Mechanistic clinical trial of β-blocker administration for reactivating cardiomyocyte division in Tetralogy of Fallot

法洛四联症中β受体阻滞剂重新激活心肌细胞分裂的机制临床试验

基本信息

批准号：
10427418
负责人：
Bernhard Kuhn
金额：
$ 67.75万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427418
关键词：
Academy Age-Months American Arrhythmia Birth Cardiac Myocytes Cardiac Surgery procedures Cardiovascular system Cell division Cells Characteristics Chest Child Clinical Clinical Trials Congenital Abnormality DNA Data Development Diagnosis Diagnostic Double-Blind Method Drug Kinetics Echocardiography Foundations Future Generations Goals Growth Guidelines Health Heart Heart Hypertrophy Heart failure Human Hypertension Hypertrophy Hypoplastic Left Heart Syndrome Infant Infant Mortality Institutes Interruption Investigation Isotopes Journals Label Long-Term Care Methods Molecular Myocardial Myocardium New England Operative Surgical Procedures Outcome Pathologic Pathology Patients Pediatric Hospitals Pediatrics Persons Pharmacology Physiologic intraventricular pressure Placebo Control Placebos Proliferating Propranolol Publishing Pulmonary Valve Stenosis Randomized Randomized Controlled Trials Receptor Signaling Regenerative research Research Research Infrastructure Right Ventricular Hypertrophy Risk Safety Sampling Signal Transduction Strawberry nevus Testing Tetralogy of Fallot Thymidine Time Ventricular Visit Work beta-adrenergic receptor cardiac magnetic resonance imaging cardiac regeneration clinical center cohort congenital heart disorder editorial experience follow-up improved in vivo infancy innovation mass spectrometric imaging neonatal mice novel preclinical study prevent primary outcome randomized trial recruit repaired response right ventricular failure right ventricular remodeling secondary outcome spelling stable isotope success ventricular hypertrophy

项目摘要

ABSTRACT Right ventricular remodeling leads to serious complications in congenital heart disease. Congenital heart disease (CHD) is the most common birth defect. Due to improved diagnostics and surgery, 1 million patients live in the US with CHD, many of whom develop right ventricular (RV) heart failure. Our understanding of the underlying pathobiology and therapies are very limited, creating a pressing research need. Patients with Tetralogy of Fallot with pulmonary stenosis (ToF/PS), the most common form of cyanotic CHD and the form most available for research, develop adverse RV remodeling, leading to heart failure and arrhythmias. It has been thought that the RV remodeling is a consequence of surgical repair. However, we have recently shown that ToF/PS patients have decreased heart muscle cell (cardiomyocyte) division, indicating the possibility of developing a new mechanistic paradigm of RV heart failure development in CHD. Increased β-adrenergic receptor signaling decreases cardiomyocyte proliferation in ToF/PS. We have taken an innovative research approach, using administration of thymidine labeled with a stable isotope tag (15N-thymidine). Proliferating cells incorporate 15N-thymidine into their DNA, which we visualize with Multi- isotope Imaging Mass Spectrometry (MIMS) analysis of pieces of RV myocardium. By detecting cardiomyocytes labeled with 15N-thymidine, MIMS revealed decreased cardiomyocyte division in ToF/PS. Our mechanistic investigations showed that overactive β-adrenergic receptor signaling inhibits cardiomyocyte division. Our pre-clinical studies in neonatal mice and cardiomyocytes from ToF/PS infants demonstrate that administration of the β-adrenergic receptor blocker propranolol increases cardiomyocyte division. β-blockers have been used in ToF/PS, but this use has been limited to preventing hypercyanotic spells. We propose a randomized, placebo-controlled (1:1), double-blinded, single-center clinical trial of 40 ToF/PS infants to test the mechanistic hypothesis that β-blocker administration in ToF/PS infants increases cardiomyocyte division and decreases RV hypertrophy. The recent success of propranolol administration in infantile hemangiomas and American Academy of Pediatrics guidelines provide the necessary pharmacokinetics and safety experience to support these studies in infants. As primary outcome, we will quantify cardiomyocyte division using our innovative 15N-thymidine labeling approach with MIMS readout. As a secondary outcome, we will characterize changes in RV and cardiomyocyte hypertrophy. This initial single-center trial will provide the foundation for future multi-center randomized controlled trials of propranolol administration in infants with ToF/PS and other types of CHD at risk for RV remodeling, such as hypoplastic left heart syndrome, with the long-term goal of preventing RV failure. The Heart Institute at Children’s Hospital of Pittsburgh is ideal for this research. We have achieved the lowest mortality of infant cardiac surgery and have the research infrastructure to carry out the proposed work.

抽象的右心室重构会导致先天性心脏病的严重并发症。心脏病 (CHD) 是最常见的出生缺陷，由于诊断和手术的改进，导致 100 万人罹患心脏病。据我们了解，生活在美国的冠心病患者中，许多人出现了右心室 (RV) 心力衰竭。潜在的病理学和治疗方法非常有限，因此患者的研究需求非常迫切。法洛四联症伴肺动脉瓣狭窄 (ToF/PS)，最常见的紫绀型 CHD 形式大多数可用于研究，发展不良的 RV 重塑，导致心力衰竭和心律失常。人们认为右心室重塑是手术修复的结果，但我们最近证明了这一点。 ToF/PS 患者的心肌细胞 (cardiomy cell) 分裂减少，表明可能开发冠心病右心室心力衰竭发展的新机械范例。 ToF/PS 中β-肾上腺素能受体信号传导的增加可降低心肌细胞增殖。采用创新的研究方法，使用稳定同位素标签标记的胸苷 (15N-胸苷) 增殖细胞将 15N-胸苷掺入其 DNA 中，我们使用 Multi- 进行可视化。通过检测对 RV 心肌进行同位素成像质谱 (MIMS) 分析。用 15N-胸苷标记的心肌细胞，MIMS 显示 ToF/PS 中心肌细胞分裂减少。机制研究表明过度活跃的 β-肾上腺素能受体信号传导抑制心肌细胞我们对新生小鼠和 ToF/PS 婴儿心肌细胞的临床前研究表明， β-肾上腺素能受体阻滞剂普萘洛尔的给药可增加心肌细胞分裂。已用于 ToF/PS，但这种用途仅限于预防紫绀性发作。对 40 名 ToF/PS 婴儿进行随机、安慰剂对照 (1:1)、双盲、单中心临床试验 ToF/PS 婴儿服用 β 受体阻滞剂可增加心肌细胞的机制假设心得安在婴儿中的应用最近取得了成功。血管瘤和美国儿科学会指南提供了必要的药代动力学和支持婴儿这些研究的安全经验作为主要结果，我们将量化心肌细胞。作为次要结果，我们使用我们创新的 15N-胸苷标记方法和 MIMS 读数。该初步单中心试验将描述 RV 和心肌细胞肥大的变化。为未来对患有普萘洛尔的婴儿进行多中心随机对照试验奠定基础 ToF/PS 和其他类型的 CHD 有 RV 重构风险，例如左心发育不全综合征，预防 RV 故障的长期目标。匹兹堡儿童医院心脏研究所是这项研究的理想场所，我们已经实现了这一目标。婴儿心脏手术死亡率最低，并拥有开展拟议工作的研究基础设施。