The heart is capable of extensive adaptive growth in response to the demands of the body. When the heart is confronted with an increased workload over a prolonged period, it tends to cope with the situation by increasing its muscle mass. The adaptive growth response of the cardiac muscle changes significantly during phylogenetic and ontogenetic development. Cold-blooded animals maintain the ability for cardiomyocyte proliferation even in adults. On the other hand, the extent of proliferation during ontogenetic development in warm-blooded species shows significant temporal limitations: whereas fetal and neonatal cardiac myocytes express proliferative potential (hyperplasia), after birth proliferation declines and the heart grows almost exclusively by hypertrophy. It is, therefore, understandable that the regulation of the cardiac growth response to the increased workload also differs significantly during development. The pressure overload (aortic constriction) induced in animals before the switch from hyperplastic to hypertrophic growth leads to a specific type of left ventricular hypertrophy which, in contrast with the same stimulus applied in adulthood, is characterized by hyperplasia of cardiomyocytes, capillary angiogenesis and biogenesis of collagenous structures, proportional to the growth of myocytes. These studies suggest that timing may be of crucial importance in neonatal cardiac interventions in humans: early definitive repairs of selected congenital heart disease may be more beneficial for the long-term results of surgical treatment.

Institute of Anatomy 1st Faculty of Medicine Charles University 128 00 Prague Czech Republic

Institute of Physiology of the Czech Academy of Sciences 142 20 Prague Czech Republic

Zobrazit více v PubMed

Adolph E.F. General and specific characteristics of physiological adaptations. Am. J. Physiol. 1956;184:18–28. doi: 10.1152/ajplegacy.1955.184.1.18. PubMed DOI

Ostadal B. Comparative aspects of cardiac adaptation. In: Ostadal B., Dhalla N.S., editors. Cardiac Adaptations. Springer; Berlin/Heidelberg, Germany: 2014. pp. 3–18.

Heallen T.R., Kadow Z.A., Wang J., Martin J.F. Determinants of Cardiac Growth and Size. Cold Spring Harb. Perspect. Biol. 2020;12:a037150. doi: 10.1101/cshperspect.a037150. PubMed DOI PMC

Yuan X., Braun T. Multimodal Regulation of Cardiac Myocyte Proliferation. Circ. Res. 2017;121:293–309. doi: 10.1161/CIRCRESAHA.117.308428. PubMed DOI

Sedmera D., Thompson R.P. Myocyte proliferation in the developing heart. Dev. Dyn. Off. Publ. Am. Assoc. Anat. 2011;240:1322–1334. doi: 10.1002/dvdy.22650. PubMed DOI PMC

Zhu F., Meng Q., Yu Y., Shao L., Shen Z. Adult Cardiomyocyte Proliferation: A New Insight for Myocardial Infarction Therapy. J. Cardiovasc. Transl. Res. 2021;14:457–466. doi: 10.1007/s12265-020-10067-8. PubMed DOI

Hesse R. Das Herzgewicht der Wirbeltiere. Zool. Jahrb. Abt. Allg. Zool. Physiol. 1921;38:243–364.

Poupa O., Ostadal B. Experimental cardiomegalies and “cardiomegalies” in free-living animals. Ann. N. Y. Acad. Sci. 1969;156:445–468. doi: 10.1111/j.1749-6632.1969.tb16744.x. PubMed DOI

Clark A.J. Comparative Physiology of the Heart. Cambridge University Press; Cambridge, UK: 1927.

Poupa O., Rakusan K., Ostadal B. Medicine and Sport Science. Volume 4. Karger Publishers; Basel, Switzerland: 1970. The effect of physical activity upon the heart of vertebrates; pp. 202–233.

Poupa O. Heart story: A view to the past. In: Ostadal B., Dhalla N.S., editors. Heart Function in Health and Disease. Kluwer Academic Publishers; Dordrecht, The Netherlands: 1993. pp. 3–22.

Farrell A.P., Smith F. Cardiac form, function and physiology. In: Gamprl A.K., Gillis T.E., Farrell A.P., Brauner C.J., editors. The Cardiovascular Systém: Morphology, Control and Function. Fish Physiology. Volume 36A. Elsevier; Amsterdam, The Netherlands: 2017. pp. 155–264.

Jones D.R., Brill R.W., Bushnell P.G. Ventricular and Arterial Dynamics of Anaesthetised and Swimming Tuna. J. Exp. Biol. 1993;182:97–112. doi: 10.1242/jeb.182.1.97. DOI

Icardo J.M. Heart morphology and anatomy. In: Gamprl A.K., Gillis T.E., Farrell A.P., Brauner C.J., editors. The Cardiovascular Systém: Morphology, Control and Function. Fish Physiology. Volume 36A. Elsevier; Amsterdam, The Netherlands: 2017. pp. 1–47.

Ostadal B., Ostadalova I., Dhalla N.S. Development of cardiac sensitivity to oxygen deficiency: Comparative and ontogenetic aspects. Physiol. Rev. 1999;79:635–659. doi: 10.1152/physrev.1999.79.3.635. PubMed DOI

Ostadal B., Schiebler T.H. The terminal blood bed in the heart of fish. Z. Fur Anat. Entwickl. 1971;134:101–110. PubMed

Ostadal B., Schiebler T.H., Rychter Z. Relations between development of the capillary wall and myoarchitecture of the rat heart. Adv. Exp. Med. Biol. 1975;53:375–388. doi: 10.1007/978-1-4757-0731-1_33. PubMed DOI

Bass A., Ostadal B., Pelouch V., Vitek V. Differences in weight parameters, myosin-ATPase activity and the enzyme pattern of energy supplying metabolism between the compact and spongious cardiac musculature of carp (Cyprinus carpio) and turtle (Testudo horsfieldi) Pflug. Arch. Eur. J. Physiol. 1973;343:65–77. doi: 10.1007/BF00586575. PubMed DOI

Tota B., Garofalo F. Fish heart growth and function: From gross morphology to cell signaling and back. Cardiac nonuniformity: From genes to shape. In: Sedmera D., Wang T., editors. Ontogeny and Phylogeny of the Vertebrate Heart. Springer; New York, NY, USA: 2012. pp. 55–74.

Farrell A.P., Farrell N.D., Jourdan H., Cox G. A perspective on the evolution of the coronary circulation in fishes and the transition to terrestrial life. In: Sedmera D., Wang T., editors. Ontogeny and Phylogeny of the Vertebrate Heart. Springer; New York, NY, USA: 2012. pp. 75–102.

Ostadal B., Rychter Z., Poupa O. Comparative aspects of the development of the terminal vascular bed in the myocardium. Physiol. Bohemoslov. 1970;19:1–7. PubMed

Becker R.O., Chapin S., Sherry R. Regeneration of the ventricular myocardium in amphibians. Nature. 1974;248:145–147. doi: 10.1038/248145a0. PubMed DOI

Chablais F., Veit J., Rainer G., Jaźwińska A. The zebrafish heart regenerates after cryoinjury-induced myocardial infarction. BMC Dev. Biol. 2011;11:21. doi: 10.1186/1471-213X-11-21. PubMed DOI PMC

Zuppo D.A., Tsang M. Zebrafish heart regeneration: Factors that stimulate cardiomyocyte proliferation. Semin. Cell Dev. Biol. 2020;100:3–10. doi: 10.1016/j.semcdb.2019.09.005. PubMed DOI PMC

Burggren W.W., Warburton S.J. Patterns of form and function in developing hearts: Contributions from non-mammalian vertebrates. Cardioscience. 1994;5:183–191. PubMed

Burggren W.W. Cardiac design in lower vertebrates: What can phylogeny reveal about ontogeny? Experientia. 1988;44:919–930. doi: 10.1007/BF01939885. PubMed DOI

Birkedal R., Laasmaa M., Branovets J., Vendelin M. Ontogeny of cardiomyocytes: Ultrastructure optimization to meet the demand for tight communication in excitation-contraction coupling and energy transfer. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2022;377:20210321. doi: 10.1098/rstb.2021.0321. PubMed DOI PMC

Rumyantsev P.P. Cardiomyocytes in the Processes of Reproduction, Differentiation, and Regeneration. Nauka; Leningrad, Russia: 1982.

Li F., Wang X., Capasso J.M., Gerdes A.M. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J. Mol. Cell. Cardiol. 1996;28:1737–1746. doi: 10.1006/jmcc.1996.0163. PubMed DOI

Porrello E.R., Mahmoud A.I., Simpson E., Hill J.A., Richardson J.A., Olson E.N., Sadek H.A. Transient regenerative potential of the neonatal mouse heart. Science. 2011;331:1078–1080. doi: 10.1126/science.1200708. PubMed DOI PMC

Bergmann O., Zdunek S., Felker A., Salehpour M., Alkass K., Bernard S., Sjostrom S.L., Szewczykowska M., Jackowska T., Dos Remedios C., et al. Dynamics of Cell Generation and Turnover in the Human Heart. Cell. 2015;161:1566–1575. doi: 10.1016/j.cell.2015.05.026. PubMed DOI

Mollova M., Bersell K., Walsh S., Savla J., Das L.T., Park S.Y., Silberstein L.E., Dos Remedios C.G., Graham D., Colan S., et al. Cardiomyocyte proliferation contributes to heart growth in young humans. Proc. Natl. Acad. Sci. USA. 2013;110:1446–1451. doi: 10.1073/pnas.1214608110. PubMed DOI PMC

Rychter Z., Rychterova V., Lemez L. Formation of the heart loop and proliferation structure of its wall as a base for ventricular septation. Herz. 1979;4:86–90. PubMed

Kirby M.L., Gale T.F., Stewart D.E. Neural crest cells contribute to normal aorticopulmonary septation. Science. 1983;220:1059–1061. doi: 10.1126/science.6844926. PubMed DOI

Kajstura J., Mansukhani M., Cheng W., Reiss K., Krajewski S., Reed J.C., Quaini F., Sonnenblick E.H., Anversa P. Programmed cell death and expression of the protooncogene bcl-2 in myocytes during postnatal maturation of the heart. Exp. Cell Res. 1995;219:110–121. doi: 10.1006/excr.1995.1211. PubMed DOI

Jonker S.S., Louey S., Giraud G.D., Thornburg K.L., Faber J.J. Timing of cardiomyocyte growth, maturation, and attrition in perinatal sheep. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2015;29:4346–4357. doi: 10.1096/fj.15-272013. PubMed DOI PMC

Anversa P., Cheng W., Liu Y., Leri A., Redaelli G., Kajstura J. Apoptosis and myocardial infarction. Basic Res. Cardiol. 1998;93((Suppl. S3)):8–12. doi: 10.1007/s003950050195. PubMed DOI

Johnson J., Mohsin S., Houser S.R. Cardiomyocyte Proliferation as a Source of New Myocyte Development in the Adult Heart. Int. J. Mol. Sci. 2021;22:7764. doi: 10.3390/ijms22157764. PubMed DOI PMC

Nakada Y., Canseco D.C., Thet S., Abdisalaam S., Asaithamby A., Santos C.X., Shah A.M., Zhang H., Faber J.E., Kinter M.T., et al. Hypoxia induces heart regeneration in adult mice. Nature. 2017;541:222–227. doi: 10.1038/nature20173. PubMed DOI

Faeh D., Moser A., Panczak R., Bopp M., Röösli M., Spoerri A. Independent at heart: Persistent association of altitude with ischaemic heart disease mortality after consideration of climate, topography and built environment. J. Epidemiol. Community Health. 2016;70:798–806. doi: 10.1136/jech-2015-206210. PubMed DOI

Johnson J., Yang Y., Bian Z., Schena G., Li Y., Zhang X., Eaton D.M., Gross P., Angheloiu A., Shaik A., et al. Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation. Circ. Res. 2023;132:723–740. doi: 10.1161/CIRCRESAHA.122.321604. PubMed DOI PMC

Leone M., Magadum A., Engel F.B. Cardiomyocyte proliferation in cardiac development and regeneration: A guide to methodologies and interpretations. Am. J. Physiol. Heart Circ. Physiol. 2015;309:H1237–H1250. doi: 10.1152/ajpheart.00559.2015. PubMed DOI

Auchampach J., Han L., Huang G.N., Kühn B., Lough J.W., O’Meara C.C., Payumo A.Y., Rosenthal N.A., Sucov H.M., Yutzey K.E., et al. Measuring cardiomyocyte cell-cycle activity and proliferation in the age of heart regeneration. Am. J. Physiol. Heart Circ. Physiol. 2022;322:H579–H596. doi: 10.1152/ajpheart.00666.2021. PubMed DOI PMC

Zebrowski D.C., Engel F.B. The cardiomyocyte cell cycle in hypertrophy, tissue homeostasis, and regeneration. Rev. Physiol. Biochem. Pharmacol. 2013;165:67–96. doi: 10.1007/112_2013_12. PubMed DOI

Alkass K., Panula J., Westman M., Wu T.D., Guerquin-Kern J.L., Bergmann O. No Evidence for Cardiomyocyte Number Expansion in Preadolescent Mice. Cell. 2015;163:1026–1036. doi: 10.1016/j.cell.2015.10.035. PubMed DOI

Pesevski Z., Sedmera D. Prenatal adaptations to overload. In: Ostadal B., Dhalla N.S., editors. Cardiac Adaptations. Springer; New York, NY, USA: Heidelberg, Germany: Dordrecht, The Netherlands: London, UK: 2013. pp. 41–58. DOI

Krejci E., Pesevski Z., Nanka O., Sedmera D. Physiological role of FGF signaling in growth and remodeling of developing cardiovascular system. Physiol. Res. 2016;65:425–435. doi: 10.33549/physiolres.933216. PubMed DOI

Laflamme M.A., Murry C.E. Heart regeneration. Nature. 2011;473:326–335. doi: 10.1038/nature10147. PubMed DOI PMC

Sedmera D., Pexieder T., Hu N., Clark E.B. Developmental changes in the myocardial architecture of the chick. Anat. Rec. 1997;248:421–432. doi: 10.1002/(SICI)1097-0185(199707)248:3<421::AID-AR15>3.0.CO;2-R. PubMed DOI

Tomanek R.J. Developmental Progression of the Coronary Vasculature in Human Embryos and Fetuses. Anat. Rec. 2016;299:25–41. doi: 10.1002/ar.23283. PubMed DOI PMC

Velkey J.M., Bernanke D.H. Apoptosis during coronary artery orifice development in the chick embryo. Anat. Rec. 2001;262:310–317. doi: 10.1002/1097-0185(20010301)262:3<310::AID-AR1040>3.0.CO;2-Y. PubMed DOI

Rakusan K., Turek Z. Protamine inhibits capillary formation in growing rat hearts. Circ. Res. 1985;57:393–398. doi: 10.1161/01.RES.57.3.393. PubMed DOI

Rakusan K. Cardiac growth, maturation and ageing. In: Zak R., editor. Growth of the Heart in Health and Disease. Raven Press; New York, NY, USA: 1984. pp. 131–164.

Lavine J.S., Poss M., Grenfell B.T. Directly transmitted viral diseases: Modeling the dynamics of transmission. Trends Microbiol. 2008;16:165–172. doi: 10.1016/j.tim.2008.01.007. PubMed DOI PMC

Tomanek R.J., Ishii Y., Holifield J.S., Sjogren C.L., Hansen H.K., Mikawa T. VEGF family members regulate myocardial tubulogenesis and coronary artery formation in the embryo. Circ. Res. 2006;98:947–953. doi: 10.1161/01.RES.0000216974.75994.da. PubMed DOI

Heallen T.R., Kadow Z.A., Kim J.H., Wang J., Martin J.F. Stimulating Cardiogenesis as a Treatment for Heart Failure. Circ. Res. 2019;124:1647–1657. doi: 10.1161/CIRCRESAHA.118.313573. PubMed DOI PMC

Galdos F.X., Guo Y., Paige S.L., VanDusen N.J., Wu S.M., Pu W.T. Cardiac Regeneration: Lessons from Development. Circ. Res. 2017;120:941–959. doi: 10.1161/CIRCRESAHA.116.309040. PubMed DOI PMC

Mahmoud A.I., Kocabas F., Muralidhar S.A., Kimura W., Koura A.S., Thet S., Porrello E.R., Sadek H.A. Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature. 2013;497:249–253. doi: 10.1038/nature12054. PubMed DOI PMC

Leu M., Ehler E., Perriard J.C. Characterisation of postnatal growth of the murine heart. Anat. Embryol. 2001;204:217–224. doi: 10.1007/s004290100206. PubMed DOI

Lopaschuk G.D., Collins-Nakai R.L., Itoi T. Developmental changes in energy substrate use by the heart. Cardiovasc. Res. 1992;26:1172–1180. doi: 10.1093/cvr/26.12.1172. PubMed DOI

Dimasi C.G., Darby J.R.T., Morrison J.L. A change of heart: Understanding the mechanisms regulating cardiac proliferation and metabolism before and after birth. J. Physiol. 2023;601:1319–1341. doi: 10.1113/JP284137. PubMed DOI PMC

Chung S., Dzeja P.P., Faustino R.S., Perez-Terzic C., Behfar A., Terzic A. Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells. Nat. Clin. Pract. Cardiovasc. Med. 2007;4((Suppl. S1)):S60–S67. doi: 10.1038/ncpcardio0766. PubMed DOI PMC

Lopaschuk G.D., Jaswal J.S. Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J. Cardiovasc. Pharmacol. 2010;56:130–140. doi: 10.1097/FJC.0b013e3181e74a14. PubMed DOI

Guimarães-Camboa N., Stowe J., Aneas I., Sakabe N., Cattaneo P., Henderson L., Kilberg M.S., Johnson R.S., Chen J., McCulloch A.D., et al. HIF1α Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes. Dev. Cell. 2015;33:507–521. doi: 10.1016/j.devcel.2015.04.021. PubMed DOI PMC

Rakusan K., Jelinek J., Korecky B., Soukupova M., Poupa O. Postnatal development of muscle fibers and capillaries in the rat heart. Physiol. Bohemoslov. 1965;14:32–37. PubMed

Ostadalova I., Kolar F., Ostadal B., Rohlicek V., Rohlicek J., Prochazka J. Early postnatal development of contractile performance and responsiveness to Ca2+, verapamil and ryanodine in the isolated rat heart. J. Mol. Cell. Cardiol. 1993;25:733–740. doi: 10.1006/jmcc.1993.1085. PubMed DOI

Dowell R.T., McManus R.E., 3rd Pressure-induced cardiac enlargement in neonatal and adult rats. Left ventricular functional characteristics and evidence of cardiac muscle cell proliferation in the neonate. Circ. Res. 1978;42:303–310. doi: 10.1161/01.RES.42.3.303. PubMed DOI

Rakusan K., Korecky B. Regression of cardiomegaly induced in newborn rats. Can. J. Cardiol. 1985;1:217–222. PubMed

Campbell S.E., Rakusan K., Gerdes A.M. Change in cardiac myocyte size distribution in aortic-constricted neonatal rats. Basic Res. Cardiol. 1989;84:247–258. doi: 10.1007/BF01907972. PubMed DOI

Campbell S.E., Korecky B., Rakusan K. Remodeling of myocyte dimensions in hypertrophic and atrophic rat hearts. Circ. Res. 1991;68:984–996. doi: 10.1161/01.RES.68.4.984. PubMed DOI

Yamamoto H., Avkiran M. Left ventricular pressure overload during postnatal development. Effects on coronary vasodilator reserve and tolerance to hypothermic global ischemia. J. Thorac. Cardiovasc. Surg. 1993;105:120–131. doi: 10.1016/S0022-5223(19)33856-5. PubMed DOI

Kolar F., Papousek F., Pelouch V., Ostadal B., Rakusan K. Pressure overload induced in newborn rats: Effects on left ventricular growth, morphology, and function. Pediatr. Res. 1998;43:521–526. doi: 10.1203/00006450-199804000-00014. PubMed DOI

Sedmera D., Thompson R.P., Kolar F. Effect of increased pressure loading on heart growth in neonatal rats. J. Mol. Cell. Cardiol. 2003;35:301–309. doi: 10.1016/S0022-2828(03)00011-7. PubMed DOI

Rakusan K. Microcirculation in the stressed heart. In: Legato M.J., editor. The Stressed Heart. Martinus Nijhoff; Boston, MA, USA: 1987. pp. 107–123.

Weber K.T., Brilla C.G., Janicki J.S. Myocardial fibrosis: Functional significance and regulatory factors. Cardiovasc. Res. 1993;27:341–348. doi: 10.1093/cvr/27.3.341. PubMed DOI

Czubryt M.P., Hale T.M. Cardiac fibrosis: Pathobiology and therapeutic targets. Cell. Signal. 2021;85:110066. doi: 10.1016/j.cellsig.2021.110066. PubMed DOI PMC

Malek Mohammadi M., Abouissa A., Azizah I., Xie Y., Cordero J., Shirvani A., Gigina A., Engelhardt M., Trogisch F.A., Geffers R., et al. Induction of cardiomyocyte proliferation and angiogenesis protects neonatal mice from pressure overload-associated maladaptation. JCI Insight. 2019;4:e128336. doi: 10.1172/jci.insight.128336. PubMed DOI PMC

Malek Mohammadi M., Abouissa A., Heineke J. A surgical mouse model of neonatal pressure overload by transverse aortic constriction. Nat. Protoc. 2021;16:775–790. doi: 10.1038/s41596-020-00434-9. PubMed DOI

Hunter L.E., Seale A.N. EDUCATIONAL SERIES IN CONGENITAL HEART DISEASE: Prenatal diagnosis of congenital heart disease. Echo Res. Pract. 2018;5:R81–R100. doi: 10.1530/ERP-18-0027. PubMed DOI PMC

Pediatric Chronic Heart Failure: Age-Specific Considerations of Medical Therapy