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: 10295053
• 负责人: Bernhard Kuhn
• 金额: $ 69.96万
• 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/10295053
• 关键词: Academy; Age-Months; American; Arrhythmia; Birth; Cardiac; 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; Failure; Foundations; Future; Generations; Goals; Growth; Guidelines; Health; Heart; Heart Hypertrophy; Heart failure; Human; Hypertension; Hypertrophy; Hypoplastic Left Heart Syndrome; Image; Infant; Infant Mortality; Institutes; Interruption; Investigation; Isotopes; Journals; Label; Long-Term Care; Magnetic Resonance Imaging; Mass Spectrum Analysis; Methods; Molecular; Myocardial; Myocardium; New England; Operative Surgical Procedures; Outcome; Pathologic; Pathology; Patients; Pediatric Hospitals; Pediatrics; Pharmacology; Physiologic intraventricular pressure; 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; Ventricular Remodeling; Visit; Work; beta-adrenergic receptor; cardiac regeneration; clinical center; cohort; congenital heart disorder; editorial; experience; follow-up; improved; in vivo; infancy; innovation; neonatal mice; novel; preclinical study; prevent; primary outcome; randomized trial; recruit; repaired; response; 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.

摘要 右心室重构是先天性心脏病的严重并发症。先天性 心脏病（CHD）是最常见的出生缺陷。由于诊断和手术的改进， 生活在美国的CHD患者，其中许多人发展为右心室（RV）心力衰竭。我们的理解 潜在的病理生物学和治疗方法是非常有限的，创造了一个紧迫的研究需求。患者 法洛四联症伴肺动脉狭窄（ToF/PS）是最常见的紫绀型CHD， 大多数可用于研究，发展不良RV重塑，导致心力衰竭和心律失常。它有 一直认为右心室重塑是手术修复的结果。然而，我们最近发现， ToF/PS患者的心肌细胞（心肌细胞）分裂减少，表明 开发了CHD中RV心力衰竭发展的新机制范例。 增加的β-肾上腺素能受体信号传导降低ToF/PS中的心肌细胞增殖。我们有 采取了一种创新的研究方法，使用稳定同位素标记的胸苷 （15 N-胸苷）。增殖细胞将15 N-胸苷掺入其DNA中，我们用多- RV心肌碎片的同位素成像质谱（MIMS）分析。通过检测 用15 N-胸苷标记的心肌细胞，MIMS显示在ToF/PS中心肌细胞分裂减少。我们 机制研究表明，过度活跃的β-肾上腺素能受体信号抑制心肌细胞 师.我们在新生小鼠和ToF/PS婴儿心肌细胞中的临床前研究表明， β-肾上腺素能受体阻断剂普萘洛尔的给药增加心肌细胞分裂。β受体阻滞剂 已经在ToF/PS中使用，但这种用途仅限于防止过度紫绀发作。我们提出了一个 在40名ToF/PS婴儿中进行的随机、安慰剂对照（1：1）、双盲、单中心临床试验， ToF/PS婴儿中β受体阻滞剂给药增加心肌细胞机制假说 分裂和减少RV肥大。普萘洛尔在婴幼儿用药中的应用 血管瘤和美国儿科学会指南提供了必要的药代动力学， 安全性经验，以支持这些婴儿研究。作为主要结果，我们将量化心肌细胞 使用我们创新的15 N-胸苷标记方法与MIMS读数进行分割。作为次要结果，我们 将表征RV和心肌细胞肥大的变化。这项初步单中心试验将提供 为未来普萘洛尔在婴儿中应用的多中心随机对照试验奠定基础 ToF/PS和其他类型的CHD有RV重塑的风险，如左心发育不良综合征， 预防RV衰竭的长期目标。 匹兹堡儿童医院的心脏研究所是这项研究的理想场所。我们实现 最低的婴儿心脏手术死亡率，并拥有开展拟议工作的研究基础设施。