Statins in the treatment of acute ischemic stroke

Current Pharmaceutical Biotechnology

Volumn 13, Issue 1, 2012, Pages 68-76

  Montecucco, Fabrizio ^a   Quercioli, Alessandra ^a,b   Mirabelli Badenier, Marisol ^c   Viviani, Giorgio Luciano ^c   Mach, François ^a  

^a GENEVA UNIVERSITY HOSPITALS   (Switzerland)

^b UNIVERSITY OF GENOA   (Italy)

^c UNIVERSITY OF GENOA   (Italy)

Author keywords

Atherosclerosis; Inflammation; Neuroprotection; Statin; Stroke; Treatment

Indexed keywords

ATORVASTATIN; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MEVINOLIN; PRAVASTATIN; ROSUVASTATIN; SIMVASTATIN;

BRAIN ATHEROSCLEROSIS; BRAIN HEMORRHAGE; BRAIN ISCHEMIA; CHOLESTEROL BLOOD LEVEL; DOSE RESPONSE; DRUG EFFICACY; DYSLIPIDEMIA; HUMAN; HYPERCHOLESTEROLEMIA; NEUROPROTECTION; NONHUMAN; OUTCOME ASSESSMENT; PLEIOTROPY; REVIEW; SECONDARY PREVENTION; STROKE; TRANSIENT ISCHEMIC ATTACK;

ANIMALS; BRAIN ISCHEMIA; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; NEUROPROTECTIVE AGENTS; PLAQUE, ATHEROSCLEROTIC; STROKE;

EID: 84855857737     PISSN: 13892010     EISSN: 18734316     Source Type: Journal    
DOI: 10.2174/138920112798868737     Document Type: Review

References (120)

1. Easton, J.D.; Saver, J.L.; Albers, G.W.; Alberts, M.J.; Chaturvedi, S.; Feldmann, E.; Hatsukami, T.S.; Higashida, R.T.; Johnston, S.C.; Kidwell, C.S.; Lutsep, H.L.; Miller, E.; Sacco, R.L.; American Heart Association; American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; Interdisciplinary Council on Peripheral Vascular Disease. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke, 2009, 40(6), 2276-2293.
2. Baldwin, K.; Orr, S.; Briand, M.; Piazza, C.; Veydt, A.; McCoy, S. Acute ischemic stroke update. Pharmacotherapy, 2010, 30(5), 493-514.
3. Adams, H.P. Jr.; del Zoppo, G.; Alberts, M.J.; Bhatt, D.L.; Brass, L.; Furlan, A.; Grubb, R.L.; Higashida, R.T.; Jauch, E.C.; Kidwell, C.; Lyden, P.D.; Morgenstern, L.B.; Qureshi, A.I.; Rosenwasser, R.H.; Scott, P.A.; Wijdicks, E.F.; American Heart Association; American Stroke Association Stroke Council; Clinical Cardiology Council; Cardiovascular Radiology and Intervention Council; Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke, 2007, 38, 1655-711.
4. Fischer, U.; Baumgartner, A.; Arnold, M.; Nedeltchev, K.; Gralla, J.; De Marchis, G.M.; Kappeler, L.; Mono, M.L.; Brekenfeld, C.; Schroth, G.; Mattle, H.P. What is minor stroke? Stroke, 2010, 41, 661-666.
5. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet, 1995, 346(8991-8992), 1647-1653.
6. Prospective Studies Collaboration; Lewington, S.; Whitlock, G.; Clarke, R.; Sherliker, P.; Emberson, J.; Halsey, J.; Qizilbash, N.; Peto, R.; Collins, R. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet, 2007, 370(9602), 1829-1839.
7. Iso, H.; Jacobs, D.R. Jr.; Wentworth, D.; Neaton, J.D.; Cohen, J.D. 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, 904-910.
8. Jacobs, D.R. Jr.; Iso, H. Total cholesterol as a risk factor in stroke. Stroke, 1991, 22, 1329-1330.
9. Lindenstrøm, 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(6946), 11-15.
10. Imamura, T.; Doi, Y.; Arima, H.; Yonemoto, K.; Hata, J.; Kubo, M.; Tanizaki, Y.; Ibayashi, S.; Iida, M.; Kiyohara, Y. LDL cholesterol and the development of stroke subtypes and coronary heart disease in a general Japanese population: the Hisayama study. Stroke, 2009, 40(2), 382-388.
11. Chirovsky, D.R.; Fedirko, V.; Cui, Y.; Sazonov, V.; Barter, P. Prospective studies on the relationship between high-density lipoprotein cholesterol and cardiovascular risk: a systematic review. Eur. J. Cardiovasc. Prev. Rehabil., 2009, 16, 404-423.
12. Amarenco, P.; Labreuche, J.; Touboul, P.J. High-density lipoprotein-cholesterol and risk of stroke and carotid atherosclerosis: a systematic review. Atherosclerosis, 2008, 196(2), 489-496.
13. Amarenco, P.; Goldstein, L.B.; Callahan, A. 3rd.; Sillesen, H.; Hennerici, M.G.; O'Neill, B.J.; Rudolph, A.E.; Simunovic, L.; Zivin, J.A.; Welch, K.M.; SPARCL Investigators. Baseline blood pressure, low-and high-density lipoproteins, and triglycerides and the risk of vascular events in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Atherosclerosis, 2009, 204(2), 515-520.
14. Amarenco, P.; Labreuche, J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol., 2009, 8(5), 453-463.
15. Baigent, C.; Keech, A.; Kearney, P.M.; Blackwell, L.; Buck, G.; Pollicino, C.; Kirby, A.; Sourjina, T.; Peto, R.; Collins, R.; Simes, R.; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective metaanalysis of data from 90,056 participants in 14 randomised trials of statins. Lancet, 2005, 366(9493), 1267-1278.
16. Amarenco, P.; Bogousslavsky, J.; Callahan, A. 3rd.; Goldstein, L.B.; Hennerici, M.; Rudolph, A.E.; Sillesen, H.; Simunovic, L.; Szarek, M.; Welch, K.M.; Zivin, J.A.; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N. Engl. J. Med., 2006, 355(6), 549-559.
17. Moride, Y.; Hegele, R.A.; Langer, A.; McPherson, R.; Miller, D.B.; Rinfret S. Clinical and public health assessment of benefits and risks of statins in primary prevention of coronary events: resolved and unresolved issues. Can. J. Cardiol., 2008, 24, 293-300.
18. Neil, H.A.; DeMicco, D.A.; Luo, D.; Betteridge, D.J.; Colhoun, H.M.; Durrington, P.N.; Livingstone, S.J.; Fuller, J.H.; Hitman, G. A; CARDS Study Investigators. Analysis of efficacy and safety in patients aged 65-75 years at randomization: Collaborative Atorvastatin Diabetes Study (CARDS). Diabetes Care, 2006, 29, 2378-2384.
19. Sever, P.S.; Poulter, N.R.; Dahlöf, B.; Wedel, H.; Collins, R.; Beevers, G.; Caulfield, M.; Kjeldsen, S.E.; Kristinsson, A.; McInnes, G.T.; Mehlsen, J.; Nieminen, M.; O'Brien, E.; Ostergren, J. Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial--lipid-lowering arm (ASCOT-LLA). Diabetes Care, 2005; 28, 1151-1157.
20. Heart Protection Study Collaborative Group. Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions. J. Vasc. Surg., 2007, 45, 645-654.
21. Knopp, R.H.; D'Emden, M.; Smilde, J.G.; Pocock, S.J. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care, 2006, 29, 1478-1485.
22. Thavendiranathan, P.; Bagai, A.; Brookhart, M.A.; Choudhry, N.K. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Intern. Med., 2006, 166, 2307-2313.
23. LaRosa, J.C.; He, J.; Vupputuri, S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA, 1999, 282, 2340-2346.
24. Hunt, D.; Young, P.; Simes, J.; Hague, W.; Mann, S.; Owensby, D.; Lane, G.; Tonkin, A. Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: Results from the LIPID trial. Ann. Intern. Med., 2001, 134(10), 931-940.
25. Shepherd, J.; Blauw, G.J.; Murphy, M.B.; Bollen, E.L.; Buckley, B.M.; Cobbe, S.M.; Ford, I.; Gaw, A.; Hyland, M.; Jukema, J.W.; Kamper, A.M.; Macfarlane, P.W.; Meinders, A.E.; Norrie, J.; Packard, C.J.; Perry, I.J.; Stott, D.J.; Sweeney, B.J.; Twomey, C.; Westendorp, R.G.; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet, 2002, 360(9346), 1623-1630.
26. Shepherd, J.; Cobbe, S.M.; Ford, I.; Isles, C.G.; Lorimer, A.R.; MacFarlane, P.W.; McKillop, J.H.; Packard, C.J. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med., 1995, 333, 1301-1307.
27. Collins, R.; Armitage, J.; Parish, S.; Sleight, P.; Peto, R.; Heart Protection Study Collaborative Group. Effects of cholesterollowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other highrisk conditions. Lancet, 2004, 363(9411), 757-767.
28. Downs, J.R.; Clearfield, M.; Weis, S.; Whitney, E.; Shapiro, D.R.; Beere, P.A.; Langendorfer, A.; Stein, E.A.; Kruyer, W.; Gotto, A.M. Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA, 1998, 279(20), 1615-1622.
29. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet, 1994, 344(8934), 1383-1389.
30. Sever, P.S.; Dahlöf, B.; Poulter, N.R.; Wedel, H.; Beevers, G.; Caulfield, M.; Collins, R.; Kjeldsen, S.E.; Kristinsson, A.; McInnes, G.T.; Mehlsen, J.; Nieminen, M.; O'Brien, E.; Ostergren, J.; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet, 2003, 361(9364), 1149-1158.
31. Colhoun, H.M.; Betteridge, D.J.; Durrington, P.N.; Hitman, G.A.; Neil, H.A.; Livingstone, S.J.; Thomason, M.J.; Mackness, M.I.; Charlton-Menys, V.; Fuller, J.H.; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet, 2004, 364(9435), 685-696.
32. Athyros, V.G.; Papageorgiou, A.A.; Mercouris, B.R.; Athyrou, V.V.; Symeonidis, A.N.; Basayannis, E.O.; Demitriadis, D.S.; Kontopoulos, A.G. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus 'usual' care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr. Med. Res. Opin. 2002, 18(4), 220-228.
33. Waters, D.D.; LaRosa, J.C.; Barter, P.; Fruchart, J.C.; Gotto, A.M. Jr.; Carter, R.; Breazna, A.; Kastelein, J.J.; Grundy, S.M. Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (treating to new targets) study. J. Am. Coll. Cardiol., 2006, 48(9), 1793-1799.
34. Knopp, R.H.; d'Emden, M.; Smilde, J.G.; Pocock, S.J. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care, 2006, 29, 1478-1485.
35. Wanner, C.; Krane, V.; März, W.; Olschewski, M.; Mann, J.F.; Ruf, G.; Ritz, E.; German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N. Engl. J. Med., 2005, 353(3), 238-248.
36. Pedersen, T.R.; Faergeman, O.; Kastelein, J.J.; Olsson, A.G.; Tikkanen, M.J.; Holme, I.; Larsen, M.L.; Bendiksen, F.S.; Lindahl, C.; Szarek, M.; Tsai, J.; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. Highdose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA, 2005, 294(19), 2437-2445.
37. Koren, M.J.; Hunninghake, D.B.; ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study. J. Am. Coll. Cardiol., 2004, 44(9), 1772-1779.
38. Schwartz, G.G.; Olsson, A.G.; Ezekowitz, M.D.; Ganz, P.; Oliver, M.F.; Waters, D.; Zeiher, A.; Chaitman, B.R.; Leslie, S.; Stern, T.; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA, 2001, 285(13), 1711-1718.
39. Grundy, S.M.; Cleeman, J.I.; Merz, C.N.; Brewer, H.B. Jr.; Clark, L.T.; Hunninghake, D.B.; Pasternak, R.C.; Smith, S.C. Jr.; Stone, N.J.; Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation, 2004, 110, 227-239.
40. Leker, R.R.; Khoury, S.T.; Rafaeli, G.; Shwartz, R.; Eichel, R.; Tanne, D.; NASIS Investigators. Prior use of statins improves outcome in patients with intracerebral hemorrhage: prospective data from the National Acute Stroke Israeli Surveys (NASIS). Stroke, 2009, 40(7), 2581-2584.
41. Meier, N.; Nedeltchev, K.; Brekenfeld, C.; Galimanis, A.; Fischer, U.; Findling, O.; Remonda, L.; Schroth, G.; Mattle, H.P.; Arnold, M. Prior statin use, intracranial hemorrhage, and outcome after intra-arterial thrombolysis for acute ischemic stroke. Stroke, 2009, 40(5), 1729-1737.
42. Elewa, H.F.; Kozak, A.; El-Remessy, A.B.; Frye, R.F.; Johnson, M.H.; Ergul, A.; Fagan, S.C. Early atorvastatin reduces hemorrhage after acute cerebral ischemia in diabetic rats. J. Pharmacol. Exp. Ther., 2009, 330(2), 532-540.
43. Risselada, R.; Straatman, H.; van Kooten, F.; Dippel, D.W.; van der Lugt, A.; Niessen, W.J.; Firouzian, A.; Herings, R.M.; Sturkenboom, M.C. Withdrawal of statins and risk of subarachnoid hemorrhage. Stroke, 2009, 40(8), 2887-2892.
44. Asberg, S.; Henriksson, K.M.; Farahmand, B.; Asplund, K.; Norrving, B.; Appelros, P.; Stegmayr, B.; Asberg, K.H.; Terént, A. Ischemic stroke and secondary prevention in clinical practice: a cohort study of 14,529 patients in the Swedish Stroke Register. Stroke, 2010, 41(7), 1338-1342.
45. Milionis, H.J.; Giannopoulos, S.; Kosmidou, M.; Panoulas, V.; Manios, E.; Kyritsis, A.P.; Elisaf, M.S.; Vemmos, K. Statin therapy after first stroke reduces 10-year stroke recurrence and improves survival. Neurology, 2009, 72(21), 1816-1822.
46. Johnson, C.; Lane, H.; Barber, P.A.; Charleston, A. Medication Compliance in Ischaemic Stroke Patients. Intern. Med. J., 2010, doi: 10.1111/j.1445-5994.2010.02209.x.
47. Pitt, B.; Waters, D.; Brown, W.V.; Schwartz, L.; Title, L.M.; Eisenberg, D.; Shurzinske, L.; McCormick, L.S. Aggressive lipidlowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators. N. Engl. J. Med., 1999, 341, 70-76.
48. LaRosa, J.C.; Grundy, S.M.; Waters, D.D.; Shear, C.; Barter, P.; Fruchart, J.C.; Gotto, A.M.; Greten, H.; Kastelein, J.J.; Shepherd, J.; Wenger, N.K.; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med., 2005, 352, 1425-1435.
49. Pedersen, T.R.; Faergeman, O.; Kastelein, J.J.; Olsson, A.G.; Tikkanen, M.J.; Holme, I.; Larsen, M.L.; Bendiksen, F.S.; Lindahl, C.; Szarek, M.; Tsai, J; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. Highdose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA, 2005, 294, 2437-2445.
50. Schwartz, G.G.; Olsson, A.G.; Ezekowitz, M.D.; Ganz, P.; Oliver, M.F.; Waters, D.; Zeiher, A.; Chaitman, B.R.; Leslie, S.; Stern, T.; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA, 2001, 285, 1711-1718.
51. Liem, A.H.; van Boven, A.J.; Veeger, N.J.; Withagen, A.J.; Robles de Medina, R.M.; Tijssen, J.G.; van Veldhuisen, D.J. FLuvastatin on risk diminishment after acute myocardial infarction study group. Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial. Eur. Heart J., 2002, 23, 1931-1937.
52. de Lemos, J.A.; Blazing, M.A.; Wiviott, S.D.; Lewis, E.F.; Fox, K.A.; White, H.D.; Rouleau, J.L.; Pedersen, T.R.; Gardner, L.H.; Mukherjee, R.; Ramsey, K.E.; Palmisano, J.; Bilheimer, D.W.; Pfeffer, M.A.; Califf, R.M.; Braunwald, E.; A to Z Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA, 2004, 292, 1307-1316.
53. Ray, K.K.; Cannon, C.P.; Cairns, R.; Morrow, D.A.; Rifai, N.; Kirtane, A.J.; McCabe, C.H.; Skene, A.M.; Gibson, C.M.; Ridker, P.M.; Braunwald, E.; PROVE IT-TIMI 22 Investigators. Relationship between uncontrolled risk factors and C-reactive protein levels in patients receiving standard or intensive statin therapy for acute coronary syndromes in the PROVE IT-TIMI 22 trial. J. Am. Coll. Cardiol., 2005, 46, 1417-1424.
54. Ovbiagele, B.; Saver, J.L. Intensive statin therapy after stroke or transient ischemic attack: a SPARCLing success? Stroke, 2007, 38: 1110-1112.
55. Hennekens, C.H.; Hollar, D.; Eidelman, R.S.; Agatston, A.S. Update for primary healthcare providers: recent statin trials and revised National Cholesterol Education Program III guidelines. Med. Gen. Med., 2006, 8, 54.
56. Stroke Council, American Heart Association; American Stroke Association. Statins after ischemic stroke and transient ischemic attack: an advisory statement from the Stroke Council, American Heart Association and American Stroke Association. Stroke, 2004, 35(4), 1023.
57. Naghavi, M.; Libby, P.; Falk, E.; Casscells, S.W.; Litovsky, S.; Rumberger, J.; Badimon, J.J.; Stefanadis, C.;, Moreno, P.; Pasterkamp, G.; Fayad, Z.; Stone, P.H.; Waxman, S.; Raggi, P.; Madjid, M.; Zarrabi, A.; Burke, A.; Yuan, C.; Fitzgerald, P.J.; Siscovick, D.S.; de Korte, C.L.; Aikawa, M.; Juhani Airaksinen, K.E.; Assmann, G.; Becker, C.R.; Chesebro, J.H.; Farb, A.; Galis, Z.S.; Jackson, C.; Jang, I.K.; Koenig, W.; Lodder, R.A.; March, K.; Demirovic, J.; Navab, M.; Priori, S.G.; Rekhter, M.D.; Bahr, R.; Grundy, S.M.; Mehran, R.; Colombo, A.; Boerwinkle, E.; Ballantyne, C.; Insull, W. Jr.; Schwartz, R.S.; Vogel, R.; Serruys, P.W.; Hansson, G.K.; Faxon, D.P.; Kaul, S.; Drexler, H.; Greenland, P.; Muller, J.E.; Virmani, R.; Ridker, P.M.; Zipes, D.P.; Shah, P.K.; Willerson, J.T. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation, 2003, 108, 1664-1672.
58. Naghavi, M.; Libby, P.; Falk, E.; Casscells, S.W.; Litovsky, S.; Rumberger, J.; Badimon, J.J.; Stefanadis, C.;, Moreno, P.; Pasterkamp, G.; Fayad, Z.; Stone, P.H.; Waxman, S.; Raggi, P.; Madjid, M.; Zarrabi, A.; Burke, A.; Yuan, C.; Fitzgerald, P.J.; Siscovick, D.S.; de Korte, C.L.; Aikawa, M.; Juhani Airaksinen, K.E.; Assmann, G.; Becker, C.R.; Chesebro, J.H.; Farb, A.; Galis, Z.S.; Jackson, C.; Jang, I.K.; Koenig, W.; Lodder, R.A.; March, K.; Demirovic, J.; Navab, M.; Priori, S.G.; Rekhter, M.D.; Bahr, R.; Grundy, S.M.; Mehran, R.; Colombo, A.; Boerwinkle, E.; Ballantyne, C.; Insull, W. Jr.; Schwartz, R.S.; Vogel, R.; Serruys, P.W.; Hansson, G.K.; Faxon, D.P.; Kaul, S.; Drexler, H.; Greenland, P.; Muller, J.E.; Virmani, R.; Ridker, P.M.; Zipes, D.P.; Shah, P.K.; Willerson, J.T. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. Circulation, 2003, 108, 1772-1778.
59. Montecucco, F.; Lenglet, S.; Gayet-Ageron, A.; Bertolotto, M.; Pelli, G.; Palombo, D.; Pane, B.; Spinella, G.; Steffens, S.; Raffaghello, L.; Pistoia, V.; Ottonello, L.; Pende, A.; Dallegri, F.; Mach, F. Systemic and intraplaque mediators of inflammation are increased in patients symptomatic for ischemic stroke. Stroke, 2010, 41(7), 1394-404.
60. Inami, N.; Nomura, S.; Shouzu, A.; Omoto, S.; Kimura, Y.; Takahashi, N.; Tanaka, A.; Nanba, M.; Shouda, Y.; Iwasaka, T. Effects of pitavastatin on adiponectin in patients with hyperlipidemia. Pathophysiol. Haemost. Thromb., 2007, 36, 1-8.
61. Kinlay, S.; Schwartz, G.G.; Olsson, A.G.; Rifai, N.; Szarek, M.; Waters, D.D.; Libby, P.; Ganz, P.; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Inflammation, statin therapy, and risk of stroke after an acute coronary syndrome in the MIRACL study. Arterioscler Thromb. Vasc. Biol., 2008, 28, 142-147.
62. Vlachopoulos, C.; Aznaouridis, K.; Dagre, A.; Vasiliadou, C.; Masoura, C.; Stefanadi, E.; Skoumas, J.; Pitsavos, C.; Stefanadis, C. Protective effect of atorvastatin on acute systemic inflammationinduced endothelial dysfunction in hypercholesterolaemic subjects. Eur. Heart J., 2007, 28, 2102-2109.
63. Blanco-Colio, L.M.; Martín-Ventura, J.L.; de Teresa, E.; Farsang, C.; Gaw, A.; Gensini, G.; Leiter, L.A.; Langer, A.; Martineau, P.; Egido, J.; ACTFAST investigators. Elevated ICAM-1 and MCP-1 plasma levels in subjects at high cardiovascular risk are diminished by atorvastatin treatment. Atorvastatin on Inflammatory Markers study: a substudy of Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration. Am. Heart J., 2007, 153, 881-888.
64. Pignatelli, P.; Sanguigni, V.; Lenti, L.; Loffredo, L.; Carnevale, R.; Sorge, R.; Violi, F. Oxidative stress-mediated platelet CD40 ligand upregulation in patients with hypercholesterolemia: effect of atorvastatin. J. Thromb. Haemost., 2007, 5, 1170-1178.
65. Hanefeld, M.; Marx, N.; Pfützner, A.; Baurecht, W.; Lübben, G.; Karagiannis, E.; Stier, U.; Forst, T. Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study. J. Am. Coll. Cardiol., 2007, 49, 290-297.
66. Goicoechea, M.; de Vinuesa, S.G.; Lahera, V.; Cachofeiro, V.; Gómez-Campderá, F.; Vega, A.; Abad, S.; Luño, J. Effects of atorvastatin on inflammatory and fibrinolytic parameters in patients with chronic kidney disease. J. Am. Soc. Nephrol., 2006, 17, S231-S235.
67. Patti, G.; Chello, M.; Pasceri, V.; Colonna, D.; Nusca, A.; Miglionico, M.; D'Ambrosio, A.; Covino, E.; Di Sciascio, G. Protection from procedural myocardial injury by atorvastatin is associated with lower levels of adhesion molecules after percutaneous coronary intervention: results from the ARMYDA-CAMs (Atorvastatin for Reduction of MYocardial Damage during Angioplasty-Cell Adhesion Molecules) substudy. J. Am. Coll Cardiol., 2006, 48, 1560-1566.
68. Muhlestein, J.B.; May, H.T.; Jensen, J.R.; Horne, B.D.; Lanman, R.B.; Lavasani, F.; Wolfert, R.L.; Pearson, R.R.; Yannicelli, H.D.; Anderson, J.L. The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIACOR (Diabetes and Combined Lipid Therapy Regimen) study. J. Am. Coll. Cardiol., 2006, 48, 396-401.
69. Sola, S.; Mir, M.Q.; Lerakis, S.; Tandon, N.; Khan, B.V. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J. Am. Coll. Cardiol., 2006, 47, 332-337.
70. Macin, S.M.; Perna, E.R.; Farías, E.F.; Franciosi, V.; Cialzeta, J.R.; Brizuela, M.; Medina, F.; Tajer, C.; Doval, H.; Badaracco, R. Atorvastatin has an important acute anti-inflammatory effect in patients with acute coronary syndrome: results of a randomized, double-blind, placebo-controlled study. Am. Heart J., 2005, 149, 451-457.
71. Blanco-Colio, L.M.; Martín-Ventura, J.L.; de Teresa, E.; Farsang, C.; Gaw, A.; Gensini, G.; Leiter, L.A.; Langer, A.; Martineau, P.; Hérnandez, G.; Egido, J.; ACTFAST investigators. Increased soluble Fas plasma levels in subjects at high cardiovascular risk: Atorvastatin on Inflammatory Markers (AIM) study, a substudy of ACTFAST. Arterioscler Thromb. Vasc. Biol., 2007, 27, 168-174.
72. Arnaud, C.; Braunersreuther, V.; Mach F. Toward immunomodulatory and anti-inflammatory properties of statins. Trends Cardiovasc. Med., 2005, 15, 202-206.
73. Ridker, P.M.; Danielson, E.; Fonseca, F.A.; Genest, J.; Gotto, A.M. Jr.; Kastelein, J.J.; Koenig, W.; Libby, P.; Lorenzatti, A.J.; MacFadyen, J.G.; Nordestgaard, B.G.; Shepherd, J.; Willerson, J.T.; Glynn, R.J.; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med., 2008, 359(21), 2195-207.
74. Crisby, M.; Nordin-Fredriksson, G.; Shah, P.K.; Yano, J.; Zhu, J.; Nilsson, J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation, 2001, 103, 926-933.
75. Puato, M.; Faggin, E.; Rattazzi, M.; Zambon, A.; Cipollone, F.; Grego, F.; Ganassin, L.; Plebani, M.; Mezzetti, A.; Pauletto, P. Atorvastatin reduces macrophage accumulation in atherosclerotic plaques: a comparison of a nonstatin-based regimen in patients undergoing carotid endarterectomy. Stroke, 2010, 41(6), 1163-1168.
76. Makris, G.C.; Lavida, A.; Nicolaides, A.N.; Geroulakos, G. The effect of statins on carotid plaque morphology: A LDL-associated action or one more pleiotropic effect of statins? Atherosclerosis, 2010, doi:10.1016/j.atherosclerosis.2010.04.032.
77. O'Driscoll, G.; Green, D.; Taylor, R.R. Simvastatin, an HMGcoenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation, 1997, 95(5), 1126-1131.
78. Feron, O.; Dessy, C.; Desager, J.P.; Balligand, J.L. Hydroxymethylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance. Circulation, 2001, 103(1), 113-118.
79. Takeuchi, S.; Kawashima, S.; Rikitake, Y.; Ueyama, T.; Inoue, N.; Hirata, K.; Yokoyama, M. Cerivastatin suppresses lipopolysaccharide-induced ICAM-1 expression through inhibition of Rho GTPase in BAEC. Biochem. Biophys. Res. Commun., 2000, 269(1), 97-102.
80. Weber, C.; Erl, W.; Weber, K.S.; Weber, P.C. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J. Am. Coll. Cardiol., 1997, 30(5), 1212-1217.
81. Montecucco, F.; Burger, F.; Pelli, G.; Poku, N.K.; Berlier, C.; Steffens, S.; Mach, F. Statins inhibit C-reactive protein-induced chemokine secretion, ICAM-1 upregulation and chemotaxis in adherent human monocytes. Rheumatology (Oxford), 2009, 48(3), 233-242.
82. Jougasaki, M.; Ichiki, T.; Takenoshita, Y.; Setoguchi, M. Statins suppress interleukin-6-induced monocyte chemo-attractant protein-1 by inhibiting Janus kinase/signal transducers and activators of transcription pathways in human vascular endothelial cells. Br. J. Pharmacol., 2010, 159(6), 1294-1303.
83. Kim, Y.S.; Ahn, Y.; Hong, M.H.; Kim, K.H.; Park, H.W.; Hong, Y.J.; Kim, J.H.; Kim, W.; Jeong, M.H.; Cho, J.G.; Park, J.C.; Kang, J.C. Rosuvastatin suppresses the inflammatory responses through inhibition of c-Jun N-terminal kinase and Nuclear Factor-kappaB in endothelial cells. J. Cardiovasc. Pharmacol., 2007, 49(6), 376-383.
84. Notarbartolo, A.; Davì, G.; Averna, M.; Barbagallo, C.M.; Ganci, A.; Giammarresi, C.; La Placa, F.P.; Patrono, C. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb. Vasc. Biol., 1995, 15(2), 247-251.
85. Höglund, K.; Blennow, K. Effect of HMG-CoA reductase inhibitors on beta-amyloid peptide levels: implications for Alzheimer's disease. CNS Drugs. 2007, 21(6), 449-462.
86. van der Most, P.J.; Dolga, A.M.; Nijholt, I.M.; Luiten, P.G.; Eisel, U.L. Statins: mechanisms of neuroprotection. Prog. Neurobiol., 2009, 88(1), 64-75.
87. Goldstein, L.B. Statins and ischemic stroke severity: cytoprotection. Curr. Atheroscler Rep., 2009, 11(4), 296-300.
88. Berger, C.; Xia, F.; Maurer, M.H.; Schwab, S. Neuroprotection by pravastatin in acute ischemic stroke in rats. Brain Res. Rev., 2008, 58(1), 48-56.
89. Zhao, Z.; Zhao, S.; Xu, N.; Yu, C.; Guan, S.; Liu, X.; Huang, L.; Liao, W.; Jia, W. Lovastatin improves neurological outcome after nucleus basalis magnocellularis lesion in rats. Neuroscience, 2010, 167(3), 954-963.
90. Mahmood, A.; Goussev, A.; Kazmi, H.; Qu, C.; Lu, D.; Chopp, M. Long-term benefits after treatment of traumatic brain injury with simvastatin in rats. Neurosurgery, 2009, 65(1), 187-191.
91. Prinz, V.; Laufs, U.; Gertz, K.; Kronenberg, G.; Balkaya, M.; Leithner, C.; Lindauer, U.; Endres, M. Intravenous rosuvastatin for acute stroke treatment: an animal study. Stroke, 2008, 39(2), 433-438.
92. Lu, D.; Goussev, A.; Chen, J.; Pannu, P.; Li, Y.; Mahmood, A.; Chopp, M. Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected to traumatic brain injury. J. Neurotrauma, 2004, 21(1), 21-32.
93. Chen, J.; Zhang, Z.G.; Li, Y.; Wang, Y.; Wang, L.; Jiang, H.; Zhang, C.; Lu, M.; Katakowski, M.; Feldkamp, C.S.; Chopp, M. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann. Neurol., 2003, 53(6), 743-751.
94. Dolga, A.M.; Granic, I.; Nijholt, I.M.; Nyakas, C.; van der Zee, E.A.; Luiten, P.G.; Eisel, U.L. Pretreatment with lovastatin prevents N-methyl-D-aspartate-induced neurodegeneration in the magnocellular nucleus basalis and behavioral dysfunction. J. Alzheimers Dis., 2009, 17(2), 327-336.
95. Dolga, A.M.; Nijholt, I.M.; Ostroveanu, A.; Ten Bosch, Q.; Luiten, P.G.; Eisel, U.L. Lovastatin induces neuroprotection through tumor necrosis factor receptor 2 signaling pathways. J. Alzheimers Dis., 2008, 13(2), 111-122.
96. Chen, J.; Zacharek, A.; Li, A.; Cui, X.; Roberts, C.; Lu, M.; Chopp, M. Atorvastatin promotes presenilin-1 expression and Notch1 activity and increases neural progenitor cell proliferation after stroke. Stroke, 2008, 39(1), 220-226.
97. Chen, J.; Zhang, C.; Jiang, H.; Li, Y.; Zhang, L.; Robin, A.; Katakowski, M.; Lu, M.; Chopp, M. Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J. Cereb. Blood Flow Metab., 2005, 25(2), 281-290.
98. García-Román, N.; Alvarez, A.M.; Toro, M.J.; Montes, A.; Lorenzo, M.J. Lovastatin induces apoptosis of spontaneously immortalized rat brain neuroblasts: involvement of nonsterol isoprenoid biosynthesis inhibition. Mol. Cell Neurosci., 2001, 17(2), 329-341.
99. Xiang, Z.; Reeves, S.A. Simvastatin induces cell death in a mouse cerebellar slice culture (CSC) model of developmental myelination. Exp. Neurol., 2009, 215(1), 41-47.
100. März, P.; Otten, U.; Miserez, A.R. Statins induce differentiation and cell death in neurons and astroglia. Glia, 2007, 55(1), 1-12.
101. Pantoni, L.; Sarti, C.; Inzitari, D. Cytokines and cell adhesion molecules in cerebral ischemia: experimental bases and therapeutic perspectives. Arterioscler Thromb. Vasc. Biol., 1998, 18(4), 503-513.
102. Liu, T.; McDonnell, P.C.; Young, P.R.; White, R.F.; Siren, A.L.; Hallenbeck, J.M.; Barone, F.C.; Feurestein, G.Z. Interleukin-1 beta mRNA expression in ischemic rat cortex. Stroke, 1993, 24(11), 1746-1750.
103. Kimura, M.; Kurose, I.; Russell, J.; Granger, D.N. Effects of fluvastatin on leukocyte-endothelial cell adhesion in hypercholesterolemic rats. Arterioscler Thromb. Vasc. Biol., 1997, 17(8), 1521-1526.
104. Pahan, K.; Sheikh, F.G.; Namboodiri, A.M.; Singh, I. Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J. Clin. Invest., 1997, 100(11), 2671-2679.
105. Liu, B.; Yu, G.; Yang, Z.; Sun, L.; Song, R.; Liu, F.; Xin, Y.; Zhang, L. Simvastatin reduces OX40 and OX40 ligand expression in human peripheral blood mononuclear cells and in patients with atherosclerotic cerebral infarction. J. Int. Med. Res., 2009, 37(3), 601-610.
106. Lee, S.H.; Kim, Y.H.; Kim, Y.J.; Yoon, B.W. Atorvastatin enhances hypothermia-induced neuroprotection after stroke. J. Neurol. Sci., 2008, 275(1-2), 64-68.
107. Nicholas, J.S.; Swearingen, C.J.; Thomas, J.C.; Rumboldt, Z.; Tumminello, P.; Patel, S.J. The effect of statin pretreatment on infarct volume in ischemic stroke. Neuroepidemiology, 2008, 31(1), 48-56.
108. Greisenegger, S.; Müllner, M.; Tentschert, S.; Lang, W.; Lalouschek, W. Effect of pretreatment with statins on the severity of acute ischemic cerebrovascular events. J. Neurol. Sci., 2004, 221(1-2), 5-10.
109. Martí-Fàbregas, J.; Gomis, M.; Arboix, A.; Aleu, A.; Pagonabarraga, J.; Belvís, R.; Cocho, D.; Roquer, J.; Rodríguez, A.; García, M.D.; Molina-Porcel, L.; Díaz-Manera, J.; Martí-Vilalta, J.L. Favorable outcome of ischemic stroke in patients pretreated with statins. Stroke, 2004, 35(5), 1117-1121.
110. Stead, L.G.; Vaidyanathan, L.; Kumar, G.; Bellolio, M.F.; Brown, R.D. Jr.; Suravaram, S.; Enduri, S.; Gilmore, R.M.; Decker, W.W. Statins in ischemic stroke: just low-density lipoprotein lowering or more? J. Stroke Cerebrovasc. Dis., 2009, 18(2), 124-127.
111. Arboix, A.; García-Eroles, L.; Oliveres, M.; Targa, C.; Balcells, M.; Massons, J. Pretreatment with statins improves early outcome in patients with first-ever ischaemic stroke: a pleiotropic effect of statins or a beneficial effect of hypercholesterolemia? BMC Neurol., 2010, 10, 47.
112. Yoon, S.S.; Dambrosia, J.; Chalela, J.; Ezzeddine, M.; Warach, S.; Haymore, J.; Davis, L.; Baird, A.E. Rising statin use and effect on ischemic stroke outcome. BMC Med., 2004, 2, 4.
113. Yeh, P.S.; Lin, H.J.; Bai, C.H.; Hsieh, F.I.; Ke, D.S.; Li, Y.H.; Taiwan Stroke Registry. Effect of in-hospital initiation of lipidlowering therapy on six-month outcomes in patients with acute ischemic stroke or transient ischemic attack. Am. J. Cardiol., 2010, 105(10), 1490-1494.
114. Montaner, J.; Chacón, P.; Krupinski, J.; Rubio, F.; Millán, M.; Molina, C.A.; Hereu, P.; Quintana, M.; Alvarez-Sabín, J. Simvastatin in the acute phase of ischemic stroke: a safety and efficacy pilot trial. Eur. J. Neurol., 2008, 15(1), 82-90.
115. Prinz, V.; Endres, M. The acute (cerebro)vascular effects of statins. Anesth. Analg., 2009, 109(2), 572-584.
116. Colivicchi, F.; Bassi, A.; Santini, M.; Caltagirone, C. Discontinuation of statin therapy and clinical outcome after ischemic stroke. Stroke, 2007, 38(10), 2652-2657.
117. Blanco, M.; Nombela, F.; Castellanos, M.; Rodriguez-Yáñez, M.; García-Gil, M.; Leira, R.; Lizasoain, I.; Serena, J.; Vivancos, J.; Moro, M.A.; Dávalos, A.; Castillo, J. Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology, 2007, 69(9), 904-910.
118. Reeves, M.J.; Gargano, J.W.; Luo, Z.; Mullard, A.J.; Jacobs, B.S.; Majid, A.; Paul Coverdell National Acute Stroke Registry Michigan Prototype Investigators. Effect of pretreatment with statins on ischemic stroke outcomes. Stroke, 2008, 39(6), 1779-1785.
119. Meier, N.; Nedeltchev, K.; Brekenfeld, C.; Galimanis, A.; Fischer, U.; Findling, O.; Remonda, L.; Schroth, G.; Mattle, H.P.; Arnold, M. Prior statin use, intracranial hemorrhage, and outcome after intra-arterial thrombolysis for acute ischemic stroke. Stroke, 2009, 40(5), 1729-1737.
120. Miedema, I.; Uyttenboogaart, M.; Koopman, K.; De Keyser, J.; Luijckx, G.J. Statin use and functional outcome after tissue plasminogen activator treatment in acute ischaemic stroke. Cerebrovasc. Dis., 29(3), 263-267.