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

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $89,713

## Abstract

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 mortalit...

## Key facts

- **NIH application ID:** 11044251
- **Project number:** 3R01HL155597-04S1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Bernhard Kuhn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $89,713
- **Award type:** 3
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11044251

## Citation

> US National Institutes of Health, RePORTER application 11044251, Mechanistic clinical trial of Beta-blocker administration for reactivating cardiomyocyte division in Tetralogy of Fallot (3R01HL155597-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11044251. Licensed CC0.

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