• Guido P L Bossers, Marie Günthel, Diederik E van der Feen, Quint A J Hagdorn, Anne-Marie C Koop, Karel van Duijvenboden, Phil Barnett, BorgdorffMarinus A JMAJCenter for Congenital Heart Diseases, Department of Pediatric Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Vincent M Christoffels, SilljéHerman H WHHWDepartment of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., BergerRolf M FRMFCenter for Congenital Heart Diseases, Department of Pediatric Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., and Beatrijs Bartelds.
• Center for Congenital Heart Diseases, Department of Pediatric Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: g.p.l.bossers@umcg.nl.
• J. Thorac. Cardiovasc. Surg. 2022 Dec 1; 164 (6): e493e510e493-e510.

ObjectivesRight ventricular (RV) failure is a leading cause of death in patients with congenital heart disease. RV failure is kept at bay during childhood. Limited proliferation of cardiomyocytes is present in the postnatal heart. We propose that cardiomyocyte proliferation improves RV adaptation to pressure load (PL). We studied adaptation in response to increased RV PL and the role of increased cardiomyocyte cell cycle activity (CCA) in rat pups growing into adulthood.MethodsWe induced RV PL at day of weaning in rats (3 weeks; 30-40 g) by pulmonary artery banding and followed rats into adulthood (300 g). We performed histological analyses and RNA sequencing analysis. To study the effects of increased cardiomyocyte cell cycle activity, we administered neuregulin-1 (NRG1), a growth factor involved in cardiac development.ResultsPL induced an increase in CCA, with subsequent decline of CCA (sham/PL at 4 weeks: 0.14%/0.83%; P = .04 and 8 weeks: 0.00%/0.00%; P = .484) and cardiac function (cardiac index: control/PL 4 weeks: 4.41/3.29; P = .468 and 8 weeks: 3.57/1.44; P = .024). RNA sequencing analysis revealed delayed maturation and increased CCA pathways. NRG1 stimulated CCA (PL vehicle/NRG1 at 2 weeks: 0.62%/2.28%; P = .003), improved cardiac function (cardiac index control vs vehicle/NRG1 at 2 weeks: 4.21 vs 3.07/4.17; P = .009/.705) and postponed fibrosis (control vs vehicle/NRG1 at 4 weeks: 1.66 vs 4.82%/2.97%; P = .009/.078) in RV PL rats during childhood.ConclusionsRV PL during growth induces a transient CCA increase. Further CCA stimulation improves cardiac function and delays fibrosis. This proof-of-concept study shows that stimulation of CCA can improve RV adaptation to PL in the postnatal developing heart and might provide a new approach to preserve RV function in patients with congenital heart disease.Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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