Published Online
on January 9, 2003

A more recent version of this article appeared on February 1, 2003

This Article Full Text (PDF) All Versions of this Article: 34/2/551    most recent 01.STR.0000054055.28435.BFv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gertz, K. Articles by Endres, M. Search for Related Content PubMed PubMed Citation Articles by Gertz, K. Articles by Endres, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ATORVASTATIN HEPTANOIC ACID PYRROLE Medline Plus Health Information Statins Stroke Related Collections Animal models of human disease Other Stroke Treatment - Medical Endothelium/vascular type/nitric oxide

Submitted on September 9, 2002
Accepted on September 13, 2002

Withdrawal of Statin Treatment Abrogates Stroke Protection in Mice

Karen Gertz MD; Ulrich Laufs MD; Ute Lindauer DVM; Georg Nickenig MD; Michael Böhm MD; Ulrich Dirnagl MD; and Matthias Endres MD^*

From the Klinik und Poliklinik für Neurologie, Charité, Humboldt-Universität Berlin, Berlin (K.G., U. Lindauer, U.D., M.E.), and Klinik für Kardiologie, Universität des Saarlandes, Homburg (U. Laufs, G.N., M.B.), Germany. Drs Gertz and Laufs contributed equally to this work.

^* To whom correspondence should be addressed. E-mail: matthias.endres{at}charite.de.

Background and Purpose--Statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) reduce stroke damage independent of lipid lowering by upregulation of endothelial nitric oxide synthase (eNOS). Acute withdrawal of statin treatment may suppress endothelial NO production and impair vascular function.

Methods--To test this hypothesis, we treated 129/SV mice with atorvastatin (10 mg/kg) for 14 days and then withdrew treatment.

Results--Treatment with atorvastatin conferred stroke protection by 40% after filamentous occlusion of the middle cerebral artery followed by reperfusion. Withdrawal of statin treatment, however, resulted in the loss of stroke protection after 2 and 4 days. In mouse aortas and brain vasculature, statins upregulated eNOS message 2.3- and 1.7-fold, respectively, as measured by reverse transcription-polymerase chain reaction. Withdrawal of statins resulted in 5- and 2.7-fold downregulation of eNOS in aorta and brain, respectively, after 2 days. Statin treatment decreased RhoA GTPase membrane expression to 48%, while withdrawal of statins resulted in 4-fold increase of RhoA in the membrane. Moreover, platelet factor 4 and -thromboglobulin in plasma were significantly downregulated by statin treatment, but withdrawal of statins resulted in a 2.9- and 3.1-fold upregulation after 2 days, respectively. Thrombus formation induced by ligature of the inferior vena cava was significantly reduced by statin treatment. When statin treatment was withdrawn, however, protection was lost between 2 and 4 days.

Conclusions--Acute termination of statin treatment results in a rapid loss of protection in mouse models of cerebral ischemia and thrombus formation independent of lipid lowering. In patients with acute or impending stroke, withdrawal of statins may impair outcome.

Key words: cerebral ischemia • HMG-CoA reductase inhibitors • nitric oxide • thrombosis

This article has been cited by other articles:

				L. B. Goldstein, P. Amarenco, J. Zivin, M. Messig, I. Altafullah, A. Callahan, M. Hennerici, M. J. MacLeod, H. Sillesen, R. Zweifler, et al. Statin Treatment and Stroke Outcome in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial Stroke, November 1, 2009; 40(11): 3526 - 3531. [Abstract] [Full Text] [PDF]

				V. Prinz and M. Endres The Acute (Cerebro)Vascular Effects of Statins Anesth. Analg., August 1, 2009; 109(2): 572 - 584. [Abstract] [Full Text] [PDF]

				S. Westphal, C. Abletshauser, and C. Luley Fluvastatin Treatment and Withdrawal: Effects on Endothelial Function Angiology, October 1, 2008; 59(5): 613 - 618. [Abstract] [PDF]

				D. A. Redelmeier MD MSHSR, D. Thiruchelvam MSc, and N. Daneman MD Delirium after elective surgery among elderly patients taking statins Can. Med. Assoc. J., September 23, 2008; 179(7): 645 - 652. [Abstract] [Full Text] [PDF]

				B. Rosengarten, D. Auch, and M. Kaps Effects of Initiation and Acute Withdrawal of Statins on the Neurovascular Coupling Mechanism in Healthy, Normocholesterolemic Humans Stroke, December 1, 2007; 38(12): 3193 - 3197. [Abstract] [Full Text] [PDF]

				M. Blanco, F. Nombela, M. Castellanos, M. Rodriguez-Yanez, M. Garcia-Gil, R. Leira, I. Lizasoain, J. Serena, J. Vivancos, M. A. Moro, et al. Statin treatment withdrawal in ischemic stroke: A controlled randomized study Neurology, August 28, 2007; 69(9): 904 - 910. [Abstract] [Full Text] [PDF]

				Y. Le Manach, G. Godet, P. Coriat, C. Martinon, M. Bertrand, M.-H. Fleron, and B. Riou The Impact of Postoperative Discontinuation or Continuation of Chronic Statin Therapy on Cardiac Outcome After Major Vascular Surgery Anesth. Analg., June 1, 2007; 104(6): 1326 - 1333. [Abstract] [Full Text] [PDF]

				H. Hong, J.-S. Zeng, D. L. Kreulen, D. I. Kaufman, and A. F. Chen Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2210 - H2215. [Abstract] [Full Text] [PDF]

				M. Endres and U. Laufs Discontinuation of Statin Treatment in Stroke Patients Stroke, October 1, 2006; 37(10): 2640 - 2643. [Abstract] [Full Text] [PDF]

				M.-Y. Tseng, M. Czosnyka, H. Richards, J. D. Pickard, and P. J. Kirkpatrick Effects of Acute Treatment With Pravastatin on Cerebral Vasospasm, Autoregulation, and Delayed Ischemic Deficits After Aneurysmal Subarachnoid Hemorrhage: A Phase II Randomized Placebo-Controlled Trial Stroke, August 1, 2005; 36(8): 1627 - 1632. [Abstract] [Full Text] [PDF]

				M. S.V. Elkind, A. C. Flint, R. R. Sciacca, and R. L. Sacco Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortality Neurology, July 26, 2005; 65(2): 253 - 258. [Abstract] [Full Text] [PDF]

				A. B. Singhal, M. A. Topcuoglu, D. J. Dorer, C. S. Ogilvy, B. S. Carter, and W. J. Koroshetz SSRI and statin use increases the risk for vasospasm after subarachnoid hemorrhage Neurology, March 22, 2005; 64(6): 1008 - 1013. [Abstract] [Full Text] [PDF]

				M. Endres and U. Laufs Effects of Statins on Endothelium and Signaling Mechanisms Stroke, November 1, 2004; 35(11_suppl_1): 2708 - 2711. [Abstract] [Full Text] [PDF]

				M. P. McGowan and for the Treating to New Target Study Group There Is No Evidence for an Increase in Acute Coronary Syndromes After Short-Term Abrupt Discontinuation of Statins in Stable Cardiac Patients Circulation, October 19, 2004; 110(16): 2333 - 2335. [Abstract] [Full Text] [PDF]

				J. Y. Streifler Editorial Comment--Statins, Stroke Outcome, and Stroke Prevention: When Should We Start Treatment? Stroke, May 1, 2004; 35(5): 1121 - 1123. [Full Text] [PDF]