Molecular Mechanisms of Myocardial Remodeling

  • Wilson S. Colucci
Part of the Basic Science for the Cardiologist book series (BASC, volume 2)


Myocardial dysfunction is a progressive condition. Early after an insult to the myocardium (e.g., myocardial infarction) there may be little or no immediate reduction in overall pump function, particularly if the damage has been mild. However, with time there is a relentless deterioration in both the structure and function of the ventricle by a process referred to as “remodeling” (1). The specific features of the remodeling process depend, to a large extent, on the nature of the underlying stimulus.


Cardiac Myocytes Atrial Natriuretic Peptide Cardiac Fibroblast Myocardial Remodel Circulation Research 
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  1. 1.
    Cohn JN. Structural basis for heart failure. Ventricular remodeling and pharmacological inhibition. Circulation 1995; 91: 2504–2507.PubMedGoogle Scholar
  2. 2.
    Katz AM. The cardiomyopathy of overload: an unnatural growth response in the hypertrophied heart. Annals of Internal Medicine 1994; 121:363–371.PubMedGoogle Scholar
  3. 3.
    Anversa P, Ricci R & Olivetti G. Quantitative structural analysis of the myocardium during growth and induced cardiac hypertrophy: A review. Journal of the American College of Cardiology 1986; 7:1140–1149.PubMedCrossRefGoogle Scholar
  4. 4.
    Simpson P & McGrath A. Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha1 adrenergic response. Journal of Clinical Investigation 1983; 72:732–738.PubMedGoogle Scholar
  5. 5.
    Knowlton KU, Michel MC, Itani M, Shubeita HE, Ishihara K, Brown JH & Chien KR. The α1A adrenergic receptor subtype mediates biochemical, molecular, and morphologic features of cultured myocardial cell hypertrophy. Journal of Biological Chemistry 1993; 268: 15374–15380.PubMedGoogle Scholar
  6. 6.
    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. Circulation Research 1993; 73:413–423.Google Scholar
  7. 7.
    Shubeita HE, McDonough PM, Harris AN, Knowlton KU, Glembotski CC, Brown JH & Chien KR. Endothelin induction of inositol phospholipid hydrolysis, sarcomere assembly, and cardiac gene expression in ventricular myocytes. A paracrine mechanism for myocardial cell hypertrophy. Journal of Biological Chemistry 1990; 265:20555–20562.PubMedGoogle Scholar
  8. 8.
    Thaik CM, Calderone A, Takahashi N & Colucci WS. Interleukin-1B modulates the growth and phenotype of neonatal rat cardiac myocytes. Journal of Clinical Investigation 1995; 96:1093–1099.PubMedGoogle Scholar
  9. 9.
    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
  10. 10.
    Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw B-A. Programmed myocyte death in end-stage heart failure. N Eng J Med 1996;335: 1182–1189.CrossRefGoogle Scholar
  11. 11.
    Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA, Quaini E, DeLoreto C, Beltrami CA, Krajewski S, Reed JC & Anversa P. Apoptosis in the failing human heart. New England Journal of Medicine 1997; 336:1131–1141.PubMedCrossRefGoogle Scholar
  12. 12.
    Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 1994;94:1621–1628.PubMedCrossRefGoogle Scholar
  13. 13.
    Kajstura J, Cheng W, Reiss K, Clark WA, Sonnenblick EH, Krajewski S, Reed JC, Olivetrti G, Anversa P. Apoptotic and necrotic myocyte cell death are independent contributing variables of infarct size in rats. Lab Invest 1996; 74: 86–107.PubMedGoogle Scholar
  14. 14.
    Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki L-M. Apoptosis in human acute myocardial infarction. Circulation 1997;95:320–323.PubMedGoogle Scholar
  15. 15.
    Liu Y, Cigola E, Cheng W, Kajstura J, Olivetti G, Hintze TH, Anversa P. Myocyte nuclear mitotic division and programmed myocyte death characterize the cardiac myopathy induced by rapid ventricular pacing in dogs. Lab Invest. 1995; 73 771–787.PubMedGoogle Scholar
  16. 16.
    Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, Hintze TH, Olivetti G, Anversa P. Stretch-induced programmed myocyte cell death. J Clin Invest 1995; 96: 2247–2259.PubMedGoogle Scholar
  17. 17.
    Teiger E, Dam T-V, Richard L, Wisnewsky C, Tea B-S, Gaboury L, Tremblay J, Schwartz K, Hamet P. Apoptosis in pressure overload-induced heart hypertrophy in the rat. J Clin Invest 1996; 97:2891–2897.PubMedGoogle Scholar
  18. 18.
    Colucci WS. Apoptosis in the heart. N Eng J Med 1996; 335: 1224–1226.CrossRefGoogle Scholar
  19. 19.
    Weber KT & Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 1991; 83:1849–1865.Google Scholar
  20. 20.
    Conrad CH, Brooks WW, Hayes JA, Sen S, Robinson KG, Bing OHL. Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hyertensive rat. Circulation 1995; 91: 161–170.PubMedGoogle Scholar
  21. 21.
    Calderone A, Takahashi N, Izzo NJ, Thaik CM & Colucci WS. Pressure-and volume-induced left ventricular hypertrophies are associated with distinct myocyte phenotypes and differential induction ofpeptide growth factor mRNAs. Circulation 1995; 92; 2385–2390.PubMedGoogle Scholar
  22. 22.
    Guarda E, Katwa LC, Myers PR, Tyagi SC, Weber KT. Effects of endothelins on collagen turnover in cardiac fibroblasts. Cardiovasc Res 1993;27:2130–2134.PubMedGoogle Scholar
  23. 23.
    Terracio L, Rubin K, Gullberg D, Balog E, Carver W, Jyring R, Borg TK. Expression of collagen binding integrins during cardiac development and hypertrophy. Circ Res 1991;68:734–744.PubMedGoogle Scholar
  24. 24.
    Burgess ML, Carver WE, Terracio L, Wilson SP, Wilson MA, Borg TK. Integrin-mediated collagen gel contraction by cardiac fibroblasts. Circ Res 1994;74:291–298.PubMedGoogle Scholar
  25. 25.
    Ikeda U, Ikeda M, Kano S, Shimada K. Neutrophil adherence to rat cardiac myocyte by proinfiammatory cytokines. J Cardiovasc Pharmacol 1994;23:647–652.PubMedGoogle Scholar
  26. 26.
    Takahashi T, Allen PD & Izumo S. Expression of A-, B-, and C-type natriuretic peptide genes in failing and developing human ventricles. Circulation Research 1992; 71:9–17.PubMedGoogle Scholar
  27. 27.
    Arai M, Alpert NR, MacLennan DH, Barton P & Periasamy M. Alterations in sarcoplasmic reticulum gene expression in human heart failure. 1993; Circulation Research 72:463–469.PubMedGoogle Scholar
  28. 28.
    Wollert KC, Taga T, Saito M, Narazaki M, Kishimoto T, Glembotski CC, Vernallis AB, Heath JK, Pennica D, Wood WI & Chien KR. Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series VIA gpl30/leukemia inhibitory factor receptor-dependent pathways. J Biol Chem 1996; 271(16):9535–45.PubMedCrossRefGoogle Scholar
  29. 29.
    Feldman AM, Weinberg EO, Ray PE and Lorell BH. Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding. Circulation Research 1993; 73:184–192.PubMedGoogle Scholar
  30. 30.
    Boluyt MO, O’Neill L, Meredith AL, Bing OHL, Brooks WW, Conrad CH, Crow MT, Lakatta EG. Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Circ Res 1994;75:23–32.PubMedGoogle Scholar
  31. 31.
    Beuckelmann DJ, Nabauer M & Erdmann E. Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation 1992; 85:1046–1055.PubMedGoogle Scholar
  32. 32.
    Takahashi T, Allen PD, Lacro RV, Marks AR, Dennis AR, Schoen FJ, Grossman W, Marsh JD & Izumo S. Expression of dihydropyridine receptor (Ca2+ channel) and calsequestrin genes in the myocardium of patients with end-stage heart failure. Journal of Clinical Investigation 1992; 90:927–935.PubMedGoogle Scholar
  33. 33.
    Feldman AM, Ray PE, Silan CM, Mercer JA, Minobe W & Bristow MR. Selective gene expression in failing human heart. Quantification of steady-state levels of messenger RNA in endomyocardial biopsies using the polymerase chain reaction. Circulation 1991; 83:1866–1872.PubMedGoogle Scholar
  34. 34.
    Brillantes A-M, Allen P, Takahashi T, Izumo S & Marks AR. Differences in cardiac calcium release channel (ryanodine receptor) expression in myocardium from patients with end-stage heart failure caused by ischemic versus dilated cardiomyopathy. Circulation Research 1992; 71:18–26.PubMedGoogle Scholar
  35. 35.
    Gómez AM, Valdivia HH, Cheng H, Lederer MR, Santana LF, Cannell MB, McCune SA, Altschuld RA, Lederer WJ. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 1997;276:800–806.PubMedCrossRefGoogle Scholar
  36. 36.
    Lowes BD, Minobe W, Abraham WT, Rizeq MN, Bohlmeyer TJ, Quaife RA, Roden RL, Dutcher DL, Robertson AD, Voelkel NF, Badesch DB, Groves BM, Gilbert EM, Bristow. Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium. J Clin Invest. 1997;100:2315–24.PubMedGoogle Scholar
  37. 37.
    Anderson PAW, Malouf NN, Oakeley AE, Pagani ED & Allen PD. Troponin T isoform expression in the normal and failing human left ventricle: a correlation with myofibrillar ATPase activity. Basic Research in Cardiology 1992; 87:117–127.PubMedGoogle Scholar
  38. 38.
    Sadoshima J-i, Jahn L, Takahashi T, Kulik TJ & Izumo S. Molecular characterizations of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy. Journal of Biological Chemistry 1992; 267:10551–10560.PubMedGoogle Scholar
  39. 39.
    Takahashi N, Calderone A, Izzo NJ Jr, Maki TM, Marsh JD & Colucci WS. Hypertrophic stimuli-induced transforming growth factor-β1 expression in rat ventricular myocytes. Journal of Clinical Investigation 1994; 94:1470–1483.PubMedGoogle Scholar
  40. 40.
    Yamazaki T, Komuro I, Kudoh S, Zou Y, Shiojima I, Hiroi Y, Mizuno T, Maemura K, Kurihara H, Aikawa R, Takano H & Yazaki Y. Endothelin-1 is involved in mechanical stress-induced cardiomyocyte hypertrophy. Journal of Biological Chemistry 1996; 271:3221–3227.PubMedCrossRefGoogle Scholar
  41. 41.
    Clark WA, Rudnick SJ, LaPres JJ, Andersen LC & LaPointe MC. Regulation of hypertrophy and atrophy in cultured adult heart cells. Circulation Research 1993; 73:1163–1176.PubMedGoogle Scholar
  42. 42.
    Mann DL, Kent RL, Parsons B & Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 85;790–804.Google Scholar
  43. 43.
    Communal C, Singh K, Pimentel D, Colucci WS. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the β-adrenergic pathway. Circulation 1998;98: 1329–1334.PubMedGoogle Scholar
  44. 44.
    Calderone A, Thaik CM, Takahashi N, Colucci WS. Norepinephrine-stimulated DNA and protein synthesis in cardiac fibroblasts are inhibited by nitric oxide and atrial natriuretic factor. Circulation 1995; 92(Suppl I):I–384.Google Scholar
  45. 45.
    Geng YJ, Ishikawa Y, Vatner DE, Wagner TE, Bishop SP, Vatner SF, Homcy CJ. Overexpression of Gsα accelerates programmed cell death (apoptosis) of cardiomyocytes in transgenic mice. Circulation 1996; 94(Suppl. 1): 1640 (abstr).Google Scholar
  46. 46.
    Kajstura J, Cigola E, Malhotra A, Li P, Cheng W, Meggs L & Anversa P. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J Cell Cardiol 1997; 29:859–870.CrossRefGoogle Scholar
  47. 47.
    Hirsch AT, Talsness CE, Schunkert H, Paul M & Dzau VJ. Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure. Circulation Research 1991; 69:475–482.PubMedGoogle Scholar
  48. 48.
    Lindpaintner K, Lu W, Niedermajer N, Schieffer B, Just H, Ganten D & Drexler H. Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat. Journal of Molecular and Cellular Cardiology 1993; 5:133–143.CrossRefGoogle Scholar
  49. 49.
    Meggs LG, Coupet J, Huang H, Cheng W, Li P, Capasso JM, Homey CJ & Anversa P (1993) Regulation of angiotensin II receptors on ventricular myocytes after myocardial infarction in rats. Circulation Research 72:1149–1162.PubMedGoogle Scholar
  50. 50.
    Sakai S, Miyauchi T, Sakurai T, Kasuya Y, Ihara M, yamaguchi I, Goto K, Sugishita Y. Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure: marked increase in endothelin-1 production in the failig heart. Circulation 1996; 93:1214–1222.PubMedGoogle Scholar
  51. 51.
    Sakai S, Miyauchi T, Kobayashi M, Yamaguchi I, Goto K & Sugishita Y. Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Letters to Nature 1996; 384:353–355.CrossRefGoogle Scholar
  52. 52.
    Colucci WS. Myocardial Endothelin. Does it play a role in myocardial failure? 1996; Circulation 93:1069–1072.49.Parker TG, Packer SE & Schneider MD. Peptide growth factors can provoke “fetal” contractile protein gene expression in rat cardiac myocytes. Journal of Clinical Investigation 1990; 85:507-514.Google Scholar
  53. 53.
    Parker TG, Packer SE & Schneider MD. Peptide growth factors can provoke “fetal” contractile protein gene expression in rat cardiac myocytes. Journal of Clinical Investigation 1990; 85:507–514.PubMedGoogle Scholar
  54. 54.
    Casscells W, Bazoberry F, Speir E, Thompson N, Flanders K, Kondaiah P, Ferrans VJ, Epstein SE & Sporn M. Transforming growth factor-1 in normal heart and in myocardial infarction. Annals of the New York Academy of Science 1990; 593:148–160.CrossRefGoogle Scholar
  55. 55.
    Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990;223:236–241.CrossRefGoogle Scholar
  56. 56.
    Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann D. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: A report from the studies of left ventricular dysfunction (SOLVD). J Am Coll Cardiol 1996;27:1201–1206.PubMedCrossRefGoogle Scholar
  57. 57.
    Torre-Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JB, Mann DL. Tumor necrosis factor-α and tumor necrosis factor receptors in the failing human heart. Circulation 1996;93:704–711.PubMedGoogle Scholar
  58. 58.
    Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, Glembotski CC, Quintana PJE & Sabbadini RA. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. Journal of Clinical Investigation 1996; 98:2854–2865.PubMedGoogle Scholar
  59. 59.
    Youker K, Smith CW, Anderson DC, Miller D, Michael LH, Rossen RD & Entman ML. Neutrophil adherence to isolated adult cardiac myocytes. Journal of Clinical Investigation 1992; 89:602–609.PubMedGoogle Scholar
  60. 60.
    Ikeda U, Ikeda M, Kano S, Shimada K. Neutrophil adherence to rat cardiac myocyte by proinflamatory cytokines. J Cardiovasc Pharmacol 1994; 23: 47–652.Google Scholar
  61. 61.
    Meier B, Radeke HH, Selle S, Younes M, Sies H, Resch, K & Habermehl GG. Human fibroblasts release reactive oxygen species in response to interleukin-1 or tumour necrosis factor-alpha. Biochem J 1989; 263:539–545.PubMedGoogle Scholar
  62. 62.
    Tzortzis JD, Siwik DA, Chang DL-F, Singh K, Commuanal C, Pagano P, Colucci WS. Chronic oxidative stress induces a hypertrophic phenotype and apoptosis in neonatal rat cardiac myocytes. Circulation 1997; 96(suppl. I): 1–605.Google Scholar
  63. 63.
    Webster KA, Discher DJ, Bishopric NH. Regulation of fos and jun immediate-early genes by redox or metabolic stress in cardiac myocytes. Circ Res 1994;74:679–686.PubMedGoogle Scholar
  64. 64.
    Murrell A C, Francis M & Bromley L. Modulation of fibroblast proliferation by oxygen free radicals. Biochem J 1990; 265:659–665.PubMedGoogle Scholar
  65. 65.
    Dhalla AK & Singal PK. Antioxidant changes in hypertrophiec and failing guinea pig hearts. American Physiological Society 1994; H1280–H1285.Google Scholar
  66. 66.
    Dhalla AK, Hill MF & Singal PK. Role of oxidative stress in transition of hypertrophy to heart failure. J Am Coll Cardiol 1996; 28:506–514.PubMedGoogle Scholar
  67. 67.
    DeBelder AJ, Radomski MW, Why JF, Richardson PJ, Martin JF. Myocardial calcium-independent nitric oxide synthase activity is present in dilated cardiomyopathy, myocarditis, and postpartum cardiomyopathy but not in ischaemic or valvar heart disease. Br Heart J 1995;74:426–430.CrossRefGoogle Scholar
  68. 68.
    Haywood GA, Tsao PS, von der Leyen HE, Mann MJ, Keeling PJ, Trindade PT, Lewis NP, Byrne CD, Rickenbacher PR, Bishopric NH, Cooke JP, McKenna WJ, Fowler MB. Expression of inducible nitric oxide synthase in human heart failure. Circulation 1996;931087–1094.Google Scholar
  69. 69.
    Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca2+-independent nitric oxide synthase in the myocardium. Br J Pharmacol 1992;105:575–580.PubMedGoogle Scholar
  70. 70.
    Balligand J-L, Ungureanu-Longrois D, Simmons WW, Pimental D, Malinski TA, Kapturczak M, Taha Z, Lowenstein C, Davidoff AJ, Kelly RA, Smith TW, Michel T. Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes: Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J Biol Chem 1994;269:27580–27588.PubMedGoogle Scholar
  71. 71.
    Hare JM, Colucci WS. Role of nitric oxide in the regulation of myocardial function. Prog Cardiovasc Dis 1995;38:155–166.PubMedCrossRefGoogle Scholar
  72. 72.
    Balligand J-L, Ungureanu D, Kelly RA, Kobzik L, Pimental D, Michel T, Smith TW. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J Clin Invest 1993;91:2314–2319.PubMedGoogle Scholar
  73. 73.
    Brady AJB, Poole-Wilson PA, Harding SE, Warren JB. Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol 1992;263:H1963–H1966.PubMedGoogle Scholar
  74. 74.
    Hare JM, Loh E, Creager MA, Colucci WS. Nitric oxide inhibits the contractile response to β-adrenergic stimulation in humans with left ventricular dysfunction. Circulation 1995;92:2198–2203.PubMedGoogle Scholar
  75. 75.
    Hare JM, Givertz MM, Creager MA, Colucci WS. Increased sensitivity to nitric oxide inhibition in patients with heart failure: Potentiation of β-adrenergic inotropic responsiveness. Circulation 1998; 97:161–166.PubMedGoogle Scholar
  76. 76.
    Yamamoto S, Tsusui H, Tagawa H, Saito K, Takahashi M, Tada H, Yamamoto M, Katoh M, Egashira K & Takeshita A. Role of myocyte nitric oxide in β-adrenergic hyporesponsiveness in heart failure. Circulation 1997; 95:1111–1114.PubMedGoogle Scholar
  77. 77.
    Pinsky DJ, Cai B, Yang X, Rodriguez C, Sciacca RR, Cannon PJ. The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta. J Clin Invest 1995;95:677–685.PubMedGoogle Scholar
  78. 78.
    Fukuo K, Hata T, Suhara T, Nakahashi T, Shinto Y, Tsujimoto Y, Morimoto S, Ogihara T. Nitric oxide induces upregulation of Fas and apoptosis in vascular smooth muscle. Hypertension 1996;27:823–826.PubMedGoogle Scholar
  79. 79.
    Wu C-F, Bishopric, Pratt RE. Atrial natriuretic peptide induce apoptosis in neonatal rat cardiac myocytes. J Biol Chem 1997; 272: 1460–14866.Google Scholar

Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • Wilson S. Colucci
    • 1
  1. 1.Boston University School of MedicineUSA

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