Molecular and Cellular Events in Myocardial Hypertrophy and Failure

  • Douglas B. Sawyer
  • Wilson S. Colucci


Whereas cardiac failure was once thought to be a static condition reflecting a damaged myocardium, it is now apparent that it reflects a dynamic process involving the continuous structural and functional reorganization, or remodeling, of the heart in response to environmental stresses and stimuli. The fundamental events that lead to cardiac remodeling occur at the molecular and cellular level in both the myocytes and the nonmyocyte cells of the heart. Observations made in failing human myocardium and in myocardium from animals with hypertrophy or failure suggest that there are multiple molecular and cellular alterations involving the excitation-contraction process, contractile and regulatory proteins, growth factors, and signaling pathways. A variety of stimuli that may be responsible for these alterations have been identified, including mechanical wall stresses, hormones, neurotransmitters, and peptide growth factors. Genetic manipulations in small animal models are refining our understanding of the stimuli and molecular events that lead to progression of heart failure. Although much remains to be learned about how these stimuli interact with signaling pathways to regulate the remodeling of the myocardium, it is now apparent that these events have an important impact on the clinical course of the patient and may offer new approaches to the prevention and treatment of myocardial failure.


Heart Failure Dilate Cardiomyopathy Cardiac Myocytes Atrial Natriuretic Peptide Ventricular Myocytes 
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  1. 1.
    Takahashi T, Allen PD, Izumo S: Expression of A-, B-, and C-type natriuretic peptide genes in failing and developing human ventricles. Circ Res 1992, 71: 9–17.PubMedCrossRefGoogle Scholar
  2. 2.
    Sadoshima J-I, Jahn L, Takahashi T, et al Molecular characterizations of the stretch-induced adaptation of cultured cardiac cells: an in vitro model of load-induced cardiac hypertrophy. J Biol Chem 1992, 267:10551–10560.Google Scholar
  3. 3.
    Simpson P, McGrath A: Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an al adrenergic response. J Clin Invest 1983, 72: 732–738.PubMedCrossRefGoogle Scholar
  4. 4.
    Sadoshima J-I, Izumo S: Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts: critical role of the AT1 receptor subtype. Circ Res 1993, 73: 413–423.PubMedCrossRefGoogle Scholar
  5. 5.
    Thaik CM, Calderone A, Takahashi N, Colucci WS: Interleukin-lb modulates the growth and phenotype of neonatal rat cardiac myocytes. J Clin Invest 1995, 96: 1093–1099.PubMedCrossRefGoogle Scholar
  6. 6.
    Crone SA, Zhao YY, Fan L, et al ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 2002, 8:459–465.Google Scholar
  7. 7.
    Calderone A, Thaik CM, Takahashi N, et al Nitric oxide, atrial natriuretic peptide, and cGMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts.J Clin Invest 1998, 101:812–818.Google Scholar
  8. 8.
    Beuckelmann DJ, Nabauer M, Erdmann E: Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation 1992, 85: 1046–1055.PubMedCrossRefGoogle Scholar
  9. 9.
    Takahashi T, Allen PD, Lacro RV, et al Expression of dihydropyridine receptor (Ca2+ channel) and calsequestrin genes in the myocardium of patients with end-stage heart failure. J Clin Invest 1992, 90:927–935.Google Scholar
  10. 10.
    Hasenfuss G, Meyer M, Schillinger W, et al Calcium handling proteins in the failing human heart. Basic Res Cardiol 1997, 92 (suppl 1):87–93.Google Scholar
  11. 11.
    Hajjar RJ, Schmidt U, Matsui T, et al Modulation of ventricular function through gene transfer in vivo. Proc Natl Acad Sci U S A 1998, 95:5251–5256.Google Scholar
  12. 12.
    Katz AM: Physiology of the Heart, edn 2. New York: Raven Press; 1992.Google Scholar
  13. 13.
    Nakao K, Minobe W, Roden R, et al Myosin heavy chain gene expression in human heart failure. J Clin Invest 1997, 100:2362–2370.Google Scholar
  14. 14.
    Kostin S, Pool L, Elsasser A, et al Myocytes die by multiple mechanisms in failing human hearts. Circ Res 2003, 92:715–724.Google Scholar
  15. 15.
    Olivetti G, Abbi R, Quaini F, et al Apoptosis in the failing human heart. N Engl J Med 1997, 336:1131–1141.Google Scholar
  16. 16.
    Communal C, Singh K, Pimentel DR, Colucci WS: Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the 3-adrenergic pathway. Circ Res 1998, 98: 1329–1334.CrossRefGoogle Scholar
  17. 17.
    Wencker D, Chandra M, Nguyen K, et al A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest 2003, 111:1497–1504.Google Scholar
  18. 18.
    Vasan RS, Sullivan LM, D’Agostino RB, et al Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study. Ann Intern Med 2003, 139:642–648.Google Scholar
  19. 19.
    Vasan RS, Sullivan LM, Roubenoff R, et al Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation 2003, 107:1486–1491.Google Scholar
  20. 20.
    Beltrami AP, Barlucchi L, Torella D, et al Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003, 114:763–776.Google Scholar
  21. 21.
    Kuramochi Y, Fukazawa R, Migita M, et al Cardiomyocyte regeneration from circulating bone marrow cells in mice. Pediatr Res 2003, 54:319–325.Google Scholar
  22. 22.
    Weber KT, Brilla CG: Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. Circulation 1991, 83: 1849–1865.PubMedCrossRefGoogle Scholar
  23. Thomas CV, Coker ML, Zellner JL, et al Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation 1998, 97:1708–1715.Google Scholar
  24. Koch WJ, Rockman HA, Samama P, et al Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a PARK inhibitor. Science 1995, 268:1350–1353.Google Scholar
  25. 25.
    Engelhardt S, Hein L, Wiesmann F, Lohse MJ: Progressive hypertrophy and heart failure in betal-adrenergic receptor transgenic mice. Proc Natl Acad Sci U S A 1999, 96: 7059–7064.CrossRefGoogle Scholar
  26. 26.
    Hirsch AT, Talsness CE, Schunkert H, et al Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure. Circ Res 1991, 69:475–482.Google Scholar
  27. 27.
    Lindpaintner K, Lu W, Niedermajer N, et al Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat. J Mol Cell Cardiol 1993, 25:133–143.Google Scholar
  28. 28.
    Meggs LG, Coupet J, Huang H, et al Regulation of angiotensin II receptors on ventricular myocytes after myocardial infarction in rats. Circ Res 1993, 72:1149–1162.Google Scholar
  29. 29.
    Sadoshima J-I, Xu Y, Slayter HS, Izumo S: Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 1993, 75: 977–984.PubMedCrossRefGoogle Scholar
  30. 30.
    Ito H, Hirata Y, Adachi S, et al Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest 1993, 92:398–403.Google Scholar
  31. 31.
    Bozkurt B, Kribbs SB, Clubb FJ, et al Pathophysiologically relevant concentrations of tumor necrosis factor-a promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998, 97:1382–1391.Google Scholar
  32. 32.
    Bryant D, Becker L, Richardson J, et al Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-a. Circulation 1998, 97:1375–1381.Google Scholar
  33. 33.
    Hill MF, Singal PK: Antioxidant and oxidative stress changes during heart failure subsequent to myocardial infarction in rats. Am J Pathol 1996, 148: 291–300.PubMedGoogle Scholar
  34. 34.
    Li Y, Huang T-T, Carlson EJ, et al Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet 1995, 11:376–381.Google Scholar
  35. 35.
    Sawyer DB, Siwik DA, Xiao L, et al Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol 2002, 34:379–388.Google Scholar
  36. 36.
    Kinugawa S, Tsutsui H, Hayashidani S, et al Treatment with dimethyliourea prevents left ventricular remodeling and failure after experimental myocardial infarction in mice: role of oxidative stress. Circ Res 2000, 87:392–398.Google Scholar

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© Springer Science+Business Media New York 2005

Authors and Affiliations

  • Douglas B. Sawyer
  • Wilson S. Colucci

There are no affiliations available

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