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(Stroke. 1998;29:2049-2054.)
© 1998 American Heart Association, Inc.

Original Contributions

Physical Activity and Stroke Incidence

The Harvard Alumni Health Study

I-Min Lee, MBBS, ScD; Ralph S. Paffenbarger, Jr, MD, DrPH

From the Department of Epidemiology, Harvard School of Public Health, Boston, Mass (I-M.L., R.S.P); Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass (I-M.L.); and Division of Epidemiology, Stanford University School of Medicine, Stanford, Calif (R.S.P.).

Correspondence to I-Min Lee, MBBS, ScD, Brigham and Women's Hospital, 900 Commonwealth Ave E, Boston, MA 02215. E-mail i-min.lee{at}channing.harvard.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—Physiologically, it appears plausible for physical activity to decrease stroke risk; however, epidemiological studies have produced mixed findings. Furthermore, few studies have examined specific kinds and intensities of activities. The purpose of this study was to examine the association between physical activity, including its various components (walking, climbing stairs, participation in sports and recreational activities), and stroke risk.

Methods—This was a prospective cohort study of 11 130 Harvard University alumni (mean age, 58 years) without cardiovascular disease and cancer at baseline. Men reported their walking, stair climbing, and participation in sports or recreation on baseline questionnaires in 1977. Stroke occurrence was assessed with another questionnaire in 1988. Death certificates were obtained for decedents through 1990 to determine strokes not previously reported (total strokes=378). We used Cox proportional hazards regression to estimate the relative risks and 95% CIs for stroke occurrence associated with physical activity.

Results—After adjustment for age, smoking, alcohol intake, and early parental death, the relative risks of stroke associated with <1000, 1000 to 1999, 2000 to 2999, 3000 to 3999, and 4000 kcal/wk of energy expenditure at baseline were 1.00 (referent), 0.76 (95% CI, 0.59 to 0.98), 0.54 (0.38 to 0.76), 0.78 (0.53 to 1.15), and 0.82 (0.58 to 1.14), respectively; P=0.05 for linear trend. Walking 20 km/wk was associated with significantly lower risk, independent of other physical activity components. Climbing stairs and activities of at least moderate intensity (4.5 METs, or multiples of resting metabolic rate) each showed U-shaped relations to stroke risk, with the risk being significantly lower at the nadir of the curve. Light intensity activities (<4.5 METs), however, were unrelated to stroke risk.

Conclusions—Physical activity is associated with decreased stroke risk in men. A decreased risk was observed at energy expenditures of 1000 to 1999 kcal/wk, with further risk decrement seen at 2000 to 2999 kcal/wk but not beyond. Confirmation of the U-shaped relation observed in these data requires similar observations in other populations.

Key Words: epidemiology • exercise • risk factors • stroke prevention

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Stroke ranks as the third leading cause of death in the United States, following coronary heart disease and cancer.¹ Every year, >150 000 persons die from this disease, while many more are disabled.¹ It primarily afflicts older individuals: >130 000 of the 150 000 stroke deaths each year occur among those aged 65 years.¹ Currently, there is limited treatment for most types of stroke. Thus, its prevention is of public health importance. Two major causes of stroke are atherosclerosis of intracranial or extracranial vessels and high blood pressure.² Therefore, in searching for prevention strategies, physical activity is promising because it has beneficial effects on the atherosclerotic process and reduces blood pressure.^{3 4} Several studies indeed show that physical activity is associated with lower stroke risk^5–17; however, other studies do not support this hypothesis.^{18 19 20 21 22 23 24} In fact, the Surgeon General's report on physical activity and health concluded that "it is unclear whether physical activity plays a protective role against stroke."²⁵

To provide further information, we examined data from an ongoing study of college alumni. Previous investigation revealed that alumni who had been varsity athletes experienced less than half the risk of subsequent stroke death.⁵ In this study we extend our observations regarding physical activity and stroke incidence among these alumni later in life.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Participants
The Harvard Alumni Health Study is an ongoing study of the predictors of chronic diseases among men matriculating as undergraduates at Harvard University between 1916 and 1950. We first mailed a health questionnaire to surviving alumni in either 1962 or 1966. After this initial survey, we periodically resurveyed all surviving alumni in the relevant classes to update information on health habits and medical history.

For this study we were interested in information from a mail survey in 1977. Potentially eligible subjects were 17 835 alumni who returned a questionnaire then. We excluded men reporting physician-diagnosed cardiovascular disease or cancer (n=2863) to avoid potential bias from men who recently may have changed their activity level because of these diseases. We further excluded men with missing data on the variables of interest: physical activity, cigarette smoking, alcohol consumption, and ages of parental death (n=673). Of the remaining 14 299 men, we successfully followed 11 130 (ie, they returned another questionnaire in 1988 or were known to have died by 1990; details below), or 78%. These 11 130 men formed the study group.

Assessment of Physical Activity and Other Predictors of Stroke
We asked alumni on the 1977 questionnaire (baseline) to estimate the number of blocks walked daily and the number of flights of stairs climbed daily and to list all sports or recreation in which they had actively participated during the past year.²⁶ For each sport or recreation listed, we asked for details regarding frequency (weeks per year) and duration (time per week when active). This assessment of physical activity has been shown to be reliable and valid.^{27 28 29 30 31 32 33}

We analyzed physical activity in 3 different ways. First, we examined the relation between total energy expended on physical activity at baseline and stroke incidence. We estimated total energy expenditure thus: walking 1 block daily rated 56 kcal/wk; climbing 1 flight of stairs daily required 28 kcal/wk. To each sport or recreation, we assigned a multiple of resting metabolic rate (MET score).³⁴ Since resting metabolic rate is 1 kcal/kg body wt per hour, we estimated the average weekly energy expenditure for that activity by multiplying its MET score by body weight and hours per year of participation, then dividing by 52.³⁵ We summed kilocalories per week from walking, stair climbing, and sports or recreation to estimate total energy expenditure. We then defined 5 categories: <1000 (31.0% of men), 1000 to 1999 (28.7%), 2000 to 2999 (18.2%), 3000 to 3999 (10.2%), and 4000 kcal/wk (11.9%).

Second, to understand the effects of specific components of physical activity, we examined separately walking, stair climbing, and sports or recreation. We categorized men into approximate fourths of distance walked (1 block=0.13 km): <5 (31.8% of men), 5 to <10 (21.3%), 10 to <20 (26.2%), and 20 km/wk (20.7%). Similarly, we grouped men into approximate fourths of flights climbed (2 flights=1 story): <10 (22.9% of men), 10 to <20 (21.2%), 20 to <35 (20.8%), and 35 stories/wk (35.1%). Because of interest in whether nonvigorous and vigorous activities have equivalent benefits,³⁶ we calculated separately energy expenditure from nonvigorous (<6 METs) and vigorous (6 METs) sports or recreation.³⁵ (Examples of vigorous activities reported by alumni include jogging or running, swimming laps, playing tennis, and shoveling snow.) For nonvigorous energy expenditure, we defined 5 categories: none (51.1% of men), 1 to <250 (13.8%), 250 to <600 (11.7%), 600 to <1400 (12.0%), and 1400 kcal/wk (11.4%). For vigorous energy expenditure, we did likewise (41.0%, 16.9%, 12.1%, 14.7%, and 15.3%, respectively). These cut points were chosen so that among those who did report some sport or recreation, men would be approximately evenly distributed among the remaining 4 categories of energy expenditure. Furthermore, the choice of identical cut points would enable direct comparison of stroke rates between, for example, men who expended 250 to <600 kcal/wk in nonvigorous activities and those who expended the same amount of energy but in vigorous activities.

With the growing recognition that it is difficult to persuade the many sedentary individuals²⁵ to take up vigorous activities, research interest lately has focused on moderate intensity physical activity.³⁷ Therefore, we analyzed physical activity in a third way. We calculated the energy expended on sports or recreation separately for light activities (<4.5 METs) and for activities of at least moderate intensity (4.5 METs). (Examples of moderate activities reported by alumni include dancing, bicycling, snorkeling, and digging or filling in garden.) We used the same cut points as before in analyses. For light energy expenditure, men distributed themselves thus: none, 63.9%; 1 to <250, 10.3%; 250 to <600, 8.2%; 600 to <1400, 8.7%; and 1400 kcal/wk, 8.9%. For energy expended on activities of 4.5 METs, the distribution was 36.4%, 15.8%, 12.7%, 16.7%, and 18.4%, respectively.

On the 1977 questionnaire, we also asked about cigarette smoking (categorized in analyses as nonsmoker, smoker of 20, or >20 cigarettes per day), alcohol consumption (<50, 50 to 199, or 200 g/wk), ages of parental death (neither, 1, or both parents died before age 65 years), weight and height (combined as body mass index; <22.5, 22.5 to <23.5, 23.5 to <24.5, 24.5 to <26.0, or 26.0 kg/m²), physician-diagnosed hypertension (no, yes, or unknown), and diabetes mellitus (no, yes, or unknown).

Ascertainment of Stroke Occurrence
In 1988 we sent another health survey to surviving alumni. Included on the 1988 survey was a question on whether a physician had ever diagnosed stroke and if so, the year of first diagnosis. Men who did not provide this information were considered lost to follow-up and excluded from study. Self-reported, physician-diagnosed chronic diseases among alumni were believed to be valid.^{38 39 40} We used death certificates to ascertain additional strokes (underlying or contributing cause of death) not reported on the 1988 questionnaire. We traced deaths occurring through 1990 using information from the alumni office to obtain death certificates. Mortality follow-up in this cohort is >99% complete.³⁸

Statistical Analyses
We used proportional hazards regression to analyze time to first stroke occurrence (ascertained from the 1988 questionnaire or death certificate) or censoring (1988 questionnaire return or death, whichever occurred later).⁴¹ There was no evidence that proportional hazards assumptions were violated. For strokes ascertained from death certificates alone, we took the date of diagnosis to be the date of death. Since this could create a potential bias, we first examined the association between physical activity and stroke risk, excluding alumni with strokes determined from death certificates. We counted only cases of stroke ascertained from the 1988 questionnaire in which date of diagnosis was known. The findings from these analyses were similar to those from analyses in which all strokes (ie, determined from the 1988 questionnaire or death certificate) were included. Therefore, we present our findings only from analyses that combined strokes ascertained from both sources.

We first modeled rate ratios (relative risks) of stroke as a function of total energy expenditure and age. We then proceeded to adjust additionally for other predictors of stroke in these data: cigarette smoking, alcohol consumption, and early parental death. Since age-adjusted and multivariate analyses yielded similar findings, only results from the latter are presented. We calculated 95% CIs for estimated relative risks and used 2-tailed tests of significance.

In secondary analyses, we examined the association between total energy expenditure and stroke risk separately for 2 time periods (chosen so that there would be approximately the same number of events in each period): 1977 to 1984 and 1985 to 1990, and for 3 age groups: <65, 65 to 74, and 75 years at study entry. We also separately analyzed a subgroup of men at lower risk of stroke: men who did not smoke, consumed <200 g/wk of alcohol, and whose parents did not die before age 65 years.

When analyzing the components of physical activity, we included indicator terms for categories of walking, stair climbing, nonvigorous (<6 METs) energy expenditure, and vigorous (6 METs) energy expenditure in multivariate models. To assess the effects of light activity and activity of at least moderate intensity, we conducted parallel analyses with energy expenditure dichotomized at 4.5 instead of 6.0 METs. Finally, we investigated the effects of walking and stair climbing among only men reporting no sports or recreation in 1977.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
At study entry, alumni were aged 58 years on average (range, 43 to 88 years) (Table 1). Their prevalence of smoking, 16.9%, was much lower than in the general population of that era (36.5% among US white men, 1979).¹ With regard to body weight, again, alumni possessed a healthier profile, being of lower body mass index than the general population of that time.⁴² Table 1 also describes the distributions of alcohol consumption, early parental death, and physician-diagnosed hypertension and diabetes mellitus among subjects.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Harvard Alumni in 1977

Between 1977 and 1990, 378 strokes occurred in 119 880 person-years. For total energy expenditure of <1000, 1000 to 1999, 2000 to 2999, 3000 to 3999, and 4000 kcal/wk, the relative risks of stroke, adjusted for age, smoking, alcohol intake, and early parental death, were 1.00 (referent), 0.76 (95% CI, 0.59 to 0.98), 0.54 (0.38 to 0.76), 0.78 (0.53 to 1.15), and 0.82 (0.58 to 1.14), respectively; P=0.05 for linear trend (Figure ). When we added a quadratic term for energy expenditure to examine how well the data fitted a U-shaped curve, this was significant at P=0.004. In assessing the roles that body mass index, hypertension, and diabetes mellitus might play in mediating the inverse association between physical activity and stroke risk, we conducted an analysis that additionally adjusted for these 3 variables. Relative risks were slightly attenuated from before: 1.00, 0.79, 0.56, 0.81, and 0.85, respectively; P=0.09 for linear trend.

View larger version (14K): [in this window] [in a new window]   Figure 1. Relative risks of stroke among Harvard alumni, 1977 to 1990, according to energy expenditure estimated in kilocalories per week from blocks walked, stairs climbed, and sports or recreational activities performed in 1977. Relative risks are adjusted for age, cigarette smoking, alcohol consumption, and early parental death. Vertical bars indicate 95% CIs.

In secondary analyses, we examined separately 2 time intervals: 1977 to 1984 (176 strokes) and 1985 to 1990 (202 strokes). Relative risks of stroke for the 5 categories of total energy expenditure during the earlier period were 1.00 (referent), 0.65, 0.55, 0.76, and 0.86, respectively; for the later period, they were 1.00, 0.86, 0.53, 0.80, and 0.78, respectively. We also investigated separately men aged <65 (n=8344), 65 to 74 (n=2259), and 75 years (n=527) at study entry; 149, 164, and 65 strokes, respectively, occurred. Among men aged <65 years, the relative risks for the 5 categories of total energy expenditure were 1.00 (referent), 0.75, 0.54, 1.02, and 0.87, respectively. For men aged 65 to 74 years, corresponding relative risks were 1.00, 0.72, 0.52, 0.44, and 0.68, respectively. Among men aged 75 years, they were 1.00, 0.89, 0.60, 1.10, and 1.28, respectively. These findings were adjusted for differences in age, smoking, alcohol consumption, and early parental death.

Next, we analyzed a subgroup of alumni at lower risk for stroke (men who did not smoke, consumed <200 g/wk of alcohol, and whose parents did not die before age 65; n=4164; 111 strokes). After adjustment for age and alcohol intake, the relative risks of stroke for the 5 categories of total energy expenditure were 1.00 (referent), 0.74, 0.56, 0.63, and 0.84, respectively.

We proceeded to explore the associations between specific components of physical activity and stroke incidence (Table 2). With walking, attaining a distance of 20 km/wk was associated with reduced risk. With stair climbing, activities at <6 METs, or activities at 6 METs, we observed a U-shaped relation of stroke rates to each physical activity component, similar to that seen for total energy expenditure. However, the quadratic terms here were not significant (P=0.12, P=0.22, and P=0.06, respectively). Noteworthy was the similarity of age-adjusted incidence rates for each level of energy expenditure at <6 METs and the corresponding level of energy expenditure at 6 METs (eg, for 250 to <600 kcal/wk, 24.0 and 22.9 per 10 000, respectively).

View this table: [in this window] [in a new window]   Table 2. Incidence Rates1 and Relative Risks2 of Stroke Among Harvard Alumni, 1977–1990, According to Different Components of Physical Activity in 1977

When we analyzed energy expenditure for sports or recreation using a 4.5 instead of a 6.0 MET cut point, we observed that activities of <4.5 METs were unrelated to stroke risk (Table 3). For activities of 4.5 METs, a U-shaped relation was seen with a significant quadratic term (P=0.04).

View this table: [in this window] [in a new window]   Table 3. Incidence Rates1 and Relative Risks2 of Stroke Among Harvard Alumni, 1977–1990, According to Activities of <4.5 and 4.5 METs in 1977

Finally, we investigated another subgroup: men reporting no sports or recreation in 1977 (n=2892; 148 strokes). The event rate was higher in this than the larger group (data not shown). The results in this subgroup were similar to those based on the larger group; however, the findings in this smaller group were no longer significant. The relative risks of stroke associated with walking <5, 5 to <10, 10 to <20, and 20 km/wk in this subgroup were 1.00 (referent), 1.15, 0.77, and 0.73, respectively; P=0.09 for linear trend. For climbing <10, 10 to <20, 20 to <35, and 35 stories/wk, they were 1.00 (referent), 1.00, 0.60, and 0.94, respectively; P=0.50 for linear trend.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In these prospective data, physical activity was associated with decreased risk of stroke in men. With higher levels of energy expenditure up to 3000 kcal/wk, risk declined steadily; beyond this, however, the association weakened. We observed similar findings even in older individuals. What kinds of activities were beneficial? The data indicated that walking 20 km/wk was associated with significantly lower risk, independent of other physical activity components. Climbing stairs and activities of at least moderate intensity (4.5 METs) each showed U-shaped relations to stroke risk, with the risk being significantly lower at the nadir of the curve. Light-intensity activities (<4.5 METs), however, were unrelated to stroke risk. Furthermore, men who participated in recreational activities experienced lower stroke rates than those who only walked or climbed stairs but did not engage in recreational activities.

It is unclear why stroke incidence rates exhibited a U-shaped relation to physical activity in this study group. Two of 3 randomized trials specifically testing exercise of different intensities suggest that higher-intensity physical activity is less effective in decreasing blood pressure than lower intensity activity.^{43 44} This could plausibly explain our observations. We did, however, explore whether the U-shaped association might be artifactual. For example, as alumni aged, perhaps those most active scaled down their activities, while the less active maintained theirs. We observed some evidence for this: of alumni falling in the least active category in 1977, 69% remained in the 2 least active categories in 1988, while 57% of alumni in the most active category in 1977 remained in the 2 most active categories in 1988. This might attenuate relative risks among the most active, the phenomenon becoming more pronounced as alumni aged. However, we observed U-shaped associations during early and late follow-up and among younger and older men. Thus, physical activity misclassification may not totally account for the U-shaped association.

Next, we wondered whether men at higher risk for stroke exercised more assiduously to ameliorate their risk. Although we did adjust for potential confounders, residual confounding might still exist. We therefore examined separately men at lower risk (nonsmokers who drank <200 g/wk of alcohol and whose parents did not die early). Findings were little changed; thus, residual confounding is less likely to have caused the U-shaped relation.

Finally, we examined the association between physical activity and coronary heart disease. The consensus is that coronary heart disease risk declines steadily with increasing activity²⁵; thus, if the observed U-shaped curve for stroke resulted from bias in the design or analysis of the present study, a U-shaped curve also might be observed for coronary heart disease in this study group. Among alumni, 1433 developed coronary heart disease (ascertained in similar fashion as for strokes) during follow-up. After adjustment for the same potential confounders, the relative risks of this disease associated with the 5 categories of total energy expenditure were 1.00 (referent), 0.84, 0.74, 0.83, and 0.71, respectively, with a highly significant linear trend (P<0.0001). Therefore, the U-shaped association between stroke rates and physical activity is less likely to be an artifact of the data. Confirmation of this finding requires similar observations in other populations.

Several investigators have examined dose-response in the relation between physical activity and stroke.^{6 8 9 10 13 14 15 16 17 20 23} Two studies also observed U-shaped relations between stroke rates and physical activity. In these 2 studies, investigators categorized physical activity into 3 levels among Italian railroad workers²⁰ and Seventh-Day Adventist men.²³ In 2 other studies in which physical activity was divided into 3 levels, stroke risk decreased at the second level but did not decline with further activity.^{14 15} Of the remaining 7 studies that assessed dose response, stroke risk declined steadily with increasing activity.^{6 8 9 10 13 16 17} These differences may have reflected the nature of the different populations studied; furthermore, physical activity assessments in the various studies are not directly comparable.

Strengths of the present study include a well-characterized study group, with detailed and valid physical activity assessment at baseline. The latter enabled investigation of specific kinds of physical activity, providing useful information for formulating public health recommendations.

However, several limitations exist. We successfully followed only 78% of eligible men. Mortality follow-up in this study group is known to be virtually complete³⁸; hence, those lost to follow-up were most likely alive as of 1990. Because they did not return a questionnaire in 1988 (or did so but did not answer the stroke question), we could not ascertain their stroke status. Men lost to follow-up (n=3169) were younger at baseline (mean age, 47.2 versus 58.0 years among those in the present study), somewhat more likely to be smoking (18.1% versus 16.9%), but less likely to be drinking 200 g/wk of alcohol (32.0% versus 35.7%) and to have both parents dying early (3.3.% versus 4.4%). The age differential is not unexpected, since virtually all those lost to follow-up were alive as of 1990, while those in the present study included deceased (therefore, older) men as of 1990. However, the energy expenditure of those lost to follow-up was quite similar to that of men in the present study (mean, 2212 versus 2104 kcal/wk). This was supported by similar distributions of body mass index in the 2 groups. Since physical activity levels were similar in the 2 groups of men, bias from incomplete follow-up is less likely.

Additionally, strokes were ascertained through self-report and death certificates. Some misclassification was likely, even though alumni self-report of physician-diagnosed chronic diseases has been shown to be valid.^{38 39 40} The misclassification is likely to be random, since physical activity information was collected before asking about stroke. Hence, the misclassification would likely have weakened findings but not created spurious inverse associations. We also were unable to examine different types of stroke since we did not pursue medical records to determine stroke subtype. Furthermore, we lacked dietary data at baseline and thus could not adjust for this. However, in about two thirds of men, we did collect dietary information in 1988. We did not see clear differences in percent fat or saturated fat intake among men with different physical activity levels, decreasing the likelihood that diet was a strong confounder. Finally, men in this study were healthier than the US general population. While this may limit the generalizability of findings, it does not preclude their internal validity.

Biologically, it is plausible for physical activity to decrease stroke risk by curtailing obesity, decreasing blood pressure, maintaining normal glucose tolerance, and improving insulin sensitivity.^{45 46} However, when we additionally adjusted in analyses for body mass index, hypertension, and diabetes mellitus, these variables explained only a very modest portion of the benefit of physical activity. Other pathways through which physical activity may decrease stroke risk include improving lipid profile, decreasing fibrinogen levels, increasing fibrinolytic activity, and reducing the tendency of platelets to aggregate.³

In conclusion, physical activity is associated with decreased stroke risk in men, including older men. A decreased risk was observed at energy expenditures of 1000 to 1999 kcal/wk, with further risk decrement seen at 2000 to 2999 kcal/wk but not beyond. Confirmation of the U-shaped relation observed in these data requires similar observations in other populations.

	Acknowledgments

 
This study was supported by grants from the National Heart, Lung, and Blood Institute (HL 34174) and the National Cancer Institute (CA 44854), US Public Health Service. We are grateful to Stacey DeCaro, Sarah E. Freeman, Tina Y. Ha, James B. Kampert, Rita W. Leung, Doris C. Rosoff, Howard D. Sesso, and Alvin L. Wing for their help with the College Alumni Health Study.

	Footnotes

 
Reprint requests to I-Min Lee, MBBS, ScD, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115.

This is report No. LXI in a series on chronic disease in former college students.

Received April 7, 1998; revision received July 13, 1998; accepted July 13, 1998.

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