Cardiomyocyte proliferation and regeneration in congenital heart disease

Abstract

Despite advances in prenatal screening and a notable decrease in mortality rates, congenital heart disease (CHD) remains the most prevalent congenital disorder in newborns globally. Current therapeutic surgical approaches face challenges due to the significant rise in complications and disabilities. Emerging cardiac regenerative therapies offer promising adjuncts for CHD treatment. One novel avenue involves investigating methods to stimulate cardiomyocyte proliferation. However, the mechanism of altered cardiomyocyte proliferation in CHD is not fully understood, and there are few feasible approaches to stimulate cardiomyocyte cell cycling for optimal healing in CHD patients. In this review, we explore recent progress in understanding genetic and epigenetic mechanisms underlying defective cardiomyocyte proliferation in CHD from development through birth. Targeting cell cycle pathways shows promise for enhancing cardiomyocyte cytokinesis, division, and regeneration to repair heart defects. Advancements in human disease modeling techniques, clustered regularly interspaced short palindromic repeats -based genome and epigenome editing, and next-generation sequencing technologies will expedite the exploration of abnormal machinery governing cardiomyocyte differentiation, proliferation, and maturation across diverse genetic backgrounds of CHD. Ongoing studies on screening drugs that regulate cell cycling are poised to translate this nascent technology of enhancing cardiomyocyte proliferation into a new therapeutic paradigm for CHD surgical interventions.

Keywords

cardiomyocytes / congenital heart disease / proliferation / regenerative medicine

References

[1] TennantPWG, PearceMS, BythellM, Rankin J. 20-year survival of children born with congenital anomalies: a population-based study. Lancet. 2010;375(9715):649-656.

[2] SunR.-R, LiuM, LuL, ZhengY, ZhangP.-Y. Congenital heart disease: causes, diagnosis, symptoms, and treatments. Cell Biochem Biophys. 2015;72(3):857-860.

[3] DaveyB, SinhaR, LeeJH, Gauthier M, FloresG. Social determinants of health and outcomes for children and adults with congenital heart disease: a systematic review. Pediatr Res. 2021;89(2):275-294.

[4] BridaM, Lovrić D, GriselliM, GilFR, Gatzoulis MA. Heart failure in adults with congenital heart disease. Int J Cardiol. 2022;357:39-45.

[5] van der BomT, ZomerAC, ZwindermanAH, MeijboomFJ, BoumaBJ, MulderBJM. The changing epidemiology of congenital heart disease. Nat Rev Cardiol. 2011;8(1):50-60.

[6] XieD.-H, FangJ.-Q, LiuZ.-Y, et al. Epidemiology and major subtypes of congenital heart defects in Hunan Province, China. Medicine (Baltim). 2018;97(31):e11770.

[7] HuangS, XiangX, ZhuX, TianJ, PanB, ZhengM. Pediatric heart failure classification based on left ventricular ejection fraction. Pediatr Discov. 2023;1(3):e50.

[8] GelbBD, ChungWK. Complex genetics and the etiology of human congenital heart disease. Cold Spring Harb Perspect Med. 2014;4(7):a013953.

[9] OttavianiG, BujaLM. Congenital heart disease: pathology, natural history, and interventions. In: Cardiovascular Pathology. Elsevier; 2022:223-264.

[10] Kalisch-SmithJI, VedN, SparrowDB. Environmental risk factors for congenital heart disease. Cold Spring Harbor Perspect Biol. 2020;12(3):a037234.

[11] ZimmermanMS, SmithAGC, SableCA, et al. Global, regional, and national burden of congenital heart disease, 1990-2017:a systematic analysis for the Global Burden of Disease Study 2017. Lancet Child Adolesc Health. 2020;4(3):185-200.

[12] BoumaBJ, MulderBJM. Changing landscape of congenital heart disease. Circ Res. 2017;120(6):908-922.

[13] TsilimigrasDI, Oikonomou EK, MorisD, SchizasD, Economopoulos KP, MylonasKS. Stem cell therapy for congenital heart disease: a systematic review. Circulation. 2017;136(24):2373-2385.

[14] MartinezJ, Zoretic S, MoreiraA, MoreiraA. Safety and efficacy of cell therapies in pediatric heart disease: a systematic review and meta-analysis. Stem Cell Res Ther. 2020;11(1):272.

[15] IshigamiS, Ohtsuki S, TaruiS, et al. Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome: the TICAP prospective phase 1 controlled trial. Circ Res. 2015;116(4):653-664.

[16] ZhangJ.-H, WilsonGF, SoerensAG, et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res. 2009;104(4):e30-e41.

[17] RanigaK, NasirA, VoNTN, et al. Strengthening cardiac therapy pipelines using human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell. 2024;31(3):292-311.

[18] AvolioE, CaputoM, MadedduP. Stem cell therapy and tissue engineering for correction of congenital heart disease. Front Cell Dev Biol. 2015;3:39.

[19] DoyleMJ, LohrJL, ChapmanCS, Koyano-Nakagawa N, GarryMG, GarryDJ. Human induced pluripotent stem cell-derived cardiomyocytes as a model for heart development and congenital heart disease. Stem Cell Rev Rep. 2015;11(5):710-727.

[20] Lewis-IsraeliYR, Wasserman AH, GabalskiMA, et al. Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease. Nat Commun. 2021;12(1):5142.

[21] MiaoY.-F, TianL, MartinM, et al. Intrinsic endocardial defects contribute to hypoplastic left heart syndrome. Cell Stem Cell. 2020;27(4):574-589.e8.

[22] ZhongJ.-X, WangS.-B, ShenW.-B, Kaushal S, YangP.-X. The current status and future of cardiac stem/progenitor cell therapy for congenital heart defects from diabetic pregnancy. Pediatr Res. 2018;83(1-2):275-282.

[23] JulianK, GargN, HibinoN, Jain R. Stem cells and congenital heart disease: the future potential clinical therapy beyond current treatment. Curr Cardiol Rev. 2023;19(2):e310522205424.

[24] GhafarzadehM, Namdari M, EatemadiA. Stem cell therapies for congenital heart disease. Biomed Pharmacother. 2016;84:1163-1171.

[25] OhH. Cell therapy trials in congenital heart disease. Circ Res. 2017;120(8):1353-1366.

[26] SadekH, OlsonEN. Toward the goal of human heart regeneration. Cell Stem Cell. 2020;26(1):7-16.

[27] LeoneM, Magadum A, EngelFB. Cardiomyocyte proliferation in cardiac development and regeneration: a guide to methodologies and interpretations. Am J Physiol Heart Circ Physiol. 2015;309(8):H1237-H1250.

[28] MatroneG, TuckerCS, DenvirMA. Cardiomyocyte proliferation in zebrafish and mammals: lessons for human disease. Cell Mol Life Sci. 2017;74(8):1367-1378.

[29] SeccoI, GiaccaM. Regulation of endogenous cardiomyocyte proliferation: the known unknowns. J Mol Cell Cardiol. 2023;179:80-89.

[30] PorrelloER, Mahmoud AI, SimpsonE, et al. Transient regenerative potential of the neonatal mouse heart. Science. 2011;331(6020):1078-1080.

[31] KikuchiK, PossKD. Cardiac regenerative capacity and mechanisms. Annu Rev Cell Dev Biol. 2012;28(1):719-741.

[32] YutzeyKE. Cardiovascular biology: switched at birth. Nature. 2014;509(7502):572-573.

[33] SedmeraD, Thompson RP. Myocyte proliferation in the developing heart. Dev Dynam. 2011;240(6):1322-1334.

[34] YesterJW, Kühn B. Mechanisms of cardiomyocyte proliferation and differentiation in development and regeneration. Curr Cardiol Rep. 2017;19(2):13.

[35] ZhaoM.-T, YeS.-Q, SuJ, GargV. Cardiomyocyte proliferation and maturation: two sides of the same coin for heart regeneration. Front Cell Dev Biol. 2020;8:594226.

[36] GünthelM, Barnett P, ChristoffelsVM. Development, proliferation, and growth of the mammalian heart. Mol Ther. 2018;26(7):1599-1609.

[37] SinghBN, YucelD, GarayBI, et al. Proliferation and maturation: janus and the art of cardiac tissue engineering. Circ Res. 2023;132(4):519-540.

[38] HofbauerP, JahnelSM, PapaiN, et al. Cardioids reveal self-organizing principles of human cardiogenesis. Cell. 2021;184(12):3299-3317.e22.

[39] ChristoffelsVM, HabetsPE, FrancoD, et al. Chamber formation and morphogenesis in the developing mammalian heart. Dev Biol. 2000;223(2):266-278.

[40] de BoerBA, van den Berg G, de BoerPAJ, MoormanAFM, Ruijter JM. Growth of the developing mouse heart: an interactive qualitative and quantitative 3D atlas. Dev Biol. 2012;368(2):203-213.

[41] RileyPR. An epicardial floor plan for building and rebuilding the mammalian heart. Curr Top Dev Biol. 2012;100:233-251.

[42] LuxánG, D’Amato G, MacGroganD, de la PompaJL. Endocardial Notch signaling in cardiac development and disease. Circ Res. 2016;118(1):e1-e18.

[43] LinCJ, LinCY, ChenC.-H, Zhou B, ChangCP. Partitioning the heart: mechanisms of cardiac septation and valve development. Development. 2012;139(18):3277-3299.

[44] NakamuraM, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018;15(7):387-407.

[45] ParedesA, Justo-Méndez R, Jiménez-BlascoD, et al. γ-Linolenic acid in maternal milk drives cardiac metabolic maturation. Nature. 2023;618(7964):365-373.

[46] PuenteBN, KimuraW, MuralidharSA, et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell. 2014;157(3):565-579.

[47] BishopSP, ZhouY, NakadaY, Zhang J.-Y. Changes in cardiomyocyte cell cycle and hypertrophic growth during fetal to adult in mammals. J Am Heart Assoc. 2021;10(2):e017839.

[48] LiuH.-H, Bersell K, KühnB. Isolation and characterization of intact cardiomyocytes from frozen and fresh human myocardium and mouse hearts. Methods Mol Biol. 2021;2158:199-210.

[49] YangX.-Y, LiL.-P, ZengC.-Y, Wang WE. The characteristics of proliferative cardiomyocytes in mammals. J Mol Cell Cardiol. 2023;185:50-64.

[50] ZhuW.-Q, ZhangE, ZhaoM, et al. Regenerative potential of neonatal porcine hearts. Circulation. 2018;138(24):2809-2816.

[51] YeL, D’Agostino G, LooSJ, et al. Early regenerative capacity in the porcine heart. Circulation. 2018;138(24):2798-2808.

[52] NguyenT, Rosa-Garrido M, SadekH, GarryDJ, ZhangJJ. Promoting cardiomyocyte proliferation for myocardial regeneration in large mammals. J Mol Cell Cardiol. 2024;188:52-60.

[53] AlkassK, PanulaJ, WestmanM, Wu T.-D, Guerquin-KernJL, BergmannO. No evidence for cardiomyocyte number expansion in preadolescent mice. Cell. 2015;163(4):1026-1036.

[54] NaqviN, SinghR, IismaaSE, et al. Cardiomyocytes replicate and their numbers increase in young hearts. Cell. 2015;163(4):783-784.

[55] BergmannO, Bhardwaj RD, BernardS, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324(5923):98-102.

[56] MollovaM, Bersell K, WalshS, et al. Cardiomyocyte proliferation contributes to heart growth in young humans. Proc Natl Acad Sci USA. 2013;110(4):1446-1451.

[57] BergmannO, ZdunekS, FelkerA, et al. Dynamics of cell generation and turnover in the human heart. Cell. 2015;161(7):1566-1575.

[58] HaubnerBJ, Schneider J, SchweigmannU, et al. Functional recovery of a human neonatal heart after severe myocardial infarction. Circ Res. 2016;118(2):216-221.

[59] YuY, WangC.-K, YeS.-Q, et al. Abnormal progenitor cell differentiation and cardiomyocyte proliferation in hypoplastic right heart syndrome. Circulation. 2024;149(11):888-891.

[60] ReeserRS, Salazar AK, PruttonKM, RoedeJR, VeDepoMC, JacotJG. Trisomy 21 alters cell proliferation and migration of iPSC-derived cardiomyocytes on type VI collagen. Cell Mol Bioeng. 2024;17(1):25-34.

[61] JinSC, HomsyJ, ZaidiS, et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet. 2017;49(11):1593-1601.

[62] RichterF, MortonSU, KimSW, et al. Genomic analyses implicate noncoding de novo variants in congenital heart disease. Nat Genet. 2020;52(8):769-777.

[63] HomsyJ, ZaidiS, ShenY.-F, et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science. 2015;350(6265):1262-1266.

[64] MortonSU, QuiatD, SeidmanJG, Seidman CE. Genomic frontiers in congenital heart disease. Nat Rev Cardiol. 2022;19(1):26-42.

[65] NeesSN, ChungWK. Genetic basis of human congenital heart disease. Cold Spring Harbor Perspect Biol. 2020;12(9):a036749.

[66] BlueGM, KirkEP, GiannoulatouE, et al. Advances in the genetics of congenital heart disease: a clinician’s guide. J Am Coll Cardiol. 2017;69(7):859-870.

[67] TheisJL, VoglerG, MissinatoMA, et al. Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome. Elife. 2020;9:e59554.

[68] ChristA, Marczenke M, WillnowTE. LRP2 controls sonic hedgehog-dependent differentiation of cardiac progenitor cells during outflow tract formation. Hum Mol Genet. 2020;29(19):3183-3196.

[69] HaoLL, MaJ, WuFZ, et al. Wdr62 variants contribute to congenital heart disease by inhibiting cardiomyocyte proliferation. Clin Transl Med. 2022;12(7):e941.

[70] Lana-ElolaE, AoidiR, LlorianM, et al. Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome. Sci Transl Med. 2024;16(731):eadd6883.

[71] LiuZ.-Q, JiangY.-M, FangF, et al. ASXL3 gene mutations inhibit cell proliferation and promote cell apoptosis in mouse cardiomyocytes by upregulating lncRNA NONMMUT063967.2. Biochem Biophys Rep. 2023;35:101505.

[72] PengJ.-Y, WangQ.-J, MengZ, et al. A loss-of-function mutation p.T256M in NDRG4 is implicated in the pathogenesis of pulmonary atresia with ventricular septal defect (PA/VSD) and tetralogy of Fallot (TOF). FEBS Open Bio. 2021;11(2):375-385.

[73] PageDJ, Miossec MJ, WilliamsSG, et al. Whole exome sequencing reveals the major genetic contributors to nonsyndromic tetralogy of fallot. Circ Res. 2019;124(4):553-563.

[74] DurbinMD, CadarAG, WilliamsCH, et al. Hypoplastic left heart syndrome sequencing reveals a novel NOTCH1 mutation in a family with single ventricle defects. Pediatr Cardiol. 2017;38(6):1232-1240.

[75] GargV, MuthAN, RansomJF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437(7056):270-274.

[76] YeS.-Q, WangC.-K, XuZ.-H, et al. Impaired human cardiac cell development due to NOTCH1 deficiency. Circ Res. 2023;132(2):187-204.

[77] YeL.-Q, YuY, ZhaoZ.-A, et al. Patient-specific iPSC-derived cardiomyocytes reveal abnormal regulation of FGF16 in a familial atrial septal defect. Cardiovasc Res. 2022;118(3):859-871.

[78] MisraC, ChangS.-W, BasuM, Huang N.-Y, GargV. Disruption of myocardial Gata4 and Tbx5 results in defects in cardiomyocyte proliferation and atrioventricular septation. Hum Mol Genet. 2014;23(19):5025-5035.

[79] BoogerdCJ, ZhuX.-M, AneasI, et al. Tbx20 is required in mid-gestation cardiomyocytes and plays a central role in atrial development. Circ Res. 2018;123(4):428-442.

[80] KirkEP, SundeM, CostaMW, et al. Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. Am J Hum Genet. 2007;81(2):280-291.

[81] KodoK, OngSG, JahanbaniF, et al. iPSC-derived cardiomyocytes reveal abnormal TGF-β signalling in left ventricular non-compaction cardiomyopathy. Nat Cell Biol. 2016;18(10):1031-1042.

[82] SanderJD, JoungJK. CRISPR-Cas systems for editing, regulating and targeting genomes. Nat Biotechnol. 2014;32(4):347-355.

[83] SeokH, DengR, CowanDB, Wang D.-Z. Application of CRISPR-Cas9 gene editing for congenital heart disease. Clin Exp Pediatr. 2021;64(6):269-279.

[84] LiuX.-Q, YagiH, SaeedS, et al. The complex genetics of hypoplastic left heart syndrome. Nat Genet. 2017;49(7):1152-1159.

[85] LiuN, OlsonEN. CRISPR modeling and correction of cardiovascular disease. Circ Res. 2022;130(12):1827-1850.

[86] LinH, McBride KL, GargV, ZhaoM.-T. Decoding genetics of congenital heart disease using patient-derived induced pluripotent stem cells (iPSCs). Front Cell Dev Biol. 2021;9:630069.

[87] GabrielGC, DevineW, RedelBK, et al. Cardiovascular development and congenital heart disease modeling in the pig. J Am Heart Assoc. 2021;10(14):e021631.

[88] HouX.-J, MuJ.-S. Generation of a TBX20 homozygous knockout stem cell line (WAe009-A-1E) by episomal vector-based CRISPR/Cas9 system. Stem Cell Res. 2024;77:103384.

[89] LianX.-J, XuJ.-J, LiJ.-S, Chien KR. Next-generation models of human cardiogenesis via genome editing. Cold Spring Harb Perspect Med. 2014;4(12):a013920.

[90] PrendivilleT, JayPY, PuWT. Insights into the genetic structure of congenital heart disease from human and murine studies on monogenic disorders. Cold Spring Harb Perspect Med. 2014;4(10):a013946.

[91] BernsteinBE, Meissner A, LanderES. The mammalian epigenome. Cell. 2007;128(4):669-681.

[92] YuanX, HuangJ.-Y, WenL, et al. Genome-wide DNA methylation analysis of discordant monozygotic twins reveals consistent sites of differential methylation associated with congenital heart disease. Genomics. 2023;115(2):110565.

[93] LyuG.-L, ZhangC, LingT, et al. Genome and epigenome analysis of monozygotic twins discordant for congenital heart disease. BMC Genom. 2018;19(1):428.

[94] WangG.-L, WangB.-B, YangP.-X. Epigenetics in congenital heart disease. J Am Heart Assoc. 2022;11(7):e025163.

[95] LageK, Greenway SC, RosenfeldJA, et al. Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development. Proc Natl Acad Sci USA. 2012;109(35):14035-14040.

[96] VecoliC, Pulignani S, AndreassiMG. Genetic and epigenetic mechanisms linking air pollution and congenital heart disease. J Cardiovasc Dev Dis. 2016;3(4):32.

[97] CuiM, WangZ.-N, Bassel-DubyR, OlsonEN. Genetic and epigenetic regulation of cardiomyocytes in development, regeneration and disease. Development. 2018;145(24):dev171983.

[98] LiuQ, MaJ, DengH, et al. Cardiac-specific methylation patterns of circulating DNA for identification of cardiomyocyte death. BMC Cardiovasc Disord. 2020;20(1):310.

[99] NelsonJS, KwokC, BragancaNE, et al. Comparison of DNA methylation patterns across tissue types in infants with tetralogy of Fallot. Birth Defects Res. 2022;114(17):1101-1111.

[100] LiuJ.-J, WuY.-D, SunH.-R, et al. Association between placental DNA methylation and fetal congenital heart disease. Mol Genet Genom. 2023;298(1):243-251.

[101] Bahado-SinghR, Vishweswaraiah S, MishraNK, GudaC, Radhakrishna U. Placental DNA methylation changes in detection of tetralogy of Fallot. Ultrasound Obstet Gynecol. 2020;55(6):768-775.

[102] ZhuY.-J, YeM, XuH.-F, et al. Methylation status of CpG sites in the NOTCH₄ promoter region regulates NOTCH₄ expression in patients with tetralogy of Fallot. Mol Med Rep. 2020;22(5):4412-4422.

[103] YuanY, GaoY, WangH.-J, Ma X.-J, MaD, HuangG.-Y. Promoter methylation and expression of the VANGL2 gene in the myocardium of pediatric patients with tetralogy of fallot. Birth Defects Res A Clin Mol Teratol. 2014;100(12):973-984.

[104] Serra-JuhéC, Cuscó I, HomsA, FloresR, Torán N, Pérez-JuradoLA. DNA methylation abnormalities in congenital heart disease. Epigenetics. 2015;10(2):167-177.

[105] García-FloresE, Calderón-Colmenero J, Borgonio-CuadraVM, et al. Epigenetic evaluation of the TBX20 gene and environmental risk factors in Mexican paediatric patients with congenital septal defects. Cells. 2023;12(4):586.

[106] ChangS.-Y, WangY.-B, XinY, et al. DNA methylation abnormalities of imprinted genes in congenital heart disease: a pilot study. BMC Med Genom. 2021;14(1):4.

[107] ZhaoX.-L, ChangS.-Y, LiuX.-L, et al. Imprinting aberrations of SNRPN, ZAC1 and INPP5F genes involved in the pathogenesis of congenital heart disease with extracardiac malformations. J Cell Mol Med. 2020;24(17):9898-9907.

[108] GrunertM, DornC, CuiH.-H, et al. Comparative DNA methylation and gene expression analysis identifies novel genes for structural congenital heart diseases. Cardiovasc Res. 2016;112(1):464-477.

[109] ZaidiS, ChoiM, WakimotoH, et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature. 2013;498(7453):220-223.

[110] GuoT.-W, ChungJH, WangT, et al. Histone modifier genes alter conotruncal heart phenotypes in 22q11.2 deletion syndrome. Am J Hum Genet. 2015;97(6):869-877.

[111] DeleaM, Massara LS, EspecheLD, et al. Genetic analysis algorithm for the study of patients with multiple congenital anomalies and isolated congenital heart disease. Genes. 2022;13(7):1172.

[112] HuangL.-Y, WangQ.-Y, GuS.-S, Cao N. Integrated metabolic and epigenetic mechanisms in cardiomyocyte proliferation. J Mol Cell Cardiol. 2023;181:79-88.

[113] YuanX.-J, BraunT. Multimodal regulation of cardiac myocyte proliferation. Circ Res. 2017;121(3):293-309.

[114] KaikkonenMU, LamMTY, GlassCK. Non-coding RNAs as regulators of gene expression and epigenetics. Cardiovasc Res. 2011;90(3):430-440.

[115] PeschanskyVJ, Wahlestedt C. Non-coding RNAs as direct and indirect modulators of epigenetic regulation. Epigenetics. 2014;9(1):3-12.

[116] RamachandranV, Bhagavatheeswaran S, ShanmugamS, et al. Deep sequencing unveils altered cardiac miRNome in congenital heart disease. Mol Genet Genom. 2022;297(4):1123-1139.

[117] YangQ, WuF, MiY.-P, et al. Aberrant expression of miR-29b-3p influences heart development and cardiomyocyte proliferation by targeting NOTCH2. Cell Prolif. 2020;53(3):e12764.

[118] ZhangQ.-J, ChengZ.-J, YuZ.-B, Zhu C, QianL.-M. Role of lncRNA uc.457 in the differentiation and maturation of cardiomyocytes. Mol Med Rep. 2019;19(6):4927-4934.

[119] LiJ, DaiL.-M, TanX.-Y, et al. A novel splicing mutation c.335-1 G > a in the cardiac transcription factor NKX2-5 leads to familial atrial septal defect through miR-19 and pyk2. Stem Cell Rev Rep. 2022;18(8):2646-2661.

[120] HuangZ.-R, LiX.-H, QiuM, et al. Weighted gene co-expression network analysis identifies key genes from extracellular vesicles as potential prognostic biomarkers for congenital pulmonary stenosis. Mol Med Rep. 2020;22(3):2528-2536.

[121] AdamovaP, LottoRR, PowellAK, Dykes IM. Are there foetal extracellular vesicles in maternal blood? Prospects for diagnostic biomarker discovery. J Mol Med (Berl). 2023;101(1-2):65-81.

[122] HoffmanJR, ParkHJ, BheriS, et al. Statistical modeling of extracellular vesicle cargo to predict clinical trial outcomes for hypoplastic left heart syndrome. iScience. 2023;26(10):107980.

[123] JinekM, Chylinski K, FonfaraI, HauerM, DoudnaJA, CharpentierE. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816-821.

[124] GilbertLA, LarsonMH, MorsutL, et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell. 2013;154(2):442-451.

[125] MaederML, LinderSJ, CascioVM, Fu Y.-F, HoQH, JoungJK. CRISPR RNA-guided activation of endogenous human genes. Nat Methods. 2013;10(10):977-979.

[126] StepperP, Kungulovski G, JurkowskaRZ, et al. Efficient targeted DNA methylation with chimeric dCas9–Dnmt3a–Dnmt3L methyltransferase. Nucleic Acids Res. 2017;45(4):1703-1713.

[127] HiltonIB, D’Ippolito AM, VockleyCM, et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol. 2015;33(5):510-517.

[128] GoyalA, Myacheva K, GroßM, KlingenbergM, Duran Arqué B, DiederichsS. Challenges of CRISPR/Cas9 applications for long non-coding RNA genes. Nucleic Acids Res. 2017;45(3):e12.

[129] GuoY, PuWT. Cardiomyocyte maturation: new phase in development. Circ Res. 2020;126(8):1086-1106.

[130] YeL.-C, QiuL.-S, ZhangH.-B, et al. Cardiomyocytes in young infants with congenital heart disease: a three-month window of proliferation. Sci Rep. 2016;6(1):23188.

[131] PolizzottiBD, Ganapathy B, WalshS, et al. Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window. Sci Transl Med. 2015;7(281):281ra45.

[132] DerksW, Bergmann O. Polyploidy in cardiomyocytes: roadblock to heart regeneration? Circ Res. 2020;126(4):552-565.

[133] KraneM, Dreßen M, SantamariaG, et al. Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome. Circulation. 2021;144(17):1409-1428.

[134] SukhachevaTV, SerovRA, NizyaevaNV, et al. Accelerated growth, differentiation, and ploidy with reduced proliferation of right ventricular cardiomyocytes in children with congenital heart defect tetralogy of fallot. Cells. 2022;11(1):175.

[135] LiuH.-H, ZhangC.-H, AmmanamanchiN, et al. Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment. Sci Transl Med. 2019;11(513):eaaw6419.

[136] González-RosaJM, Sharpe M, FieldD, et al. Myocardial polyploidization creates a barrier to heart regeneration in zebrafish. Dev Cell. 2018;44(4):433-446.e7.

[137] LamYY, KeungW, ChanCH, et al. Single-cell transcriptomics of engineered cardiac tissues from patient-specific induced pluripotent stem cell-derived cardiomyocytes reveals abnormal developmental trajectory and intrinsic contractile defects in hypoplastic right heart syndrome. J Am Heart Assoc. 2020;9(20):e016528.

[138] BenavidezOJ, Gauvreau K, Del NidoP, BachaE, Jenkins KJ. Complications and risk factors for mortality during congenital heart surgery admissions. Ann Thorac Surg. 2007;84(1):147-155.

[139] JavedF, Aleysae NA, Al-MahboshAY, et al. Complications after surgical repair of congenital heart disease in infants. an experience from tertiary care center. J Saudi Heart Assoc. 2021;33(4):271-278.

[140] HirschJC, JacobsML, AndropoulosD, et al. Protecting the infant brain during cardiac surgery: a systematic review. Ann Thorac Surg. 2012;94(4):1365-1373. discussion1373.

[141] RaissadatiA, HaukkaJ, PätiläT, NieminenH, Jokinen E. Chronic disease burden after congenital heart surgery: a 47-year population-based study with 99% follow-up. J Am Heart Assoc. 2020;9(9):e015354.

[142] von GiseA, LinZ.-Q, SchlegelmilchK, et al. YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc Natl Acad Sci USA. 2012;109(7):2394-2399.

[143] HeallenT, ZhangM, WangJ, et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science. 2011;332(6028):458-461.

[144] YeL.-C, YinM, XiaY, JiangC, HongH.-F, Liu J.-F. Decreased yes-associated protein-1 (YAP1) expression in pediatric hearts with ventricular septal defects. PLoS One. 2015;10(10):e0139712.

[145] El KhoudarySR, FabioA, YesterJW, et al. Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot. Int J Cardiol. 2021;339:36-42.

[146] ShaddyRE, BoucekMM, HsuDT, et al. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA. 2007;298(10):1171-1179.

[147] NoroziK, Bahlmann J, RaabB, et al. A prospective, randomized, double-blind, placebo controlled trial of beta-blockade in patients who have undergone surgical correction of tetralogy of Fallot. Cardiol Young. 2007;17(4):372-379.

[148] RamakrishnanS, GhatiN, AhujaRS, et al. Efficacy and safety of propranolol in infants with heart failure due to moderate-to-large ventricular septal defect (VSD-PHF study) -A prospective randomized trial. Ann Pediatr Cardiol. 2021;14(3):331-340.

[149] PezhoumanA, NguyenNB, KayM, Kanjilal B, NoshadiI, ArdehaliR. Cardiac regeneration–Past advancements, current challenges, and future directions. J Mol Cell Cardiol. 2023;182:75-85.

[150] SharmaA, McKeithan WL, SerranoR, et al. Use of human induced pluripotent stem cell-derived cardiomyocytes to assess drug cardiotoxicity. Nat Protoc. 2018;13(12):3018-3041.

[151] AhmedMS, NguyenNUN, NakadaY, et al. Identification of FDA-approved drugs that induce heart regeneration in mammals. Nat Cardiovasc Res. 2024;3(3):372-388.

[152] PernaF, Telesca A, ScacciavillaniR, et al. Clinical impact of cardiac fibrosis on arrhythmia recurrence after ablation in adults with congenital heart disease. J Cardiovasc Dev Dis. 2023;10(4):168.

[153] DisertoriM, Masè M, RavelliF. Myocardial fibrosis predicts ventricular tachyarrhythmias. Trends Cardiovasc Med. 2017;27(5):363-372.

[154] FogliaMJ, PossKD. Building and re-building the heart by cardiomyocyte proliferation. Development. 2016;143(5):729-740.

[155] HassinkRJ, Pasumarthi KB, NakajimaH, et al. Cardiomyocyte cell cycle activation improves cardiac function after myocardial infarction. Cardiovasc Res. 2008;78(1):18-25.

[156] HashimotoH, OlsonEN, Bassel-DubyR. Therapeutic approaches for cardiac regeneration and repair. Nat Rev Cardiol. 2018;15(10):585-600.

[157] GabisoniaK, Prosdocimo G, AquaroGD, et al. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature. 2019;569(7756):418-422.

[158] AbouleisaRRE, SalamaABM, OuQ.-H, et al. Transient cell cycle induction in cardiomyocytes to treat subacute ischemic heart failure. Circulation. 2022;145(17):1339-1355.

[159] HillMC, KadowZA, LongH.-L, et al. Integrated multi-omic characterization of congenital heart disease. Nature. 2022;608(7921):181-191.

[160] YesterJW, LiuH.-H, GyngardF, et al. Use of stable isotope-tagged thymidine and multi-isotope imaging mass spectrometry (MIMS) for quantification of human cardiomyocyte division. Nat Protoc. 2021;16(4):1995-2022.

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