(Paragraph #20) In this prospective analysis of middle-aged men, vigorous exercise was associated with a lower risk of CHD. A three hour per week increase in vigorous-intensity physical activity was associated with a 22% (95% CI 2%, 39%) lower risk of MI. In multivariable models including pre-existing CVD-related conditions, potential biological mediators of effect— HDL-C, vitamin D, Apo B, and hemoglobin A1c —attenuated the relative risk by 70% (95% CI 12%, 127%).
Other studies have investigated the potential mediators between physical activity and risk CHD, finding that biomarkers explain 22 – 40% of the inverse association (2
). Inflammatory factors have been identified as mediators in all studies, explaining 13 – 28% of the association between exercise and CHD. Hamer et al (11
) found that CRP and fibrinogen explained 13.2% of the association between physical activity and total CVD, which is similar to what we found. In the Women’s Health Study (18
), inflammatory markers explained 20.9%, novel lipids11.1%, traditional lipids 13.4%, HbA1c 5%, and BMI 6.8%. All risk factors combined explained 35.5% of the risk reduction. A larger proportion of the inverse association between physical activity and CHD risk was explained by the potential mediators we investigated when compared to previous studies. Potential explanations for this difference may be better exercise assessment in our cohort with the repeated measures of activity over 4 years and the greater variability in moderate and vigorous physical activity in this cohort of men.
We also found a modest proportion of the physical activity-CHD association was explained by serum 25-hydroxyvitamin D (25[OH]D), which was not accounted for in previous studies. Although not a traditional cardiovascular risk factor, low levels of serum 25(OH)D have previously been found to be associated with increased risk of MI (8
). Additionally, physical activity has been associated with increased levels of serum 25(OH)D likely due to increased sun exposure, a strong determinant of serum 25(OH)D (9
There are several possible mechanisms by which physical activity decreases risk of CHD. One pathway is through anti-atherogenic effects resulting from improved inflammation, lipid profile, insulin sensitivity, and body fat (3
). In the current analysis, we found these pathways explain approximately 45-70% of the decreased risk of CHD associated with physical activity. Additionally, physical activity may induce favorable changes in blood viscosity, blood pressure, and hemostatic factors that decrease risk of thrombogenesis and thrombosis (5
). Physical activity also decreases myocardial O2
demand and improves coronary blood flow and endothelial function which decrease risk of myocardial ischemia. Decreased risk of ventricular arrhythmias results from increased vagal tone and decreased adrenergic activity (9
). Future studies are necessary to determine which of the above mechanisms account for the remainder of risk reduction.
(Paragraph #24) Strengths of our study include the prospective design, detailed information on physical activity and covariates, a wide range of cardiovascular biomarkers, long duration of follow-up for the endpoint of MI, and strict criteria for defining coronary events.
(Paragraph #25) Our study also has limitations that should be considered. In a mediator analysis, we must be aware of potential confounders for the main effect association and the association between mediators and CHD. We adjusted for age, smoking, diet, alcohol use, and pre-existing disease. Unmeasured confounding by other variables, particularly biomarkers or genes that may be associated with both mediator and CHD, remains a potential limitation.
(Paragraph #26) Our study population, consisting of male health professionals, is not representative of the general population. Therefore, we cannot necessarily generalize our results to other populations with different educational levels, incomes, or distributions of race and ethnicity. Nonetheless, the relative homogeneity of the cohort in socioeconomic status may actually enhance the internal validity of this study.
We measured biomarkers at a single point in time. One measurement may not reflect true levels over time. To examine the potential impact of measurement error, we used data from men in a reproducibility study to correct for random within-person measurement error in HDL-C (27
). After correcting for measurement error, we found that HDL-C explained 50% of the physical activity-CHD association, compared to the uncorrected estimate of 38%.
(Paragraph #28) The mediators determined to explain the greatest proportion of association may be statistical intermediates, but may not be in the causal pathway. The pathway between physical activity and CHD is likely quite complex; thus, the most significant mediators may simply be markers of various pathways and not causal components. Additionally, as we fit the parsimonious model by selecting mediators with the most significant percent change when modeled separately, the 70% attenuation of the PA-CHD association may be optimistic.
(Paragraph #29) Measurement error in physical activity is unlikely to bias our results because data were assessed prospectively; thus, errors in physical activity are likely to be non-differential with respect to subsequent MI status. In addition, reporting error is unlikely to be associated with measurement of biomarkers. Random misclassifications would be expected to lead to underestimation of the true association.
(Paragraph #30) Engaging in regular vigorous-intensity activity is associated with a lower risk of MI among men. This inverse association can be partially explained by the beneficial effects of physical activity on HDL-C, vitamin D, Apo B, and HbA1c. While the inverse association attributable to these biomarkers is substantial, future research should explore benefits of exercise beyond these biomarkers of risk.