A change of heart: understanding the mechanisms regulating cardiac proliferation and metabolism before and after birth

Mammalian cardiomyocytes undergo major maturational changes in preparation for birth and postnatal life. Immature cardiomyocytes contribute to cardiac growth via proliferation and thus the heart has the capacity to regenerate. To prepare for postnatal life, structural and metabolic changes associated with increased cardiac output and function must occur. This includes exit from the cell cycle, hypertrophic growth, mitochondrial maturation and sarcomeric protein isoform switching. However, these changes come at a price: the loss of cardiac regenerative capacity such that damage to the heart in postnatal life is permanent. This is a significant barrier to the development of new treatments for cardiac repair and contributes to heart failure. The transitional period of cardiomyocyte growth is a complex and multifaceted event. In this review, we focus on studies that have investigated this critical transition period as well as novel factors that may regulate and drive this process. We also discuss the potential use of new biomarkers for the detection of myocardial infarction and, in the broader sense, cardiovascular disease.

[1]  K. Nguyen,et al.  Investigating the Transient Regenerative Potential of Cardiac Muscle Using a Neonatal Pig Partial Apical Resection Model , 2022, Bioengineering.

[2]  J. Zhong,et al.  Targeting the microRNA-34a as a Novel Therapeutic Strategy for Cardiovascular Diseases , 2022, Frontiers in Cardiovascular Medicine.

[3]  R. Muñoz-Chápuli,et al.  The Insulin-like Growth Factor Signalling Pathway in Cardiac Development and Regeneration , 2021, International journal of molecular sciences.

[4]  Wuqiang Zhu,et al.  Metabolic Profile in Neonatal Pig Hearts , 2021, Frontiers in Cardiovascular Medicine.

[5]  Jianyi(Jay) Zhang,et al.  Changes in Cardiomyocyte Cell Cycle and Hypertrophic Growth During Fetal to Adult in Mammals , 2021, Journal of the American Heart Association.

[6]  Sathish Kumar Jayapal,et al.  Global Burden of Cardiovascular Diseases and Risk Factors, 1990–2019 , 2020, Journal of the American College of Cardiology.

[7]  Catherine L. Worth,et al.  Cells of the adult human heart , 2020, Nature.

[8]  K. Pillman,et al.  Large-scale transcriptome-wide profiling of microRNAs in human placenta and maternal plasma at early to mid gestation , 2020, medRxiv.

[9]  D. Brooks,et al.  Identification of Novel miRNAs Involved in Cardiac Repair Following Infarction in Fetal and Adolescent Sheep Hearts , 2020, Frontiers in Physiology.

[10]  Lijuan Zhang,et al.  Circulating Exosomal miRNA as Diagnostic Biomarkers of Neurodegenerative Diseases , 2020, Frontiers in Molecular Neuroscience.

[11]  Y. Sadovsky,et al.  Placental small extracellular vesicles: Current questions and investigative opportunities. , 2020, Placenta.

[12]  O. Bergmann,et al.  Polyploidy in Cardiomyocytes , 2020, Circulation research.

[13]  M. Mayr,et al.  Pkm2 Regulates Cardiomyocyte Cell Cycle and Promotes Cardiac Regeneration , 2020, Circulation.

[14]  Raghu Kalluri,et al.  The biology, function, and biomedical applications of exosomes , 2020, Science.

[15]  J. McDonald,et al.  Mitochondrial Substrate Utilization Regulates Cardiomyocyte Cell Cycle Progression , 2020, Nature Metabolism.

[16]  Shuhong Zhao,et al.  Dynamics of cardiomyocyte and muscle stem cell proliferation in pig. , 2020, Experimental cell research.

[17]  Michael J Paulsen,et al.  Natural Heart Regeneration in a Neonatal Rat Myocardial Infarction Model , 2020, Cells.

[18]  H. Sucov,et al.  Cardiomyocyte Polyploidy and Implications for Heart Regeneration. , 2020, Annual review of physiology.

[19]  K. Yutzey,et al.  Scar Formation with Decreased Cardiac Function Following Ischemia/Reperfusion Injury in 1 Month Old Swine , 2019, Journal of cardiovascular development and disease.

[20]  K. Yutzey,et al.  Cardiomyocyte cell cycling, maturation, and growth by multinucleation in postnatal swine , 2019, bioRxiv.

[21]  A. Lewandowski,et al.  The Transitional Heart: From Early Embryonic and Fetal Development to Neonatal Life , 2019, Fetal Diagnosis and Therapy.

[22]  Rob J. Kulathinal,et al.  The developmental origins of sex-biased expression in cardiac development , 2019, Biology of Sex Differences.

[23]  Florence Mei Kuen Tang,et al.  microRNA-1 inhibits cardiomyocyte proliferation in mouse neonatal hearts by repressing CCND1 expression , 2019 .

[24]  K. Wang,et al.  MiR-34a promotes myocardial infarction in rats by inhibiting the activity of SIRT1. , 2019, European review for medical and pharmacological sciences.

[25]  K. Yutzey,et al.  Postnatal Cardiac Development and Regenerative Potential in Large Mammals , 2019, Pediatric Cardiology.

[26]  S. Houser,et al.  Transient Introduction of miR-294 in the Heart Promotes Cardiomyocyte Cell Cycle Reentry After Injury. , 2019, Circulation research.

[27]  Fabio Bernini,et al.  MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs , 2019, Nature.

[28]  A. Arnold,et al.  Gene-by-Sex Interactions in Mitochondrial Functions and Cardio-Metabolic Traits. , 2019, Cell metabolism.

[29]  K. Thornburg,et al.  Down‐regulation of MEIS1 promotes the maturation of oxidative phosphorylation in perinatal cardiomyocytes , 2019, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  M. Yartsev,et al.  Evidence for hormonal control of heart regenerative capacity during endothermy acquisition , 2019, Science.

[31]  D. Brooks,et al.  Differential Response to Injury in Fetal and Adolescent Sheep Hearts in the Immediate Post-myocardial Infarction Period , 2019, Front. Physiol..

[32]  Y. Zhang,et al.  Exosomes: biogenesis, biologic function and clinical potential , 2019, Cell & Bioscience.

[33]  S. Wan,et al.  The Exosome-Derived Biomarker in Atherosclerosis and Its Clinical Application , 2019, Journal of Cardiovascular Translational Research.

[34]  Jianyi(Jay) Zhang,et al.  Regenerative Potential of Neonatal Porcine Hearts , 2018, Circulation.

[35]  L. Ye,et al.  Early Regenerative Capacity in the Porcine Heart , 2018, Circulation.

[36]  Janna L Morrison,et al.  Improving pregnancy outcomes in humans through studies in sheep. , 2018, American journal of physiology. Regulatory, integrative and comparative physiology.

[37]  W. Yuan,et al.  Effect of exosomal miRNA on cancer biology and clinical applications , 2018, Molecular Cancer.

[38]  Q. Tang,et al.  miR-133: A Suppressor of Cardiac Remodeling? , 2018, Front. Pharmacol..

[39]  R. Ventura-clapier,et al.  Maturation of Cardiac Energy Metabolism During Perinatal Development , 2018, Front. Physiol..

[40]  Kimberley C. W. Wang,et al.  The role of miRNA regulation in fetal cardiomyocytes, cardiac maturation and the risk of heart disease in adults , 2018, The Journal of physiology.

[41]  L. Cai,et al.  miRNAS in cardiovascular diseases: potential biomarkers, therapeutic targets and challenges , 2018, Acta Pharmacologica Sinica.

[42]  Marina C Costa,et al.  The circulating non-coding RNA landscape for biomarker research: lessons and prospects from cardiovascular diseases , 2018, Acta Pharmacologica Sinica.

[43]  I. McMillen,et al.  Maternal undernutrition in late gestation increases IGF2 signalling molecules and collagen deposition in the right ventricle of the fetal sheep heart , 2018, The Journal of physiology.

[44]  D. Navajas,et al.  The local microenvironment limits the regenerative potential of the mouse neonatal heart , 2018, Science Advances.

[45]  M. Lalowski,et al.  Characterizing the Key Metabolic Pathways of the Neonatal Mouse Heart Using a Quantitative Combinatorial Omics Approach , 2018, Front. Physiol..

[46]  K. Wu,et al.  MicroRNA-34a modulates the Notch signaling pathway in mice with congenital heart disease and its role in heart development. , 2018, Journal of molecular and cellular cardiology.

[47]  K. Botting,et al.  Adverse Intrauterine Environment and Cardiac miRNA Expression , 2017, International journal of molecular sciences.

[48]  J. Krieger,et al.  Early Postnatal Cardiomyocyte Proliferation Requires High Oxidative Energy Metabolism , 2017, Scientific Reports.

[49]  M. Pellegrini,et al.  Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis , 2017, eLife.

[50]  D. Fairweather,et al.  Sex Determines Cardiac Myocyte Stretch and Relaxation. , 2017, Circulation. Cardiovascular genetics.

[51]  M. Ramialison,et al.  Multicellular Transcriptional Analysis of Mammalian Heart Regeneration , 2017, Circulation.

[52]  David E James,et al.  Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest , 2017, Proceedings of the National Academy of Sciences.

[53]  J. Morrison,et al.  Feasibility of detecting myocardial infarction in the sheep fetus using late gadolinium enhancement CMR imaging , 2017, Journal of Cardiovascular Magnetic Resonance.

[54]  Chenwei,et al.  Suppression of miR-34a Expression in the Myocardium Protects Against Ischemia-Reperfusion Injury Through SIRT1 Protective Pathway. , 2017 .

[55]  Cassady E Rupert,et al.  IGF1 and NRG1 Enhance Proliferation, Metabolic Maturity, and the Force-Frequency Response in hESC-Derived Engineered Cardiac Tissues , 2017, Stem cells international.

[56]  I. König,et al.  Sex in basic research: concepts in the cardiovascular field. , 2017, Cardiovascular research.

[57]  K. Moreau,et al.  Sex Hormones and Cardiometabolic Health: Role of Estrogen and Estrogen Receptors , 2017, Endocrinology.

[58]  Kimberley C. W. Wang,et al.  Akt signaling as a mediator of cardiac adaptation to low birth weight. , 2017, The Journal of endocrinology.

[59]  Diana C. Canseco,et al.  Hypoxia induces heart regeneration in adult mice , 2016, Nature.

[60]  W. Liu,et al.  Suppression of miR-34a Expression in the Myocardium Protects Against Ischemia-Reperfusion Injury Through SIRT1 Protective Pathway. , 2017, Stem cells and development.

[61]  P. Schulze,et al.  MicroRNAs in heart failure: Non-coding regulators of metabolic function. , 2016, Biochimica et biophysica acta.

[62]  Johan Garssen,et al.  Exosomes and Exosomal miRNA in Respiratory Diseases , 2016, Mediators of inflammation.

[63]  A. Zeiher,et al.  Inhibition of let-7 augments the recruitment of epicardial cells and improves cardiac function after myocardial infarction. , 2016, Journal of molecular and cellular cardiology.

[64]  L. Leinwand,et al.  The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease. , 2016, Circulation research.

[65]  R. Harding,et al.  Three-dimensional direct measurement of cardiomyocyte volume, nuclearity, and ploidy in thick histological sections , 2016, Scientific Reports.

[66]  Jinfen Liu,et al.  Cardiomyocytes in Young Infants With Congenital Heart Disease: a Three-Month Window of Proliferation , 2016, Scientific Reports.

[67]  W. Pu,et al.  Recounting Cardiac Cellular Composition. , 2016, Circulation research.

[68]  C. Gieger,et al.  Characterization of whole-genome autosomal differences of DNA methylation between men and women , 2015, Epigenetics & Chromatin.

[69]  K. Thornburg,et al.  Timing of cardiomyocyte growth, maturation, and attrition in perinatal sheep , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[70]  K. Botting,et al.  Regulation of microRNA during cardiomyocyte maturation in sheep , 2015, BMC Genomics.

[71]  Jens R. Nyengaard,et al.  Dynamics of Cell Generation and Turnover in the Human Heart , 2015, Cell.

[72]  Yi-Dong Lin,et al.  MicroRNA-34a Plays a Key Role in Cardiac Repair and Regeneration Following Myocardial Infarction. , 2015, Circulation research.

[73]  Kavitha T. Kuppusamy,et al.  Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes , 2015, Proceedings of the National Academy of Sciences.

[74]  S. Lehnart,et al.  Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-induced augmentation of β-adrenoceptor-stimulated contractility in early cardiac hypertrophy. , 2015, Circulation research.

[75]  M. Neeman,et al.  ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation , 2015, Nature Cell Biology.

[76]  C. D. dos Remedios,et al.  Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window , 2015, Science Translational Medicine.

[77]  D. Tosh,et al.  IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb. , 2015, American journal of physiology. Regulatory, integrative and comparative physiology.

[78]  K. Meganathan,et al.  Signaling molecules, transcription growth factors and other regulators revealed from in-vivo and in-vitro models for the regulation of cardiac development. , 2015, International journal of cardiology.

[79]  B. C. Bernardo,et al.  Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets , 2015, Archives of Toxicology.

[80]  A. Tonevitsky,et al.  Circulating microRNAs , 2015, Biochemistry (Moscow).

[81]  T. Alexy,et al.  TNF-α alters the release and transfer of microparticle-encapsulated miRNAs from endothelial cells. , 2014, Physiological genomics.

[82]  E. Olson,et al.  A neonatal blueprint for cardiac regeneration. , 2014, Stem cell research.

[83]  E. Schadt,et al.  Downregulation of Carnitine Acyl-Carnitine Translocase by miRNAs 132 and 212 Amplifies Glucose-Stimulated Insulin Secretion , 2014, Diabetes.

[84]  W. Koch,et al.  Inhibition of Let-7 microRNA attenuates myocardial remodeling and improves cardiac function postinfarction in mice , 2014, Pharmacology research & perspectives.

[85]  A. Forhead,et al.  Thyroid hormones in fetal growth and prepartum maturation. , 2014, The Journal of endocrinology.

[86]  Paul M. Rindler,et al.  The Oxygen-Rich Postnatal Environment Induces Cardiomyocyte Cell-Cycle Arrest through DNA Damage Response , 2014, Cell.

[87]  R. Graham,et al.  A Proliferative Burst during Preadolescence Establishes the Final Cardiomyocyte Number , 2014, Cell.

[88]  J. Gorman,et al.  Mammalian fetal cardiac regeneration after myocardial infarction is associated with differential gene expression compared with the adult. , 2014, The Annals of thoracic surgery.

[89]  Paul M. Rindler,et al.  The Oxygen-Rich Postnatal Environment Induces Cardiomyocyte Cell-Cycle Arrest through DNA Damage Response , 2014, Cell.

[90]  C. Kendziorski,et al.  Metabolic gene profile in early human fetal heart development. , 2014, Molecular human reproduction.

[91]  Kimberley C. W. Wang,et al.  Exposure to rosiglitazone, a PPAR-γ agonist, in late gestation reduces the abundance of factors regulating cardiac metabolism and cardiomyocyte size in the sheep fetus. , 2014, American journal of physiology. Regulatory, integrative and comparative physiology.

[92]  D. Roden,et al.  Differential activation of natriuretic peptide receptors modulates cardiomyocyte proliferation during development , 2014, Development.

[93]  I. McMillen,et al.  Regulation of fetal lung development in response to maternal overnutrition , 2013, Clinical and experimental pharmacology & physiology.

[94]  Kimberley C. W. Wang,et al.  Alteration of cardiac glucose metabolism in association to low birth weight: experimental evidence in lambs with left ventricular hypertrophy. , 2013, Metabolism: clinical and experimental.

[95]  B. Friguet,et al.  Proteome Modulation in H9c2 Cardiac Cells by microRNAs miR-378 and miR-378* , 2013, Molecular & Cellular Proteomics.

[96]  C. Hamm,et al.  Release kinetics of circulating muscle-enriched microRNAs in patients undergoing transcoronary ablation of septal hypertrophy. , 2013, Journal of the American College of Cardiology.

[97]  Elizabeth A. McClellan,et al.  The hypoxia-inducible microRNA cluster miR-199a∼214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation. , 2013, Cell metabolism.

[98]  R. Tian,et al.  Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. , 2013, Circulation research.

[99]  S. Bhattacharya,et al.  Glucocorticoid receptor is required for foetal heart maturation. , 2013, Human molecular genetics.

[100]  Seth A. Reini,et al.  Cortisol stimulates proliferation and apoptosis in the late gestation fetal heart: differential effects of mineralocorticoid and glucocorticoid receptors. , 2013, American journal of physiology. Regulatory, integrative and comparative physiology.

[101]  C. Roberts,et al.  Maternal undernutrition around the time of conception and embryo number each impact on the abundance of key regulators of cardiac growth and metabolism in the fetal sheep heart , 2013, Journal of Developmental Origins of Health and Disease.

[102]  I. Komuro,et al.  Circulating p53-Responsive MicroRNAs Are Predictive Indicators of Heart Failure After Acute Myocardial Infarction , 2013, Circulation research.

[103]  J. Gorman,et al.  Mammalian cardiac regeneration after fetal myocardial infarction requires cardiac progenitor cell recruitment. , 2013, The Annals of thoracic surgery.

[104]  Kwok-Kin Wong,et al.  Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. , 2013, The Journal of clinical investigation.

[105]  Fatih Kocabaş,et al.  Meis1 regulates postnatal cardiomyocyte cell cycle arrest , 2013, Nature.

[106]  Dionne A. Graham,et al.  Cardiomyocyte proliferation contributes to heart growth in young humans , 2013, Proceedings of the National Academy of Sciences.

[107]  Annamaria Colao,et al.  The circulating level of FABP3 is an indirect biomarker of microRNA-1. , 2013, Journal of the American College of Cardiology.

[108]  Richard T. Lee,et al.  Mammalian Heart Renewal by Preexisting Cardiomyocytes , 2012, Nature.

[109]  T. Preiss,et al.  A heterozygous variant in the human cardiac miR-133 gene, MIR133A2, alters miRNA duplex processing and strand abundance , 2013, BMC Genetics.

[110]  Diana C. Canseco,et al.  Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family , 2012, Proceedings of the National Academy of Sciences.

[111]  L. Zentilin,et al.  Functional screening identifies miRNAs inducing cardiac regeneration , 2012, Nature.

[112]  Corinna Singleman,et al.  Analysis of postembryonic heart development and maturation in the zebrafish, Danio rerio , 2012, Developmental dynamics : an official publication of the American Association of Anatomists.

[113]  Jie Zheng,et al.  Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). , 2012, Oncology letters.

[114]  T. Aitman,et al.  Complete cardiac regeneration in a mouse model of myocardial infarction , 2012, Aging.

[115]  A. Jobe,et al.  Physiology of transition from intrauterine to extrauterine life. , 2012, Clinics in perinatology.

[116]  Kimberley C. W. Wang,et al.  Activation of IGF‐2R stimulates cardiomyocyte hypertrophy in the late gestation sheep fetus , 2012, The Journal of physiology.

[117]  S. Kauppinen,et al.  Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function , 2012, Proceedings of the National Academy of Sciences.

[118]  K. Botting,et al.  Early origins of heart disease: Low birth weight and determinants of cardiomyocyte endowment , 2012, Clinical and experimental pharmacology & physiology.

[119]  L. Noronha,et al.  Immunohistochemical expression of cell differentiation and growth in neonate cardiomyocytes. , 2012, Arquivos brasileiros de cardiologia.

[120]  Kimberley C. W. Wang,et al.  IGF-2R-Mediated Signaling Results in Hypertrophy of Cultured Cardiomyocytes from Fetal Sheep1 , 2012, Biology of reproduction.

[121]  K. Poss,et al.  Regulation of zebrafish heart regeneration by miR-133. , 2012, Developmental biology.

[122]  Yong Li,et al.  A novel miR‐155/miR‐143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells , 2012, The EMBO journal.

[123]  V. Regitz-Zagrosek,et al.  Transcriptome characterization of estrogen-treated human myocardium identifies myosin regulatory light chain interacting protein as a sex-specific element influencing contractile function. , 2012, Journal of the American College of Cardiology.

[124]  E. Olson,et al.  Inhibition of miR-15 Protects Against Cardiac Ischemic Injury , 2012, Circulation research.

[125]  P. Stork,et al.  Thyroid hormone drives fetal cardiomyocyte maturation , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[126]  E. Olson,et al.  Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs , 2011, Proceedings of the National Academy of Sciences.

[127]  S. Fichtlscherer,et al.  Transcoronary Concentration Gradients of Circulating MicroRNAs , 2011, Circulation.

[128]  Kimberley C. W. Wang,et al.  Fetal growth restriction and the programming of heart growth and cardiac insulin‐like growth factor 2 expression in the lamb , 2011, The Journal of physiology.

[129]  G. Dorn,et al.  miR-15 Family Regulates Postnatal Mitotic Arrest of Cardiomyocytes , 2011, Circulation research.

[130]  K. Thornburg,et al.  Regulation of the cardiomyocyte population in the developing heart. , 2011, Progress in biophysics and molecular biology.

[131]  J. Brüning,et al.  IGF signaling directs ventricular cardiomyocyte proliferation during embryonic heart development , 2011, Development.

[132]  E. Olson,et al.  Transient Regenerative Potential of the Neonatal Mouse Heart , 2011, Science.

[133]  E. Rooij,et al.  The Art of MicroRNA Research , 2011 .

[134]  J. Gorman,et al.  Regenerative healing following foetal myocardial infarction. , 2010, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[135]  K. Thornburg,et al.  Atrial natriuretic peptide inhibits angiotensin II‐stimulated proliferation in fetal cardiomyocytes , 2010, The Journal of physiology.

[136]  G. Lopaschuk,et al.  Energy Metabolic Phenotype of the Cardiomyocyte During Development, Differentiation, and Postnatal Maturation , 2010, Journal of cardiovascular pharmacology.

[137]  R. Harding,et al.  Cardiac remodelling as a result of pre-term birth: implications for future cardiovascular disease. , 2010, European heart journal.

[138]  K. Nakao,et al.  Inhibition of TRPC6 Channel Activity Contributes to the Antihypertrophic Effects of Natriuretic Peptides-Guanylyl Cyclase-A Signaling in the Heart , 2010, Circulation research.

[139]  Federica Limana,et al.  Circulating microRNAs are new and sensitive biomarkers of myocardial infarction , 2010, European heart journal.

[140]  S. Cook,et al.  MicroRNA-223 regulates Glut4 expression and cardiomyocyte glucose metabolism. , 2010, Cardiovascular research.

[141]  C. Marchant,et al.  Intrauterine growth restriction delays surfactant protein maturation in the sheep fetus. , 2010, American journal of physiology. Lung cellular and molecular physiology.

[142]  Y. Matsuki,et al.  Secretory Mechanisms and Intercellular Transfer of MicroRNAs in Living Cells*♦ , 2010, The Journal of Biological Chemistry.

[143]  T. D. de Gruijl,et al.  Functional delivery of viral miRNAs via exosomes , 2010, Proceedings of the National Academy of Sciences.

[144]  Yue Li,et al.  Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. , 2010, European heart journal.

[145]  J. C. Belmonte,et al.  Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation , 2010, Nature.

[146]  D. Catalucci,et al.  Reciprocal Regulation of MicroRNA-1 and Insulin-Like Growth Factor-1 Signal Transduction Cascade in Cardiac and Skeletal Muscle in Physiological and Pathological Conditions , 2009, Circulation.

[147]  G. Hirokawa,et al.  Plasma miR-208 as a biomarker of myocardial injury. , 2009, Clinical chemistry.

[148]  Louis Hue,et al.  The Randle cycle revisited: a new head for an old hat. , 2009, American journal of physiology. Endocrinology and metabolism.

[149]  D. Srivastava,et al.  MicroRNA regulation of cardiovascular development. , 2009, Circulation research.

[150]  Samuel Bernard,et al.  Evidence for Cardiomyocyte Renewal in Humans , 2008, Science.

[151]  E. Olson,et al.  microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. , 2008, Genes & development.

[152]  F. Hanley,et al.  Dynamics of human myocardial progenitor cell populations in the neonatal period. , 2008, The Annals of thoracic surgery.

[153]  Yariv Yogev,et al.  Serum MicroRNAs Are Promising Novel Biomarkers , 2008, PloS one.

[154]  Seth A. Reini,et al.  Cardiac corticosteroid receptors mediate the enlargement of the ovine fetal heart induced by chronic increases in maternal cortisol. , 2008, The Journal of endocrinology.

[155]  W. R. MacLellan,et al.  Cardiac myocyte cell cycle control in development, disease, and regeneration. , 2007, Physiological reviews.

[156]  K. Thornburg,et al.  Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart. , 2007, Journal of applied physiology.

[157]  Danish Sayed,et al.  MicroRNAs Play an Essential Role in the Development of Cardiac Hypertrophy , 2007, Circulation research.

[158]  K. Thornburg,et al.  Thyroid hormone inhibits proliferation of fetal cardiac myocytes in vitro. , 2007, The Journal of endocrinology.

[159]  A. Vinogradov,et al.  Genome multiplication as adaptation to tissue survival: evidence from gene expression in mammalian heart and liver. , 2007, Genomics.

[160]  T. Visser,et al.  Developmental control of iodothyronine deiodinases by cortisol in the ovine fetus and placenta near term. , 2006, Endocrinology.

[161]  K. Thornburg,et al.  Cortisol stimulates cell cycle activity in the cardiomyocyte of the sheep fetus. , 2006, Endocrinology.

[162]  J. Mendell,et al.  MicroRNAs in cell proliferation, cell death, and tumorigenesis , 2006, British Journal of Cancer.

[163]  J. Buckingham Glucocorticoids: exemplars of multi‐tasking , 2006, British journal of pharmacology.

[164]  Yong Zhao,et al.  Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis , 2005, Nature.

[165]  J. Segar,et al.  Effects of cortisol on cardiac myocytes and on expression of cardiac genes in fetal sheep. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[166]  C. Adler,et al.  Variability of cardiomyocyte DNA content, ploidy level and nuclear number in mammalian hearts , 1996, Virchows Archiv.

[167]  E. Lumbers,et al.  Growth and maturation of cardiac myocytes in fetal sheep in the second half of gestation. , 2003, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[168]  Á. Raya,et al.  Activation of Notch signaling pathway precedes heart regeneration in zebrafish , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[169]  J. Maylie,et al.  Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes , 2003, The Journal of physiology.

[170]  M. Keating,et al.  Heart Regeneration in Zebrafish , 2002, Science.

[171]  Michael Fill,et al.  Ryanodine receptor calcium release channels. , 2002, Physiological reviews.

[172]  M. Ostrowski,et al.  Cell proliferation in the growing human heart: MIB-1 immunostaining in preterm and term infants at autopsy. , 2001, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[173]  T. Horio,et al.  Inhibitory regulation of hypertrophy by endogenous atrial natriuretic peptide in cultured cardiac myocytes. , 2000, Hypertension.

[174]  K. Fukuda,et al.  Angiotensin II potentiates DNA synthesis in AT-1 transformed cardiomyocytes. , 1998, Journal of molecular and cellular cardiology.

[175]  O. Carretero,et al.  Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. , 1997, The Journal of clinical investigation.

[176]  P. Anversa,et al.  Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. , 1997, Journal of molecular and cellular cardiology.

[177]  R. Ascuitto,et al.  Substrate metabolism in the developing heart. , 1996, Seminars in perinatology.

[178]  Jeffrey S. Robinson,et al.  Placental Restriction Alters the Functional Development of the Pituitary-Adrenal Axis in the Sheep Fetus during Late Gestation , 1996, Pediatric Research.

[179]  M. Franklin,et al.  Cardiomyocyte DNA synthesis and binucleation during murine development. , 1996, The American journal of physiology.

[180]  A. Gerdes,et al.  Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. , 1996, Journal of molecular and cellular cardiology.

[181]  G Olivetti,et al.  Aging, cardiac hypertrophy and ischemic cardiomyopathy do not affect the proportion of mononucleated and multinucleated myocytes in the human heart. , 1996, Journal of molecular and cellular cardiology.

[182]  A. Fowden,et al.  The effects of thyroid hormones on oxygen and glucose metabolism in the sheep fetus during late gestation. , 1995, The Journal of physiology.

[183]  T. Jung Growth and Hyperplasia of Cardiac Muscle Cells , 1994 .

[184]  G. Lopaschuk,et al.  Developmental changes in energy substrate use by the heart. , 1992, Cardiovascular research.

[185]  J. Schaper,et al.  Human fetal heart development after mid-term: morphometry and ultrastructural study. , 1992, Journal of molecular and cellular cardiology.

[186]  R. Johnstone,et al.  The Jeanne Manery-Fisher Memorial Lecture 1991. Maturation of reticulocytes: formation of exosomes as a mechanism for shedding membrane proteins. , 1992, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[187]  G. Lopaschuk,et al.  Glycolysis is predominant source of myocardial ATP production immediately after birth. , 1991, The American journal of physiology.

[188]  H. Schuler,et al.  Palmitate oxidation by isolated working fetal and newborn pig hearts. , 1989, The American journal of physiology.

[189]  R. Ascuitto,et al.  Ventricular function and fatty acid metabolism in neonatal piglet heart. , 1989, The American journal of physiology.

[190]  K. Pringle Human Fetal Lung Development and Related Animal Models , 1986, Clinical obstetrics and gynecology.

[191]  C H Rodeck,et al.  Effect of gestational age on fetal and intervillous blood gas and acid-base values in human pregnancy. , 1986, Fetal therapy.

[192]  P. Pfitzer,et al.  Mitoses and binucleated cells in perinatal human hearts , 1985, Virchows Archiv. B, Cell pathology including molecular pathology.

[193]  S. Oparil,et al.  Myocardial cell hypertrophy or hyperplasia. , 1984, Hypertension.

[194]  M. Heymann,et al.  Myocardial Consumption of Oxygen and Carbohydrates in Newborn Sheep , 1981, Pediatric Research.

[195]  R. Stillman,et al.  Direct evidence of sudden rise in fetal corticoids late in human gestation , 1980, Nature.

[196]  M. Heymann,et al.  Myocardial oxygen and carbohydrate consumption in fetal lambs in utero and in adult sheep. , 1980, The American journal of physiology.

[197]  M. Kaplan,et al.  Surge of fetal plasma triiodothyronine before birth in sheep. , 1978, American journal of obstetrics and gynecology.

[198]  P. Nathanielsz,et al.  Changes in the fetal thyroid axis after induction of premature parturition by low dose continuous intravascular cortisol infusion to the fetal sheep at 130 days of gestation. , 1978, Endocrinology.

[199]  H. Versmold,et al.  Longitudinal studies of plasma aldosterone, corticosterone, deoxycorticosterone, progesterone, 17-hydroxyprogesterone, cortisol, and cortisone determined simultaneously in mother and child at birth and during the early neonatal period. I. Spontaneous delivery. , 1978, The Journal of clinical endocrinology and metabolism.

[200]  P. Pfitzer,et al.  Number of nuclei in isolated myocardial cells of pigs , 1974, Virchows Archiv. B, Cell pathology.

[201]  P. Nathanielsz,et al.  Thyroid function in the foetal lamb during the last third of gestation. , 1973, The Journal of endocrinology.

[202]  P. Holt,et al.  Plasma corticosterone concentrations in the perinatal rat. , 1968, The Biochemical journal.

[203]  J. Barcroft THE CONDITIONS OF FŒTAL RESPIRATION , 1933 .