Samar R El Khoudary1, Anthony Fabio1, Jessie W Yester2, Matthew L Steinhauser3, Adam B Christopher4, Frank Gyngard5, Phillip S Adams6, Victor O Morell7, Melita Viegas7, Jose P Da Silva7, Luciana F Da Silva7, Mario Castro-Medina7, Andrew McCormick8, Miguel Reyes-Múgica9, Michelle Barlas10, Honghai Liu2, Dawn Thomas11, Niyatie Ammanamanchi2, Rachel Sada11, Megan Cuda11, Elizabeth Hartigan11, David K Groscost4, Bernhard Kühn12. 1. Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh. 2. Division of Cardiology, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA; Pediatric Institute for Heart Regeneration and Therapeutics (I-HRT), UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA. 3. Aging Institute, University of Pittsburgh, Bridgeside Point 1, 5th Floor, 100 Technology Drive, Pittsburgh, PA 15219, USA; UPMC Heart and Vascular Institute, UPMC Presbyterian, 200 Lothrop St., Pittsburgh, PA 15213, USA. 4. Division of Cardiology, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA. 5. Center for NanoImaging, Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 65 Landsdowne St, Rm 535, Cambridge, MA 02139, USA. 6. Department of Anesthesiology and Perioperative Medicine, UPMC Children's Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, USA. 7. Pediatric Cardiothoracic Surgery, UPMC Children's Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, USA. 8. Vascular Anomaly Center, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA. 9. Division of Pediatric Pathology, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA. 10. Investigational Drug Service, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA. 11. Clinical Research Support Services (CRSS), UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA. 12. Division of Cardiology, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA; Pediatric Institute for Heart Regeneration and Therapeutics (I-HRT), UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, 4401 Penn Ave, Pittsburgh, PA 15224, USA; McGowan Institute of Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA. Electronic address: Bernhard.kuhn2@CHP.edu.
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).
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).
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