Skip to main content

How Do HMG-CoA Reductase Inhibitors Prevent Stroke?

American Journal of Cardiovascular Drugs volume 2, pages 7–14 (2002)Cite this article

Abstract

Stroke is a heterogeneous disorder with significantly high morbidity and mortality. The relationship between serum cholesterol level and the incidence of stroke remains controversial. Recent evidence from primary and secondary prevention trials suggests that treatment with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors may reduce the incidence of stroke in patients with coronary artery disease (CAD). In this review, we attempt to outline and describe the potential mechanisms of HMG-CoA reductase inhibitors in the prevention of stroke.

In addition to their lipid-lowering action HMG-CoA reductase inhibitors appear to exert their beneficial effects by various nonlipid-lowering mechanisms including anti-inflammatory effects, effect on endothelial function and coagulation cascade. Treatment with HMG-CoA reductase inhibitors is associated with decreased progression, plaque stablilization and even regression of atheromatous plaque in the carotid arteries. HMG-CoA reductase inhibitors also inhibit the coagulation cascade at various levels such as activation of prothrombin, factor V, factor X and liberation of tissue factor in response to vascular injury. Inhibition of fibrinolysis occurs secondary to inhibition of plasmin generation. Pravastatin therapy is associated with a reduction in the size of aortic atheroma which is an independent risk factor for stroke. Lastly, left ventricular dysfunction after acute myocardial infarction is associated with an increased risk of stroke and HMG-CoA reductase inhibitors may indirectly decrease the incidence of stroke by reducing coronary events. Most of these effects are independent of the cholesterol-lowering effects of HMG-CoA reductase inhibitors. In conclusion, HMG-CoA reductase inhibitors may have a role in primary prevention of stroke in patients with CAD.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

49,54 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Table I
Table II
Fig. 1

References

  1. Heart and stroke facts. Dallas (TX): American Heart Association, 1996: 11

  2. The brain at risk — understanding and preventing stroke. Englewood (CO): National Stroke Association, 1997; 1-27

  3. Cerebral Embolism Task Force. Cardiogenic brain embolism. Arch Neurol 1986 Jan; 43(1): 71–84

    Article  Google Scholar 

  4. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450 000 people in 45 prospective cohorts. Lancet 1995; 346: 1647–52

    Article  Google Scholar 

  5. Consensus Conference: Lowering blood cholesterol to prevent heart disease. JAMA 1985;253: 2080–6

    Article  Google Scholar 

  6. Tyroler HA. Review of lipid-lowering clinical trials in relation to observational epidemiological studies. Circulation 1987; 76: 515–22

    PubMed  Article  CAS  Google Scholar 

  7. Lindenstrom E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. BMJ 1994; 309: 11–5

    PubMed  Article  CAS  Google Scholar 

  8. Atkins D, Psaty BM, Koepsell TD, et al. Cholesterol reduction and the risk for stroke in men: a meta-analysis of randomized, controlled trials. Ann Intern Med. 1993; 119: 136–45

    PubMed  CAS  Google Scholar 

  9. Iso H, Jacobs Jr DR, Wentworth D, et al. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989; 320: 904–10

    PubMed  Article  CAS  Google Scholar 

  10. Cupples LA, D’Agostino RB. Some risk factors related to the annual incidence of cardiovascular disease and death using pooled biennial measurements. The Framingham Heart Study: an epidemiologic investigation of cardiovascular disease. Section 34. Washington, DC: U.S. Department of Health and Human Services; 1987. Publication no.: NHI 87–2703

    Google Scholar 

  11. WHO cooperative trial on primary prevention of ischemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Report of the committee of principal investigators. Lancet 1984; 2: 600-4

    Google Scholar 

  12. Kagan A, McGee DL, Yano K, et al. Serum cholesterol and mortality in a Japanese-American population: the Honolulu Heart Program. Am J Epidemiol 1981; 114: 11–20

    PubMed  CAS  Google Scholar 

  13. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317: 1237–45

    PubMed  Article  CAS  Google Scholar 

  14. Sacks FM, Pfeffer MA, Moye LA, et al. For the Cholesterol and recurrent Events Trial Investigators. The Effect of Pravastatin on Coronary Events After Myocardial Infarction in Patients with Average Cholesterol Levels. N Engl J Med 1996; 335: 1001–9

    PubMed  Article  CAS  Google Scholar 

  15. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–8

    Google Scholar 

  16. Shepherd J, Cobbe SM, Ford I, et al., for the West of Scotland Coronary Prevention Study Group. Prevention of coronary disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–7

    PubMed  Article  CAS  Google Scholar 

  17. Furberg CD, Adams HP, Applegate HP, et al., for Asymptomatic Carotid Artery Progression Study Research Group. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation 1994; 90(4): 1679–87

    PubMed  Article  CAS  Google Scholar 

  18. Herbert PR, Gaziano J, Michael MD. Cholesterol lowering with statin drugs, risk of stroke and total mortality: an overview of randomized trials. JAMA 1997; 278:313–21

    Article  Google Scholar 

  19. Byington RP, Davis BR, Plehn JF, et al. Reduction of stroke events with pravastatin: the prospective pravastatin pooling project. Circulation 2001; 103(3): 387–92

    PubMed  Article  CAS  Google Scholar 

  20. White HD, Simes RJ, Anderson NE, et al. Pravastatin therapy and risk of stroke. N Engl J Med 2000; 343: 317–26

    PubMed  Article  CAS  Google Scholar 

  21. The Long-Term Intervention with Pravastatin in Ischemic 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: 1349–57

    Article  Google Scholar 

  22. Rubins HB, Davenport J, Babikian V, et al., for the Veterans Affairs HDL Intervention Trial (VA-HIT) study group. Reduction in Stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol. Circulation 2001; 103: 2828–33

    Article  CAS  Google Scholar 

  23. O’Leary DH, Polak JF, Kronmal RA, et al. Carotid artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999; 340: 14–22

    PubMed  Article  Google Scholar 

  24. Byington RP, Furberg CD, Crouse 3rd JR, et al. Pravastatin, lipids and atherosclerosis in the carotid arteries (PLAC II). Am J Cardiol 1995; 76: 54C–9C

    PubMed  Article  CAS  Google Scholar 

  25. Salonen R, Nyyssonen K, Porkkala E, et al., for Kuopio Atherosclerosis Prevention Study: a population based primary prevention trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995; 92: 1758–64

    PubMed  Article  CAS  Google Scholar 

  26. Hoffman R, Brook GJ, Aviram M. Hypolipidemic drugs reduce lipoprotein susceptibility to undergo lipid peroxidation: in vitro and ex vivo studies. Atherosclerosis 1992; 93: 105–13

    PubMed  Article  CAS  Google Scholar 

  27. Giroux LM, Davignon J, Naruszewicz M. Simvastatin inhibits the oxidation of low density lipoproteins by activated human monocyte-derived macrophages. Biochim Biophys Acta 1993; 1165: 335–8

    PubMed  Article  CAS  Google Scholar 

  28. Davies, MJ. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995. Circulation 1996; 94: 2013–20

    PubMed  Article  CAS  Google Scholar 

  29. Libby P. Molecular basis of acute coronary syndromes. Circulation 1995; 91: 2844–50

    PubMed  Article  CAS  Google Scholar 

  30. Lee RT, Libby P. The unstable atheroma. Arterioscler Thromb Vasc Biol 1997; 17: 1859–67

    PubMed  Article  CAS  Google Scholar 

  31. Rabbani R, Topol EJ. Strategies to achieve coronary arterial plaque stabilization. Cardiovasc Res 1999; 41: 402–17

    PubMed  Article  CAS  Google Scholar 

  32. Shiomi M, Ito T, Tsukada T, et al. Reduction of serum cholesterol levels alters lesional composition of atherosclerotic plaques. Effect of pravastatin sodium on atherosclerosis in mature WHHL rabbits. Arterioscler Thromb Vasc Biol 1995; 15: 1938–44

    PubMed  Article  CAS  Google Scholar 

  33. Milita C, Nordin-Fredriksson G, Shah PK, et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases and cell death in human carotid plaques, Implication for plaque stabilization. Circulation 2001; 103: 926–33

    Article  Google Scholar 

  34. Ballantyne CM. Newer risk markers and surrogate endpoints in atherosclerosis management. Clin Cardiol 2001 Aug; 24 Suppl. 8: III13–7

    PubMed  CAS  Google Scholar 

  35. Ridker PM, Rifai N, Pfeffer MA, et al. for the Cholesterol and Recurrent Events (CARE) Investigators. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999; 100: 230–5

    PubMed  Article  CAS  Google Scholar 

  36. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973–9

    PubMed  Article  CAS  Google Scholar 

  37. Muir KW, Weir CJ, Alwan W, et al. C-reactive protein and outcome after ischemic stroke. Stroke 1999; 30: 981–5

    PubMed  Article  CAS  Google Scholar 

  38. Kuller L, Tracy R, Shaten J, et al. Relationship of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol 1996; 144: 537–47

    PubMed  Article  CAS  Google Scholar 

  39. Tracy RP, Lemaitre RN, Psaty BM, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biology 1997 Jun 17(6): 1121–7

    Article  CAS  Google Scholar 

  40. Hashimoto H, Kitagawa K, Hougaku H, et al. C-reactive protein is an independent predictor of the rate of increase in early carotid atherosclerosis. Circulation 2001; 104(1): 63–7

    PubMed  Article  CAS  Google Scholar 

  41. Tracy RP, Psaty BM, Macy E, et al. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol 1997 Oct; 17(10): 2167–76

    PubMed  Article  CAS  Google Scholar 

  42. Rosenson RS, Tangney CC, Casey LC. Inhibition of proinflammatory cytokine production by pravastatin. Lancet 1999; 353: 983–4

    PubMed  Article  CAS  Google Scholar 

  43. Domenico F, Sandro P, Stefania B, et al. Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia. J Am Coll Cardiol 2000; 36: 427–31

    Article  Google Scholar 

  44. Ridker PM, Rifai N, Clearfield M, et al. for the Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344: 1959–65

    PubMed  Article  CAS  Google Scholar 

  45. Anderson TJ, Gerhard MD, Meredith IT, et al. Systemic nature of endothelial dysfunction in atherosclerosis. Am J Cardiol 1995; 75: 71B–4B

    PubMed  Article  CAS  Google Scholar 

  46. Faraci FM. Brian Jr JE. Nitric oxide and the cerebral circulation. Stroke 1994; 25(3): 692–703

    PubMed  Article  CAS  Google Scholar 

  47. Liao JK, Shin WS, Lee WY, et al. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem 1995; 270: 319–24

    PubMed  Article  CAS  Google Scholar 

  48. Laufs U, Gertz K, Huang P, et al. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decrease platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke 2000; 31(10): 2442–9

    PubMed  Article  CAS  Google Scholar 

  49. Endres M, Laufs U, Huang Z, et al. Stroke protection by 3-hydroxy-3-methyl-glutaryl (HMG)CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA 1998; 95: 8880–5

    PubMed  Article  CAS  Google Scholar 

  50. Radomski MW, Palmer RMJ, Moncada S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci U S A 1990; 87: 5193–7

    PubMed  Article  CAS  Google Scholar 

  51. Amin-Hanjani S, Stagliano NE, Yamada M, et al. Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthesis in mice. Stroke 2001; 32: 980–6

    PubMed  Article  CAS  Google Scholar 

  52. O’Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-Coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997; 95: 1126–31

    PubMed  Article  Google Scholar 

  53. Carr S, Farb A, Pearce WH, et al. Atherosclerotic plaque rupture in symptomatic carotid artery stenosis. J Vasc Surg 1996; 23: 755–66

    PubMed  Article  CAS  Google Scholar 

  54. Rosenson RS, Lowe GDO. Effects of lipids and lipoproteins on thrombosis and rheology. Atherosclerosis 1998; 140: 271–80

    PubMed  Article  CAS  Google Scholar 

  55. Undas A, Brummel KE, Musial J, et al. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation 2001; 103: 2248–53

    PubMed  Article  CAS  Google Scholar 

  56. Notarbartolo A, Davi G, Averna M, et al. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb Vasc Biol 1995; 15: 247–51

    PubMed  Article  CAS  Google Scholar 

  57. Colli S, Eligini S, Lalli M, et al. Vastatins inhibit tissue factor in cultured human macrophages. Arterioscler Thromb Vasc Biol 1997; 17: 265–72

    PubMed  Article  CAS  Google Scholar 

  58. Isaacsohn J, Setaro JF, Nicholas C, et al. Effects of lovastatin therapy on plasminogen activator inhibitor-1 antigen levels. Am J Cardiol 1994; 74: 735–7

    PubMed  Article  CAS  Google Scholar 

  59. Lopez S, Peiretti F, Nalbone G. Effect of atorvastatin on plasminogen activator inhibitor type-1 synthesis in human monocytes/macrophages. J Cardiovasc Pharmacol 2001; 37: 762–8

    PubMed  Article  CAS  Google Scholar 

  60. Nakanishi M, Goldstein JL, Brown MS. Multivalent control of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mevalonate-derived product inhibits translation of mRNA and accelerates degradation of enzyme. J Biol Chem. 1988 Jun 25; 263(18): 8929–37

    PubMed  CAS  Google Scholar 

  61. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990; 343: 425–30

    PubMed  Article  CAS  Google Scholar 

  62. Glomset JA, Gelb JE, Farnsworth CC. Geranylgeranylated proteins. Biochem Soc Trans 1992; 20: 479–84

    PubMed  CAS  Google Scholar 

  63. Balch WE. Low molecular weight GTP-binding proteins (LMGPs) involved in vesicular transport: binary switches or biological transducers? Trends Biochem Sci 1990; 15: 469–72

    Article  Google Scholar 

  64. Kinsella BT, O’Mahoney DJ. Lipid modification of G proteins. Trends Cardiovasc Med 1994; 4: 27–34

    PubMed  Article  CAS  Google Scholar 

  65. Nemerson Y. Tissue factor and haemostasis. Blood 1988; 71: 1–8

    PubMed  CAS  Google Scholar 

  66. Wilcox JN, Smith KM, Schwartz SM, et al. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A 1989; 86: 2839–43

    PubMed  Article  CAS  Google Scholar 

  67. Tipping PG, Malliaros J, Holdsworth SR. Procoagulant activity expression by macrophages from atheromatous vascular plaques. Atherosclerosis 1989; 79: 237–43

    PubMed  Article  CAS  Google Scholar 

  68. Avellone G, Di Garbo V, Cordova R, et al. Changes induced by pravastatin treatment on hemostatic and fibrinolytic patterns in patients with type IIB hyper-lipoproteinemia. Curr Ther Res Clin Exp 1994; 55: 1335–44

    Article  Google Scholar 

  69. Amarenco P, Duyckaerts C, Tzourio C, et al. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Eng J Med 1992; 326: 221–5

    Article  CAS  Google Scholar 

  70. Dressier FA, Craig WR, Castello R, et al. Mobile aortic atheroma and systemic emboli: efficacy of anticoagulation and influence of plaque morphology on recurrent stroke. J Am Coll Cardiol 1998; 31: 134–8

    Article  Google Scholar 

  71. Tunnick PA, Perez JL, Kronzon I. Protruding atheromas in the thoracic aorta and systemic embolization. Ann Intern Med 1991; 115: 423–7

    Google Scholar 

  72. The French Study of Aortic Plaques in Stroke Group. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Eng J Med 1996; 334: 1216–21

    Article  Google Scholar 

  73. Lazar JM, Uretsky BF, Denys BG, et al. Predisposing risk factors and natural history of acute neurologic complications of left-sided cardiac catheterization. Am J Cardiol 1995; 75: 1056–60

    PubMed  Article  CAS  Google Scholar 

  74. Segal AZ, Abernethy WB, Palacios IF, et al. Stroke as a complication of cardiac catheterization: risk factors and clinical features. Neurology 2001; 56(7): 975–7

    PubMed  Article  CAS  Google Scholar 

  75. Cernaianu AC, Vassilidze TV, Flum DR, et al. Predictors of stroke after cardiac surgery. J Card Surg 1995; 10: 334–9

    PubMed  Article  CAS  Google Scholar 

  76. Pitsavos CE, Aggeli KI, Barbetseas JD, et al. Effects of pravastatin on thoracic aortic atherosclerosis in patients with heterozygous familial hypercholesterolemia. Am J Cardiol 1998; 82: 1484–888

    PubMed  Article  CAS  Google Scholar 

  77. Martin R, Bogousslavsky J. Mechanisms of late stroke after myocardial infarct: the Lausanne Stroke Registry. J Neurol Neurosurg Psychiatry 1993; 56: 760–4

    PubMed  Article  CAS  Google Scholar 

  78. Loh E, St John Sutton M, Wun C-CC, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997; 336: 251–7

    PubMed  Article  CAS  Google Scholar 

  79. Kjekshus J, Pedersen TR, Olsson AG, et al. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail 1997; 3: 249–54

    PubMed  Article  CAS  Google Scholar 

  80. Levy S. Factors predisposing to the development of atrial fibrillation. Pacing Clin Electrophysiol 1997; 20: 2670–4

    PubMed  Article  CAS  Google Scholar 

  81. Anonymous. Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials. Arch Intern Med 1998; 158(12): 1316-20

  82. Stroke Prevention in Atrial Fibrillation Investigators. Risk factors for thromboembolism during aspirin therapy in patients with atrial fibrillation: the Stroke Prevention in Atrial Fibrillation study. J Stroke Cerebrovasc Dis 1995; 5: 147–57

    Article  Google Scholar 

Download references

Author information

Affiliations

  1. Division of Cardiology, Department of Internal Medicine, University of Missouri, Columbia, USA

    Ashwani Bedi

  2. Director, Division of Cardiology, Department of Medicine, University of Missouri, One Hospital Drive, DC034.00, Room MC314, Columbia, MO, 65212, USA

    Gregory C. Flaker

Authors
  1. Ashwani Bedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregory C. Flaker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gregory C. Flaker.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bedi, A., Flaker, G.C. How Do HMG-CoA Reductase Inhibitors Prevent Stroke?. Am J Cardiovasc Drugs 2, 7–14 (2002). https://doi.org/10.2165/00129784-200202010-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00129784-200202010-00002

Keywords

  • Simvastatin
  • Pravastatin
  • Serum Cholesterol Level
  • Carotid Plaque
  • Tissue Factor Expression