期刊
INTERNATIONAL JOURNAL OF CARDIOLOGY
卷 339, 期 -, 页码 36-42出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.ijcard.2021.07.020
关键词
Congenital heart disease; Tetralogy of Fallot; Cardiomyocyte division; Beta-blocker; Ventricular hypertrophy
资金
- National Institutes of Health [NIH R01HL155597, R01HL151415, R01HL106302]
- Department of Pediatrics
- Richard King Mellon Institute for Pediatric Research at UPMC Children's Hospital of Pittsburgh
- Leducq Foundation [15CVD03]
- NIH [T32HD071834]
- Sang Park Endowed Fellowship Fund for Cardiology Fellows research
- NIH, National Center for Advancing Translational Sciences (NCATS) [UL1 TR001857, KL2 TR001856, TL1 TR001858]
- HeartFest [DP2CA216362]
This study aims to evaluate the use of propranolol in infants with ToF/PS to increase cardiomyocyte division and potentially reduce adverse RV remodeling. The trial design includes a randomized, double-blind, placebo-controlled methodology with the primary endpoint being cardiomyocyte division.
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 p-adrenergic receptor signaling inhibits cardiomyocyte division in ToF/PS infants, providing a conceptual basis for the hypothesis that treatment with the beta-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 N-15-thymidine administration with Multi-isotope Imaging Mass Spectrometry (MIMS) analysis of resected myocardial specimens. The secondary end-points 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.
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