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Pharmacological Modulation of Cardiovascular Remodeling: A Guide to Heart Failure Therapy

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Abstract

Cardiac remodeling is a complex process, which involves genetic, molecular and cellular changes in cardiomyocytes and the interstitium, leading to progressive structural and functional alterations, including cardiac dilatation, interstitial fibrosis, and a reduction in contractility and relaxation. As cardiac function worsens, ventricular dysfunction, heart failure and end-stage heart disease are the ultimate consequences.

Underlying mechanisms include myocardial stretch and neurohormonal and cytokine activation. Consequently, therapies aiming counteracting these mechanisms have proven successful in attenuating or even preventing cardiac remodeling. In particular, ACE inhibition, beta-blockade and aldosterone antagonism have proven to be effective in modulating the process of remodeling and in reducing the occurrence of adverse events in heart failure.

Of interest, although several other antagonists of neurohormonal, including endothelin, or of cytokine activation have been shown to effectively modulate remodeling, studies thus far have been negative in terms of event reduction in heart failure. Whereas insight in cardiovascular remodeling has already significantly contributed to existing management strategies in heart failure, further studies in different mechanisms may provide additional therapeutic measures.

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References

  1. Cowie MR,Wood DA,Coats AJS, et al. Survival of patients with a new diagnosis of heart failure: A population based study. Heart 2000; 83: 505-510.

    Google Scholar 

  2. Remme WJ,Kruijssen HACM,Look MP,Bootsma M,de Leeuw PW. Systemic and cardiac neuroendocrine activation and severity of myocardial ischemia in humans. J Am Coll Cardiol 1994; 23: 82-91.

    Google Scholar 

  3. Hutchins GM,Bulkley BH. Infarct expansion extension:Two different complications of acute myocardial infarction. AmJ Cardiol 1978; 41: 1127-1133.

    Google Scholar 

  4. Weisman H,Bush DE,Mannisi JA,Bulkley BH. Global cardiac remodeling after acute myocardial infarction: A study in the rat model. Am J Cardiol 1993; 21: 673-682.

    Google Scholar 

  5. Anversa P,Olivetti G,Capasso JM. Cellular basis of ventricular remodeling after myocardial infarction. Am J Cardiol 1991; 68: 7D-16D.

    Google Scholar 

  6. McKay RG,Pfeffer MA,Pasternak RC,Markis JE,Come PC,Nakao S. Left ventricular remodeling after myocardial infarction: A corollary to infarct expansion. Circulation 1986; 74: 693-702.

    Google Scholar 

  7. Gaudron P,Eilles C,Kugler I,Ertl G. Progressive left ventricular dysfunction and remodeling after myocardial infarction. Circulation 1993; 87: 755-763.

    Google Scholar 

  8. Olivetti G,Capasso JM,Sonnenblick EH,Anversa P. Side-to-side slippage of myocytes in ventricular wall remodeling acutely after myocardial infarction in rats. Circ Res 1990; 67: 23-34.

    Google Scholar 

  9. Weber KT,Brilla CG. Pathological hypertrophy and the cardiac interstitium: Fibrosis and the renin-angiotensinaldosterone system. Circulation 1991; 83: 1849-1865.

    Google Scholar 

  10. St. John Sutton M,Pfeffer MA,Plappert T, et al. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction: The protective effects of captopril. Circulation 1994; 89: 68-75.

    Google Scholar 

  11. Hammermeister KE,Chikos PM,Fisher L,Dodge HT. Relationship of cardiothoracic ratio and plain film heart volume to late survival. Circulation 1979; 59: 89-95.

    Google Scholar 

  12. White HD,Norris RM,Brown MA,Brandt PWT,Whitlock RML,Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987; 76: 44-51.

    Google Scholar 

  13. Esler M,Jennings G,Korner P, et al. Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension 1988; 11: 3-20.

    Google Scholar 

  14. Ju H,Zhao S,Tappia PS,Panagia V,Dixon IMC. Expression of Gqα and PLC-β in scar and border tissue in heart failure due to myocardial infarction. Circulation 1998; 97: 892-899.

    Google Scholar 

  15. Ollivier JP,BouchetVA. Prospects for cardioreparation. Am J Cardiol 1992; 70: 27C-36C.

    Google Scholar 

  16. Schunkert H,Jackson B,Tang SS, et al. Distribution and functional significance of cardiac angiotensin converting enzyme in hypertrophied rat hearts. Circulation 1993; 1328-1339.

  17. Schieffer B,Wirger A,Meybrunn M, et al. Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat. Circulation 1994; 89: 2273-2282.

    Google Scholar 

  18. Jugdutt BI,Khan MI,Jugdutt SJ,Blinston GE. Effect of enalapril on ventricular remodeling and function during healing after anterior myocardial infarction in the dog. Circulation 1995; 91: 802-812.

    Google Scholar 

  19. McDonald KM,D'Aloia A,Parrish T, et al. Functional impact of an increase in ventricular mass after myocardial damage and its attenuation by converting enzyme inhibition.J Card Fail 1998; 4: 203-212.

    Google Scholar 

  20. Kim S,Yoshiyama M,Izumi Y, et al. Effects of combination of ACE inhibitor and angiotensin receptor blocker on cardiac remodeling,cardiac function and survival in rat heart failure. Circulation 2001; 103: 148-154.

    Google Scholar 

  21. Van Kats JP,Duncker DJ,Haitsma DB, et al. Angiotensinconverting enzyme inhibition and angiotensin II type 1 receptor blockade prevent cardiac remodeling in pigs after myocardial infarction.Role of tissue angiotensin II. Circulation 2000; 102: 1556-1563.

    Google Scholar 

  22. Bonvalet JP,Alfaidy N,Farman N,Lombès M. Aldosterone: Intracellular receptors in human heart. Eur Heart J 1995; 16(Suppl): 92-97.

    Google Scholar 

  23. Lombès M,Eugene E,Lessana A,Farman N,Bonvalet JP. Prerequisite for cardiac aldosterone action.Mineralcorticoid receptor and 11 β-hydroxysteroid dehydrogenase in the human heart. Circulation 1995; 92: 175-182.

    Google Scholar 

  24. Mizuno Y,Yoshimura M,Yasue H, et al. Aldosterone production is activated in failing ventricle in humans. Circulation 2001; 103: 72-77.

    Google Scholar 

  25. Zannad F,Alla F,Dousset B,Perez A,Pitt B, on behalf of the RALES Investigators. Limitations of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure. Circulation 2000; 102: 2700-2706.

    Google Scholar 

  26. Nguyen QT,Cernacek P,Calderoni A, et al. EndothelinAreceptor blockade causes adverse left ventricular remodeling but improves pulmonary artery pressure after infarction in the rat. Circulation 1998; 98: 2323-2330.

    Google Scholar 

  27. Mishima T,Tanimura M,Suzuki G, et al. Effects of long-term therapy with bosentan on the progression of left ventricular dysfunction and remodeling in dogs with heart failure. JAm Coll Cardiol 2000; 35: 222-229.

    Google Scholar 

  28. Yamazaki T,Komuro I,Kudoh S, et al. Role of ion channels and exchangers in mechanical stretch-induced cardiomyocyte hypertrophy. Circ Res 1998; 82: 430-437.

    Google Scholar 

  29. Kass DA,Baughman KL,Pak PH, et al. Reverse remodeling from cardiomyoplasty in human heart failure. Circulation 1995; 91: 2314-2318.

    Google Scholar 

  30. 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.

    Google Scholar 

  31. Yokoyama T,Vaca L,Rossen RD,Durante W,Hazarika P,Mann DL. Cellular basis for the negative inotropic effects of tumor necrosis factor-α in the adult mammalian heart. J Clin Invest 1993; 92: 2303-2312.

    Google Scholar 

  32. Ungureanu-Longrois D,Balligand JL,Simmons SW, et al. Induction of nitric oxide synthase activiety by cytokines in ventricular myocytes is necessary but not sufficient to decrease contractile responsiveness to β-adrenergic agonists. Circ Res 1995; 77: 494-502.

    Google Scholar 

  33. Li X,Moody MR,Engel D, et al. Cardiac-specific overexpression of tumor necrosis factor-α causes oxidative stress and contractile dysfunction in mouse diaphragm. Circulation 2000; 102: 1690-1696.

    Google Scholar 

  34. Nakamura K,Fushimi K,Kouchi H, et al. Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-α and angiotensin II. Circulation 1998; 98: 794-799.

    Google Scholar 

  35. Feuerstein GZ,Young PR. Apoptosis in cardiac diseases: Stress-and mitogen-activated signaling pathways. Cardiovasc Res 2000; 45: 560-569.

    Google Scholar 

  36. Wollert KC,Heineke J,Westermann J, et al. The cardiac Fas (APO-1/CD95) receptor/Fas ligand system. Circulation 2000; 101: 1172-1178.

    Google Scholar 

  37. Kajstura J,Leri A,Finato N,di Loreto C,Bertrami CA,Anversa P. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci 1998; 95: 8801-8805.

    Google Scholar 

  38. Kubota T,McTiernan CF,Frye CS, et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-α. Circ Res 1997; 81:627-635.

  39. Li YY,Feldman AM,Sun Y,McTiernan CF. Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation 1998; 98: 1728-1734.

    Google Scholar 

  40. McDonald KM,Mock J,D'Aloia A, et al. Bradykinin antagonism inhibits the antigrowth effect of converting enzyme inhibition in the dog myocardium after discrete transmural myocardial necrosis. Circulation 1995; 91: 2043-2048.

    Google Scholar 

  41. Greenberg B,Quinones MA,Koilpillai C, et al. for the SOLVD Investigators. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Circulation 1995; 91: 2573-2581.

    Google Scholar 

  42. The SOLVD Investigators. Effects of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293-302.

    Google Scholar 

  43. McDonald KM,Garr M,Carlyle PF, et al. Relative effects of α1-adrenoceptor blockade,converting enzyme inhibitor therapy,and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog. Circulation 1994; 90: 3034-3046.

    Google Scholar 

  44. McKelvie RS,Yusuf S,Pericak D, et al. for the RESOLVD Pilot Study Investigators. Comparison of candesartan,enalapril,and their combination in congestive heart failure.RESOLVD Pilot Study. Circulation 1999; 100: 1056-1064.

    Google Scholar 

  45. Gilbert EM,Anderson JL,Deitchman D, et al. Long-term beta-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: A double-blind randomized study of bucindolol versus placebo. Am J Med 1990; 88: 223-229.

    Google Scholar 

  46. Bristow MR,Gilbert EM,Abraham WT, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 1996; 94: 2807-2816.

    Google Scholar 

  47. Australia/New Zealand Heart Failure Research Collaborative Group. Randomised,placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet 1997; 349: 375-380.

    Google Scholar 

  48. Lowes BD,Gill EA,Abraham WT, et al. Effects of carvedilol on left ventricular mass,chamber geometry and mitral regurgitation in chronic heart failure. Am J Cardiol 1999; 83: 1201-1205.

    Google Scholar 

  49. Sanderson JE,Chan SKW,Yip G, et al. Beta-blockade in heart failure.A comparison of carvedilol with metoprolol. J Am Coll Cardiol 1999; 34: 1522-1528.

    Google Scholar 

  50. Groenning BA,Nilsson JC,Sondergaard L,Fritz-Hansen T,Larsson HBW,Hildebrandt PR. Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol 2000; 36: 2072-2080.

    Google Scholar 

  51. Metra M,Giubbini R,Nodari S,Boldi E,Modena MG,Dei Cas L. Differential effects of β-blockers in patients with heart failure.A prospective,randomized,double-blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation 2000; 102: 546-551.

    Google Scholar 

  52. Poole-Wilson PA,Swedberg K,Cleland JGF, et al. for the COMET investigators.Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): Randomized controlled trial. Lancet 2003; 362:7-13.

    Google Scholar 

  53. Tsutamoto T,Wada A,Maeda K, et al. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol 2001; 37: 1228-1233.

    Google Scholar 

  54. Spinale FG,Walker JD,Mukherjee R,Iannini JP,Keever AT,Gallagher KP. Concomitant endothelin receptor subtype-A blockade during the progression of pacing-induced congestive heart failure in rabbits. Circulation 1997; 95: 1918-1929.

    Google Scholar 

  55. Mulder P,Richard V,Bouchart F,Derumeaux G,Müunter K,Thuillez C. Selective ETA receptor blockade prevents left ventricular remodeling and detioration of cardiac function in experimental heart failure. Cardiovasc Res 1998; 39: 600-608.

    Google Scholar 

  56. Mulder P,Boujedaini H,Richard V, et al. Selective endothelin-A versus combined endothelin-A/endothelin-B receptor blockade in rat chronic heart failure. Circulation 2000; 102: 491-493.

    Google Scholar 

  57. Hu K,Gaudron P,Schmidt TJ,Hoffmann KD,Ertl G. Aggravation of left ventricular remodeling by a novel specific endothelin ETA antagonist EMD94246 in rats with experimental myocardial infarction. J Cardiovasc Pharmacol 1998; 32: 505-508.

    Google Scholar 

  58. Fraccarollo D,Hu K,Galuppo P,Gaudron P,Ertl G. Chronic endothelin receptor blockade attenuates progressive ventricular dilation and improves cardiac function in rats with myocardial infarction. Circulation 1997; 96: 3963-3973.

    Google Scholar 

  59. Bozkurt B,Torre-Amione G,SmithWarren M, et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation 2001; 103: 1044-1047.

    Google Scholar 

  60. McClean DR,Ikram H,Garlick AH,Richards AM,Nicholls MG,Crozier IG. The clinical,cardiac,renal,arterial and neurohormonal effects of omapatrilat,a vasopeptidase inhibitor,in patients with chronic heart failure. J Am Coll Cardiol 2000; 36: 479-486.

    Google Scholar 

  61. Rouleau JL,Pfeffer MA,Stewart DJ, et al. for theIMPRESS investigators. Comparison of vasopeptidase inhibitor,omapatrilat,and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet 2000; 356: 615-620.

    Google Scholar 

  62. Shimada T,Yoshiyama M,Takeuchi K, et al. Long acting calcium antagonist amlodipine prevents left ventricular remodeling after myocardial infarction in rats. Cardiovasc Res 1998; 37: 618-626.

    Google Scholar 

  63. Yamazaki T,Komuro I,Zou Y, et al. Efficient inhibition of the development of cardiac remodeling by a long-acting calcium antagonist amlodipine. Hypertension 1998; 31(part 1): 32-38.

    Google Scholar 

  64. Mahmarian JJ,Moyé LA,Chinoy DA, et al. Transdermal nitroglycerin patch therapy improves left ventricular function and prevents remodeling after acute myocardial infarction. Circulation 1998; 97: 2017-2024.

    Google Scholar 

  65. Cohn JN,Johnson G,Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303-310.

    Google Scholar 

  66. Remme WJ,Swedberg K, for the Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001; 22: 1527-1560.

    Google Scholar 

  67. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure.Results of the North Scandinavian enalapril survival study. N Engl J Med 1987; 316: 1429-1435.

    Google Scholar 

  68. The SOLVD Investigators. Effects of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327: 685-691.

    Google Scholar 

  69. Pfeffer MA,Braunwald E,Moye LA, et al. For the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction and myocardial infarction.Results of the Survival and Ventricular Enlargement Trial. NEngl J Med 1992; 327: 669-677.

    Google Scholar 

  70. Acute Infarction Ramipril Efficacy (AIRE) Investigators. Effects of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993; 342: 821-828.

    Google Scholar 

  71. Køber L,Torp-Pedersen C,Carlsen JE, et al. For the Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995; 333: 1670-1676.

    Google Scholar 

  72. Packer M,Bristow MR,Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349-1355.

    Google Scholar 

  73. CIBIS-II Investigators and Committees. The Cardiac Insuf-ficiency Bisoprolol Study II (CIBIS-II). Lancet 1999; 353: 9-13.

    Google Scholar 

  74. Hjalmarson A,Godstein S,Fagerberg B, et al. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 1999; 353: 2001-2007.

    Google Scholar 

  75. Packer M,Coats AJS,Fowler MB, et al. for the Carvedilol Prospective Randomized Cumulative Survival Study Group (COPERNICUS). Effect of carvedilol on survival in severe chronic heart failure. New Engl J Med 2001; 344: 1651-1658.

    Google Scholar 

  76. The CAPRICORN Investigators. Effects of carvedilol on outcome after myocardial infarction in patients with left ventricular dysfunction: The CAPRICORN randomized trial. Lancet 2001; 357: 1385-1389.

    Google Scholar 

  77. Pitt B,Zannad F,Remme WJ, et al. The effect of spironolactone on moribidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation (RALES) Study Investigators. N Engl J Med 1999; 341: 709-717.

    Google Scholar 

  78. Pitt B,Remme WJ,Zannad F, et al. Eplerenone,a selective aldosterone blocker,in patients with left ventricular dysfunction after myocardial infarction. New Engl J Med 2003; 348: 1309-1321.

    Google Scholar 

  79. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomized trial-The Losartan Heart Failure Survival Study ELITE II.

  80. Cohn JN,Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345: 1667-1675.

    Google Scholar 

  81. Mylona P,Cleland JGF. Update of REACH-1 and MERITHF clinical trials in heart failure. EJHF 1991; 1: 197-200.

    Google Scholar 

  82. Louis A,Cleland JGF,Crabbe S, et al. Clinical trials update: CAPRICORN,COPERNICUS,MIRACLE,STAF,RITZ-2,RECOVER AND RENAISSANCE and cachexia and cholesterol in heart failure.Highlights of the Scientific Sessions of the American College of Cardiology, 2001. Eur J Heart Fail 2001; 3: 381-387.

    Google Scholar 

  83. Packer M,Califf RM,Konstam MA, et al. for the OVERTURE Study Group. Comparison of omapatrilat and enalapril in patients with chronic heart failure. Circulation 2002; 106: 920-926.

    Google Scholar 

  84. Komajda M,Follath F,Swedberg K, et al. The Euro Heart Failure Survey programme:ASurvey on the Quality of Care Among Patients with Heart Failure in Europe: Treatment. Eur Heart J 2003; 24: 464-474.

    Google Scholar 

  85. Hobbs FDR,Jones MI,Allan TF, et al. European survey of primary care physician perceptions on heart failure 360 Remme diagnosis and management (EURO-HF). Eur Heart J 2000; 21: 1877-1887.

    Google Scholar 

  86. Remme WJ on behalf of the CARMEN Steering Committee and Investigators. The carvedilol and ACE-inhibitor remodeling mild heart failure evaluation trial (CARMEN)-Rationale and design. Cardiovasc Drugs Ther 2001; 15: 69-77.

    Google Scholar 

  87. Remme WJ,Riegger G,Hildebrandt P, et al. for the CARMEN Investigators. Do patients necessarily have to start with an angiotensin converting enzyme inhibitor in the treatment of heart failure? Results of the CARMEN (Carvedilol Ace inhibitor Remodeling Mild heart failure EvaluatioN) Study. J AmColl Cardiol 2003; 41: 162A.

    Google Scholar 

  88. Remme WJ,Riegger G,Ryden L, et al. for the CARMEN Investigators. Does baseline heart rate determine the effect of carvedilol on ventricular remodeling in heart failure? Results of the CARMEN (Carvedilol Ace inhibitor Remodeling Mild heart failure EvaluatioN) Study. Eur Heart J 2003; 24 (abstract-suppl.): 711.

    Google Scholar 

  89. Emanueli C,Maestri R,Corradi D, et al. Dilated and failing cardiomyopathy in bradykinin B2 receptor knockout mice. Circulation 1999; 100: 2359-2365.

    Google Scholar 

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Remme, W. Pharmacological Modulation of Cardiovascular Remodeling: A Guide to Heart Failure Therapy. Cardiovasc Drugs Ther 17, 349–360 (2003). https://doi.org/10.1023/A:1027351808326

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