权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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。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，100 万人生活在美国的冠心病患者中，许多人出现右心室 (RV) 心力衰竭。我们的理解潜在的病理学和治疗方法非常有限，因此产生了紧迫的研究需求。患者患有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，但会产生不良的 RV 重塑，导致心力衰竭和心律失常。它有人们认为右心室重塑是手术修复的结果。然而，我们最近展示了 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制范例。 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。我们有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-可视化对 RV 心肌碎片进行同位素成像质谱 (MIMS) 分析。通过检测用 15N-胸苷标记的心肌细胞，MIMS 显示 ToF/PS 中心肌细胞分裂减少。我们的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分配。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。 β-受体阻滞剂已用于 ToF/PS，但这种用途仅限于预防紫绀性发作。我们提出一个对 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分裂并减少 RV 肥大。普萘洛尔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这些婴儿研究的安全经验。作为主要结果，我们将量化心肌细胞使用我们创新的 15N-胸苷标记方法和 MIMS 读数进行划分。作为次要结果，我们将表征 RV 和心肌细胞肥大的变化。这个初步的单中心试验将提供为未来对婴儿进行普萘洛尔给药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。