Wednesday, August 20, 2025 8/20/2025

Mechanistic clinical trial of Beta-blocker administration for reactivating cardiomyocyte division in Tetralogy of Fallot

Award Number: R01HL155597
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Mechanistic clinical trial of Beta-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 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $552,102 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cardiovascular Diseases Research	005	5	6/6/2025	NON-COMPETING CONTINUATION	$55,210
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cardiovascular Diseases Research	004	5	4/3/2025	NON-COMPETING CONTINUATION	$496,892
2025	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cardiovascular Diseases Research	003	4	2/20/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,001,351
2025	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	001	3	2/20/2025	NON-COMPETING CONTINUATION	-$694,289
2025	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	002	3	2/20/2025	SUPPLEMENT FOR EXPANSION	-$77,541
2025	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	2	2/20/2025	NON-COMPETING CONTINUATION	-$229,521
														Subtotal = $552,102

Issue Date FY: 2024 ( Subtotal = $681,297 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cardiovascular Diseases Research	004	4	5/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$48,293
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cardiovascular Diseases Research	002	4	4/26/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$543,291
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cardiovascular Diseases Research	003	4	4/27/2024	SUPPLEMENT FOR EXPANSION	$89,713
2024	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	001	3	4/26/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	3	4/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $681,297

Issue Date FY: 2023 ( Subtotal = $771,830 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	001	3	8/17/2023	SUPPLEMENT FOR EXPANSION	$77,541
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	3	6/8/2023	NON-COMPETING CONTINUATION	$694,289
														Subtotal = $771,830

Issue Date FY: 2022 ( Subtotal = $677,514 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	2	5/28/2022	NON-COMPETING CONTINUATION	$677,514
														Subtotal = $677,514

Issue Date FY: 2021 ( Subtotal = $699,571 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	1	6/11/2021	NEW	$699,571
														Subtotal = $699,571

Grand Total All Awards = $3,382,314

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Mechanistic clinical trial of Beta-blocker administration for reactivating cardiomyocyte division in Tetralogy of Fallot

Award Number: R01HL155597

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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