R01HL155597

Mechanistic Clinical Trial of β-Blocker Administration for Reactivating Cardiomyocyte Division in Tetralogy of Fallot

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 a 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.

Weill Medical College Of Cornell University

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

New York, New York 100654805 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the End Date has been shortened from 06/30/26 to 04/30/26 and the total obligations have increased 383% from $699,571 to $3,382,314.