Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot.

Abstract

BACKGROUND:

Patients with Tetralogy of Fallot with pulmonary stenosis (ToF/PS), the most common form of cyanotic congenital heart disease (CHD), develop adverse right ventricular (RV) remodeling, leading to late heart failure and arrhythmia. We recently demonstrated that overactive β-adrenergic receptor signaling inhibits cardiomyocyte division in ToF/PS infants, providing a conceptual basis for the hypothesis that treatment with the β-adrenergic receptor blocker, propranolol, early in life would increase cardiomyocyte division. No data are available in ToF/PS infants on the efficacy of propranolol as a possible novel therapeutic option to increase cardiomyocyte division and potentially reduce adverse RV remodeling.

METHODS:

Using a randomized, double-blind, placebo-controlled trial, we will evaluate the effect of propranolol administration on reactivating cardiomyocyte proliferation to prevent adverse RV remodeling in 40 infants with ToF/PS. Propranolol administration (1 mg/kg po QID) will begin at 1 month of age and last until surgical repair. The primary endpoint is cardiomyocyte division, quantified after 15N-thymidine administration with Multi-isotope Imaging Mass Spectrometry (MIMS) analysis of resected myocardial specimens. The secondary endpoints are changes in RV myocardial and cardiomyocyte hypertrophy.

CONCLUSION:

This trial will be the first study in humans to assess whether cardiomyocyte proliferation can be pharmacologically increased. If successful, the results could introduce a paradigm shift in the management of patients with ToF/PS from a purely surgical approach, to synergistic medical and surgical management. It will provide the basis for future multi-center randomized controlled trials of propranolol administration in infants with ToF/PS and other types of CHD with RV hypertension.

CLINICAL TRIAL REGISTRATION:

The trial protocol was registered at clinicaltrials.gov (NCT04713657).

• Authors: Samar R El Khoudary, Anthony Fabio, Jessie W Yester, Matthew L Steinhauser, Adam B Christopher, Frank Gyngard, Phillip S Adams, Victor O Morell, Melita Viegas, Jose P Da Silva, Luciana F Da Silva, Mario Castro-Medina, Andrew McCormick, Miguel Reyes-Múgica, Michelle Barlas, Honghai Liu, Dawn Thomas, Niyatie Ammanamanchi, Rachel Sada, Megan Cuda, Elizabeth Hartigan, David K Groscost, Bernhard Kühn
• Journal: International journal of cardiology (Int J Cardiol) Vol. 339 Pg. 36-42 (09 15 2021) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 34265312 (Publication Type: Clinical Trial Protocol, Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Receptors, Adrenergic, beta-2

Topics

• Humans
• Infant
• Myocytes, Cardiac
• Pulmonary Valve Stenosis
• Randomized Controlled Trials as Topic
• Receptors, Adrenergic, beta-2
• Tetralogy of Fallot (diagnostic imaging, surgery)
• Ventricular Remodeling