Exercise as Stroke Prophylaxis

Background: Stroke is the third most common cause of death in industrialized countries, accounting for more than 10% of deaths over age 65. Most strokes are due to arteriosclerosis. Regular physical activity lowers arterial blood pressure and body weight and improves glucose and lipid metabolism, thereby slowing the development of arteriosclerosis and its cardiovascular complications, particularly myocardial infarction.
This review focuses on the question whether physical activity might also have a preventive effect on cerebral infarction and hemorrhage.
Methods: This analysis is based on 33 prospective cohort studies and 10 case-control studies that addressed the potential effect of physical activity on stroke-related morbidity and mortality.
Results: Our meta-analysis shows that physical activity reduces the risk of all types of stroke (infarction, -hemorrhage, and stroke of unspecified type). The relative risk (RR) of fatal or non-fatal cerebral infarction is 0.75, while the corresponding figures for cerebral hemorrhage and stroke of unspecified type are 0.67 and 0.71, respec-tively. The reduction of risk is only statistically significant for men. The case-control studies show an RR of 0.32 for men and women combined.
Conclusions: When a multivariate analysis is performed that takes other vascular risk factors into account, physical activity is found to have an independent protective effect against cerebrovascular events. The effect is statistically significant only for men, not for women.
Key words: stroke, cerebral hemorrhage, risk of stroke, physical activity, health-related behavior

Stroke is the third most common cause of death in industrialized countries (1). About 30% of all deaths before age 65 and 50% of all deaths thereafter are due to cardiovascular diseases, and one-fifth of these are due to stroke (2). Every third stroke has a fatal outcome (3). Stroke is also the most important cause of disability: 15% to 30% of stroke patients have persistent deficits, which often lead them to require nursing home care (4). Despite advances in stroke treatment, including systemic clot-lysis therapy, the opportunities for treatment remain limited (1).

The risk of stroke doubles every ten years after age 55; the risk of stroke is 50% higher in men than in women from age 55 to 75, but the risk in the two sexes equalizes thereafter (4). The main treatable causes of stroke are the following (4):

• Cardiovascular diseases
• Arterial hypertension
• Smoking
• Diabetes mellitus
• Carotid stenosis
• Atrial fibrillation
• Dyslipidemia
• Overweight
• Excessive alcohol consumption
• Hypercoagulable states
• The consumption of oral contraceptive drugs.

Regular exercise lowers arterial blood pressure, reduces weight, and improves glucose and lipid metabolism, endothelial function, and the rheological properties of the blood (2, 3, 5). Accordingly, regular exercise also lowers the risk of myocardial infarction (2).

This review article concerns the question whether regular exercise can also lower the risk of suffering or dying from a stroke, and, if so, whether ischemic or hemorrhagic strokes, or both, can be prevented by exercise.

Methods
The PubMed database was searched for original articles dealing with the frequency of ischemic or hemorrhagic strokes in physically active and physically inactive persons. The search terms employed were “stroke” AND “physical activity” OR “sport” AND “prevention” (for all listed years; last update December 2008). Many of the 535 publications retrieved were experimental studies, review articles, or studies on therapeutic aspects and the like. Thus, only a few publications were relevant to the question we sought to answer: this was the case for 33 prospective cohort studies and 10 case-control studies. In addition to these publications, all of the studies included in previously published meta-analyses (3, 6) were included in the present meta-analysis as well.

In all of the studies included in the present analysis, the level of physical activity of each person included in the study was determined from statements made by the participants themselves. The quantitative assessment of physical activity over long periods of time is impractical because of the immense amount of work it would require, and it has thus not been carried out in any study to date. Data from men and women in the cohort studies were analyzed separately as far as possible; in the case-control studies, this distinction could not be drawn, because of the relatively low number of study participants. The present study does not differentiate between occupational and leisure-time physical activity, as its goal is to determine the effect of exercise as such on stroke.

The risk of stroke in physically active persons was calculated in relation to the risk seen in the least physically active group of participants in each of the studies reviewed for the present article. Among the physically active persons, the groups that had the lowest risk of stroke in comparison to physically inactive persons were included in the calculation. The studies listed were subjected to a meta-analysis. All calculations were performed with the aid of the “meta” packet in the “R” statistics software, version 2.8.0 (7). The cohort studies were meta-analyzed separately from the case-control studies.

More specifically, within the class of cohort studies, separate meta-analyses were performed for three subgroups—ischemic, hemorrhagic, and undifferentiated stroke—and for men and women. The “undifferentiated stroke” subgroup consisted of pub-lications in which no diagnostic imaging was carried out, as well as those that grouped the patients with ischemic stroke together with those with intracerebral (sometimes also subarachnoid) hemorrhage. Subarachnoid hemorrhage was not considered in a separate category, as it is rare compared to other types of stroke. The studies in which subarachnoid hemorrhage was listed as an entity in its own right were not eliminated, because a small number of patients with subarachnoid hemorrhage might also be concealed in the statistics of the other studies in which no imaging was performed. The meta-analysis included only those studies whose results were available as an estimate of the strength of the effect accompanied by a confidence interval. The results from the individual studies were combined on a logarithmic scale. Because of heterogeneity among studies, a random-effects model was used consistently. In the Figures, the relative risk (RR) is always shown on a logarithmic scale. The meta-analytic estimators were retransformed back onto the original RR scale.

Results
In a meta-analysis of 18 cohort and 5 case-control studies, Lee et al. (3) concluded that the RR of stroke, or of fatal stroke, is 27% lower in very physically active persons than in those whose level of physical activity is low (RR = 0.73, 95% confidence interval [95% CI]: 0.67–0.79, p<0.001). Even persons who were only moderately physically active had a significantly reduced risk, with RR = 0.80. The risk of both ischemic stroke and intracerebral hemorrhage was reduced. In the cohort studies, the risk reduction for a fatal or non-fatal stroke in very active, as compared to relatively inactive, persons was 21% for ischemic events (RR = 0.79, 95% CI: 0.69–0.91, p<0.001) and 34% for hemorrhagic events (RR = 0.66, 95% CI: 0.48–0.91, p<0.001). The risk reduction remained significant, though of lesser magnitude, for only moderately physically active persons.

In a further meta-analysis, Wendel-Vos et al. (7) distinguished occupational physical activity from physical activity during free time. They reviewed 24 cohort and 7 case-control studies and calculated that a high level of physical activity during free time, as compared with a low one, reduced the risk of all types of stroke by 22% (RR = 0.78, 95% CI: 0.71–0.85, p<0.001), the risk of ischemic stroke by 21% (RR = 0.79, 95% CI: 0.69–0.91, p<0.001), and the risk of intracerebral hemorrhage by 26% (RR = 0.74, 95% CI: 0.57–0.96, p < 0.001). In contrast, when they studied occupational physical activity, they found that moderate physical -activity on the job lowered the risk of stroke to a greater extent than a high level of physical activity on the job (36% versus 23%), although they did not state whether this difference was statistically significant. Alevizos et al. (8) also concluded in their review that exercise reduces the risk of stroke. There is as yet no definitive answer to the question whether the extent and intensity of physical activity are significantly correlated with its preventive effect (5). The literature does not even contain a uniform definition of different levels of physical activity, let alone a quantitative measure.

The authors’ findings
eTables e1 (pdf) and e2 (pdf) show the relative risk that a physically active person will suffer a stroke or die from one, as compared to the least physically active group of study participants in each study. The eTables also contain further details about the level of activity in each of the groups being compared, and about the duration of observation in each study. The studies listed often give the risk of stroke in various subpopulations; in the present analysis, the two groups presented for comparison are always the group with the lowest level of physical activity as a control group, and the group with the highest level of physical activity or the one with the greatest risk reduction.

Cohort studies
28 of the 33 cohort studies were included in the meta-analysis because both effect estimators and confidence intervals were reported on.

Ischemic stroke
12 of the 14 studies in which ischemic strokes were studied were combined in a meta-analysis. These studies yielded a total of 20 individual comparisons for meta-analysis: RR = 0.75 (95% CI: 0.67–0.84, p < 0.0001; Q = 30.13, p = 0.05, I2 = 36.9%).

Cerebral hemorrhage
7 of the 9 studies in which the risk of cerebral hemorrhage was studied were combined in a meta-analysis. These 7 studies yielded a total of 12 individual comparisons for meta-analysis: RR = 0.67 (95% CI: 0.52–0.86, p = 0.0013; Q = 13.20, p = 0.28, I2 = 16.7%).

Stroke of undifferentiated type
23 of the 27 studies in which the risk of stroke was studied without any differentiation between ischemic and hemorrhagic events were combined in a meta-analysis. These studies yielded a total of 23 individual comparisons for meta-analysis: RR = 0.71 (95% CI: 0.64–0.80, p<0.0001; Q = 97.1, p<0.0001, I2 = 64%).

Case-control studies
Results for ischemic strokes were reported in 7 of the 10 case-control studies. Meta-analysis yielded the following results: RR = 0.32 (95% CI: 0.17–0.59, p = 0.0003; Q = 26.1, p = 0.0002, I2 = 77%). Two studies gave results for cerebral hemorrhages: one result was barely significant, the other insignificant. The results for strokes of undifferentiated type from two studies were significant.

The relative risks that were calculated separately for men and women are given in the Table (gif ppt). The results of our meta-analysis are given in Figures 1–6 and are, in general, consistent with the findings of Lee et al. (3) and Wendel-Vos et al. (7).

16 studies in which physical activity was graded on a scale with three or more levels showed that the risk of stroke declined with increasing physical activity (9, 11, 12, 15, 18, 20, 25, e1, e2, e3, e5, e7, e10, e12, e16, e17). Eight studies revealed a U-shaped dependence, i.e., the risk of stroke was less with intermediate degrees of physical activity than with lower or higher physical activity (10, 11, 15, 18, 20, e3, e8, e11). On the other hand, five studies revealed an inverted U-shaped dependence, in which the risk of stroke was highest for an intermediate degree of activity (9, 15, 18, e5, e15). In the four studies in which physical activity was graded on a scale with at least four levels, the risk of stroke was found to depend on the level of physical activity in an unsystematic way (10, 11, 12, 21). A number of studies appear in our tables more than once, because many studies involved several different populations or types of activity (e.g., on the job or during free time). Nonetheless, the differences in risk between the different levels of activity were mostly insignificant.

Discussion
The studies available to date show that regular exercise can lower the risk of a fatal or non-fatal stroke (infarct, cerebral hemorrhage, or—rarely—subarachnoid hemorrhage) by about 20% to 30%. There is a trend suggesting that a higher level of physical activity is more effective than a lower one for the prevention of ischemic stroke. Not all of the relevant studies yielded significant results, as is usually the case in epidemiology. Inadequate cohort size may explain this in some cases.

In the present meta-analysis, which is based on 33 cohort studies, the risk of a fatal or non-fatal ischemic stroke was lowered by 24% in women and by 27% in men, while that of a cerebral hemorrhage was lowered by 8% in women and by 40% in men. For strokes that were not radiologically classified as being either ischemic or hemorrhagic, the risk was 29% lower and 28% lower (in women and men, respectively) than in the physically inactive persons constituting the control group, but only the risk reduction in men was statistically significant. It remains an open question whether the insignificant results in women were due to the smaller number of studies including women. In the case-control studies, the risk reduction for men and women combined reached the very high figure of 68%.

As can be seen from Figures 1 (gif ppt) –6 (gif ppt), there was one study for each type of stroke that actually showed the risk of stroke in physically active men to be higher than in physically inactive men. In women, a higher risk associated with physical activity was seen in two studies on ischemic stroke, one on cerebral hemorrhage, and three on undifferentiated strokes. All other studies showed that physically active persons were less likely to have a stroke. No case-control study indicated a higher risk for physically active persons.

The statistically significant preventive effect of physical activity on stroke in all of the calculations undertaken here (in agreement with two earlier meta-analyses [3, 7]) does not preclude the possibility that such an effect might be absent in certain subgroups. Thus, voluntary exercise during one’s free time might conceivably have a different effect from compulsory exercise on the job. The effect might also vary from one ethnic group to another. It is known, for example, that black US-Americans suffer strokes at least twice as commonly as their white compatriots, and tend to have them at different sites and with different pathophysiological mechanisms (e28).

A clear dependence of the magnitude of risk reduction on the extent of physical activity (i.e., a dose-response effect) has not yet been demonstrated. Most studies indicate, however, that the risk is less with higher levels of activity. There may be a saturation -effect, however, or even an increased risk when physical activity is very frequent or very intense.

Most of the original articles that we evaluated here to calculate the risk of a fatal or non-fatal stroke took a number of the known risk factors for vascular disease into account, e.g., high blood pressure, diabetes mellitus, lipid metabolic disorders, obesity, smoking, and alcohol consumption. Nonetheless, some publications left some risk factors out of consideration (e.g., dietary habits) and did not assess others precisely or in detail (e.g., only overall cholesterol concentrations were given, rather than subfractions), as to do otherwise would presumably have been too expensive and impractical in cohort studies involving up to 70 000 study participants. Thus, it remains conceivable that a beneficial effect of exercise on the vascular risk factors that have already been recognized accounts for at least some of the observed risk reduction. Postulated mechanisms of risk reduction that are currently under discussion include an antihypertensive effect of exercise and a beneficial effect on lipid metabolism, e.g., a reduction of elevated concentrations of HDL-cholesterol. It has also been proposed that the effect may be mediated by an improvement in endothelial function—for example, increased activity of endothelial nitric oxide synthase (eNOS) (5) and of extracellular superoxide dismutase (ecSOD) expression: nitric oxide, a potent vasodilator, inhibits platelet aggregation and adhesion (1). Other mechanisms that may play a role include a lowering of blood viscosity, a tendency toward platelet aggregation, and increased fibrinolysis (8). Further factors include a reduction of the plasma fibrinogen concentration, increased activity of plasma tissue plasminogen activator, and a raised concentration of HDL-cholesterol (8, 17).

In view of the fact that the multivariate analyses of most of the studies reviewed here took account of the more important known cerebrovascular risk factors that can be positively influenced by exercise (obesity, glucose metabolism, arterial blood pressure, platelet aggregation tendency [e27]), one may suspect that the “gross” preventive effect of exercise is actually higher than the “net” effect on the order of 8% to 40% that is cited above. As already mentioned, the lowest risk of stroke was not always seen in the group of subjects who were most physically active; in some studies, a group with intermediate physical activity had the lowest risk. Yet, when we performed our meta-analysis, we used the data from the group whose risk was lowest in each study. It follows, therefore, that if we had compared only the (nearly) identical levels of physical activity across studies, we would have arrived at a somewhat lower figure for the reduction of stroke risk by physical activity.

The risk reduction for cerebrovascular events is of the same order of magnitude as that for coronary heart disease. The risk of coronary heart disease in men who exercise regularly in their free time is 24% lower than that of men who are physically inactive in their free time. In women, there is an analogous risk reduction of 23%. The effect is less pronounced at intermediate levels of physical activity (e29). Traveling to work on foot or by bicycle has been shown to lower the risk of cardiovascular events significantly only in women: RR = 0.87 (95% CI: 0.77–0.98, p = 0.02; for men, RR = 0.91, 95% CI: 0.80–1.04) (e30).

Although the description of physical activity was not quite uniform across studies, the type of activity reported in most of them corresponded to aerobic exercise. Even the types of highly intense physical activity that were named in most studies were usually leisure sports such as jogging, swimming, cycling, or the like. Walking is considered to be a mildly to moderately intense form of physical activity (3). The term “intense physical activity” in the epidemiological studies cited here thus has little to do with what an athlete would consider intense activity, i.e., an anaerobic or competitive stress. No data on this type of activity are available. Thus, regular cardiovascular exercise with moderately intense physical activity for at least 30 minutes per day is recommended (4) for persons who do not get adequate exercise on the job. Moderately intense physical activity can be provided by, for example, rapid walking, cycling, moderately fast swimming, or slow canoeing.

Conflict of interest statement
The authors declare that they have no conflict of interest as defined by the guidelines of the International Committee of Medical Journal Editors.

Manuscript received on 29 July 2008, revised version accepted on 26 March 2009.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Carl D. Reimers
Klinik für Neurologie, Zentralklinik Bad Berka
Robert-Koch-Allee 9
99438 Bad Berka, Germany
[e-mail]

@For e-references please refer to:
www.aerzteblatt-international.de/ref4409
e-Tables can be accessed at:
www.aerzteblatt-international.de/article09m715

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