Cardiomyocytes in congenital heart disease: Overcoming cytokinesis failure in tetralogy of Fallot

Central MessageBlockage of beta-adrenergic signaling counteracts cytokinesis failure and promotes cardiomyocyte proliferation through ECT2 upregulation in infants with ToF/PS.This Invited Expert Opinion provides a perspective on the following papers: 1. Sci Transl Med. 2019;11(513):eaaw6419. https://doi.org/10.1126/scitranslmed.aaw6419. 2. N Engl J 2020;382(3):291-293. https://doi.org/10.1056/NEJMcibr1913824.See Commentaries pages 1591 1592. Blockage ToF/PS. This https://doi.org/10.1056/NEJMcibr1913824. See Feature Editor's Introduction—As cardiac surgeons, we may not have journal Science Translational Medicine at top our reading lists. Therefore, associate congenital editors thought it would be appropriate to bring attention readership report by Liu colleagues,1Liu H. Zhang C.H. Ammanamanchi N. Suresh S. Lewarchik C. Rao K. et al.Control β-adrenergic receptors indicates an approach for regulating endowment.Sci 2019; 11: eaaw6419Crossref PubMed Scopus (33) Google Scholar which appeared late 2019 received comment The New England Journal early 2020.2Yutzey K.E. Cytokinesis, beta-blockers, heart disease.N 2020; 382: 291-293Crossref (6) preliminary evidence that patients tetralogy Fallot demonstrate myocardial administration standard beta-blockade help restore successful cytokinesis. Cytokinesis is typically replication nuclear material without cell division resulting multinucleated cells. Why this potentially important? In theory, leads reduction total myocyte number higher percentage myocytes respond less favorably both normal abnormal stress growth stimuli. set up milieu more prone later life. It appears do know if occurs left ventricle, other conotruncal abnormalities or even forms disease. But these 2 theoretical suppositions are true, then disposal simple, cheap medicine treat cellular-level problem might implications long-term function. pleased honored world-class expert, Dr Olaf Bergmann, provide commentary colleagues' report.3Bergmann O. Clearing mist: renewal human hearts.Eur Heart J. 40: 1037-1038Crossref (5) So put away your scalpels, debates about type timing repair, concerns preservation valve infundibulum, so forth, turn cellular level considerations enjoy Bergmann's perspective. Ronald Woods, MD, PhD Tetralogy pulmonary stenosis (ToF/PS) most common cyanotic disease involves ventricular septal defect, stenosis, overriding aorta, right hypertrophy. As myocardium restricted its ability generate new cardiomyocytes,3Bergmann Scholar,4Bergmann Zdunek Felker A. Salehpour M. Alkass Bernard al.Dynamics generation turnover heart.Cell. 2015; 161: 1566-1575Abstract Full Text PDF (497) only option condition surgical repair within first years life correct morphological abnormalities. Patients repaired ToF/PS still show increased incidence adulthood5Murphy J.G. Gersh B.J. Mair D.D. Fuster V. McGoon M.D. Ilstrup D.M. al.Long-term outcome undergoing Fallot.N 1993; 329: 593-599Crossref (823) require lifelong specialized medical care.6Baumgartner Bonhoeffer P. De Groot N.M. de Haan F. Deanfield J.E. Galie al.ESC guidelines management grown-up (new version 2010).Eur 2010; 31: 2915-2957Crossref (1733) Cardiomyocyte cycle activity rare adult heart4Bergmann Scholar,7Mollova Bersell Walsh Savla Das L.T. Park S.-y. al.Cardiomyocyte contributes young humans.Proc Natl Acad U S 2013; 110: 1446-1451Crossref (432) but can triggered pathological conditions such as infarction congestive However, does necessarily lead progression cytokinesis, last stage mitosis when cleavage furrow formed separate daughter cells from each other, premature exit, multinucleation polyploidy.8Derks W. Bergmann Polyploidy cardiomyocytes: roadblock regeneration?.Circ Res. 126: 552-565Crossref (32) Multinucleated cardiomyocytes enter frequently considered responsive regulators than diploid mononucleated cardiomyocytes.9Bersell Arab Haring B. Kuhn Neuregulin1/ErbB4 induces injury.Cell. 2009; 138: 257-270Abstract (672) Scholar, 10Kühn del Monte Hajjar R.J. Chang Y.S. Lebeche D. Keating M.T. Periostin differentiated repair.Nat 2007; 13: 962-969Crossref (498) 11Senyo S.E. Steinhauser M.L. Pizzimenti C.L. Yang V.K. Cai L. Wang al.Mammalian pre-existing cardiomyocytes.Nature. 493: 433-436Crossref (825) healthy hearts, 1% all newly generated per year.4Bergmann Although rate supposed childhood infancy,4Bergmann debated whether capacity renew already sufficient allow robust regeneration injured neonatal hearts,12Haubner Schneider Schweigmann U. Schuetz T. Dichtl Velik-Salchner al.Functional recovery after severe infarction.Circ 2016; 118: 216-221Crossref (147) documented mouse hearts.13Porrello E.R. Mahmoud A.I. Simpson E. Hill J.A. Richardson Olson E.N. Sadek H.A. Transient regenerative potential heart.Science. 2011; 331: 1078-1080Crossref (1455) colleagues1Liu investigated altered authors1Liu analyzed biopsies 12 children surgery compared specimens subjects no known heart, completed birth.4Bergmann ToF/PS, binucleation continues until second postnatal month reaching approximately 60%, 2- 3-fold increase hearts. high depend genetic alterations aberrations their consequences To directly assess activity, performed pulse-chase experiment 1 patient nonradioactive tracer 15N-thymidine age, biopsy was consecutively 7 months age. Seven percent were labeled, indicating developmental stage, divide. because there control included, possible similar been seen age-matched sample. Of note, incorporation into genomic DNA identified 20% binucleated cardiomyocytes, progressed karyokinesis (division nuclei) failed perform These experiments suggest triggers mainly failure, months. A tempting idea overcome mitotic block repairing ToF/PS-related defects. Ect2 has shown key protein triggering constriction furrow.14Gonzalez-Rosa J.M. Sharpe Field Soonpaa M.H. L.J. Burns C.E. C.G. Myocardial polyploidization creates barrier Zebrafish.Dev Cell. 2018; 44: 433-446.e7Abstract (113) showed downregulated during perinatal period gradually declines increases, rodent heart. overexpression did cycling se vitro, found 2-fold along constant S-phase arguing specific positive effect completion Using transgenic system lower expression (alpha-MHC-Cre; Ect2flox/flox), 3.2-fold day (P1). reduced 50%, critical duplication fetal development. With single-cell transcriptional analysis, findings also apply cardiomyocytes. unavailability tissue neonates, comparison Thus, one cannot exclude observed downregulation consequence difference stages being linked Hippo-Yes-associated (Hippo-Yap) pathway determines organ size tightly controlling apoptosis, regulate embryogenesis rodents.15Heallen Morikawa Y. Leach Tao G. Willerson J.T. Johnson R.L. Martin J.F. Hippo impedes regeneration.Development. 140: 4683-4690Crossref (262) 16Lin Z. von Gise Zhou Gu Ma Q. Jiang al.Cardiac-specific YAP activation improves function survival experimental murine MI model.Circ 2014; 115: 354-363Crossref (208) 17Wang Heallen heart: pivotal roles development, disease, regeneration.Nat Rev Cardiol. 15: 672-684Crossref (107) looked interaction Yap1 (yes-associated 1), terminal effector pathway, Ect2. Tead (TEA domain family member), binding partner Yap1, 5 sites promoter, showing enhancement promoter activity. Accordingly, Tead1 led decrease Hippo-Yap involved regulation Prompted pathway,18Yu F.X. Zhao Panupinthu Jewell J.L. Lian I. L.H. al.Regulation Hippo-YAP G-protein-coupled receptor signaling.Cell. 2012; 150: 780-791Abstract (955) explored several strategies affects treatment beta-blockers propranolol alprenolol improved adverse remodeling model. development difficult compare cultured organotypic slices conducted, supporting finding regulates alleviated treatment. quantifying polyploidization,19Adler C.P. [DNA growing hearts children. Biochemical cytophotometric investigations (author's transl)].Beitr Pathol. 1976; 158: 173-202Crossref Scholar,20Herget G.W. Neuburger Plagwitz R. Adler content, ploidy nuclei infarction.Cardiovasc 1997; 36: 45-51Crossref (75) could interpreted overestimated. occurring study further suggests rescues upregulating (Figure Table 1). Beta-blockers widely used pediatric hypertrophic cardiomyopathy safety profile population seems favorable.22Graham E.M. Bandisode V.M. Bradley S.M. Crawford Jr., F.A. Simsic Atz A.M. Effect preoperative use postoperative Fallot.Am 2008; 101: 693-695Abstract (10) Ideally, beta-blocker therapy delivered thereby adjunctively reducing risk developing ask why functional yet described, decades ToF.23Cumming G.R. Propranolol Fallot.Circulation. 1970; 41: 13-15Crossref (15) Moreover, randomized any dysfunction surgically treated ToF/PS.24Norozi Bahlmann Raab Alpers Arnhold J.O. Kuehne al.A prospective, randomized, double-blind, placebo controlled trial who undergone correction Fallot.Cardiol Young. 17: 372-379Crossref (51) suggested should start obtain likely generation. Later onset minor rescued divisions completing build sustainable amounts myocardium. Previous data Kühn's group demonstrated neonate events dramatically those controls.25Polizzotti B.D. Ganapathy Choudhury Bennett D.G. al.Neuregulin stimulation mice reveals therapeutic window.Sci 7: 281ra245Crossref (132) necessary complement proposed strategy measures stimulate proliferation, previously reported,26Leone Engel F.B. Advances based polyploidization.Clin (Lond). 133: 1229-1253Crossref (28) clinical improvement ToF/PS.Table 1Summary findingsCytokinesis feature ToF/PSEct2 increases cardiomyocytesThe Hippo/YAP cytokinesisBeta-blockers counteract cardiomyocytesBeta-blocker–induced endowment infarctionToF/PS, stenosis. Open table tab