Skip to main content

Advertisement

SpringerLink
Log in

Nonlipid-lowering effects of statins

  • Published:
Current Treatment Options in Cardiovascular Medicine Aims and scope Submit manuscript

Optional statement

Statins have been shown to effectively reduce cardiovascular events in patients with hypercholesterolemia, diabetes, and coronary disease, and after an acute coronary syndrome in several large-scale clinical trials. Interestingly, numerous studies have suggested that statins exert potentially important effects independent of lipid lowering (ie, improve endothelial function, reduce oxidant stress), and have direct antiinflammatory, antithrombotic, and plaque-stabilizing effects. These beneficial effects may contribute to cardiovascular protection by statin therapy beyond low-density lipoprotein (LDL) cholesterol lowering. Therefore, it remains unclear at present to what extent the beneficial cardiovascular effects of statin treatment are dependent on LDL cholesterol lowering (ie, whether the same effect would be achieved by other modes of lipid lowering). Consequently, statins should be used as a first-line therapy for lipid lowering. Importantly, the observation of LDL cholesterol-independent effects of statins has stimulated clinical studies testing a wider use of statin treatment for diseases that are not thought to be related to increased LDL cholesterol levels, such as in patients with chronic heart failure (in particular dilated cardiomyopathy) and even in inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Landmesser U, Hornig B, Drexler H: Endothelial function: a critical determinant in atherosclerosis? Circulation 2004, 109:II27-II33.

    Article  PubMed  Google Scholar 

  2. Fichtlscherer S, Breuer S, Zeiher AM: Prognostic value of systemic endothelial dysfunction in patients with acute coronary syndromes: further evidence for the existence of the “vulnerable” patient. Circulation 2004, 110:1926–1932.

    Article  PubMed  Google Scholar 

  3. Loscalzop J: Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ Res 2001, 88:756–762.

    Google Scholar 

  4. De Caterina R, Libby P, Peng HB, et al.: Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995, 96:60–68.

    Article  PubMed  Google Scholar 

  5. Laufs U, La Fata V, Plutzky J, et al.: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998, 12:1129–1135.

    Google Scholar 

  6. Hattori Y, Nakanishi N, Akimoto K, et al.: HMG-CoA reductase inhibitor increases GTP cyclohydrolase I mRNA and tetrahydrobiopterin in vascular endothelial cells. Arterioscler Thromb Vasc Biol 2003, 23:176–182.

    Article  PubMed  CAS  Google Scholar 

  7. 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, 6:1004–1010.

    Article  PubMed  CAS  Google Scholar 

  8. 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, 110:1933–1939.

    Article  PubMed  CAS  Google Scholar 

  9. Endres M, Laufs U, Huang Z, et al.: Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 1998, 95:8880–8885.

    Article  PubMed  CAS  Google Scholar 

  10. Wassmann S, Faul A, Hennen B, et al.: Rapid effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition on coronary endothelial function. Circ Res 2003, 93:e98-e103. Demonstrates that a single oral 40-mg dose of pravastatin significantly attenuated coronary endothelial dysfunction in patients with coronary disease without any effects on serum cholesterol levels, suggesting a direct LDL cholesterol-independent effect of statin treatment on endothelial function.

    Article  PubMed  CAS  Google Scholar 

  11. Landmesser U, Bahlmann F, Mueller M, et al.: Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005, 111:2356–2363. Compares the effect of 4 weeks of treatment with simvastatin or ezetimibe, dosed to achieve a similar reduction of LDL cholesterol levels, on endothelial function in patients with CHF. Statin treatment but not ezetimibe therapy improved endothelial function, strongly suggesting that prolonged statin therapy exerts beneficial effects on endothelial function independent of lipid lowering. This may help to explain beneficial effects of statins in patients with CHF independent of LDL cholesterol.

    Article  PubMed  CAS  Google Scholar 

  12. Walter DH, Rittig K, Bahlmann FH, et al.: Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrowderived endothelial progenitor cells. Circulation 2002, 105:3017–3024.

    Article  PubMed  CAS  Google Scholar 

  13. 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, 22:1567–1572.

    Article  PubMed  CAS  Google Scholar 

  14. 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, 108:391–397.

    Article  PubMed  CAS  Google Scholar 

  15. Spyridopoulos I, Haendeler J, Urbich C, et al.: Statins enhance migratory capacity by upregulation of the telomere repeat-binding factor TRF2 in endothelial progenitor cells. Circulation 2004, 110:3136–3142.

    Article  PubMed  CAS  Google Scholar 

  16. Vasa M, Fichtscherer S, Adler K, et al.: Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001, 103:2885–2890.

    PubMed  CAS  Google Scholar 

  17. Schmidt-Lucke C, Rossig L, Fichtlscherer S, et al.: Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation 2005, 111:2981–2987.

    Article  PubMed  Google Scholar 

  18. Laufs U, Marra D, Node K, et al.: 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem 1999, 274:21926–21931.

    Article  PubMed  CAS  Google Scholar 

  19. Yang Z, Kozai T, van der Loo B, et al.: HMG-CoA reductase inhibition improves endothelial cell function and inhibits smooth muscle cell proliferation in human saphenous veins. J Am Coll Cardiol 2000, 36:1691–1697.

    Article  PubMed  CAS  Google Scholar 

  20. Harrison D, Griendling KK, Landmesser U, et al.: Role of oxidative stress in atherosclerosis. Am J Cardiol 2003, 91:7A-11A.

    Article  PubMed  CAS  Google Scholar 

  21. Spiekermann S, Landmesser U, Dikalov S, et al.: Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation 2003, 107:1383–1389.

    Article  PubMed  CAS  Google Scholar 

  22. Heymes C, Bendall JK, Ratajczak P, et al.: Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol 2003, 41:2164–2171.

    Article  PubMed  CAS  Google Scholar 

  23. 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, 108:1567–1574. Provides important evidence indicating inhibition of small g protein and oxidant stress in patients with ischemic and dilated cardiomyopathy on statin treatment. These findings may help to explain beneficial effects of statins independent of LDL cholesterol in patients with heart failure.

    Article  PubMed  CAS  Google Scholar 

  24. 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 Rac1 GTPase. Mol Pharmacol 2001, 59:646–654.

    PubMed  CAS  Google Scholar 

  25. Haendeler J, Hoffmann J, Zeiher AM, et al.: Antioxidant effects of statins via S-nitrosylation and activation of thioredoxin in endothelial cells: a novel vasculoprotective function of statins. Circulation 2004, 110:856–861.

    Article  PubMed  CAS  Google Scholar 

  26. Ross R: Atherosclerosis—an inflammatory disease. N Engl J Med 1999, 340:115–126.

    Article  PubMed  CAS  Google Scholar 

  27. Libby P, Ridker PM, Maseri A: Inflammation and atherosclerosis. Circulation 2002, 105:1135–1143.

    Article  PubMed  CAS  Google Scholar 

  28. Hansson GK: Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005, 16:1685–1695.

    Article  Google Scholar 

  29. Scalia R, Gooszen ME, Jones SP, et al.: Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice. Circulation 2001, 103:2598–2603.

    PubMed  CAS  Google Scholar 

  30. Pruefer D, Makowski J, Schnell M, et al.: Simvastatin inhibits inflammatory properties of Staphylococcus aureus alpha-toxin. Circulation 2002, 106:2104–2110.

    Article  PubMed  CAS  Google Scholar 

  31. Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al.: Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 2001, 7:687–692.

    Article  PubMed  CAS  Google Scholar 

  32. Kwak B, Mulhaupt F, Myit S, et al.: Statins as a newly recognized type of immunomodulator. Nat Med 2000, 6:1399–1402. Suggests immunomodulation by statin treatment may help to explain the reduced rejection observed in heart transplant patients who received statin therapy.

    Article  PubMed  CAS  Google Scholar 

  33. Kobashigawa JA, Katznelson S, Laks H, et al.: Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995, 333:621–627.

    Article  PubMed  CAS  Google Scholar 

  34. Liuzzo G, Biasucci LM, Gallimore JR, et al.: The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 1994, 331:417–424.

    Article  PubMed  CAS  Google Scholar 

  35. Ridker PM, Hennekens CH, Buring JE, et al.: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000, 342:836–843.

    Article  PubMed  CAS  Google Scholar 

  36. Ridker PM, Cannon CP, Morrow D, et al.: C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005, 352:20–28.

    Article  PubMed  CAS  Google Scholar 

  37. Albert MA, Danielson E, Rifai N, Ridker PM: Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001, 286:64–70.

    Article  PubMed  CAS  Google Scholar 

  38. Ridker PM: Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003, 108:2292–2297.

    Article  PubMed  Google Scholar 

  39. Maseri A, Fuster V: Is there a vulnerable plaque? Circulation 2003, 107:2068–2071.

    Article  PubMed  Google Scholar 

  40. Shah PK, Falk E, Badimon JJ, et al.: Human monocytederived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation 1995, 92:1565–1569.

    PubMed  CAS  Google Scholar 

  41. Moreno PR, Falk E, Palacios IF, et al.: Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 1994, 90:775–778.

    PubMed  CAS  Google Scholar 

  42. Aikawa M, Rabkin E, Sugiyama S, et al.: An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 2001, 103:276–283.

    PubMed  CAS  Google Scholar 

  43. Fukumoto Y, Libby P, Rabkin E, et al.: Statins alter smooth muscle cell accumulation and collagen content in established atheroma of watanabe heritable hyperlipidemic rabbits. Circulation 2001, 103:993–999.

    PubMed  CAS  Google Scholar 

  44. Bourcier T, Libby P: HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. Arterioscler Thromb Vasc Biol 2000, 20:556–562.

    PubMed  CAS  Google Scholar 

  45. Takemoto M, Node K, Nakagami H, et al.: Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest 2001, 108:1429–1437.

    Article  PubMed  CAS  Google Scholar 

  46. 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, 104:576–581.

    PubMed  CAS  Google Scholar 

  47. 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, 108:839–843.

    Article  PubMed  CAS  Google Scholar 

  48. Horwich TB, MacLellan WR, Fonarow GC: Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol 2004, 43:642–648.

    Article  PubMed  CAS  Google Scholar 

  49. 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, 42:1933–1940.

    Article  PubMed  CAS  Google Scholar 

  50. Collins R, Armitage J, Parish S, et al.: Effects of cholesterollowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004, 363:757–767.

    Article  PubMed  CAS  Google Scholar 

  51. Endres M: Statins and stroke. J Cereb Blood Flow Metab 2005, 25:1093–1110.

    Article  PubMed  CAS  Google Scholar 

  52. Moonis M, Kane K, Schwiderski U, et al.: HMG-CoA reductase inhibitors improve acute ischemic stroke outcome. Stroke 2005, 36:1298–1300.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medizinische Hochschule Hannover, Abteilung Kardiologie und Angiologie, Carl Neuberg Str.1, 30625, Hannover, Germany

    Ulf Landmesser MD

Authors
  1. Sajoscha Sorrentino MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ulf Landmesser MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sorrentino, S., Landmesser, U. Nonlipid-lowering effects of statins. Curr Treat Options Cardio Med 7, 459–466 (2005). https://doi.org/10.1007/s11936-005-0031-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11936-005-0031-1

Keywords

Search

Navigation