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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：
10630817
负责人：
Bernhard Kuhn
金额：
$ 69.43万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10630817
关键词：
Academy Adrenergic beta-Antagonists Age Months American Arrhythmia Birth Cardiac Myocytes Cardiac Surgery procedures Cardiovascular Surgical Procedures Cell Proliferation Cell division Characteristics 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 Interruption Investigation Isotopes Journals Label Long-Term Care Medicine Methods Molecular Myocardial Myocardium New England Operative Surgical Procedures Outcome Pathologic Pathology Patients Pediatric Hospitals Pediatrics Persons Physiologic intraventricular pressure Placebo Control Placebos Proliferating Propranolol Protocols documentation 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 Supraventricular tachycardia Testing Tetralogy of Fallot Thoracic Surgical Procedures Thymidine Time Ventricular Visit Visualization 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 pharmacologic postnatal preclinical study prevent primary outcome randomized trial recruit repaired response right ventricular failure right ventricular remodeling secondary outcome skills 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.

摘要