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ARTICLES: D. Deplanque, I. Masse, C. Lefebvre, C. Libersa, D. Leys, and R. Bordet Prior TIA, lipid-lowering drug use, and physical activity decrease ischemic stroke severity Neurology 2006; 67: 1403-1410 [Abstract] [Full text] [PDF]

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Prior TIA, lipid-lowering drug use, and physical activity decrease ischemic stroke severity

Marc Gotkine, Israel Steiner   (4 December 2006)

Reply from the Authors

Dominique Deplanque, Isabelle Masse, Catherine Lefebvre, Christian Libersa, Didier Leys, Régis Bordet   (4 December 2006)

Prior TIA, lipid-lowering drug use, and physical activity decrease ischemic stroke severity 4 December 2006
Marc Gotkine, Neurology Department, Hadassah University Hospital, Ein Kerem (MG) and Mount Scopus (IS) Department of Neurology, Hadassah University Hospital, Ein Kerem, Jerusalem, Israel, Israel Steiner Send Correspondence to journal: Re: Prior TIA, lipid-lowering drug use, and physical activity decrease ischemic stroke severity marcgotkine{at}gmail.com Marc Gotkine, et al.	We read with interest the article by Deplanque et al in which lipid- lowering drugs (LLDs)were shown to be associated with decreased stroke severity. [1] They concluded that this was likely due to the neuroprotective effects of these drugs. We proposed another mechanism that may explain these findings: that hypercholesterolemia, by enhancing atherosclerosis and chronically compromising blood tissue supply, could trigger local compensatory mechanisms which ultimately reduce ischemia-induced tissue injury. [2] This may increase the brain's tolerance to sudden disruption of circulation and partially protect the tissue from acute ischemia. High serum cholesterol levels are associated with less severe presentation and improved short-term functional outcome in stroke patients. [3] Similar mechanisms may underlie the phenomenon of decreased stroke severity in smokers [4] and of reduced myocardial injury following acute myocardical infarction in angina sufferers. [5] It is reasonable to assume that patients taking LLDs were more likely to have been exposed to an extended period of hypercholesterolemia than those never treated with LLDs. The apparent benefit of taking LLD’s prior to an ischemic stroke may partially reflect adaptive-protective mechanisms triggered by the preceding hypercholesterolemia rather than the neuroprotective effects of the drugs themselves. It would be interesting to know the pre-treatment cholesterol levels of the LLD-treated patients compared to the pre-stroke cholesterol levels of the untreated patients. References 1. Deplanque D, Masse I, Lefebvre C, et al. Prior TIA, lipid-lowering drug use, and physical activity decrease ischemic stroke severity. Neurology 2006;67:1403-1410. 2. Steiner I, Biran I. Better outcome after stroke with higher serum cholesterol levels. Neurology 2000;55:1941-1942. 3. Vauthey C, de Freitas GR, van Melle G, Devuyst G, Bogousslavsky J. Better outcome after stroke with higher serum cholesterol levels. Neurology 2000;54:1944-1949. 4. Karepov VG, Hass Y, Borenstein NM, Korczyn AD. Smoking reduces stroke severity. Neurology 1998; 50 (suppl 4): A113. 5. Anzai T, Yoshikawa T, Asakura Y, et al. Effect on short-term prognosis and left ventricular function of angina pectoris prior to first Q-wave anterior wall acute myocardial infarction. Am J Cardiol 1994; 74: 755–759. Disclosure: The authors report no conflicts of interest.
Reply from the Authors 4 December 2006
Dominique Deplanque, Department of Pharmacology - EA 1046 Faculty of Medicine, F-59045 Lille, France, Isabelle Masse, Catherine Lefebvre, Christian Libersa, Didier Leys, Régis Bordet Send Correspondence to journal: Re: Reply from the Authors d-deplanque{at}chru-lille.fr Dominique Deplanque, et al.	We thank Drs. Gotkine and Steiner for their comments on our study. [1] We agree that aside from the potential neuroprotective effect of LLDs in stroke, the mechanisms involved in the development of a brain tolerance to ischemia must be identified. Several studies have discussed whether chronic hypercholesterolemia could induce such a protective effect. [3,4] In Alzheimer’s disease, the results conflict; several studies suggest a deleterious effect of mid-life hypercholesterolemia, while late-life hypercholesterolemia might have some beneficial effects. [6] According to the methodology used and delay between stroke onset and cholesterol measurements, the results vary which leads to misinterpretation. Our study was not designed to answer this question so conclusions can not be definitive. Nevertheless, there is a growing body of evidence supporting the hypothesis that brain can adapt to injuries such as cerebral ischemia. [1,7] Experimental studies on preconditioning have shown that various conditions can initiate reactions in cells and tissues that lead after some time to neuroprotection. Although transient ischemia is typical of preconditioning stimulus, ischemic tolerance could be induced by exposing brain to various endogenous and exogenous stimuli (hypoxia, oxidative stress, inflammatory cytokines, lipopolysaccharide, linolenic acid, anesthetics) that converge downstream on fundamental mechanisms that ultimately account for the protection. They are based on the enhancement of cell survival through the modulation of various cellular and molecular pathways including variations at gene level. [7] Given these data, targeting mechanisms of cytoprotection is an important strategy for new therapeutic approaches. Because physical activity and LLDs have previously been experimentally demonstrated as possible inducers of brain ischemic tolerance [8,9], our study suggests the possibility to develop a prophylactic neuroprotection in humans. [1] In addition to experimental studies examining brain ischemic tolerance pathways, both physical activity and LLDs should now be prospectively evaluated to determine whether they are effective to reduce the severity of brain ischemia. The question of whether the decreased severity of stroke in patients under LLDs is due to an increased brain tolerance induced by LLDs themselves or by a chronically compromised blood tissue supply as suggested by Drs Gotkine and Steiner can only be solved by randomized controlled trials in patients with similar baseline cholesterol levels. According to a recent presentation of results from the SPARCL trial, it seems that patients randomized in the statin arm have less severe recurrent strokes. [10] The hypothesis of Drs. Gotkine and Steiner is then unlikely to play an important role. References 6.Mielke MM, Zandi PP, Sjogren M, et al. High total cholesterol levels in late life associated with a reduced risk of dementia. Neurology 2005;64:1689-1695. 7.Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 2006;7:437-448. 8.Endres M, Gertz K, Lindauer U, et al. Mechanisms of stroke protection by physical activity. Ann Neurol 2003;54:582-590. 9.Bordet R, Ouk T, Pétrault O, et al. PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases. Bioch Soc Trans 2006;34:1341-1346. 10.Goldstein LB and The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. The SPARCL trial: effect of statins on stroke severity. Ann Neurol 2006;60(S10):S85. Disclosure: The authors report no conflicts of interest.