Several prospective studies have shown that CRF is inversely associated with CVD mortality in asymptomatic women and men (12
). Only a few studies in men have reported on CRF and risk of nonfatal CVD events (17
). To evaluate the true role of CRF in primary CVD prevention, it is important to determine whether CRF is related to incident events that are survived and not merely to mortality, and whether protection is conferred both in women and men. The present study demonstrated that higher CRF was associated with significantly lower rates of nonfatal CVD events. The inverse pattern of association was present in women and men, and in those with a low or a moderate/high pretest probability of CVD. Significant associations generally persisted after considering the potential confounding or modifying effects of physical activity status and other risk factors, although some associations were attenuated in women due to low statistical power. Inverse patterns of association also were seen between CRF and nonfatal CHD events and when MI and stroke were considered separately. This investigation is one of the largest prospective studies, and to our knowledge the first in women to relate an objectively measured CRF exposure with the incidence of several nonfatal CVD endpoints in initially asymptomatic adults.
Three of the study findings deserve further comment. First, CRF predicted primary CVD events independent of reported physical activity status. Because physical activity assessment was crude in the present study caution must be taken when considering the implications of this finding. Accurate questionnaire-based assessment of physical activity habits is difficult, particularly in women (11
). This partly may explain the lack of association between physical activity and CVD in the present women. Our findings suggest that assessment of CRF in asymptomatic women and men may provide important prognostic information above that obtained from self-reported physical activity habits. Clinicians should, therefore, consider the benefits and feasibility of more routine exercise testing.
In men, the inverse gradient of CVD risk across CRF groups remained significant after adjustment for confounding by age, smoking, family history of CVD, abnormal exercise ECG responses, and factors that may be intermediate in the causal pathway between CRF and CVD (BMI, dyslipidemia, hypertension, and diabetes). The present findings of a strong independent association between CRF and nonfatal CVD in men are consistent with previous ACLS findings on CRF and CVD mortality (12
), with findings in Finnish men on CRF and nonfatal CVD (17
), and with findings from studies that have related CRF (15
) or reported physical activity (5
) with combined fatal/nonfatal CVD in men. Similar patterns of association generally were seen in women. Lack of a significant association in the fully adjusted model that included biological intermediates may be due to the small number of cases and is consistent with some (5
) but not all (7
) studies on PA or CRF and CVD risk in women. For example, CRF predicted CVD mortality risk in women and men in the Lipid Research Clinics study (16
), whereas it was significantly associated with combined fatal/nonfatal CHD events in men but not women in the Framingham Heart Study (20
). Additional prospective data on CRF exposures and nonfatal CVD events are needed in women to expand on the findings reported here and elsewhere.
A second major finding was that the inverse association between CRF and CVD generally was consistent in strata of other CVD predictors. The prognostic value of CRF is particularly noteworthy in men who were older and who had diabetes, exercise ECG abnormalities, or co-existing risk factors at baseline. A sharp rise in the risk of a first CVD event occurs in adults ages 45 to 60 (1
). We observed that men ages 55 years or older had a 3-fold higher risk of CVD events than their younger counterparts. Diabetes and multiple co-existing risk factors now are seen as coronary risk equivalents in asymptomatic adults (33
). In our study, 10-year CVD risk was 50 percent greater in men with diabetes and was 3-fold greater in men with ≥2 risk factors than in men without either condition. Abnormal exercise ECG responses also are predictive of CVD events (20
) and were associated with a 2-fold higher risk of CVD events among men in our study. Even in these high-risk subgroups of men, higher functional capacity was associated with significantly lower CVD event rates. Stratified analyses were more variable in women, however greater functional capacity tended to be associated with lower CVD risk across risk factor stratum. CVD rates also were lower across incremental CRF groups in women with ≥2 risk factors. Statistical significance of these cross-tabulations in women was limited by the small number of events.
Collectively, the present results suggest that CRF is an important prognostic factor for nonfatal CVD in asymptomatic men beyond information obtained from the exercise electrocardiogram and traditional risk factors. Higher CRF is protective against CVD events in those with a moderate/high or a low pretest probability of CVD. Assessing functional capacity in asymptomatic women likely is of similar benefit to CVD risk assessment as in men (8
); however, additional data are needed to confirm the suggestive findings reported here.
A third noteworthy issue is the variety of CVD endpoints that were related to baseline CRF levels. A recent review of published prospective data on physical activity, CRF, and CVD outcomes indicated that the strongest inverse associations were for CVD mortality in men, and that additional data are needed in women and on nonfatal endpoints such as MI and stroke (35
). In the present women and men, CRF not only was inversely related with total CVD events, but also with MI, and with MI and coronary revascularization combined. MI or sudden death is the first clinical manifestation in many adults, among whom risk factors often are normal or only slightly elevated (33
). The findings reported herein and elsewhere (13
) suggest that low CRF is a significant predictor of atherothrombotic CVD events independent of the presence or absence of traditional risk factors. Assessment of CRF in clinical settings could, therefore be an important tool to facilitate more effective primary CVD prevention. Effective strategies are needed to better integrate exercise testing into CVD risk assessment (36
CRF also was inversely associated with stroke incidence in men, which is consistent with findings on CRF and stroke mortality in the ACLS (37
) and in Finnish studies (19
). Others have reported inverse associations between physical activity and stroke in women (4
). The inverse trend in stroke events across CRF groups was not significant in the present women, which may partly be due to the small number of stroke events. We were not able to differentiate between hemorrhagic and ischemic strokes, and stroke subtype modifies the association between physical activity and stroke risk (4
). Additional studies on activity, fitness, and stroke are needed to expand on our suggestive findings of an inverse association.
Strengths of the current study include the extensive baseline examination to detect subclinical disease, the use of measured risk factors and of maximal exercise testing to quantify CRF, the large person-years of follow-up, and the variety of CVD endpoints. We also accounted for variable patterns of survey responses in our analyses, an approach not typically used in cohort studies such as ours (4
). The inverse associations generally were graded and independent of traditional risk factors, which strengthens causal inferences. Biological plausibility for these associations may, for example, be through enhanced endothelial cell function and coronary flow reserve, reduced myocardial oxygen demand under a variety of circumstances, higher myocardial arrhythmia threshold, improved endogenous thrombolytic activity, and lower levels of circulating atherothrombotic cytokines which may promote coronary plaque stabilization (11
The homogeneity of our population sample in sociodemographic factors enhances the internal validity of our findings by reducing confounding by these factors. Although the self-referred origin and homogeneity of our cohort also may be seen as a weakness, we believe that our data are no less meaningful than those from population samples of adults referred to exercise testing for clinical reasons (39
), or data from other selected cohorts that have been influential in preventive cardiology (6
). Our findings should be generalized carefully to other adult populations. We did not have sufficient information on medication usage, menopausal status, or dietary habits to include in our analysis. It is possible that residual confounding by these factors may exist, although it seems unlikely that it would account for all of the observed association between CRF and CVD. Future studies should include such information to expand on the findings reported here. Women tend to manifest CVD events 10 years later than men. In the present study the age distribution in women was insufficient for grouped analysis beyond 55 years of age. Genetics clearly contribute to maximal CRF (40
). Nonetheless, CRF can be enhanced in most individuals through participation in moderate and vigorous physical activities, such as brisk walking, bicycling, and jogging, for 30 minutes or more on most days of the week (2
We conclude that CRF is a significant determinant of nonfatal primary CVD events in women and men. Assessment of CRF provides important prognostic information independent of exercise ECG responses and traditional risk factors, and in those with high and low pretest probabilities of CVD. Exercise testing to assess functional capacity may enhance CVD risk stratification beyond conventional office-based methods in asymptomatic adults. We believe that clinicians should consider the benefits of assessing CRF, and should vigilantly counsel their sedentary patients to become more physically active and improve their CRF as a cornerstone of primary CVD prevention.