Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of physiological and pathological cardiac hypertrophy

Nature Reviews Cardiology volume 15, pages 387–407 (2018)Cite this article

Subjects

Abstract

Cardiomyocytes exit the cell cycle and become terminally differentiated soon after birth. Therefore, in the adult heart, instead of an increase in cardiomyocyte number, individual cardiomyocytes increase in size, and the heart develops hypertrophy to reduce ventricular wall stress and maintain function and efficiency in response to an increased workload. There are two types of hypertrophy: physiological and pathological. Hypertrophy initially develops as an adaptive response to physiological and pathological stimuli, but pathological hypertrophy generally progresses to heart failure. Each form of hypertrophy is regulated by distinct cellular signalling pathways. In the past decade, a growing number of studies have suggested that previously unrecognized mechanisms, including cellular metabolism, proliferation, non-coding RNAs, immune responses, translational regulation, and epigenetic modifications, positively or negatively regulate cardiac hypertrophy. In this Review, we summarize the underlying molecular mechanisms of physiological and pathological hypertrophy, with a particular emphasis on the role of metabolic remodelling in both forms of cardiac hypertrophy, and we discuss how the current knowledge on cardiac hypertrophy can be applied to develop novel therapeutic strategies to prevent or reverse pathological hypertrophy.

Key points

  • The heart initially undergoes hypertrophy in response to haemodynamic overload to increase contractility and reduce ventricular wall stress, but this adaptive hypertrophy transitions to heart failure through pathological remodelling.

  • There are two types of hypertrophy, physiological and pathological, which differ in their underlying molecular mechanisms, cardiac phenotype, and prognosis.

  • The type of hypertrophic stimuli and the nature of the downstream signalling mechanisms largely determine the fate of cardiac hypertrophy, which is either physiological or pathological.

  • Prioritizing the regulators of pathological hypertrophy on the basis of their clinical relevance for therapeutic targeting is important to improve the outcomes in patients with pathological hypertrophy and heart failure.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of physiological and pathological hypertrophy.
Fig. 2: General features of physiological and pathological hypertrophy.
Fig. 3: Physiological hypertrophy signalling pathways.
Fig. 4: Pathological hypertrophy signalling pathways.

Similar content being viewed by others

References

  1. Braunwald, E. Heart failure. JACC Heart Fail. 1, 1–20 (2013).

    Article  PubMed  Google Scholar 

  2. Schiattarella, G. G. & Hill, J. A. Inhibition of hypertrophy is a good therapeutic strategy in ventricular pressure overload. Circulation 131, 1435–1447 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  3. Redfield, M. M. Heart failure with preserved ejection fraction. N. Engl. J. Med. 375, 1868–1877 (2016).

    Article  PubMed  Google Scholar 

  4. Dunlay, S. M., Roger, V. L. & Redfield, M. M. Epidemiology of heart failure with preserved ejection fraction. Nat. Rev. Cardiol. 14, 591–602 (2017).

    Article  PubMed  Google Scholar 

  5. Mohammed, S. F. et al. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 131, 550–559 (2015).

    Article  PubMed  Google Scholar 

  6. Maillet, M., van Berlo, J. H. & Molkentin, J. D. Molecular basis of physiological heart growth: fundamental concepts and new players. Nat. Rev. Mol. Cell Biol. 14, 38–48 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. van Berlo, J. H., Maillet, M. & Molkentin, J. D. Signaling effectors underlying pathologic growth and remodeling of the heart. J. Clin. Invest. 123, 37–45 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Bernardo, B. C., Weeks, K. L., Pretorius, L. & McMullen, J. R. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol. Ther. 128, 191–227 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Tham, Y. K., Bernardo, B. C., Ooi, J. Y., Weeks, K. L. & McMullen, J. R. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch. Toxicol. 89, 1401–1438 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Shimizu, I. & Minamino, T. Physiological and pathological cardiac hypertrophy. J. Mol. Cell. Cardiol. 97, 245–262 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Perrino, C. et al. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J. Clin. Invest. 116, 1547–1560 (2006).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Vega, R. B., Konhilas, J. P., Kelly, D. P. & Leinwand, L. A. Molecular Mechanisms Underlying Cardiac Adaptation to Exercise. Cell Metab. 25, 1012–1026 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. McMullen, J. R. et al. Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Proc. Natl Acad. Sci. USA 104, 612–617 (2007).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Tsujita, Y. et al. Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy. Proc. Natl Acad. Sci. USA 103, 11946–11951 (2006).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Turkbey, E. B. et al. The impact of obesity on the left ventricle: the Multi-Ethnic Study of Atherosclerosis (MESA). JACC Cardiovasc. Imaging 3, 266–274 (2010).

    Google Scholar 

  16. Devereux, R. B. et al. Impact of diabetes on cardiac structure and function: the strong heart study. Circulation 101, 2271–2276 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Saltiel, A. R. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Neri Serneri, G. G. et al. Increased cardiac sympathetic activity and insulin-like growth factor-I formation are associated with physiological hypertrophy in athletes. Circ. Res. 89, 977–982 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Olszanecka, A., Dragan, A., Kawecka-Jaszcz, K., Fedak, D. & Czarnecka, D. Relationships of insulin-like growth factor-1, its binding proteins, and cardiometabolic risk in hypertensive perimenopausal women. Metabolism 69, 96–106 (2017).

    Article  CAS  PubMed  Google Scholar 

  20. Riehle, C. et al. Insulin receptor substrates are essential for the bioenergetic and hypertrophic response of the heart to exercise training. Mol. Cell. Biol. 34, 3450–3460 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Kim, J. et al. Insulin-like growth factor I receptor signaling is required for exercise-induced cardiac hypertrophy. Mol. Endocrinol. 22, 2531–2543 (2008).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. McMullen, J. R. et al. The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase(p110alpha) pathway. J. Biol. Chem. 279, 4782–4793 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Troncoso, R., Ibarra, C., Vicencio, J. M., Jaimovich, E. & Lavandero, S. New insights into IGF-1 signaling in the heart. Trends Endocrinol. Metab. 25, 128–137 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. McMullen, J. R. et al. Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc. Natl Acad. Sci. USA 100, 12355–12360 (2003).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Weeks, K. L. et al. Phosphoinositide 3-kinase p110alpha is a master regulator of exercise-induced cardioprotection and PI3K gene therapy rescues cardiac dysfunction. Circ. Heart Fail. 5, 523–534 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. DeBosch, B. et al. Akt1 is required for physiological cardiac growth. Circulation 113, 2097–2104 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Skurk, C. et al. The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling. J. Biol. Chem. 280, 20814–20823 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. O’Neill, B. T. et al. A conserved role for phosphatidylinositol 3-kinase but not Akt signaling in mitochondrial adaptations that accompany physiological cardiac hypertrophy. Cell Metab. 6, 294–306 (2007).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Bueno, O. F. et al. The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J. 19, 6341–6350 (2000).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Bostrom, P. et al. C/EBPbeta controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell 143, 1072–1083 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Bezzerides, V. J. et al. CITED4 induces physiologic hypertrophy and promotes functional recovery after ischemic injury. JCI Insight 1, e85904 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  32. Pantos, C., Mourouzis, I. & Cokkinos, D. V. New insights into the role of thyroid hormone in cardiac remodeling: time to reconsider? Heart Fail. Rev. 16, 79–96 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Fisher, D. A. & Klein, A. H. Thyroid development and disorders of thyroid function in the newborn. N. Engl. J. Med. 304, 702–712 (1981).

    Article  CAS  PubMed  Google Scholar 

  34. Morkin, E. Control of cardiac myosin heavy chain gene expression. Microsc. Res. Tech. 50, 522–531 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Chang, K. C. et al. Thyroid hormone improves function and Ca2+ handling in pressure overload hypertrophy. Association with increased sarcoplasmic reticulum Ca2+-ATPase and alpha-myosin heavy chain in rat hearts. J. Clin. Invest. 100, 1742–1749 (1997).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Pantos, C. et al. Thyroid hormone at supra-physiological dose optimizes cardiac geometry and improves cardiac function in rats with old myocardial infarction. J. Physiol. Pharmacol. 60, 49–56 (2009).

    CAS  PubMed  Google Scholar 

  37. Trivieri, M. G. et al. Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction. Proc. Natl Acad. Sci. USA 103, 6043–6048 (2006).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Belke, D. D., Gloss, B., Swanson, E. A. & Dillmann, W. H. Adeno-associated virus-mediated expression of thyroid hormone receptor isoforms-alpha1 and -beta1 improves contractile function in pressure overload-induced cardiac hypertrophy. Endocrinology 148, 2870–2877 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Calvert, J. W. et al. Exercise protects against myocardial ischemia-reperfusion injury via stimulation of beta(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols. Circ. Res. 108, 1448–1458 (2011).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Huang, P. L. et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377, 239–242 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Lee, P. C. et al. Impaired wound healing and angiogenesis in eNOS-deficient mice. Am. J. Physiol. 277, H1600–H1608 (1999).

    CAS  PubMed  Google Scholar 

  42. Li, W. et al. Premature death and age-related cardiac dysfunction in male eNOS-knockout mice. J. Mol. Cell. Cardiol. 37, 671–680 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Rainer, P. P. & Kass, D. A. Old dog, new tricks: novel cardiac targets and stress regulation by protein kinase G. Cardiovasc. Res. 111, 154–162 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Tamirisa, P., Blumer, K. J. & Muslin, A. J. RGS4 inhibits G-protein signaling in cardiomyocytes. Circulation 99, 441–447 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Rogers, J. H. et al. RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload. J. Clin. Invest. 104, 567–576 (1999).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Takimoto, E. et al. Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J. Clin. Invest. 119, 408–420 (2009).

    PubMed Central  CAS  PubMed  Google Scholar 

  47. de Waard, M. C. et al. Beneficial effects of exercise training after myocardial infarction require full eNOS expression. J. Mol. Cell. Cardiol. 48, 1041–1049 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Oka, T., Akazawa, H., Naito, A. T. & Komuro, I. Angiogenesis and cardiac hypertrophy: maintenance of cardiac function and causative roles in heart failure. Circ. Res. 114, 565–571 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Carmeliet, P. et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nat. Med. 5, 495–502 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Moslehi, J. J. Cardiovascular toxic effects of targeted cancer therapies. N. Engl. J. Med. 375, 1457–1467 (2016).

    Article  CAS  PubMed  Google Scholar 

  51. Hudlicka, O., Brown, M. & Egginton, S. Angiogenesis in skeletal and cardiac muscle. Physiol. Rev. 72, 369–417 (1992).

    Article  CAS  PubMed  Google Scholar 

  52. Hamasaki, S. et al. Attenuated coronary flow reserve and vascular remodeling in patients with hypertension and left ventricular hypertrophy. J. Am. Coll. Cardiol. 35, 1654–1660 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Togni, M. et al. Instantaneous coronary collateral function during supine bicycle exercise. Eur. Heart J. 31, 2148–2155 (2010).

    Article  PubMed  Google Scholar 

  54. Mobius-Winkler, S. et al. Coronary collateral growth induced by physical exercise: results of the impact of intensive exercise training on coronary collateral circulation in patients with stable coronary artery disease (EXCITE) Trial. Circulation 133, 1438–1448 (2016).

    Article  CAS  PubMed  Google Scholar 

  55. Elkayam, U. Clinical characteristics of peripartum cardiomyopathy in the United States: diagnosis, prognosis, and management. J. Am. Coll. Cardiol. 58, 659–670 (2011).

    Article  PubMed  Google Scholar 

  56. Patten, I. S. et al. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature 485, 333–338 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Goland, S. et al. Angiogenic imbalance and residual myocardial injury in recovered peripartum cardiomyopathy patients. Circ. Heart Fail. 9, e003349 (2016).

    Article  CAS  PubMed  Google Scholar 

  58. Damp, J. et al. Relaxin-2 and soluble Flt1 levels in peripartum cardiomyopathy: results of the multicenter IPAC study. JACC Heart Fail. 4, 380–388 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  59. Semenza, G. L. Hypoxia-inducible factor 1 and cardiovascular disease. Annu. Rev. Physiol. 76, 39–56 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Shiojima, I. et al. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J. Clin. Invest. 115, 2108–2118 (2005).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Shiojima, I. & Walsh, K. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev. 20, 3347–3365 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Izumiya, Y. et al. Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload. Hypertension 47, 887–893 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Sano, M. et al. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature 446, 444–448 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Ravi, R. et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev. 14, 34–44 (2000).

    PubMed Central  CAS  PubMed  Google Scholar 

  65. Heineke, J. et al. Cardiomyocyte GATA4 functions as a stress-responsive regulator of angiogenesis in the murine heart. J. Clin. Invest. 117, 3198–3210 (2007).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Arany, Z. et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature 451, 1008–1012 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Torry, R. J. et al. Hypoxia increases placenta growth factor expression in human myocardium and cultured neonatal rat cardiomyocytes. J. Heart Lung Transplant 28, 183–190 (2009).

    Article  PubMed Central  PubMed  Google Scholar 

  68. Accornero, F. et al. Placental growth factor regulates cardiac adaptation and hypertrophy through a paracrine mechanism. Circ. Res. 109, 272–280 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Shindo, T. et al. Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling. Nat. Med. 8, 856–863 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Chintalgattu, V. et al. Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress. J. Clin. Invest. 120, 472–484 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Tromp, J. et al. Biomarker profiles in heart failure patients with preserved and reduced ejection fraction. J. Am. Heart Assoc. 6, e003989 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  72. Odiete, O., Hill, M. F. & Sawyer, D. B. Neuregulin in cardiovascular development and disease. Circ. Res. 111, 1376–1385 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Hirai, M. et al. Adaptor proteins NUMB and NUMBL promote cell cycle withdrawal by targeting ERBB2 for degradation. J. Clin. Invest. 127, 569–582 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  74. Waring, C. D. et al. The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation. Eur. Heart J. 35, 2722–2731 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Fukazawa, R. et al. Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase/Akt. J. Mol. Cell. Cardiol. 35, 1473–1479 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Bersell, K., Arab, S., Haring, B. & Kuhn, B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 138, 257–270 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. D’Uva, G. et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat. Cell Biol. 17, 627–638 (2015).

    Article  CAS  PubMed  Google Scholar 

  78. Gemberling, M., Karra, R., Dickson, A. L. & Poss, K. D. Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish. eLIFE 4, e05871 (2015).

    Article  PubMed Central  CAS  Google Scholar 

  79. Polizzotti, B. D. et al. Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window. Sci. Transl. Med. 7, 281ra45 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Lyon, R. C., Zanella, F., Omens, J. H. & Sheikh, F. Mechanotransduction in cardiac hypertrophy and failure. Circ. Res. 116, 1462–1476 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. De Acetis, M. et al. Cardiac overexpression of melusin protects from dilated cardiomyopathy due to long-standing pressure overload. Circ. Res. 96, 1087–1094 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Brancaccio, M. et al. Melusin, a muscle-specific integrin beta1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload. Nat. Med. 9, 68–75 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Fernandes, T., Barauna, V. G., Negrao, C. E., Phillips, M. I. & Oliveira, E. M. Aerobic exercise training promotes physiological cardiac remodeling involving a set of microRNAs. Am. J. Physiol. Heart Circ. Physiol. 309, H543–H552 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Liu, X. et al. miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell Metab. 21, 584–595 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Chorghade, S. et al. Poly(A) tail length regulates PABPC1 expression to tune translation in the heart. eLIFE 6, e24139 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  86. Zhang, L. et al. Phospholipase cepsilon hydrolyzes perinuclear phosphatidylinositol 4-phosphate to regulate cardiac hypertrophy. Cell 153, 216–227 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Newton, A. C., Antal, C. E. & Steinberg, S. F. Protein kinase C mechanisms that contribute to cardiac remodelling. Clin. Sci. 130, 1499–1510 (2016).

    Article  CAS  Google Scholar 

  88. Braz, J. C. et al. PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nat. Med. 10, 248–254 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Kadambi, V. J. et al. Cardiac-specific overexpression of phospholamban alters calcium kinetics and resultant cardiomyocyte mechanics in transgenic mice. J. Clin. Invest. 97, 533–539 (1996).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Luo, W. et al. Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Circ. Res. 75, 401–409 (1994).

    Article  CAS  PubMed  Google Scholar 

  91. Ling, H. et al. Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice. J. Clin. Invest. 119, 1230–1240 (2009).

    Article  PubMed Central  PubMed  Google Scholar 

  92. Backs, J. et al. The delta isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. Proc. Natl Acad. Sci. USA 106, 2342–2347 (2009).

    Article  PubMed Central  PubMed  Google Scholar 

  93. Ago, T. et al. A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy. Cell 133, 978–993 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Zhang, C. L. et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479–488 (2002).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Haberland, M., Montgomery, R. L. & Olson, E. N. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat. Rev. Genet. 10, 32–42 (2009).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Gallo, P. et al. Inhibition of class I histone deacetylase with an apicidin derivative prevents cardiac hypertrophy and failure. Cardiovasc. Res. 80, 416–424 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Molkentin, J. D. et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215–228 (1998).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  98. Wilkins, B. J. et al. Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ. Res. 94, 110–118 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Rose, B. A., Force, T. & Wang, Y. Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol. Rev. 90, 1507–1546 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Lymperopoulos, A., Rengo, G. & Koch, W. J. Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ. Res. 113, 739–753 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Sato, P. Y., Chuprun, J. K., Schwartz, M. & Koch, W. J. The evolving impact of g protein-coupled receptor kinases in cardiac health and disease. Physiol. Rev. 95, 377–404 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Woodall, M. C., Ciccarelli, M., Woodall, B. P. & Koch, W. J. G protein-coupled receptor kinase 2: a link between myocardial contractile function and cardiac metabolism. Circ. Res. 114, 1661–1670 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  103. Schumacher, S. M. & Koch, W. J. Noncanonical roles of G Protein-coupled receptor kinases in cardiovascular signaling. J. Cardiovasc. Pharmacol. 70, 129–141 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Martini, J. S. et al. Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes. Proc. Natl Acad. Sci. USA 105, 12457–12462 (2008).

    Article  PubMed Central  PubMed  Google Scholar 

  105. Hullmann, J. E. et al. GRK5-mediated exacerbation of pathological cardiac hypertrophy involves facilitation of nuclear NFAT activity. Circ. Res. 115, 976–985 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  106. Traynham, C. J. et al. Differential role of G protein-coupled receptor kinase 5 in physiological versus pathological cardiac hypertrophy. Circ. Res. 117, 1001–1012 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Gold, J. I., Gao, E., Shang, X., Premont, R. T. & Koch, W. J. Determining the absolute requirement of G protein-coupled receptor kinase 5 for pathological cardiac hypertrophy: short communication. Circ. Res. 111, 1048–1053 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Morel, E. et al. cAMP-binding protein Epac induces cardiomyocyte hypertrophy. Circ. Res. 97, 1296–1304 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Metrich, M. et al. Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy. Circ. Res. 102, 959–965 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Pereira, L. et al. Epac2 mediates cardiac beta1-adrenergic-dependent sarcoplasmic reticulum Ca2+ leak and arrhythmia. Circulation 127, 913–922 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Okumura, S. et al. Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses. J. Clin. Invest. 124, 2785–2801 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Pereira, L. et al. Novel Epac fluorescent ligand reveals distinct Epac1 versus Epac2 distribution and function in cardiomyocytes. Proc. Natl Acad. Sci. USA 112, 3991–3996 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Sciarretta, S., Forte, M., Frati, G. & Sadoshima, J. New insights into the role of mTOR signaling in the cardiovascular system. Circ. Res. 122, 489–505 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Zhang, D. et al. MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J. Clin. Invest. 120, 2805–2816 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  116. Sadoshima, J. & Izumo, S. Rapamycin selectively inhibits angiotensin II-induced increase in protein synthesis in cardiac myocytes in vitro. Potential role of 70-kD S6 kinase in angiotensin II-induced cardiac hypertrophy. Circ. Res. 77, 1040–1052 (1995).

    Article  CAS  PubMed  Google Scholar 

  117. Shioi, T. et al. Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation 107, 1664–1670 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. McMullen, J. R. et al. Deletion of ribosomal S6 kinases does not attenuate pathological, physiological, or insulin-like growth factor 1 receptor-phosphoinositide 3-kinase-induced cardiac hypertrophy. Mol. Cell. Biol. 24, 6231–6240 (2004).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Sciarretta, S. et al. mTORC2 regulates cardiac response to stress by inhibiting MST1. Cell Rep. 11, 125–136 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  120. Holtwick, R. et al. Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J. Clin. Invest. 111, 1399–1407 (2003).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Takimoto, E. et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat. Med. 11, 214–222 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Lee, D. I. et al. Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature 519, 472–476 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Pinto, A. R. et al. Revisiting cardiac cellular composition. Circ. Res. 118, 400–409 (2016).

    Article  CAS  PubMed  Google Scholar 

  124. Leask, A. Getting to the heart of the matter: new insights into cardiac fibrosis. Circ. Res. 116, 1269–1276 (2015).

    Article  CAS  PubMed  Google Scholar 

  125. Kakkar, R. & Lee, R. T. Intramyocardial fibroblast myocyte communication. Circ. Res. 106, 47–57 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. Pellieux, C. et al. Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2. J. Clin. Invest. 108, 1843–1851 (2001).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  127. Schultz, J. E. et al. Fibroblast growth factor-2 mediates pressure-induced hypertrophic response. J. Clin. Invest. 104, 709–719 (1999).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  128. Kuwahara, F. et al. Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation 106, 130–135 (2002).

    Article  CAS  PubMed  Google Scholar 

  129. Divakaran, V. et al. Adaptive and maladptive effects of SMAD3 signaling in the adult heart after hemodynamic pressure overloading. Circ. Heart Fail. 2, 633–642 (2009).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  130. Zhang, D. et al. TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nat. Med. 6, 556–563 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Koitabashi, N. et al. Pivotal role of cardiomyocyte TGF-beta signaling in the murine pathological response to sustained pressure overload. J. Clin. Invest. 121, 2301–2312 (2011).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  132. Schafer, S. et al. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature 552, 110–115 (2017).

    PubMed Central  CAS  PubMed  Google Scholar 

  133. Takeda, N. et al. Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. J. Clin. Invest. 120, 254–265 (2010).

    Article  CAS  PubMed  Google Scholar 

  134. Bang, C. et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J. Clin. Invest. 124, 2136–2146 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  135. Frieler, R. A. & Mortensen, R. M. Immune cell and other noncardiomyocyte regulation of cardiac hypertrophy and remodeling. Circulation 131, 1019–1030 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  136. Testa, M. et al. Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J. Am. Coll. Cardiol. 28, 964–971 (1996).

    Article  CAS  PubMed  Google Scholar 

  137. Melendez, G. C. et al. Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats. Hypertension 56, 225–231 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Hirota, H., Yoshida, K., Kishimoto, T. & Taga, T. Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc. Natl Acad. Sci. USA 92, 4862–4866 (1995).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  139. Zhao, L. et al. Deletion of interleukin-6 attenuates pressure overload-induced left ventricular hypertrophy and dysfunction. Circ. Res. 118, 1918–1929 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  140. Hirota, H. et al. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell 97, 189–198 (1999).

    Article  CAS  PubMed  Google Scholar 

  141. Kubota, T. et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ. Res. 81, 627–635 (1997).

    Article  CAS  PubMed  Google Scholar 

  142. Sun, M. et al. Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dysfunction after pressure overload state. Circulation 115, 1398–1407 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Nishikawa, K. et al. Left ventricular hypertrophy in mice with a cardiac-specific overexpression of interleukin-1. Am. J. Physiol. Heart Circ. Physiol. 291, H176–H183 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Honsho, S. et al. Pressure-mediated hypertrophy and mechanical stretch induces IL-1 release and subsequent IGF-1 generation to maintain compensative hypertrophy by affecting Akt and JNK pathways. Circ. Res. 105, 1149–1158 (2009).

    Article  CAS  PubMed  Google Scholar 

  145. Van Tassell, B. W. et al. Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study). Am. J. Cardiol. 113, 321–327 (2014).

    Article  CAS  PubMed  Google Scholar 

  146. Van Tassell, B. W. et al. Interleukin-1 blockade in recently decompensated systolic heart failure: results from REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ. Heart Fail. 10, e004373 (2017).

    PubMed  PubMed Central  Google Scholar 

  147. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  CAS  PubMed  Google Scholar 

  148. Verma, S. K. et al. Interleukin-10 treatment attenuates pressure overload-induced hypertrophic remodeling and improves heart function via signal transducers and activators of transcription 3-dependent inhibition of nuclear factor-kappaB. Circulation 126, 418–429 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  149. Sobirin, M. A. et al. Activation of natural killer T cells ameliorates postinfarct cardiac remodeling and failure in mice. Circ. Res. 111, 1037–1047 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Kallikourdis, M. et al. T cell costimulation blockade blunts pressure overload-induced heart failure. Nat. Commun. 8, 14680 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  151. Tirziu, D., Giordano, F. J. & Simons, M. Cell communications in the heart. Circulation 122, 928–937 (2010).

    Article  PubMed Central  PubMed  Google Scholar 

  152. Chen, W. Y., Hong, J., Gannon, J., Kakkar, R. & Lee, R. T. Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33. Proc. Natl Acad. Sci. USA 112, 7249–7254 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  153. Sanada, S. et al. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J. Clin. Invest. 117, 1538–1549 (2007).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  154. Appari, M. et al. C1q-TNF-related protein-9 promotes cardiac hypertrophy and failure. Circ. Res. 120, 66–77 (2017).

    Article  CAS  PubMed  Google Scholar 

  155. Sun, Y. et al. C1q/tumor necrosis factor-related protein-9, a novel adipocyte-derived cytokine, attenuates adverse remodeling in the ischemic mouse heart via protein kinase A activation. Circulation 128, S113–S120 (2013).

    Article  CAS  PubMed  Google Scholar 

  156. Eder, P. & Molkentin, J. D. TRPC channels as effectors of cardiac hypertrophy. Circ. Res. 108, 265–272 (2011).

    Article  CAS  PubMed  Google Scholar 

  157. Kuwahara, K. et al. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J. Clin. Invest. 116, 3114–3126 (2006).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  158. Onohara, N. et al. TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. EMBO J. 25, 5305–5316 (2006).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  159. Bush, E. W. et al. Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling. J. Biol. Chem. 281, 33487–33496 (2006).

    Article  CAS  PubMed  Google Scholar 

  160. Seo, K. et al. Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy. Proc. Natl Acad. Sci. USA 111, 1551–1556 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  161. Takahashi, S. et al. Nitric oxide-cGMP-protein kinase G pathway negatively regulates vascular transient receptor potential channel TRPC6. J. Physiol. 586, 4209–4223 (2008).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  162. Wu, X., Eder, P., Chang, B. & Molkentin, J. D. TRPC channels are necessary mediators of pathologic cardiac hypertrophy. Proc. Natl Acad. Sci. USA 107, 7000–7005 (2010).

    Article  PubMed Central  PubMed  Google Scholar 

  163. Makarewich, C. A. et al. Transient receptor potential channels contribute to pathological structural and functional remodeling after myocardial infarction. Circ. Res. 115, 567–580 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  164. Correll, R. N. et al. STIM1 elevation in the heart results in aberrant Ca(2)(+) handling and cardiomyopathy. J. Mol. Cell. Cardiol. 87, 38–47 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  165. Troupes, C. D. et al. Role of STIM1 (stromal interaction molecule 1) in hypertrophy-related contractile dysfunction. Circ. Res. 121, 125–136 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Luo, X. et al. STIM1-dependent store-operated Ca(2)(+) entry is required for pathological cardiac hypertrophy. J. Mol. Cell. Cardiol. 52, 136–147 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Benard, L. et al. Cardiac Stim1 silencing impairs adaptive hypertrophy and promotes heart failure through inactivation of mTORC2/Akt signaling. Circulation 133, 1458–1471 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  168. Burke, M. A., Cook, S. A., Seidman, J. G. & Seidman, C. E. Clinical and mechanistic insights into the genetics of cardiomyopathy. J. Am. Coll. Cardiol. 68, 2871–2886 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  169. Marian, A. J. & Braunwald, E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ. Res. 121, 749–770 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Davis, J. et al. A tension-based model distinguishes hypertrophic versus dilated cardiomyopathy. Cell 165, 1147–1159 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  171. Teekakirikul, P. et al. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-beta. J. Clin. Invest. 120, 3520–3529 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  172. Papait, R. et al. Genome-wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy. Proc. Natl Acad. Sci. USA 110, 20164–20169 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  173. Zhang, Q. J. et al. The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J. Clin. Invest. 121, 2447–2456 (2011).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  174. Thienpont, B. et al. The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy. J. Clin. Invest. 127, 335–348 (2017).

    Article  PubMed  Google Scholar 

  175. Han, P. et al. Epigenetic response to environmental stress: assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts. Biochim. Biophys. Acta 1863, 1772–1781 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Papait, R. et al. Histone methyltransferase G9a is required for cardiomyocyte homeostasis and hypertrophy. Circulation 136, 1233–1246 (2017).

    Article  CAS  PubMed  Google Scholar 

  177. Wang, Z. et al. The long noncoding RNA chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat. Med. 22, 1131–1139 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  178. Fatica, A. & Bozzoni, I. Long non-coding RNAs: new players in cell differentiation and development. Nat. Rev. Genet. 15, 7–21 (2014).

    Article  CAS  PubMed  Google Scholar 

  179. Mercer, T. R., Dinger, M. E. & Mattick, J. S. Long non-coding RNAs: insights into functions. Nat. Rev. Genet. 10, 155–159 (2009).

    Article  CAS  PubMed  Google Scholar 

  180. Batista, P. J. & Chang, H. Y. Long noncoding RNAs: cellular address codes in development and disease. Cell 152, 1298–1307 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  181. Harada, M. et al. MicroRNA regulation and cardiac calcium signaling: role in cardiac disease and therapeutic potential. Circ. Res. 114, 689–705 (2014).

    Article  CAS  PubMed  Google Scholar 

  182. Marks, A. R. Calcium cycling proteins and heart failure: mechanisms and therapeutics. J. Clin. Invest. 123, 46–52 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  183. Meguro, T. et al. Cyclosporine attenuates pressure-overload hypertrophy in mice while enhancing susceptibility to decompensation and heart failure. Circ. Res. 84, 735–740 (1999).

    Article  CAS  PubMed  Google Scholar 

  184. Maillet, M. et al. Heart-specific deletion of CnB1 reveals multiple mechanisms whereby calcineurin regulates cardiac growth and function. J. Biol. Chem. 285, 6716–6724 (2010).

    Article  CAS  PubMed  Google Scholar 

  185. Maron, B. J., Doerer, J. J., Haas, T. S., Tierney, D. M. & Mueller, F. O. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980–2006. Circulation 119, 1085–1092 (2009).

    Article  PubMed  Google Scholar 

  186. Maron, B. J. Distinguishing hypertrophic cardiomyopathy from athlete’s heart physiological remodelling: clinical significance, diagnostic strategies and implications for preparticipation screening. Br. J. Sports Med. 43, 649–656 (2009).

    Article  CAS  PubMed  Google Scholar 

  187. Shimizu, I. et al. Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. J. Clin. Invest. 120, 1506–1514 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  188. Strom, C. C. et al. Expression profiling reveals differences in metabolic gene expression between exercise-induced cardiac effects and maladaptive cardiac hypertrophy. FEBS J. 272, 2684–2695 (2005).

    Article  CAS  PubMed  Google Scholar 

  189. Zhang, L. et al. Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy. Circ. Heart Fail. 6, 1039–1048 (2013).

    Article  CAS  PubMed  Google Scholar 

  190. Liew, C. W. et al. Multiphasic regulation of systemic and peripheral organ metabolic responses to cardiac hypertrophy. Circ. Heart Fail. 10, e003864 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  191. Doenst, T., Nguyen, T. D. & Abel, E. D. Cardiac metabolism in heart failure: implications beyond ATP production. Circ. Res. 113, 709–724 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  192. Neubauer, S. The failing heart—an engine out of fuel. N. Engl. J. Med. 356, 1140–1151 (2007).

    Article  PubMed  Google Scholar 

  193. Huss, J. M. et al. The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload. Cell Metab. 6, 25–37 (2007).

    Article  CAS  PubMed  Google Scholar 

  194. Sung, M. M. et al. Cardiomyocyte-specific ablation of CD36 accelerates the progression from compensated cardiac hypertrophy to heart failure. Am. J. Physiol. Heart Circ. Physiol. 312, H552–H560 (2017).

    Article  PubMed  Google Scholar 

  195. Boudina, S. et al. Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart. Circulation 119, 1272–1283 (2009).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  196. Chiu, H. C. et al. A novel mouse model of lipotoxic cardiomyopathy. J. Clin. Invest. 107, 813–822 (2001).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  197. Finck, B. N. et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J. Clin. Invest. 109, 121–130 (2002).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  198. Yagyu, H. et al. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J. Clin. Invest. 111, 419–426 (2003).

    Article  PubMed Central  PubMed  Google Scholar 

  199. Chiu, H. C. et al. Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circ. Res. 96, 225–233 (2005).

    Article  CAS  PubMed  Google Scholar 

  200. Son, N. H. et al. Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice. J. Clin. Invest. 117, 2791–2801 (2007).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  201. Cheng, L. et al. Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat. Med. 10, 1245–1250 (2004).

    Article  CAS  PubMed  Google Scholar 

  202. Lai, L. et al. Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach. Circ. Heart Fail. 7, 1022–1031 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  203. Vega, R. B., Horton, J. L. & Kelly, D. P. Maintaining ancient organelles: mitochondrial biogenesis and maturation. Circ. Res. 116, 1820–1834 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  204. Aubert, G., Vega, R. B. & Kelly, D. P. Perturbations in the gene regulatory pathways controlling mitochondrial energy production in the failing heart. Biochim. Biophys. Acta 1833, 840–847 (2013).

    Article  CAS  PubMed  Google Scholar 

  205. Doenst, T. et al. Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload. Cardiovasc. Res. 86, 461–470 (2010).

    Article  CAS  PubMed  Google Scholar 

  206. Razeghi, P. et al. Metabolic gene expression in fetal and failing human heart. Circulation 104, 2923–2931 (2001).

    Article  CAS  PubMed  Google Scholar 

  207. Kolwicz, S. C. Jr et al. Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. Circ. Res. 111, 728–738 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  208. Choi, Y. S. et al. Preservation of myocardial fatty acid oxidation prevents diastolic dysfunction in mice subjected to angiotensin II infusion. J. Mol. Cell. Cardiol. 100, 64–71 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  209. Burelle, Y. et al. Regular exercise is associated with a protective metabolic phenotype in the rat heart. Am. J. Physiol. Heart Circ. Physiol. 287, H1055–H1063 (2004).

    Article  CAS  PubMed  Google Scholar 

  210. Burkart, E. M. et al. Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart. J. Clin. Invest. 117, 3930–3939 (2007).

    PubMed Central  CAS  PubMed  Google Scholar 

  211. Huss, J. M., Torra, I. P., Staels, B., Giguere, V. & Kelly, D. P. Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol. Cell. Biol. 24, 9079–9091 (2004).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  212. Fan, W. & Evans, R. PPARs and ERRs: molecular mediators of mitochondrial metabolism. Curr. Opin. Cell Biol. 33, 49–54 (2015).

    Article  CAS  PubMed  Google Scholar 

  213. Rowe, G. C., Jiang, A. & Arany, Z. PGC-1 coactivators in cardiac development and disease. Circ. Res. 107, 825–838 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  214. Barger, P. M., Brandt, J. M., Leone, T. C., Weinheimer, C. J. & Kelly, D. P. Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth. J. Clin. Invest. 105, 1723–1730 (2000).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  215. Fan, W. & Evans, R. M. Exercise mimetics: impact on health and performance. Cell Metab. 25, 242–247 (2017).

    Article  CAS  PubMed  Google Scholar 

  216. Jager, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  217. Narkar, V. A. et al. AMPK and PPARdelta agonists are exercise mimetics. Cell 134, 405–415 (2008).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  218. Vettor, R. et al. Exercise training boosts eNOS-dependent mitochondrial biogenesis in mouse heart: role in adaptation of glucose metabolism. Am. J. Physiol. Endocrinol. Metab. 306, E519–E528 (2014).

    Article  CAS  PubMed  Google Scholar 

  219. Boudina, S. & Abel, E. D. Diabetic cardiomyopathy revisited. Circulation 115, 3213–3223 (2007).

    Article  PubMed  Google Scholar 

  220. Schilling, J. D. & Mann, D. L. Diabetic cardiomyopathy: bench to bedside. Heart Fail. Clin. 8, 619–631 (2012).

    Article  PubMed Central  PubMed  Google Scholar 

  221. Szczepaniak, L. S., Victor, R. G., Orci, L. & Unger, R. H. Forgotten but not gone: the rediscovery of fatty heart, the most common unrecognized disease in America. Circ. Res. 101, 759–767 (2007).

    Article  CAS  PubMed  Google Scholar 

  222. Rijzewijk, L. J. et al. Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging. J. Am. Coll. Cardiol. 54, 1524–1532 (2009).

    Article  CAS  PubMed  Google Scholar 

  223. Rijzewijk, L. J. et al. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J. Am. Coll. Cardiol. 52, 1793–1799 (2008).

    Article  PubMed  Google Scholar 

  224. Goldberg, I. J., Trent, C. M. & Schulze, P. C. Lipid metabolism and toxicity in the heart. Cell Metab. 15, 805–812 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  225. Wang, G. et al. Direct binding to ceramide activates protein kinase Czeta before the formation of a pro-apoptotic complex with PAR-4 in differentiating stem cells. J. Biol. Chem. 280, 26415–26424 (2005).

    Article  CAS  PubMed  Google Scholar 

  226. Koves, T. R. et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 7, 45–56 (2008).

    Article  CAS  PubMed  Google Scholar 

  227. Bikman, B. T. & Summers, S. A. Ceramides as modulators of cellular and whole-body metabolism. J. Clin. Invest. 121, 4222–4230 (2011).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  228. Chavez, J. A. & Summers, S. A. A ceramide-centric view of insulin resistance. Cell Metab. 15, 585–594 (2012).

    Article  CAS  PubMed  Google Scholar 

  229. Park, T. S. et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J. Lipid Res. 49, 2101–2112 (2008).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  230. Russo, S. B. et al. Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes. J. Clin. Invest. 122, 3919–3930 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  231. Son, N. H. et al. PPARgamma-induced cardiolipotoxicity in mice is ameliorated by PPARalpha deficiency despite increases in fatty acid oxidation. J. Clin. Invest. 120, 3443–3454 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  232. Ji, R. et al. Increased de novo ceramide synthesis and accumulation in failing myocardium. JCI Insight 2, e82922 (2017).

    Article  PubMed Central  Google Scholar 

  233. Reforgiato, M. R. et al. Inhibition of ceramide de novo synthesis as a postischemic strategy to reduce myocardial reperfusion injury. Basic Res. Cardiol. 111, 12 (2016).

    Article  CAS  PubMed  Google Scholar 

  234. Zhang, Y. et al. Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overload. JCI Insight 1, e85484 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  235. Lee, S. Y. et al. Cardiomyocyte specific deficiency of serine palmitoyltransferase subunit 2 reduces ceramide but leads to cardiac dysfunction. J. Biol. Chem. 287, 18429–18439 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  236. Schooneman, M. G., Vaz, F. M., Houten, S. M. & Soeters, M. R. Acylcarnitines: reflecting or inflicting insulin resistance? Diabetes 62, 1–8 (2013).

    Article  CAS  PubMed  Google Scholar 

  237. Bedi, K. C. Jr et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation 133, 706–716 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  238. Sansbury, B. E. et al. Metabolomic analysis of pressure-overloaded and infarcted mouse hearts. Circ. Heart Fail. 7, 634–642 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  239. Ahmad, T. et al. Prognostic implications of long-chain acylcarnitines in heart failure and reversibility with mechanical circulatory support. J. Am. Coll. Cardiol. 67, 291–299 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  240. Geraldes, P. & King, G. L. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ. Res. 106, 1319–1331 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  241. Jornayvaz, F. R. & Shulman, G. I. Diacylglycerol activation of protein kinase Cepsilon and hepatic insulin resistance. Cell Metab. 15, 574–584 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  242. Chokshi, A. et al. Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation 125, 2844–2853 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  243. Liu, L. et al. Cardiomyocyte-specific loss of diacylglycerol acyltransferase 1 (DGAT1) reproduces the abnormalities in lipids found in severe heart failure. J. Biol. Chem. 289, 29881–29891 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  244. Newgard, C. B. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 15, 606–614 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  245. Jang, C. et al. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat. Med. 22, 421–426 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  246. Sun, H. et al. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 133, 2038–2049 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  247. Shao, D. & Tian, R. Glucose transporters in cardiac metabolism and hypertrophy. Compr. Physiol. 6, 331–351 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  248. Sen, S. et al. Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart. J. Am. Heart Assoc. 2, e004796 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  249. Sharma, S., Guthrie, P. H., Chan, S. S., Haq, S. & Taegtmeyer, H. Glucose phosphorylation is required for insulin-dependent mTOR signalling in the heart. Cardiovasc. Res. 76, 71–80 (2007).

    Article  CAS  PubMed  Google Scholar 

  250. Ritterhoff, J. & Tian, R. Metabolism in cardiomyopathy: every substrate matters. Cardiovasc. Res. 113, 411–421 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  251. Ussher, J. R., Jaswal, J. S. & Lopaschuk, G. D. Pyridine nucleotide regulation of cardiac intermediary metabolism. Circ. Res. 111, 628–641 (2012).

    Article  CAS  PubMed  Google Scholar 

  252. Mirtschink, P. et al. HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease. Nature 522, 444–449 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  253. Cotter, D. G., Schugar, R. C. & Crawford, P. A. Ketone body metabolism and cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 304, H1060–H1076 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  254. Lopaschuk, G. D. Metabolic modulators in heart disease: past, present, and future. Can. J. Cardiol. 33, 838–849 (2017).

    Article  PubMed  Google Scholar 

  255. Lommi, J. et al. Blood ketone bodies in congestive heart failure. J. Am. Coll. Cardiol. 28, 665–672 (1996).

    Article  CAS  PubMed  Google Scholar 

  256. Aubert, G. et al. The failing heart relies on ketone bodies as a fuel. Circulation 133, 698–705 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  257. Schugar, R. C. et al. Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling. Mol. Metab. 3, 754–769 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  258. Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117–2128 (2015).

    Article  CAS  PubMed  Google Scholar 

  259. Lopaschuk, G. D. & Verma, S. Empagliflozin’s fuel hypothesis: not so soon. Cell Metab. 24, 200–202 (2016).

    Article  CAS  PubMed  Google Scholar 

  260. Ferrannini, E. et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 65, 1190–1195 (2016).

    Article  CAS  PubMed  Google Scholar 

  261. Shimazu, T. et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).

    Article  CAS  PubMed  Google Scholar 

  262. Taegtmeyer, H., Hems, R. & Krebs, H. A. Utilization of energy-providing substrates in the isolated working rat heart. Biochem. J. 186, 701–711 (1980).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  263. Horton, J. L. et al. Mitochondrial protein hyperacetylation in the failing heart. JCI Insight 1, e84897 (2016).

    Article  PubMed Central  Google Scholar 

  264. Nakamura, M. & Sadoshima, J. Heart over mind: metabolic control of white adipose tissue and liver. EMBO Mol. Med. 6, 1521–1524 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  265. Shimano, M., Ouchi, N. & Walsh, K. Cardiokines: recent progress in elucidating the cardiac secretome. Circulation 126, e327–e332 (2012).

    Article  PubMed  Google Scholar 

  266. de Bold, A. J. Thirty years of research on atrial natriuretic factor: historical background and emerging concepts. Can. J. Physiol. Pharmacol. 89, 527–531 (2011).

    Article  CAS  PubMed  Google Scholar 

  267. Grueter, C. E. et al. A cardiac microRNA governs systemic energy homeostasis by regulation of MED13. Cell 149, 671–683 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  268. Baskin, K. K. et al. MED13-dependent signaling from the heart confers leanness by enhancing metabolism in adipose tissue and liver. EMBO Mol. Med. 6, 1610–1621 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  269. Fuster, J. J., Ouchi, N., Gokce, N. & Walsh, K. Obesity-induced changes in adipose tissue microenvironment and their impact on cardiovascular disease. Circ. Res. 118, 1786–1807 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  270. Ouchi, N., Parker, J. L., Lugus, J. J. & Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 11, 85–97 (2011).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  271. Shibata, R. et al. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat. Med. 10, 1384–1389 (2004).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  272. Fang, X. et al. Adipocyte-specific loss of PPARgamma attenuates cardiac hypertrophy. JCI Insight 1, e89908 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  273. Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251–262 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  274. Mihaylova, M. M. & Shaw, R. J. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13, 1016–1023 (2011).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  275. Tian, R., Musi, N., D’Agostino, J., Hirshman, M. F. & Goodyear, L. J. Increased adenosine monophosphate-activated protein kinase activity in rat hearts with pressure-overload hypertrophy. Circulation 104, 1664–1669 (2001).

    Article  CAS  PubMed  Google Scholar 

  276. Shao, D. et al. A redox-dependent mechanism for regulation of AMPK activation by thioredoxin1 during energy starvation. Cell Metab. 19, 232–245 (2014).

  277. Kim, T. T. & Dyck, J. R. Is AMPK the savior of the failing heart? Trends Endocrinol. Metab. 26, 40–48 (2015).

    Article  CAS  PubMed  Google Scholar 

  278. Lee, C. F. et al. Normalization of NAD+ redox balance as a therapy for heart failure. Circulation 134, 883–894 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  279. Nakamura, M., Bhatnagar, A. & Sadoshima, J. Overview of pyridine nucleotides review series. Circ. Res. 111, 604–610 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  280. Koentges, C., Bode, C. & Bugger, H. SIRT3 in cardiac physiology and disease. Front. Cardiovasc. Med. 3, 38 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  281. Sundaresan, N. R. et al. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J. Clin. Invest. 119, 2758–2771 (2009).

    PubMed Central  CAS  PubMed  Google Scholar 

  282. Pillai, V. B. et al. Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat. Commun. 6, 6656 (2015).

    Article  CAS  PubMed  Google Scholar 

  283. Zhang, R. et al. Short-term administration of nicotinamide mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure. J. Mol. Cell. Cardiol. 112, 64–73 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Martin, A. S. et al. Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model. JCI Insight 2, 93885 (2017).

    Article  PubMed  Google Scholar 

  285. Sundaresan, N. R. et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat. Med. 18, 1643–1650 (2012).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  286. Tang, X. et al. SIRT2 acts as a cardioprotective deacetylase in pathological cardiac hypertrophy. Circulation 136, 2051–2067 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. Alcendor, R. R. et al. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ. Res. 100, 1512–1521 (2007).

    Article  CAS  PubMed  Google Scholar 

  288. Oka, S. et al. PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. Cell Metab. 14, 598–611 (2011).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  289. Luo, Y. X. et al. SIRT4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity. Eur. Heart J. 38, 1389–1398 (2017).

    Article  PubMed  Google Scholar 

  290. Tzahor, E. & Poss, K. D. Cardiac regeneration strategies: staying young at heart. Science 356, 1035–1039 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  291. Eschenhagen, T. et al. Cardiomyocyte regeneration: a consensus statement. Circulation 136, 680–686 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  292. Cai, M. X. et al. Exercise training activates neuregulin 1/ErbB signaling and promotes cardiac repair in a rat myocardial infarction model. Life Sci. 149, 1–9 (2016).

    Article  CAS  PubMed  Google Scholar 

  293. Fero, M. L. et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility inp27(Kip1)-deficient mice. Cell 85, 733–744 (1996).

    Article  CAS  PubMed  Google Scholar 

  294. Kiyokawa, H. et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function ofp27(Kip1). Cell 85, 721–732 (1996).

    Article  CAS  PubMed  Google Scholar 

  295. Nakayama, K. et al. Mice lackingp27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85, 707–720 (1996).

    Article  CAS  PubMed  Google Scholar 

  296. Hauck, L. et al. Protein kinase CK2 links extracellular growth factor signaling with the control of p27(Kip1) stability in the heart. Nat. Med. 14, 315–324 (2008).

    Article  CAS  PubMed  Google Scholar 

  297. Matsuda, T. et al. Distinct roles of GSK-3alpha and GSK-3beta phosphorylation in the heart under pressure overload. Proc. Natl Acad. Sci. USA 105, 20900–20905 (2008).

    Article  PubMed Central  PubMed  Google Scholar 

  298. Pan, D. The hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  299. Yu, F. X., Zhao, B. & Guan, K. L. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163, 811–828 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  300. Yamamoto, S. et al. Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy. J. Clin. Invest. 111, 1463–1474 (2003).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  301. Heallen, T. et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  302. Maejima, Y. et al. Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat. Med. 19, 1478–1488 (2013).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  303. Del, Re,D. P. et al. Mst1 promotes cardiac myocyte apoptosis through phosphorylation and inhibition of Bcl-xL. Mol. Cell 54, 639–650 (2014).

    Article  CAS  Google Scholar 

  304. Nakamura, M., Zhai, P., Del Re, D. P., Maejima, Y. & Sadoshima, J. Mst1-mediated phosphorylation of Bcl-xL is required for myocardial reperfusion injury. JCI Insight 1, e86217 (2016).

    PubMed Central  PubMed  Google Scholar 

  305. Huang, J., Wu, S., Barrera, J., Matthews, K. & Pan, D. The hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating yorkie, the drosophila homolog of YAP. Cell 122, 421–434 (2005).

    Article  CAS  PubMed  Google Scholar 

  306. von Gise, A. et al. YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc. Natl Acad. Sci. USA 109, 2394–2399 (2012).

    Article  Google Scholar 

  307. Del Re, D. P. et al. Yes-associated protein isoform 1 (Yap1) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury. J. Biol. Chem. 288, 3977–3988 (2013).

    Article  CAS  PubMed  Google Scholar 

  308. Wang, P. et al. The alteration of Hippo/YAP signaling in the development of hypertrophic cardiomyopathy. Basic Res. Cardiol. 109, 435 (2014).

    Article  CAS  PubMed  Google Scholar 

  309. Xin, M. et al. Regulation of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation and embryonic heart size. Sci. Signal 4, ra70 (2011).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  310. Xin, M. et al. Hippo pathway effector Yap promotes cardiac regeneration. Proc. Natl Acad. Sci. USA 110, 13839–13844 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  311. Lin, Z. et al. Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model. Circ. Res. 115, 354–363 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  312. Li, J. et al. Alpha-catenins control cardiomyocyte proliferation by regulating Yap activity. Circ. Res. 116, 70–79 (2015).

    Article  CAS  PubMed  Google Scholar 

  313. Morikawa, Y., Heallen, T., Leach, J., Xiao, Y. & Martin, J. F. Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. Nature 547, 227–231 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  314. Leach, J. P. et al. Hippo pathway deficiency reverses systolic heart failure after infarction. Nature 550, 260–264 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  315. Mo, J. S. et al. Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat. Cell Biol. 17, 500–510 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  316. Wang, W. et al. AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat. Cell Biol. 17, 490–499 (2015).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  317. DeRan, M. et al. Energy stress regulates hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep. 9, 495–503 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  318. Smith, J. S., Lefkowitz, R. J. & Rajagopal, S. Biased signalling: from simple switches to allosteric microprocessors. Nat. Rev. Drug Discov. https://doi.org/10.1038/nrd.2017.229 (2018).

Download references

Acknowledgements

The authors thank D. Zablocki (Rutgers New Jersey Medical School, Newark, NJ, USA) for the critical reading of the manuscript. M.N. is funded by an AHA Scientist Development Grant (17SDG33660358). J.S. is funded by the Leducq Foundation Transatlantic Network of Excellence and the US Public Health Service grants.

Reviewer information

Nature Reviews Cardiology thanks S. Lavandero, K. Walsh, M. A. Sussman, and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Authors and Affiliations

  1. Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ, USA

    Michinari Nakamura & Junichi Sadoshima

Authors
  1. Michinari Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junichi Sadoshima
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors researched data for the article, discussed its content, wrote the manuscript, and reviewed and edited it before submission.

Corresponding author

Correspondence to Junichi Sadoshima.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Laplace’s law

A physical law stating that the wall stress (WS) of a sphere (ventricle) is proportional to the intracavity (ventricular) pressure (P) and the chamber radius (R), and inversely proportional to the ventricular wall thickness (T), given by the formula WS = P*R/2T.

Cardiac remodelling

Process of structural and functional changes in the heart in response to mechanical stress, neurohormonal activation, and myocardial injury that lead to progressively dilated hearts and impaired contractile function.

Coronary flow reserve

The ratio between maximal and resting coronary flow, which is thought to reflect the capacity of the coronary arteries to dilate and increase coronary flow in response to metabolic demand.

Store-operated Ca2+ entry

Ca2+ influx through the Ca2+ channels in the plasma membrane that is triggered when intracellular Ca2+ stores are depleted.

Athlete’s heart

Dilated and hypertrophied heart observed in athletes, particularly those engaged in endurance training, that is mostly adaptive and benign.

Glycolysis

Metabolic process in which glucose is converted into pyruvate in the cytosol, generating two molecules of ATP.

Fatty acid oxidation

Catabolic processes in which fatty acyl-CoA is sequentially oxidized to generate acetyl-CoA, which is then used in the tricarboxylic acid cycle.

Anaplerosis

Chemical reactions that replenish the tricarboxylic acid cycle intermediates that were extracted for biosynthesis (cataplerosis).

Mechanical unloading

Clinical interventions to reduce ventricular pressure and/or volume with the help of circulatory assist devices in patients with heart failure.

Biased ligands

Ligands that selectively affect some, but not all, of the many signalling pathways of a given receptor.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakamura, M., Sadoshima, J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol 15, 387–407 (2018). https://doi.org/10.1038/s41569-018-0007-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-018-0007-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing