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Drugs

, Volume 66, Issue 2, pp 145–154 | Cite as

HMG-CoA Reductase Inhibitors in Chronic Heart Failure

Potential Mechanisms of Benefit and Risk
  • Ulrich LaufsEmail author
  • Florian Custodis
  • Michael Böhm
Leading Article

Abstract

HMG-CoA reductase inhibitors (statins) have been shown to reduce mortality and cardiovascular morbidity in patients with hyperlipidaemia and those with coronary artery disease. However, evidence for statin treatment in patients with chronic heart failure (CHF) remains a subject of debate. Patients with heart failure were generally excluded in the existing trials and a different patient population with a distinct pattern of morbidity and treatment was studied. In addition, no safety data are available for statins in patients with heart failure, where there are potential concerns about coenzyme Q10 depletion and excessive low-density lipoprotein reduction.

This review summarises the clinical and preclinical evidence for potential beneficial effects of statins in CHF. In experimental systems, statins have been shown to improve cardiac function through antioxidative and anti-inflammatory action. Statins improve endothelial function, may reduce neurohormonal activation, and stimulate endothelial progenitor cells. Some of these effects occur independently of cholesterol lowering and can be explained by inhibition of isoprenylation of signal transducing proteins of the family of Rho guanosine triphosphatases. Two ongoing controlled randomised trials (CORONA [Controlled Rosuvastatin Multinational Study in Heart Failure] and GISSI-HF [Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico — Heart Failure]) will help us to assess whether the described beneficial effects of statins in heart failure outweigh the potential negative effects and translate into the reduction of clinical endpoints.

Keywords

Statin Chronic Heart Failure Rosuvastatin Statin Treatment Chronic Heart Failure Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This article was invited by the commissioning editor of Drugs and was written and funded by the authors. The authors have received research grants and lecture fees from pharmaceutical companies selling statin drugs (AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Sharp and Dohme, Novartis, Pfizer and Sankyo).

References

  1. 1.
    National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). The National Cholesterol Education Program Adult Treatment Panel III Report, 2001. Bethesda (MD): National Heart, Lung, and Blood Institute, 2002. NIH publication no. 02-5215Google Scholar
  2. 2.
    Heart Protection Study Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7–22CrossRefGoogle Scholar
  3. 3.
    The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293–302CrossRefGoogle Scholar
  4. 4.
    Scandinavian Simvastatin Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–9Google Scholar
  5. 5.
    Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335: 1001–9Google Scholar
  6. 6.
    The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349–57CrossRefGoogle Scholar
  7. 7.
    Böhm M, Hjalmarson A, Kjekshus J, et al. Do we need a clinical trial in heart failure with statins? Z Kardiol 2005; 94: 223–30PubMedCrossRefGoogle Scholar
  8. 8.
    Anker SD, Negassa A, Coats AJ, et al. Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study. Lancet 2003; 361: 1077–83PubMedCrossRefGoogle Scholar
  9. 9.
    Rauchhaus M, Clark AL, Doehner W, et al. The relationship between cholesterol and survival in patients with chronic heart failure. J Am Coll Cardiol 2003; 42: 1933–40PubMedCrossRefGoogle Scholar
  10. 10.
    Anker SD, Steinborn W, Strassburg S. Cardiac cachexia. Ann Med 2004; 36: 518–29PubMedCrossRefGoogle Scholar
  11. 11.
    Anker SD, von Haehling S. Inflammatory mediators in chronic heart failure: an overview. Heart 2004; 90: 464–70PubMedCrossRefGoogle Scholar
  12. 12.
    Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult. Circulation 2005; 20(112): e154–235CrossRefGoogle Scholar
  13. 13.
    Kjekshus J, Perdersen TR, Olsson A, et al. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail 1997; 3(4): 249–54PubMedCrossRefGoogle Scholar
  14. 14.
    Node K, Fujita M, Kitakaze M, et al. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation 2003 Aug 19; 108: 839–43PubMedCrossRefGoogle Scholar
  15. 15.
    Laufs U, Wassmann S, Schackmann S, et al. Beneficial effects of statins in patients with non-ischemic heart failure. Z Kardiol 2004; 93: 103–8PubMedCrossRefGoogle Scholar
  16. 16.
    Hognestad A, Dickstein K, Myhre E, et al. Effect of combined statin and beta-blocker treatment on one-year morbidity and mortality after acute myocardial infarction associated with heart failure. Am J Cardiol 2004; 93: 603–6PubMedCrossRefGoogle Scholar
  17. 17.
    Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005; 45: 89–118PubMedCrossRefGoogle Scholar
  18. 18.
    Laufs U, Liao JK, Böhm M. Lipid management with statins: the lower the better? Z Kardiol 2004; 93: 4–9PubMedCrossRefGoogle Scholar
  19. 19.
    Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001; 292: 1160–4PubMedCrossRefGoogle Scholar
  20. 20.
    Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990; 343: 425–30PubMedCrossRefGoogle Scholar
  21. 21.
    Sorescu D, Griendling KK. Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail 2002; 8: 132–40PubMedCrossRefGoogle Scholar
  22. 22.
    Zafari AM, Harrison DG. Free radicals in heart failure: therapeutic targets for old and new drugs. Congest Heart Fail 2002; 8: 129–30PubMedCrossRefGoogle Scholar
  23. 23.
    Sawyer DB, Siwik DA, Xiao L, et al. Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol 2002; 34: 379–88PubMedCrossRefGoogle Scholar
  24. 24.
    Keith M, Geranmayegan A, Sole MJ, et al. Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol 1998; 31: 1352–6PubMedCrossRefGoogle Scholar
  25. 25.
    Li JM, Gall NP, Grieve DJ, et al. Activation of NADPH oxidase during progression of cardiac hypertrophy to failure. Hypertension 2002; 40: 477–84PubMedCrossRefGoogle Scholar
  26. 26.
    Bendall JK, Cave AC, Heymes C, et al. Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 2002; 105: 293–6PubMedCrossRefGoogle Scholar
  27. 27.
    Keith M, Geranmayegan A, Sole MJ, et al. Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol 1998; 31: 1352–6PubMedCrossRefGoogle Scholar
  28. 28.
    MacCarthy PA, Grieve DJ, Li JM, et al. Impaired endothelial regulation of ventricular relaxation in cardiac hypertrophy: role of reactive oxygen species and NADPH oxidase. Circulation 2001; 104: 2967–74PubMedCrossRefGoogle Scholar
  29. 29.
    Aikawa R, Nawano M, Gu Y, et al. Insulin prevents cardiomyocytes from oxidative stress-induced apoptosis through activation of PI3 kinase/Akt. Circulation 2000; 102: 2873–9PubMedCrossRefGoogle Scholar
  30. 30.
    Xiao L, Pimentel DR, Wang J, et al. Role of reactive oxygen species and NAD(P)H oxidase in alpha(1)-adrenoceptor signaling in adult rat cardiac myocytes. Am J Physiol Cell Physiol 2002; 282: C926–34PubMedGoogle Scholar
  31. 31.
    Laufs U, Kilter H, Konkol C, et al. Impact of HMG CoA reductase inhibition on small GTPases in the heart. Cardiovasc Res 2002; 53: 911–20PubMedCrossRefGoogle Scholar
  32. 32.
    Maack C, Kartes T, Kilter H, et al. Oxygen free radical release in human failing myocardium is associated with increased activity of Rac1-GTPase and represents a target for statin treatment. Circulation 2003; 108: 1567–74PubMedCrossRefGoogle Scholar
  33. 33.
    Takemoto M, Node K, Nakagami H, et al. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest 2001; 108: 1429–37PubMedGoogle Scholar
  34. 34.
    Wassmann S, Laufs U, Baumer AT, et al. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Racl GTPase. Mol Pharmacol 2001; 59: 646–54PubMedGoogle Scholar
  35. 35.
    Dechend R, Fiebeler A, Park JK, et al. Amelioration of angiotensin II-induced cardiac injury by a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor. Circulation 2001; 104: 576–81PubMedCrossRefGoogle Scholar
  36. 36.
    Hayashidani S, Tsutsui H, Shiomi T, et al. Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 2002 Feb 19; 105: 868–73PubMedCrossRefGoogle Scholar
  37. 37.
    Lorell BH, Carabello BA. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation 2000; 102: 470–9PubMedCrossRefGoogle Scholar
  38. 38.
    Sussman MA, Welch S, Walker A, et al. Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active racl. J Clin Invest 2000; 105: 875–86PubMedCrossRefGoogle Scholar
  39. 39.
    Ito M, Adachi T, Pimentel DR, et al. Statins inhibit beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes via a Rac1-dependent mechanism. Circulation 2004; 110: 412–8PubMedCrossRefGoogle Scholar
  40. 40.
    Clerk A, Sugden PH. Small guanine nucleotide-binding proteins and myocardial hypertrophy. Circ Res 2000; 86: 1019–23PubMedCrossRefGoogle Scholar
  41. 41.
    Hirooka Y, Imaizumi T, Tagawa T, et al. Effects of L-arginine on impaired acetylcholine-induced and ischemic vasodilation of the forearm in patients with heart failure. Circulation 1994; 90: 658–68PubMedCrossRefGoogle Scholar
  42. 42.
    Wassmann S, Faul A, Hennen B, et al. Rapid effect of 3-hydrox-y-3-methylglutaryl coenzyme a reductase inhibition on coronary endothelial function. Circ Res 2003; 93: e98–103PubMedCrossRefGoogle Scholar
  43. 43.
    Laufs U. Beyond lipid-lowering: effects of statins on endothelial nitric oxide. Eur J Clin Pharmacol 2003; 58: 719–31PubMedGoogle Scholar
  44. 44.
    Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 2000; 6: 1004–10PubMedCrossRefGoogle Scholar
  45. 45.
    Fulton D, Gratton JP, McCabe TJ, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999; 399: 597–601PubMedCrossRefGoogle Scholar
  46. 46.
    Dimmeler S, Fleming I, Fisslthaler B, et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999; 399: 601–5PubMedCrossRefGoogle Scholar
  47. 47.
    Wassmann S, Laufs U, Muller K, et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol 2002; 22: 300–5PubMedCrossRefGoogle Scholar
  48. 48.
    Di Napoli P, Taccardi AA, Grilli A, et al. Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia/reperfusion injury in rat hearts. Cardiovasc Res 2005; 66(3): 462–71PubMedCrossRefGoogle Scholar
  49. 49.
    Wolfram S, Dendorfer A, Schutt M, et al. Simvastatin acutely reduces myocardial reperfusion injury in vivo by activating the phosphatidylinositide 3-kinase/Akt pathway. J Cardiovasc Pharmacol 2004; 44: 348–55CrossRefGoogle Scholar
  50. 50.
    Ikeda Y, Young LH, Lefer AM. Rosuvastatin, a new HMG-CoA reductase inhibitor, protects ischemic reperfused myocardium in normocholesterolemic rats. J Cardiovasc Pharmacol 2003; 41: 649–56PubMedCrossRefGoogle Scholar
  51. 51.
    Landmesser U, Engberding N, Bahlmann FH, et al. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation 2004; 110: 1933–9PubMedCrossRefGoogle Scholar
  52. 52.
    Yamakuchi M, Greer JJ, Cameron SJ, et al. HMG-CoA reductase inhibitors inhibit endothelial exocytosis and decrease myocardial infarct size. Circ Res 2005; 96: 1185–92PubMedCrossRefGoogle Scholar
  53. 53.
    Kwak B, Mulhaupt F, Myit S, et al. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6: 1399–402PubMedCrossRefGoogle Scholar
  54. 54.
    Mulhaupt F, Matter CM, Kwak BR, et al. Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells. Cardiovasc Res 2003; 59: 755–66PubMedCrossRefGoogle Scholar
  55. 55.
    Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352: 20–8PubMedCrossRefGoogle Scholar
  56. 56.
    Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005; 352: 29–38PubMedCrossRefGoogle Scholar
  57. 57.
    Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291: 1071–80PubMedCrossRefGoogle Scholar
  58. 58.
    Shiroshita-Takeshita A, Schram G, Lavoie J, et al. Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrial-tachycardia remodeling in dogs. Circulation 2004; 110: 2313–9PubMedCrossRefGoogle Scholar
  59. 59.
    Trochu JN, Mital S, Zhang X, et al. Preservation of NO production by statins in the treatment of heart failure. Cardiovasc Res 2003; 60: 250–8PubMedCrossRefGoogle Scholar
  60. 60.
    Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964–7PubMedCrossRefGoogle Scholar
  61. 61.
    Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003; 348: 593–600PubMedCrossRefGoogle Scholar
  62. 62.
    Badorff C, Brandes RP, Popp R, et al. Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes. Circulation 2003; 107: 1024–32PubMedCrossRefGoogle Scholar
  63. 63.
    Assmus B, Urbich C, Aicher A, et al. HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circ Res 2003 May 16; 92(9): 1049–55PubMedCrossRefGoogle Scholar
  64. 64.
    Dimmeler S, Aicher A, Vasa M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 2001; 108: 391–7PubMedGoogle Scholar
  65. 65.
    Werner N, Priller J, Laufs U, et al. Bone marrow-derived progenitor cells modulate vascular reendothelialization and neointimal formation: effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition. Arterioscler Thromb Vasc Biol 2002; 22: 1567–72PubMedCrossRefGoogle Scholar
  66. 66.
    Vasa M, Fichtischerer S, Adler K, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001; 103: 2885–90PubMedCrossRefGoogle Scholar
  67. 67.
    Laufs U, Böhm M. Cardiac effects of statins: advancements and open questions. Cardiovasc Res 2005; 66: 427–9PubMedCrossRefGoogle Scholar
  68. 68.
    Kjekshus J, Dunselman P, Blideskog M, et al. A statin in the treatment of heart failure? Controlled Rosuvastatin Multinztional Study in Heart Failure (CORONA): study design and baseline characteristics. CORONA Study Group. Eur J Heart Fail 2005 Oct; 7(6): 1059–69PubMedCrossRefGoogle Scholar
  69. 69.
    Tavazzi L, Tognoni G, Franzosi MG, et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. GISSI-HF Investigators. Eur J Heart Fail 2004 Aug; 6(5): 635–41Google Scholar

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© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische IntensivmedizinUniversitätsklinikum des SaarlandesHomburg/SaarGermany

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