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Physical activity and cardiovascular disease: evidence for a dose response

KOHL, HAROLD W. III

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Medicine and Science in Sports and Exercise: June 2001 - Volume 33 - Issue 6 - p S472-S483
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Abstract

Since the seminal and visionary studies of London Civil Servants (32), nearly a half-century of research has led to the immutable conclusion that physical inactivity is a prominent part of the causality constellation that increases the risk of cardiovascular disease. The cumulative effect of this body of work has led leading health authorities around the world at the dawn of this new millennium to make physical activity promotion for cardiovascular health part of broad ranging health policy and goals (3,8,37,38,54). This situation is in sharp contrast to the prevailing health concerns at the start of the previous century when control of infectious diseases was paramount.

Coronary heart disease (CHD) and stroke (CVA) are two manifestations of cardiovascular disease (CVD) in which there have been a variety of investigations of the role of preventive and therapeutic role of physical activity. Each outcome has several plausible biologic mechanisms through which physical activity has been hypothesized to interrupt or delay the pathogenic onset or development. These physiologic and biologic relationships between physical activity and health outcomes have been reviewed extensively (54).

Although these advances have been spectacular, much remains to be learned. Early observational studies in this area focused on bivariate categorization of activity status (categorization of study participants as active/inactive; active jobs/inactive jobs; leisure activity/no leisure activity) as a method of comparison and contrast of outcomes of interest. Only more recently have questions arisen regarding the “shape” of the relationship between physical activity and cardiovascular health. This natural progression of inquiry requires an understanding of a continuum of exposure instead of bivariate categorization, and how that continuum is related to the outcome of interest. Further, important interactions and effect-modifications such as those associated with gender, age, and ethnic identity differences for these dose-response questions become much more prominent when thought is extended past the bivariate case.

The purpose of this paper is to review available evidence regarding a dose-response relation between physical activity and fatal and nonfatal cardiovascular disease. Outcomes included are fatal and nonfatal stroke (ischemic and hemorrhagic) and fatal and nonfatal coronary (ischemic) heart disease. This review is limited to published studies with documented clinical manifestation of disease as outcomes. Studies in which biologic, pathologic, or diagnostic indicators of cardiovascular disease have been used as outcomes (without clinical manifestation) are excluded from this review. Further, to evaluate the potential dose-response pattern, studies that relied solely on a bivariate categorization of “exposure” of physical activity have been excluded.

This paper is organized into three separate sections according to the type of cardiovascular disease outcome reported: all CVD combined, CHD, and CVA. Tabulations for each of the three outcomes focus on critical points of study design, results, and interpretation. Tables are presented in each section summarizing key observational research findings as to the type of population studied, a brief description of assessment of the antecedent variable (physical activity) used in the study, the main outcome under consideration, and the main findings of the analyses. Further, if a dose-response association was observed in the study, the outcome is indicated either positively or negatively. Finally, each table also provides a brief area for ancillary comments related to the study.

CURRENT STATUS OF KNOWLEDGE

Cardiovascular disease.

A summary of major population-based studies of physical activity and/or fitness as they relate to risk of CVD is highlighted in Table 1. All studies investigated CVD mortality as an endpoint, whereas only one reported on CVD incidence (fatal or nonfatal disease).

Table 1
Table 1:
Population-based studies of association of physical activity as related to cardiovascular disease (CVD): English literature, 1953–August 2000.

Five major observational studies (eight publications) have evaluated the association between physical activity and the risk of CVD and allow evaluation of a possible dose-response relation (4,17,18,26,29,35,45,49). All were prospective in design, were in large populations, and had long-term follow-up periods (follow-up times ranged from 5 to 26 yr). Four publications included women and two focused exclusively on women (45,49). Four of the eight studies focused exclusively on fatal CVD, whereas the remainder included a mixture of fatal and nonfatal outcomes. Among the eight publications, two showed no evidence of a dose response relation between physical activity and CVD risk (26,49); one reported mixed results using various physical activity indices, and the remaining five were judged to demonstrate convincing evidence of a dose-response relation. Of note, the two most recent studies (4,45) observed dose-response relations, the former among older men and the latter among women. All studies relied on a single baseline point estimate of physical activity, in some cases assessed up to 26 yr before the end of the observational period.

Taken together, the major observational studies relating the risk of CVD incidence and mortality to physical activity indicate that the relation is likely causal, and the majority provide convincing evidence for a dose-response relation. A limitation of these studies, however, is that CVD is a large collection of diseases and disorders, many which may not be related to the atherosclerotic process or other biologic mechanisms that may be affected by physical activity. Further, the baseline assessment of physical activity as it relates to a CVD event in the distant future (up to 26 yr in the studies reviewed) does not take into account changes in behavior and clinical and physiologic status during the follow-up period. Thus, proximity of the exposure to the outcome becomes critical in these studies and points to the need for studies that assess changes in exposure, potential confounding variables, and outcome risk over time.

Coronary heart disease.

Beginning with the seminal work by Morris et al. (32), nearly 50 yr of work have accumulated a vast literature on the role that physical activity may play in the risk of CHD. These studies have examined the issue in populations worldwide and have examined physical activity as it relates to both occupation and leisure pursuits. Thorough and methodologically rigorous reviews have been published on the association of physical activity with CHD (2,5,39, and others) and have concluded that physical inactivity is causally linked to an increased risk of CHD. A substantial subset of these studies allows evaluation of the possibility of a dose-response relation. A summary of these major studies relating risk of CHD to dose of physical activity is presented in Table 2.

Table 2
Table 2:
Population-based studies of association of physical activity as related to coronary heart disease (CHD): English literature, 1953–August 2000.
Table 2
Table 2:
Continued
Table 2
Table 2:
Continued
Table 2
Table 2:
Continued

Twenty-three major observational studies, represented by 31 publications relating dose of physical activity to risk of CHD have been published since 1958 (6,9,10,11,16,19,23–25,28,30,31,33,34,36,40–42,44,46–48,50–53,56). Studies published before 1978 relied almost exclusively on determination of physical activity exposure by creating occupational classifications based on physical demands of job tasks. Thereafter, physical activity pursuits during leisure-time formed the bases for antecedent variable definition for most studies. Moreover, most studies before 1978 were not able to statistically control for potentially confounding variables. Thus, point estimates of risk are based on age-adjusted incidence alone in these studies.

One of the 23 studies was a large case series (31), one was a case-comparison design (24), and one was a secondary analysis of a large randomized clinical trial on CHD (25), although the original purpose of the study was not a physical activity intervention. The remainder of the studies were prospective in design, were in large populations, and had long-term follow-up periods (follow-up times ranged from 3 to 26 yr). Four publications (all published since 1995) included women, and two focused exclusively on women (24,52).

Most studies focused on age ranges of participants associated with risk of CHD (30–88 yr), and 9 of the 23 studies focused exclusively on fatal CHD whereas the remainder included a mixture of fatal and nonfatal outcomes. All studies but one (56) relied on a single point estimate of physical activity at the baseline assessment and related that to risk of CHD during follow-up.

Twenty of the reviewed studies were judged to provide support for a dose-response relation between physical activity and CHD. An additional three studies (9,33,47) provided mixed support for such a relation depending on the indices of physical activity used or cohort characteristics (data stratification) presented. Eight studies did not support the conclusion of a dose-response relation between physical activity and CHD (16,40,42,44,51). Results in these varied from null associations (16,40,42,51) to suggestions of threshold (41,48) to a “U”-shaped relation with a successively higher relative risk of CHD evident at the highest physical activity levels investigated (4,48).

The bulk of the existing scientific work on physical activity and cardiovascular disease has focused on CHD as the outcome. Since the earliest studies among London busmen (32), techniques for measuring physical activity have become more sophisticated, more populations have come under observation, and follow-up experience has grown. As stated previously, other, more methodologically rigorous reviews (2,39) have concluded that physical activity is causally and inversely related to CHD risk. Studies published since those reviews do not provide any indication to conclude otherwise. Physical activity is inversely related to risk of CHD, and the bulk of the observational studies suggest this inverse relation to be a dose response.

Stroke.

Stroke incidence and mortality is a major public health problem in developed countries. Atherosclerosis of the extra- and intracranial arteries is thought to be the general underlying pathologic basis of both CHD and thromboembolic (ischemic) stroke. Hypertensive disease, although a risk factor for CHD and thromboembolic stroke, is thought to be the major pathologic determinant of hemorrhagic stroke. A review of physical activity, physical fitness, and stroke has been published (21). A summary of literature of population-based observational studies of physical activity as they relate to stroke as an outcome is highlighted in Table 3.

Table 3
Table 3:
Population-based studies of association of physical activity as related to stroke (CVA): English literature, 1953–August 2000.
Table 3
Table 3:
Continued

The published literature from population-based observational studies relating physical activity to risk of CVA closely parallels that of CVD and CHD in terms of designs and populations under observation. Fifteen major studies (16 separate publications) that provide evidence toward evaluation of a physical activity dose–stroke response are available for review. Of these, four have analyzed the relation among women (14,15,20,43). Two of the 15 studies on physical activity and stroke were of a case-comparison design (14,43), with the remaining 13 being prospective, cohort studies with follow-up periods between 5 and 26 yr. Seven studies concentrated on fatal stroke as outcomes, one exclusively on nonfatal stroke and the remainder on a combination of fatal and nonfatal outcomes.

Six of the studies were judged to provide evidence of a dose-response relation (18,35,14,43,15,55), eight studies provided no support for a dose-response relation (4,7,10,12,22,26,27,41), and two provided mixed support (varying results in separate subanalyses) (1,20). Strikingly, several studies reported prominent “U”-shaped distributions of the relation between physical activity and risk of stroke (7,22,26,28).

Taken together, these findings suggest a questionable dose-response association between physical activity and risk of stroke. Indeed, they raise the question of the presence of any form of inverse association. Several of the studies are unable to separate out various subtypes of stroke (hemorrhagic vs occlusive). The importance of this observation lies in the fact that the pathophysiology of the two types of stroke is very different, and it is possible that physical activity may be differentially related to one type (occlusive) and not the other. Moreover, as with the CVD literature, all studies relate physical activity measured at baseline to stroke outcomes that are measured sometimes many years in the future. No studies have presented information on behavioral changes in physical activity and how that may relate to the change in the risk of stroke over time.

Physical activity is causally and inversely related to the risk of death due to CHD. A variety of mechanisms are available to explain this phenomenon. Given the probability of common pathophysiologic mechanisms in CHD and ischemic stroke, namely atherosclerosis, it follows that physical inactivity would also adversely affect the risk of stroke. Moreover, physical activity is known to indirectly do so and to positively be associated with blood pressure, clotting factors, glucose tolerance, and smoking habits (54), all factors that have been associated with increased risk of stroke. Although attractive as a hypothesis, the currently available data are equivocal concerning the role that physical activity may play in the risk of stroke. Existing studies do not show the consistencies noted in the association that are seen for CVD and CHD and do not support the conclusion of a dose-response relation.

SUMMARY AND FUTURE RESEARCH PRIORITIES

Physical activity appears to be inversely associated with the risk of CVD and specifically CHD in a dose-response fashion. The strength and the consistency of the evidence that has accumulated over the years has lead others to conclude that physical activity is causally linked to the incidence of CVD and particularly CHD. The evidence summarized in this review, including recent studies, supports those conclusions. Although the results of individual studies are variable in terms of point estimates of risk, the pattern that emerges when studies are taken together, is one of lower risk of CVD with ensuing higher levels of physical activity.

The role that physical activity may play in the risk of stroke is not as clear however. Although stroke is a cardiovascular disease, a much larger proportion is attributable to CHD. Therefore, the discrepant results seen among studies of CVD and CHD and studies of stroke may be attributed to the large proportion of CVD that is actually CHD in origin. When CHD and stroke are studied individually, the inverse association is readily apparent for CHD but not for stroke. Many studies designed to detect a dose-response gradient have been unable to do so, and there is some suggestion of a nonlinear, “U-shaped” relation. More work is needed to determine if physical activity is similarly related to risk of stroke as it is to risk of CHD.

Several unresolved issues are apparent when considering the relation between physical activity and cardiovascular disease. First, is physical activity, physical fitness, or some combination of both related to risk of CVD and CHD? Although physical activity is a behavior, it has many physiological effects on the circulatory, metabolic, and musculoskeletal systems. Most studies have used physical activity measures rather than fitness, and only two studies have jointly assessed both (13,51). The crudeness of existing physical activity measures as well as the genetic contributions to physical fitness continue to plague existing research. More work, with better measures of physical activity and joint measurement of physical fitness, is necessary to help quantify the environmental versus genetic contributions to reduced risk of CVD and CHD.

Second, there are few data on changes in physical activity or physical fitness as they relate to CVD risk. All studies but one (56) have relied on a single, baseline measure of physical activity or fitness and related that measure to risk of CVD or CHD sometime in the future. Follow-up periods in existing studies extend up to 26 yr. It is therefore more difficult to interpret these long-term follow-up studies without some measure of change during the course of the study. Behavioral changes and changes in health status and the like are more likely to occur with longer periods of follow-up observation, and, without an assessment other than that which was taken at baseline, there is a substantial probability that misclassification will occur.

There are no population-based observational studies that address the appropriate physical activity profile necessary to reduce the risk of CVD. There is convincing evidence of a dose-response relation between physical activity and/or physical fitness and risk of CVD and CHD in the populations studied. This has been translated in current recommendations that moderate intensity physical activity is sufficient to provide reduced risk of CVD and CHD (37). What is unavailable, however, is an assessment of the optimal way for which that dose should be accumulated (i.e., type, intensity, frequency of bouts, duration of bouts, and various interactions). There is no evidence that accumulation of a total dose of physical activity over an extended period of time at a relatively low intensity provides any protection against an increased risk of CVD or CHD although recent work (44) suggests that, after controlling for total energy expenditure, the duration of the exercise session becomes less important in predicting CHD risk. More work is needed to determine the type of exercise dose that is necessary for various population subgroups.

Studies in women and minority groups are glaringly lacking. Initial cohort studies of CVD and CHD were begun in white men because of the disproportionate disease burden in men compared with women as well as for convenience. The inertia of tradition apparently has made it difficult to gather similar data in women and blacks, Hispanics, and Asians. Such data are critical to complete our understanding and to provide appropriate, more targeted, intervention efforts. Despite the dose-response relation observed for physical activity and CVD and CHD, these data are largely gathered from observations among white men. Further study in women and other ethnic groups may reveal different pat-terns to the association such as a threshold or nonlinear relation.

Address for correspondence: International Life Sciences Institute, Center for Health Promotion, 2295 Parklake Drive, Suite 450, Atlanta, GA 30345; E-mail: hkohl@ilsi.org.

REFERENCES

1. Abbott, R. D., B. L. Rodriguez, C. M. Burchfield, and J. D. Curb. Physical activity in older middle-aged men and reduced risk of stroke: the Honolulu Heart Program. Am. J. Epidemiol. 139: 881–893, 1994.
2. Berlin, J. A., and G. A. Colditz. A meta-analysis of physical activity in the prevention of coronary heart disease. Am. J. Epidemiol. 132: 612–628, 1990.
3. Bijnen, F. C., C. J. Caspersen, and W. L. Mosterd. Physical inactivity as a risk factor for coronary heart disease: a WHO and International Society and Federation of Cardiology position statement. Bull. W. H. O. 72: 1–4, 1994.
4. Bijnen, F. V. H., C. J. Caspersen, E. J. M. Feskens, W. H. M. Saris, W. L. Mosterd, and D. Kromhout. Physical activity and 10-year mortality from cardiovascular diseases and all causes. Arch. Intern. Med. 158: 1499–1505, 1998.
5. Blair, S. N. Physical activity, fitness, and coronary heart disease. In:Physical Activity, Fitness, and Health: International Proceedings and Consensus Statement, C. Bouchard, R. J. Shephard, and T. Stephens (Eds.). Champaign, IL: Human Kinetics, 1994, pp. 579–590.
6. Donahue, R. P., R. D. Abbott, D. M. Reed, and K. Yano. Physical activity and coronary heart disease in middle-aged and elderly men: the Honolulu Heart Program. Am. J. Public Health 78: 683–685, 1988.
7. Evenson, K. R., W. D. Rosamond, J. Cai, et al. Physical activity and ischemic stroke risk. Stroke 30: 1333–1339, 1999.
8. Fletcher, G. F., S. N. Blair, J. Blumenthal, et al. Statement on exercise: benefits and recommendations for physical activity programs for all Americans. A statement for health professionals by the Committee on Exercise and Cardiac Rehabilitation of the Council on Clinical Cardiology, American Heart Association. Circulation 86: 340–344, 1992.
9. Folsom, A. R., D. K. Arnett, R. G. Hutchinson, F. Liao, L. X. Clegg, and L. S. Cooper. Physical activity and incidence of coronary heart disease in middle-aged women and men. Med. Sci. Sport Exerc. 29: 901–909, 1997.
10. Garcia-Palmieri, M. R., R. Costas, Jr., M. Cruz-Vidal, P. Sorlie, and R. J. Havlik. Increased physical activity: a protective factor against heart attacks in Puerto Rico. Am. J. Cardiol. 50: 749–755, 1982.
11. Haapanen, N., S. Miilunpalo, I. Vuori, P. Oja, and M. Pasanen. Association of leisure time physical activity with the risk of coronary heart disease, hypertension, and diabetes in middle-aged men and women. Int. J. Epidemiol. 26: 739–747, 1997.
12. Harmsen, P., A. Rosengren, A. Tsipogianni, and L. Wilhelmsen. Risk factors for stroke in middle-aged men in Göteburg, Sweden. Stroke 21: 223–229, 1990.
13. Hein, H. O., P. Suadicani, and F. Gyntelberg. Physical fitness or physical activity as a predictor of ischaemic heart disease? A 17-year follow-up in the Copenhagen Male Study. J. Intern. Med. 232: 471–479, 1992.
14. Herman, B., P. I. M. Schmitz, A. C. M. Leyten, et al. Multivariate logistic analysis of risk factors for stroke in Tilburg, The Netherlands. Am. J. Epidemiol. 118: 514–525, 1983.
15. Hu, F. B., M. J. Stampfer, G. A. Colditz, et al. Physical activity and risk of stroke in women. JAMA 283: 2961–2967, 2000.
16. Johansson, S., A. Rosengren, A. Tsipogianni, G. Ulvenstam, I. Wiklund, and L. Wilhelmsen. Physical inactivity as a risk factor for primary and secondary coronary events in Göteburg, Sweden. Eur. Heart J. 9: 8–19, 1988.
17. Kannel, W. B., A. Belanger, R. D’Agostino,and I. Israel. Physical activity and physical demand on the job and risk of cardiovascular disease and death: the Framingham Study. Am. Heart J. 112: 820–825, 1986.
18. Kannel, W. B., and P. Sorlie. Some health benefits of physical activity: the Framingham Study. Arch. Intern. Med. 139: 857–861, 1979.
19. Kaprio, J., U. M. Kujala, M. Koskenvuo, and S. Sarno. Physical activity and other risk factors in male twin-pairs discordant for coronary heart disease. Atherosclerosis 150: 193–200, 2000.
20. Kiely, D. K., P. A. Wolf, L. A. Cupples, A. S. Beiser, and W. B. Kannel. Physical activity and risk of stroke: the Framingham Study. Am. J. Epidem. 140: 608–620, 1994.
21. Kohl, H. W., and J. D. Mckenzie. Physical activity, physical fitness, and stroke. In:Physical Activity, Fitness, and Health: International Proceedings and Consensus Statement, C. Bouchard, R. J. Shephard, and T. Stevens (Eds.). Champaign, IL: Human Kinetics, 1994, pp. 609–621.
22. Lee, I-M., and R. S. Paffenbarger,Jr. Physical activity and stroke incidence. Stroke 29: 2049–2054, 1998.
23. Lee, I-M., H. D. Sesso, and R. S. Paffenbarger,Jr. Physical activity and coronary heart disease in men: does the duration of the exercise episodes predict risk? Circulation 102: 981–986, 2000.
24. Lemaitre, R. N., S. R. Heckbert, B. M. Psaty, and D. S. Siscovick. Leisure-time physical activity and the risk of nonfatal myocardial infarction in postmenopausal women. Arch. Intern. Med. 155: 2302–2308, 1995.
25. Leon, A. S., J. Connett, D. R. Jacobs, Jr., and R. Rauramaa. Leisure-time physical activity levels and risk of CHD and death: the Multiple Risk Factor Intervention Trial. JAMA 258: 2388–2395, 1987.
26. Lindsted, K. D., S. Tonstad, and J. W. Kuzma. Self-report of physical activity and patterns of mortality in Seventh-day Adventist men. J. Clin. Epidemiol. 44: 355–364, 1991.
27. Menotti, A., A. Keys, H. Blackburn, et al. Twenty year stoke mortality and prediction in twelve cohorts of the Seven Countries Study. Int. J. Epidemiol. 19: 309–315, 1990.
28. Menotti, A., and F. Seccareccia. Physical activity at work and job responsibility as risk factors for fatal coronary heart disease and other causes of death. J. Epidemiol. Community Health 39: 325–329, 1985.
29. Mensink, G. B. M., M. Deketh, M. D. M. Mul, A. J. Schuit, and H. Hoffmeister. Physical activity and its association with cardiovascular risk factors and mortality. Epidemiology 7: 391–397, 1996.
30. Morris, J. N., D. G. Clayton, M. G. Everitt, A. M. Semmence, and E. H. Burgess. Exercise in leisure time: coronary attack and death rates. Br. Heart J. 63: 325–334, 1990.
31. Morris, J. N., and M. D. Crawford. Coronary heart disease and physical activity of work: evidence of a national necropsy survey. Br. Med. J. 2: 1485–1496, 1958.
32. Morris, J. N., J. A. Heady, P. A. B. Raffle, C. G. Roberts, and J. W. Parks. Coronary heart disease and physical activity of work. Lancet 265:1053–1057, 1111–1120, 1953.
33. Paffenbarger, R. S., Jr., and W. E. Hale. Work activity and coronary heart disease mortality. N. Engl. J. Med. 292: 545–550, 1975.
34. Paffenbarger, R. S., Jr., W. E. Hal, R. J. Brand, and R. T. Hyde. Work-energy level, personal characteristics, and fatal heart attack: a birth-cohort effect. Am. J. Epidemiol. 5: 200–213, 1977.
35. Paffenbarger, R. S., Jr, R. T. Hyde, A. L. Wing, and C. H. Steinmetz. A natural history of athleticism and cardiovascular health. JAMA 252: 491–495, 1984.
36. Paffenbarger, R. S., Jr., A. L. Wing, and R. T. Hyde. Physical activity as an index of heart attack risk in college alumni. Am. J. Epidemiol. 108: 161–175, 1978.
37. Pate, R. R., M. Pratt, S. N. Blair, et al. Physical activity and public health: a recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 273: 402–407, 1995.
38. Physical Activity and Cardiovascular Health. NIH Consensus Development Panel on Physical Activity and Cardiovascular Health. JAMA 276:241–246, 1996.
39. Powell, K. E., P. D. Thompson, C. J. Caspersen, and J. S. Kendrick. Physical activity and the incidence of coronary heart disease. Ann. Rev. Public Health 8: 253–287, 1987.
40. Rodriguez, B. L., J. D. Curb, C. M. Burchfiel, et al. Physical activity and 23-year incidence of coronary heart disease morbidity and mortality among middle-aged men: the Honolulu Heart Program. Circulation 89: 2540–2544, 1994.
41. Rosengren, A., and L. Wilhelmsen. Physical activity protects against coronary death and deaths from all causes in middle-aged men. Ann. Epidemiol. 7: 69–75, 1997.
42. Rosenman, R. H., R. D. Bawol, and M. Oscherwitz. A 4-year prospective study of the relationship of difficult habitual vocational physical activity to risk and incidence of coronary heart disease in volunteer federal employees. Ann. N.Y. Acad. Sci. 301: 627–641, 1977.
43. Sacco, R. L., R. Gan, B. Boden-Albala, et al. Leisure-time physical activity and ischemic stroke risk. Stroke 29: 380–387, 1998.
44. Seccareccia, F., and A. Menotti. Physical activity, physical fitness, and mortality in a sample of middle aged men followed-up 25 years. J. Sports Med. Phys. Fitness l32: 206–213, 1992.
45. Sesso, H. D., R. S. Paffenbarger,Jr., T. Ha, and I-M. Lee. Physical activity and cardiovascular disease risk in middle-aged and older women. Am. J. Epidemiol. 150: 408–416, 1999.
46. Sesso, H. D., R. S. Paffenbarger,Jr., and I-M. Lee. Physical activity and coronary heart disease in men: the Harvard Alumni Health Study. Circulation 102: 975–980, 2000.
47. Shaper, A. G., G. Wannamethee, and M. Walker. Physical activity, hypertension, and risk of heart attack in men without evidence of ischaemic heart disease. J. Hum. Hypertens. 8: 3–10, 1994.
48. Shaper, A. G., and G. Wannamethee. Physical activity and ischaemic heart disease in middle-aged British men. Br. Med. J. 66: 384–394, 1991.
49. Sherman, S. E., R. B. D’Agostino, J. L. Cobb, and W. B. Kannel. Physical activity and mortality in women in the Framingham Heart Study. Am. Heart J. 128: 879–884, 1994.
50. Slattery, M. L., D. R. Jacobs, Jr., and M. Z. Nichaman. Leisure time physical activity and coronary heart disease death: the U.S. Railroad Study. Circulation 79:304–311, 1989.
51. Sobolski, J., M. Kornitzer, G. de Backer, et al. Protection against ischemic heart disease in the Belgian Fitness Study: physical fitness rather than physical activity? Am. J. Epidemiol. 125: 601–610, 1987.
52. Stampfer, M. J., F. B. Hu, J. E. Manson, E. B. Rimm, and W. C. Willett. Primary prevention of coronary heart disease in women through diet and lifestyle. N. Engl. J. Med. 343: 16–22, 2000.
53. Taylor, H. L., E. Klepetar, A. Keys, W. Parlin, H. Blackburn, and T. Puchner. Death rates among physically active and sedentary employees of the railroad industry. Am. J. Public Health 52: 1697–1707, 1962.
54. U.S. Department of Health and Human Services. Physical Activity and Health: A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, S/N 017-023-00196-5, 1996.
55. Wannamethee, G., and A. G. Shaper. Physical activity and stroke in British middle-aged men. Br. Med. J. 304: 597–601, 1992.
56. Wannamethee, S. G., A. G. Shaper, and M. Walker. Changes in physical activity, mortality, and incidence of coronary heart disease in older men. Lancet 351 (9116): 1603–1608, 1998.
Keywords:

CORONARY HEART DISEASE; STROKE; CARDIOVASCULAR DISEASE; ISCHEMIC HEART DISEASE; DOSE RESPONSE

© 2001 Lippincott Williams & Wilkins, Inc.