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

• 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
• 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

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 右心室重塑导致先天性心脏病的严重并发症。先天性 心脏病（CHD）是最常见的先天缺陷。由于诊断和手术的改进，100万 患者居住在美国的冠心病，其中许多人会出现右心（RV）心力衰竭。我们的理解 潜在的病理生物学和疗法中的疗法非常有限，从而产生了紧迫的研究需求。患者 Fallot技术与肺狭窄（TOF/PS），最常见的蓝毒冠心和形式 大多数可用于研究，会产生不良的RV重塑，导致心力衰竭和心律不齐。它有 当时认为RV重塑是手术修复的结果。但是，我们最近显示了 TOF/PS患者的心肌细胞（心肌细胞）分裂改善了，表明可能性 在CHD中开发了RV心力衰竭发展的新机械范式。 β-肾上腺素受体信号的增加会下降TOF/PS的心肌细胞增殖。我们有 采用了一种创新的研究方法，使用用稳定同位素标签标记的胸苷 （15n-胸腺定）。增殖细胞将15N-胸腺氨酸掺入其DNA中，我们将其视为多数 同位素成像质谱法（MIMS）分析RV心肌片。通过检测 MIMS标记为15n-胸苷的心肌细胞显示，TOF/PS的心肌细胞分裂降低。我们的 机械研究表明，过度活跃的β-肾上腺素受体信号传导抑制心肌细胞 分配。我们在TOF/PS婴儿的新生小鼠和心肌细胞中进行的临床前研究表明 β-肾上腺素受体阻滞剂普萘洛尔的给药增加了心肌细胞分裂。 β受体阻滞剂 已在TOF/PS中使用，但此用途仅限于防止过度透明咒语。我们提出了一个 随机，安慰剂对照（1：1），40个TOF/PS婴儿的双盲，单中心临床试验进行测试 TOF/PS婴儿的β受体阻滞剂给药增加了心肌细胞的机理假设 分裂并减少RV肥大。普萘洛尔给药的最新成功 血管瘤和美国儿科指南提供必要的药代动力学和 安全经验以支持婴儿的这些研究。作为主要结果，我们将量化心肌细胞 使用MIMS读数的创新15N-胸腺定标签方法进行划分。作为次要结果，我们 将表征RV和心肌细胞肥大的变化。最初的单中心试验将提供 未来的多中心随机对照试验的基础 TOF/PS和其他有RV重塑风险的CHD（例如左心脏综合征） 预防RV故障的长期目标。 匹兹堡儿童医院的心脏研究所是这项研究的理想选择。我们已经实现了 婴儿心脏手术的死亡率最低，并具有研究基础设施来进行拟议的工作。