研究者詳細 - 王　英正

論文 - 王　英正

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Eight‐Year Outcomes of Cardiosphere‐Derived Cells in Single Ventricle Congenital Heart Disease 査読

Kenta Hirai, Ryusuke Sawada, Tomohiro Hayashi, Toru Araki, Naomi Nakagawa, Maiko Kondo, Kenji Yasuda, Takuya Hirata, Tomoyuki Sato, Yuki Nakatsuka, Michihiro Yoshida, Shingo Kasahara, Kenji Baba, Hidemasa Oh

13 ( 22 ) e038137 2024年11月

Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy. 国際誌

Kenta Hirai, Daiki Ousaka, Yosuke Fukushima, Maiko Kondo, Takahiro Eitoku, Yusuke Shigemitsu, Mayuko Hara, Kenji Baba, Tatsuo Iwasaki, Shingo Kasahara, Shinichi Ohtsuki, Hidemasa Oh

Science translational medicine 12 ( 573 ) 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although cardiosphere-derived cells (CDCs) improve cardiac function and outcomes in patients with single ventricle physiology, little is known about their safety and therapeutic benefit in children with dilated cardiomyopathy (DCM). We aimed to determine the safety and efficacy of CDCs in a porcine model of DCM and translate the preclinical results into this patient population. A swine model of DCM using intracoronary injection of microspheres created cardiac dysfunction. Forty pigs were randomized as preclinical validation of the delivery method and CDC doses, and CDC-secreted exosome (CDCex)-mediated cardiac repair was analyzed. A phase 1 safety cohort enrolled five pediatric patients with DCM and reduced ejection fraction to receive CDC infusion. The primary endpoint was to assess safety, and the secondary outcome measure was change in cardiac function. Improved cardiac function and reduced myocardial fibrosis were noted in animals treated with CDCs compared with placebo. These functional benefits were mediated via CDCex that were highly enriched with proangiogenic and cardioprotective microRNAs (miRNAs), whereas isolated CDCex did not recapitulate these reparative effects. One-year follow-up of safety lead-in stage was completed with favorable profile and preliminary efficacy outcomes. Increased CDCex-derived miR-146a-5p expression was associated with the reduction in myocardial fibrosis via suppression of proinflammatory cytokines and transcripts. Collectively, intracoronary CDC administration is safe and improves cardiac function through CDCex in a porcine model of DCM. The safety lead-in results in patients provide a translational framework for further studies of randomized trials and CDCex-derived miRNAs as potential paracrine mediators underlying this therapeutic strategy.

DOI： 10.1126/scitranslmed.abb3336

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新しい手術方法の開発「治療から再生へ-再生医療の進歩」小児心不全に対する再生医療のUpdate

平井健太, 大月審一, 馬場健児, 近藤麻衣子, 栄徳隆裕, 福嶋遥佑, 重光祐輔, 原真祐子, 笠原真悟, 王英正

日本小児循環器学会雑誌 36 ( Suppl.2 ) s2 - 114 2020年11月

ラット下大静脈絞扼術モデルを用いた下半身うっ血負荷が心肺に与える影響解析フォンタン循環の病態解明に向けて

逢坂大樹, 後藤拓弥, 平井健太, 笠原真悟, 王英正

日本小児循環器学会雑誌 35 ( Suppl.1 ) s1 - 382 2019年6月

ラットを用いた心臓内幹細胞経静脈投与後の血行動態および安全性評価

後藤拓弥, 逢坂大樹, 平井健太, 笠原真悟, 王英正

日本小児循環器学会雑誌 35 ( Suppl.1 ) s1 - 170 2019年6月

ラット下大静脈絞扼術による下半身うっ血負荷が心肺に与える影響およびhemodynamic preconditioningの効果検証フォンタン循環への応用にむけて

逢坂大樹, 後藤拓弥, 平井健太, 笠原真悟, 王英正

日本循環器学会学術集会抄録集 83回 CP32 - 7 2019年3月

Impact of Cardiac Progenitor Cells on Heart Failure and Survival in Single Ventricle Congenital Heart Disease. 国際誌

Toshikazu Sano, Daiki Ousaka, Takuya Goto, Shuta Ishigami, Kenta Hirai, Shingo Kasahara, Shinichi Ohtsuki, Shunji Sano, Hidemasa Oh

Circulation research 122 ( 7 ) 994 - 1005 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

RATIONALE: Intracoronary administration of cardiosphere-derived cells (CDCs) in patients with single ventricles resulted in a short-term improvement in cardiac function. OBJECTIVE: To test the hypothesis that CDC infusion is associated with improved cardiac function and reduced mortality in patients with heart failure. METHODS AND RESULTS: We evaluated the effectiveness of CDCs using an integrated cohort study in 101 patients with single ventricles, including 41 patients who received CDC infusion and 60 controls treated with staged palliation alone. Heart failure with preserved ejection fraction (EF) or reduced EF was stratified by the cardiac function after surgical reconstruction. The main outcome measure was to evaluate the magnitude of improvement in cardiac function and all-cause mortality at 2 years. Animal studies were conducted to clarify the underlying mechanisms of heart failure with preserved EF and heart failure with reduced EF phenotypes. At 2 years, CDC infusion increased ventricular function (stage 2: +8.4±10.0% versus +1.6±6.4%, P=0.03; stage 3: +7.9±7.5% versus -1.1±5.5%, P<0.001) compared with controls. In all available follow-up data, survival did not differ between the 2 groups (log-rank P=0.225), whereas overall patients treated by CDCs had lower incidences of late failure (P=0.022), adverse events (P=0.013), and catheter intervention (P=0.005) compared with controls. CDC infusion was associated with a lower risk of adverse events (hazard ratio, 0.411; 95% CI, 0.179-0.942; P=0.036). Notably, CDC infusion reduced mortality (P=0.038) and late complications (P<0.05) in patients with heart failure with reduced EF but not with heart failure with preserved EF. CDC-treated rats significantly reversed myocardial fibrosis with differential collagen deposition and inflammatory responses between the heart failure phenotypes. CONCLUSIONS: CDC administration in patients with single ventricles showed favorable effects on ventricular function and was associated with reduced late complications except for all-cause mortality after staged procedures. Patients with heart failure with reduced EF but not heart failure with preserved EF treated by CDCs resulted in significant improvement in clinical outcome. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01273857 and NCT01829750.

DOI： 10.1161/CIRCRESAHA.117.312311

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Transcoronary cell infusion with the stop-flow technique in children with single-ventricle physiology. 国際誌

Takahiro Eitoku, Kenji Baba, Maiko Kondou, Yoshihiko Kurita, Yousuke Fukushima, Kenta Hirai, Shinichi Ohtsuki, Shuta Ishigami, Shunji Sano, Hidemasa Oh

Pediatrics international : official journal of the Japan Pediatric Society 60 ( 3 ) 240 - 246 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Almost all reports on cardiac regeneration therapy have referred to adults, and only a few have focused on transcoronary infusion of cardiac progenitor cells using the stop-flow technique in children. METHODS: Intracoronary autologous cardiosphere-derived cell (CDC) transfer was conducted at Okayama University as a phase 1 clinical trial for seven patients with hypoplastic left heart syndrome between January 2011 and December 2012, and as a phase 2 clinical trial for 34 patients with single-ventricle physiology between July 2013 and March 2015. RESULTS: A total of 41 patients with single-ventricle physiology underwent transcoronary infusion of CDC with the stop-flow technique. The median age was 33 months (range, 5-70 months) and the median weight was 10.1 kg (range, 4.1-16.0 kg). Transient adverse events occurred during the procedure, including ST-segment elevation or depression, hypotension, bradycardia, and coronary artery vasospasm. All patients completely recovered. There were no major procedure-related adverse events. In this study, transcoronary infusion of CDC using the stop-flow technique was successfully completed in all patients. CONCLUSION: Transcoronary infusion of CDC using the stop-flow technique in children is a feasible and safe procedure.

DOI： 10.1111/ped.13485

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小児循環器領域におけるiPS細胞研究の展望単心室症における自己心臓内幹細胞治療の臨床と先天性心疾患におけるiPS細胞の研究の現況と展望

新井禎彦, 石神修大, 小林純子, 後藤拓弥, 佐野俊和, 大月審一, 王英正, 小谷恭弘, 黒子洋介, 笠原真悟, 佐野俊二

日本小児循環器学会雑誌 33 ( Suppl.1 ) s1 - 126 2017年7月

Cell Therapy Trials in Congenital Heart Disease. 国際誌

Hidemasa Oh

Circulation research 120 ( 8 ) 1353 - 1366 2017年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Dramatic evolution in medical and catheter interventions and complex surgeries to treat children with congenital heart disease (CHD) has led to a growing number of patients with a multitude of long-term complications associated with morbidity and mortality. Heart failure in patients with hypoplastic left heart syndrome predicated by functional single ventricle lesions is associated with an increase in CHD prevalence and remains a significant challenge. Pathophysiological mechanisms contributing to the progression of CHD, including single ventricle lesions and dilated cardiomyopathy, and adult heart disease may inevitably differ. Although therapeutic options for advanced cardiac failure are restricted to heart transplantation or mechanical circulatory support, there is a strong impetus to develop novel therapeutic strategies. As lower vertebrates, such as the newt and zebrafish, have a remarkable ability to replace lost cardiac tissue, this intrinsic self-repair machinery at the early postnatal stage in mice was confirmed by partial ventricular resection. Although the underlying mechanistic insights might differ among the species, mammalian heart regeneration occurs even in humans, with the highest degree occurring in early childhood and gradually declining with age in adulthood, suggesting the advantage of stem cell therapy to ameliorate ventricular dysfunction in patients with CHD. Although effective clinical translation by a variety of stem cells in adult heart disease remains inconclusive with respect to the improvement of cardiac function, case reports and clinical trials based on stem cell therapies in patients with CHD may be invaluable for the next stage of therapeutic development. Dissecting the differential mechanisms underlying progressive ventricular dysfunction in children and adults may lead us to identify a novel regenerative therapy. Future regenerative technologies to treat patients with CHD are exciting prospects for heart regeneration in general practice.

DOI： 10.1161/CIRCRESAHA.117.309697

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Intracoronary Cardiac Progenitor Cells in Single Ventricle Physiology: The PERSEUS (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) Randomized Phase 2 Trial. 国際誌

Shuta Ishigami, Shinichi Ohtsuki, Takahiro Eitoku, Daiki Ousaka, Maiko Kondo, Yoshihiko Kurita, Kenta Hirai, Yosuke Fukushima, Kenji Baba, Takuya Goto, Naohiro Horio, Junko Kobayashi, Yosuke Kuroko, Yasuhiro Kotani, Sadahiko Arai, Tatsuo Iwasaki, Shuhei Sato, Shingo Kasahara, Shunji Sano, Hidemasa Oh

Circulation research 120 ( 7 ) 1162 - 1173 2017年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

RATIONALE: Patients with single ventricle physiology are at high risk of mortality resulting from ventricular dysfunction. The preliminary results of the phase 1 trial showed that cardiosphere-derived cells (CDCs) may be effective against congenital heart failure. OBJECTIVE: To determine whether intracoronary delivery of autologous CDCs improves cardiac function in patients with single ventricle physiology. METHODS AND RESULTS: We conducted a phase 2 randomized controlled study to assign in a 1:1 ratio 41 patients who had single ventricle physiology undergoing stage 2 or 3 palliation to receive intracoronary infusion of CDCs 4 to 9 weeks after surgery or staged reconstruction alone (study A). The primary outcome measure was to assess improvement in cardiac function at 3-month follow-up. Four months after palliation, controls had an alternative option to receive late CDC infusion on request (study B). Secondary outcomes included ventricular function, heart failure status, somatic growth, and health-related quality of life after a 12-month observation. At 3 months, the absolute changes in ventricular function were significantly greater in the CDC-treated group than in the controls (+6.4% [SD, 5.5] versus +1.3% [SD, 3.7]; P=0.003). In study B, a late CDC infusion in 17 controls increased the ventricular function at 3 months compared with that at baseline (38.8% [SD, 7.7] versus 34.8% [SD, 7.4]; P<0.0001). At 1 year, overall CDC infusion was associated with improved ventricular function (41.4% [SD, 6.6] versus 35.0% [SD, 8.2]; P<0.0001) and volumes (P<0.001), somatic growth (P<0.0001) with increased trophic factors production, such as insulin-like growth factor-1 and hepatocyte growth factor, and quality of life, along with a reduced heart failure status (P<0.0001) and cardiac fibrosis (P=0.014) relative to baseline. CONCLUSIONS: Intracoronary infusion of CDCs after staged palliation favorably affected cardiac function by reverse remodeling in patients with single ventricle physiology. This impact may improve heart failure status, somatic growth, and quality of life in patients and reduce parenting stress for their families. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01829750.

DOI： 10.1161/CIRCRESAHA.116.310253

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Challenges to success in heart failure: Cardiac cell therapies in patients with heart diseases. 国際誌

Hidemasa Oh, Hiroshi Ito, Shunji Sano

Journal of cardiology 68 ( 5 ) 361 - 367 2016年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Heart failure remains the leading cause of death worldwide, and is a burgeoning problem in public health due to the limited capacity of postnatal hearts to self-renew. The pathophysiological changes in injured hearts can sometimes be manifested as scar formation or myocardial degradation, rather than supplemental muscle regeneration to replenish lost tissue during the healing processes. Stem cell therapies have been investigated as a possible treatment approach for children and adults with potentially fatal cardiovascular disease that does not respond to current medical therapies. Although the heart is one of the least regenerative organs in mammals, discoveries made during the past few decades have improved our understanding of cardiac development and resident stem/progenitor pools, which may be lineage-restricted subpopulations during the post-neonatal stage of cardiac morphogenesis. Recently, investigation has specifically focused on factors that activate either endogenous progenitor cells or preexisting cardiomyocytes, to regenerate cardiovascular cells and replace the damaged heart tissues. The discovery of induced pluripotent stem cells has advanced our technological capability to direct cardiac reprogramming by essential factors that are crucial for heart field completion in each stage. Cardiac tissue engineering technology has recently shown progress in generating myocardial tissue on human native cardiac extracellular matrix scaffolds. This review summarizes recent advances in the field of cardiac cell therapies with an emphasis on cellular mechanisms, such as bone marrow stem cells and cardiac progenitor cells, which show the high potential for success in preclinical and clinical meta-analysis studies. Expanding our current understanding of mechanisms of self-renewal in the neonatal mammalian heart may lead to the development of novel cardiovascular regenerative medicines for pediatric heart diseases.

DOI： 10.1016/j.jjcc.2016.04.010

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機能的単心室における冠動脈バルーン閉鎖下心筋幹細胞注入の実際

栄徳隆裕, 馬場健児, 近藤麻衣子, 栗田佳彦, 福嶋遥佑, 平井健太, 大月審一, 石上修大, 佐野俊二, 王英正

Journal of JPIC 1 ( 1 ) 13 - 19 2016年8月

記述言語：日本語出版者・発行元：(一社)日本先天性心疾患インターベンション学会

背景:心筋再生医療は,成人を対象としたものがほとんどで小児を対象とした臨床研究は極めて少ない.また当院で実施した小児の機能的単心室症に対する自己心臓内幹細胞移植の際に我々が行っている冠動脈バルーン閉鎖下心筋幹細胞注入の小児におけるまとまった報告は少ない.方法:岡山大学病院において冠動脈バルーン閉鎖下心筋幹細胞注入による自己心臓内幹細胞移植が第1相試験として2011年1月から2012年12月までに左心低形成症候群患者を対象に7例,また第2相試験として2013年7月から2015年3月までに機能的単心室症患者を対象に34例,合計41例に行われた.小児に対する冠動脈バルーン閉鎖下心筋幹細胞注入の手技,有害事象に関して検討を行った.結果:対象41例の自己心臓内幹細胞移植時の年齢と体重はそれぞれ中央値33ヵ月,10.1kgであった.冠動脈バルーン閉鎖下心筋幹細胞注入時に心電図上ST変化,血圧低下,脈拍低下,冠動脈攣縮を認めたが,いずれも一過性であり,重篤な合併症を認めず,全例で安全に手技を完遂できた.結語:冠動脈バルーン閉鎖下心筋幹細胞注入は機能的単心室症を有する小児においても安全に施行可能である.(著者抄録)

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Dissecting the Left Heart Hypoplasia by Pluripotent Stem Cells

Junko Kobayashi, Shunji Sano, Hidemasa Oh

337 - 339 2016年

記述言語：英語出版者・発行元：Springer

The genetic background of hypoplastic left heart syndrome (HLHS) is still unknown. Cardiac differentiation from pluripotent stem cells (PSCs) can recapitulate the cardiogenesis in vitro, and PSC technology could be useful to dissect the diseases with the complex mechanisms. In the past few years, some researches were reported to seek the pathogenesis of HLHS by using PSCs. This paper reports the achievements.

DOI： 10.1007/978-4-431-54628-3

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Transcoronary infusion of cardiac progenitor cells in hypoplastic left heart syndrome: Three-year follow-up of the Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single-Ventricle Physiology (TICAP) trial. 国際誌

Suguru Tarui, Shuta Ishigami, Daiki Ousaka, Shingo Kasahara, Shinichi Ohtsuki, Shunji Sano, Hidemasa Oh

The Journal of thoracic and cardiovascular surgery 150 ( 5 ) 1198 - 1207 2015年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Our aim was to assess midterm safety and clinical outcomes of intracoronary infusion of cardiosphere-derived cells (CDCs) after staged palliation in patients with hypoplastic left heart syndrome (HLHS). METHODS: In this prospective, controlled study, 14 consecutive patients with HLHS who were undergoing 2- or 3-stage surgical palliations were assigned to receive intracoronary CDC infusion 1 month after cardiac surgery (n = 7), followed by 7 patients allocated to a control group with standard care alone. The primary end point was to assess procedural feasibility and safety; the secondary end point was to evaluate cardiac function and heart failure status through 36-month follow-up. RESULTS: No complications, including tumor formation, were reported within 36 months after CDC infusion. Echocardiography showed significantly greater improvement in right ventricular ejection fraction (RVEF) in infants receiving CDCs than in controls at 36 months (+8.0% ± 4.7% vs +2.2% ± 4.3%; P = .03). These cardiac function improvements resulted in reduced brain natriuretic peptide levels (P = .04), lower incidence of unplanned catheter interventions (P = .04), and higher weight-for-age z score (P = .02) at 36 months relative to controls. As independent predictors of treatment responsiveness, absolute changes in RVEF at 36 months were negatively correlated with age, weight-for-age z score, and RVEF at CDC infusion. CONCLUSIONS: Intracoronary CDC infusion after staged procedure in patients with HLHS is safe and improves RVEF, which persists during 36-month follow-up. This therapeutic strategy may enhance somatic growth and reduce incidence of heart failure.

DOI： 10.1016/j.jtcvs.2015.06.076

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小児循環器領域と女性医師出産後も心臓血管外科研修を継続するための要件とは何か育児中に学位取得、心臓血管外科研修をして考えたこと

小林純子, 樽井俊, 藤井泰宏, 小谷恭弘, 川畑拓也, 黒子洋介, 吉積功, 新井禎彦, 笠原真悟, 王英正, 佐野俊二

日本小児循環器学会雑誌 31 ( Suppl.1 ) s1 - 134 2015年7月

Current Management of Severe CHF by Mechanical Support and Cardiac Transplant 左心低形成症候群に対する心筋幹細胞を用いた再生医療

佐野俊二, 樽井俊, 石神修大, 小林純子, 後藤拓弥, 奥山倫弘, 逢坂大樹, 黒子洋介, 馬場健児, 大月審一, 新井禎彦, 笠原真悟, 王英正

日本小児循環器学会雑誌 31 ( Suppl.1 ) s1 - 147 2015年7月

左心低形成症候群に対する心臓内幹細胞自家移植療法第I相臨床試験(TICAP trial)18ヵ月長期成績

石神修大, 樽井俊, 後藤拓弥, 奥山倫弘, 逢坂大樹, 小林純子, 藤井泰宏, 黒子洋介, 川畑拓也, 小谷泰弘, 新井禎彦, 笠原真悟, 佐野俊二, 王英正

日本心臓血管外科学会雑誌 44 ( 3 ) viii - xii 2015年5月

記述言語：日本語出版者・発行元：(NPO)日本心臓血管外科学会

左心低形成症候群14例を対象とした心臓内幹細胞自家移植療法の第I相臨床試験の結果を報告した。移植群7例においては両方向グレン手術あるいはフォンタン手術時に、右心房から採取した心臓組織から幹細胞を分離培養し、術後1ヵ月で30万個/kgの心筋幹細胞の選択的冠動脈内注入を行った。移植群で幹細胞注入に伴う心筋逸脱酵素の上昇はなく、心筋虚血症などの合併症もなかった。心臓超音波で評価した移植群の右室駆出率は、移植後3ヵ月から有意な改善を認め、18ヵ月時点では移植前と比較して平均+7.1%と効果が持続した。一方非移植群7例では+2.1%の改善にとどまり、細胞治療による改善効果が示された。またカテーテル検査値に基づく評価では、移植群で心筋弾性能やポンプ機能の改善を認め、心不全症状も著明に改善し、成長障害に対する有意な成長促進がみられた。非移植群では心不全症状の軽減や身体成長の改善は観察されなかった。

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小児心不全に対する心臓内自己幹細胞移植療法による右室リモデリング退縮効果の解明

石神修大, 後藤拓弥, 奥山倫弘, 逢坂大樹, 新井禎彦, 笠原真悟, 佐野俊二, 王英正

日本外科学会定期学術集会抄録集 115回 CR - 2 2015年4月

Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome: the TICAP prospective phase 1 controlled trial. 国際誌

Shuta Ishigami, Shinichi Ohtsuki, Suguru Tarui, Daiki Ousaka, Takahiro Eitoku, Maiko Kondo, Michihiro Okuyama, Junko Kobayashi, Kenji Baba, Sadahiko Arai, Takuya Kawabata, Ko Yoshizumi, Atsushi Tateishi, Yosuke Kuroko, Tatsuo Iwasaki, Shuhei Sato, Shingo Kasahara, Shunji Sano, Hidemasa Oh

Circulation research 116 ( 4 ) 653 - 64 2015年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

RATIONALE: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. OBJECTIVE: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. METHODS AND RESULTS: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P=0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P=0.049), improved somatic growth (P=0.0005), reduced heart failure status (P=0.003), and lower incidence of coil occlusion for collaterals (P=0.007). CONCLUSIONS: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01273857.

DOI： 10.1161/CIRCRESAHA.116.304671

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