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).

Keywords: Beta-blocker; Cardiomyocyte division; Congenital heart disease; Tetralogy of Fallot; Ventricular hypertrophy.

Conflict of interest statement

Disclosures

BK and HL are inventors on a patent application (PCT/US20/41808; 62/873,483) filed by the University Pittsburgh that covers the use of β-blockers for preventing increased cardiomyocyte cytokinesis failure in pediatric patients. The authors declare that they have no further competing financial or other interests.

Copyright © 2021 Elsevier B.V. All rights reserved.

Figures

Fig. 1.

The proposed study will quantify the basic mechanisms of heart growth, i.e., cardiomyocyte division and hypertrophy. The measurement for the primary outcome is cardiomyocyte division, and for the secondary outcome, cardiomyocyte and myocardial hypertrophy. β-Adrenergic receptor (β-AR) signaling inhibits cardiomyocyte division and stimulates cardiac hypertrophy. Cardiomyocyte division is the mechanism of proliferation, which counterbalances cardiac hypertrophy. If the results of the primary outcome show that cardiomyocyte division is increased, this may counteract cardiomyocyte hypertrophy and, thereby, reduce adverse cardiac hypertrophy.

Fig. 2.

Diagram of the nial design depicts temporal relationship of assessments to study drug administration. The administration of 15N-thymidine enables direct quantification of cardiomyocyte division to compare propranolol and placebo at the end of the study period. Echocardiograms and cardiac MRIs will be performed at baseline (before begin of propranolol administration) and at the end of the study period (24 h after the last dose of propranolol) to avoid biasing the researchers who might recognize a lower heart rate in propranolol-ueated study patients.

Fig. 3.

The effect size of propranolol-increased cardiomyocyte division in mice and available results defining the similar proportion of binucleated caidiomyocytes in infants with ToF/PS provide an estimate of the anticipated effect size. (A) Mice naturally have increased cardiomyocyte cytokinesis failure, leading to the formation of 63% bi- and multi-nucleated cardiomyocytes by eight days after birth. Propranolol administration decreases the cytokinesis failure, resulting in 50% bi- and multi-nucleated cardiomyocytes, a 13% decrease. (B) Infants with ToF/PS have increased cardiomyocyte cytokinesis failure, leading to the development of 54% multinucleated cardiomyocytes by 6 months after birth. Because the underlying molecular mechanisms are the same in humans and in mice, the propranolol-induced decrease of cytokinesis failure is anticipated to be proportional to the effect in mice, reducing the percentage of bi- and multinucleated cardiomyocytes from 54 to 43% (indicated in the red dotted bar). Humans with no heart disease have 20% multinucleated cardiomyocytes, shown in the black bar, indicating that the anticipated effect size is a conseivative estimate. Results are from Liu et al., Sci Transi Med 2019.