reported to be useful to identify patients with sustained beneficial response to oral calcium-channel blockers (CCBs), but there is a risk of exacerbation during the testing with oral CCBs. Therefore, we developed a testing method utilizing intravenous nicardipine, a short-acting CCB, and examined the safety and usefulness of acute vasoreactivity testing with nicardipine in PAH patients. Acute vasoreactivity testing with nicardipine was performed in 65 PAH patients. Nicardipine was administered by short-time continuous infusion (1 μg·kg⁻¹·min⁻¹ for 5 min and 2 μg·kg⁻¹·min⁻¹ for 5 min) followed by bolus injection (5 μg/kg). Hemodynamic responses were continuously measured using a right heart catheter. Acute responders were defined as patients who showed a decrease in mean pulmonary artery pressure of at least 10 mmHg to an absolute level below 40 mmHg with preserved or increased cardiac output. Two acute responders and sixty-three non-acute responders were identified. There was no hemodynamic instability requiring additional inotropic agents or death during the testing. Acute responders had good responses to long-term oral CCBs. The acute vasoreactivity testing with nicardipine might be safe and useful for identifying CCB responders in PAH patients.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Takotsubo cardiomyopathy (TTC), also known as transient left ventricular (LV) apical ballooning syndrome, is characterized by transient LV dysfunction. We present the case of a 72-year-old man who was diagnosed as having TTC after surgery for two lung tumors. The patient was treated with induction chemoradiotherapy (CRT) followed by pulmonary resections for double primary non-small cell lung cancers (NSCLC): cT4N1M0 disease in the right lung and cT2N0M0 in the left lung. Induction CRT was performed. A right upper lobectomy was initially performed, and a left upper divisionectomy was subsequently performed. At 3 days after the second surgery, he developed dyspnea and general fatigue accompanied by a T-wave inversion on electrocardiography (ECG). An echocardiogram revealed akinesis at the apex with a 30 % ejection fraction. He was diagnosed as having TTC and recovered with supportive care. This case is the first report of TTC occurring after tri-modality therapy for NSCLC.

DOI： 10.1007/s11748-012-0058-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Remodeling of the pulmonary artery by an inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) is problematic in the treatment of idiopathic pulmonary arterial hypertension (IPAH). Effective treatment that achieves reverse remodeling is required. The aim of this study was to assess the pro-apoptotic effects of imatinib, a platelet-derived growth factor (PDGF)-receptor tyrosine kinase inhibitor, on PASMCs obtained from patients with IPAH. METHODS: PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. Cellular proliferation was assessed by (3)H-thymidine incorporation. Pro-apoptotic effects of imatinib were examined using TUNEL and caspase-3,7 assays and using transmission electron microscopy. RESULTS: Treatment with imatinib (0.1 to 10 μg/mL) significantly inhibited PDGF-BB (10 ng/mL)-induced proliferation of PASMCs from IPAH patients. Imatinib (1 μg/mL) did not induce apoptosis in quiescent IPAH-PASMCs, but it had a pro-apoptotic effect on IPAH-PASMCs stimulated with PDGF-BB. Imatinib did not induce apoptosis in normal control PASMCs with or without PDGF-BB stimulation. PDGF-BB induced phosphorylation of Akt at 15 min, and Akt phosphorylation was inhibited by imatinib in IPAH-PASMCs. Akt-I-1/2 (1 μmol/L), an Akt inhibitor, in the presence of PDGF-BB significantly increased apoptotic cells compared with the control condition. Thus, Akt-I-1/2 could mimic the effects of imatinib on PASMCs. CONCLUSION: Imatinib has anti-proliferative and pro-apoptotic effects on IPAH-PASMCs stimulated with PDGF. The inhibitory effect of imatinib on Akt phosphorylation induced by PDGF plays an important role in the pro-apoptotic effect.

DOI： 10.1016/j.ijcard.2011.02.024

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 50-year-old man diagnosed with liver cirrhosis type C was referred to our hospital because of right heart failure with pulmonary hypertension. Echocardiography revealed enlargement of the right atrium and ventricle with severe tricuspid regurgitation. The peak flow velocity of tricuspid regurgitation by continuous wave Doppler echocardiography was 452 cm/s. Right heart catheterization demonstrated severe pulmonary hypertension [pulmonary arterial pressure (PAP) systolic/diastolic/mean = 73/20/41 mmHg and pulmonary vascular resistance (PVR) = 509 dyn s cm-5] with portal hypertension. We diagnosed the patient as having portopulmonary hypertension (PoPH). Although we treated the patient with a prostacyclin analog, tricuspid regurgitation velocity was increased to 480 cm/s four years after the start of the therapy. To select drugs for the treatment of PoPH, we performed an acute vasoreactivity test of sildenafil during right heart catheterization. Since single administration of sildenafil (20 mg) decreased PAP (93/30/55-77/27/44 mmHg) and PVR (908-833 dyn s cm-5), we added sildenafil (20 mg, t.i.d.) to the prostacyclin analog. Tricuspid regurgitation velocity decreased to 403 cm/s one year after the addition of sildenafil. An acute vasoreactivity test of sildenafil during right heart catheterization was useful for the decision of the drug to be used in the treatment of PoPH.

DOI： 10.1016/j.jccase.2011.04.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The appropriate dose range of epoprostenol is thought to be 25-40 ng · kg(-1) · min(-1) based on the results of previous studies showing that epoprostenol therapy reduced mean pulmonary artery pressure (mPAP) by 12-22% and pulmonary vascular resistance (PVR) by 32-53% compared with baseline values in patients with idiopathic pulmonary arterial hypertension (IPAH). However, the efficacy of treatment of IPAH patients with epoprostenol >40 ng · kg(-1) · min(-1) has not been determined and this was the aim of the present study. METHODS AND RESULTS: The study group comprised 16 consecutive patients, none of whom died; 2 dropped out because they could not be titrated up as needed to the highest effective epoprostenol dose. Hemodynamics were evaluated in 14 IPAH patients who received high-dose epoprostenol monotherapy. The mean epoprostenol dosage was 107 ± 40 ng · kg(-1) · min(-1) (range, 54-190 ng · kg(-1) · min(-1)) and the mean duration of high-dose epoprostenol therapy was 1,355 ± 627 days (range, 582-2,410 days). Significant decreases from baseline values were seen in mPAP (from 66 ± 16 to 47 ± 12 mmHg, P<0.001) and PVR (from 21.6 ± 8.3 to 6.9 ± 2.9 Wood units, P<0.001). Compared with the baseline state, high-dose epoprostenol therapy reduced mPAP by 30% and PVR by 68%. CONCLUSIONS: The present study suggests high-dose epoprostenol therapy is a new treatment strategy for IPAH.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/CIR.0b013e3181e037c1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterized by inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) leading to occlusion of pulmonary arterioles. Inhibition of platelet-derived growth factor (PDGF) signaling is starting to garner attention as a targeted therapy for IPAH. We assessed the inhibitory effects of simvastatin, a 3-hydroxy-3-methylglutanyl coenzyme A reductase inhibitor, on PDGF-induced proliferation and migration of PASMCs obtained from 6 patients with IPAH who underwent lung transplantation. PDGF stimulation caused a significantly higher growth rate of PASMCs from patients with IPAH than that of normal control PASMCs as assessed by (3)H-thymidine incorporation. Simvastatin (0.1 micromol/L) significantly inhibited PDGF-induced cell proliferation of PASMCs from patients with IPAH but did not inhibit proliferation of normal control cells at the same concentration. Western blot analysis revealed that simvastatin significantly increased the expression of cell cycle inhibitor p27. PDGF significantly increased the migration distance of IPAH-PASMCs compared with that of normal PASMCs, and simvastatin (1 micromol/L) significantly inhibited PDGF-induced migration. Immunofluorescence staining revealed that simvastatin (1 micromol/L) inhibited translocation of Rho A from the cytoplasm to membrane and disorganized actin fibers in PASMCs from patients with IPAH. In conclusion, simvastatin had inhibitory effects on inappropriate PDGF signaling in PASMCs from patients with IPAH.

DOI： 10.1097/FJC.0b013e3181c0419c

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: To determine the effect of intravenous administration of nicorandil on slow coronary flow (SCF) phenomenon in patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: In a preliminary study, 6 mg of nicorandil showed optimal efficacy for vasodilatation without causing significant haemodynamic instability. In the main study, a total of 408 patients were randomly assigned to receive intravenous administration of 6 mg of nicorandil immediately before PCI. The number of patients in the nicorandil group was 206 [acute coronary syndrome (ACS): 47, non-ACS: 159] and that in the control group was 202 (ACS: 61, non-ACS: 141). Nicorandil significantly decreased the incidence of post-procedural SCF phenomenon in both the ACS and non-ACS groups. The rate of target vessel revascularization (TVR) was significantly lower in the nicorandil group than in the control group in ACS patients. CONCLUSION: Our simple procedure prevented SCF phenomenon not only in patients with ACS but also in patients with non-ACS without any adverse effect. Additionally our procedure reduced the rate of TVR in patients with ACS.

DOI： 10.1093/eurheartj/ehp077

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The pulmonary vascular changes induced by epoprostenol in patients with idiopathic pulmonary artery hypertension (IPAH) have not been reported by a clinical study. METHODS AND RESULTS: Analysis 1 compared the wedged pulmonary angiography (PAG) findings prior to initiation of epoprostenol therapy (n=24) with those after initiation (n=16). Analysis 2 compared the PAG findings prior to and after initiation of epoprostenol therapy (n=9) in the same pulmonary arteries in the same subjects. In analysis 1, a "cotton grass-like" stain originating from the peripheral pulmonary vessels (each vessel could not be distinguished on angiography) was not observable in any of 24 cases before initiation of epoprostenol therapy, but was visible in 13 of 16 cases after (p<0.0001). In analysis 2, the diameter of subsegmental arteries changed from 3.0+/-0.9 mm (mean +/- standard deviation) to 3.7+/-1.2 mm (p=0.004) between the 2 time periods. Cotton grass-like stain was not found in any cases before epoprostenol, but in all 9 cases after chronic use (p=0.004). CONCLUSIONS: After initiating epoprostenol therapy, cotton grass-like stain appeared in most patients with IPAH. The possible reason for this is release of severe vasoconstriction and/or emergence of neovascularization.

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Combination therapy has been proposed in treatment algorithms for idiopathic pulmonary arterial hypertension (IPAH), so the additional effects of bosentan in IPAH patients already treated with high-dose epoprostenol (EPO) was evaluated in the present study. METHODS AND RESULTS: Bosentan (62.5 mg twice daily) was administered to 8 IPAH patients already being treated with high-dose EPO (average dose 99.6+/-43.4 ng . kg(-1) . min(-1)). Hemodynamics were assessed at baseline and at 2 days and then 1 year after the initiation of bosentan. Because a remarkable elevation of mixed venous oxygen saturation was observed at the initiation of bosentan, the dosage of EPO was reduced in 7 patients (from 99.6+/-43.4 to 82.8+/-31.3 ng . kg(-1) . min(-1), p<0.05). There was a significant decrease from the baseline value for systolic pulmonary artery pressure (80.1+/-19.3 to 66.8+/-16.5 mmHg, p<0.05). These effects were maintained for 1 year without progression of PAH in 6 patients whose condition had been stabilized at baseline. CONCLUSIONS: The additional use of bosentan for IPAH patients whose condition has been stabilized by high-dose EPO is safe and effective.

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Most of the patients with pulmonary arterial hypertension (PAH) receiving intravenous epoprostenol have experienced catheter-related infections during long-term treatment. Catheter hub was reported to be the most important source of catheter-related infections. To prevent the catheter-related infections, we have introduced a closed hub system and compared the incidence of catheter-related infections with that in patients using a non-closed hub system. METHODS AND RESULTS: We evaluated the results obtained on 24 occasions in 20 patients with PAH between June 1999 and December 2005. On 11 occasions, a non-closed hub system was used and on 13 cases a closed hub system. We classified the catheter-related infection into a catheter-related bloodstream infection (CRBSI) group or a tunnel infection group based on the pathway of bacteria. The CRBSI rate was 0.89 per 1,000 catheter days in the non-closed hub system group vs 0.10 per 1,000 catheter days in the closed hub system group. Kaplan-Meier analysis showed that the risk of CRBSI significantly decreased in the closed hub system group. None of the patients died as a direct consequence of catheter-related infection during the study period. CONCLUSIONS: We successfully prevented CRBSI by using a closed hub system.

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 56-year-old man was admitted to our hospital because of mass lesions at the levels of the right upper and lower lung regions on a chest plain radiograph. Chest computed tomography showed tumors which projected from the pleura of the right upper and lower lung fields. One particular point of interest was the complete separation of the tumors from each other. Malignant mesothelioma was diagnosed by biopsy of the pleura via echogram. Both chemotherapy and radiotherapy were administered because of brain metastasis and direct rib invasion. Under this combined therapy, sudden anemia and hypotension appeared due to splenic hemorrhage, which suggested splenic metastasis of the malignant mesothelioma. Multiple metastases in, for example, the spleen, brain, lung, liver, duodenum, small intestine, kidney, adrenal gland, vertebra, thyroid gland, and lymph nodes were confirmed by autopsy. Distant metastasis is rare for malignant mesothelioma, and we report here a case of splenic metastasis with splenic hemorrhage in malignant mesothelioma.

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