{Reference Type}: Clinical Trial Protocol
{Title}: Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot.
{Author}: El Khoudary SR;Fabio A;Yester JW;Steinhauser ML;Christopher AB;Gyngard F;Adams PS;Morell VO;Viegas M;Da Silva JP;Da Silva LF;Castro-Medina M;McCormick A;Reyes-Múgica M;Barlas M;Liu H;Thomas D;Ammanamanchi N;Sada R;Cuda M;Hartigan E;Groscost DK;Kühn B;
{Journal}: Int J Cardiol
{Volume}: 339
{Issue}: 0
{Year}: 09 2021 15
{Factor}: 4.039
{DOI}: 10.1016/j.ijcard.2021.07.020
{Abstract}: 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.<BR>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.<BR>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.<BR>The trial protocol was registered at clinicaltrials.gov (NCT04713657).