Physical Activity as Anti‐Inflammatory Therapy for Cardiovascular Disease

Field: Medicine (Health Sciences)

High levels of physical activity have multiple salutary effects on health, including the ability to reduce blood pressure, increase bone density and fibrinolytic activity, improve body composition, lipid profile and glucose tolerance, and enhance mood. Over the past few years, evidence has accumulated that regular physical activity provides another important health benefit as an anti-inflammatory agent. This editorial will review the evidence for, and potential importance of, this anti-inflammatory effect of regular exercise in the primary and secondary prevention of cardiovascular disease. It has traditionally been thought that the progression of atherosclerotic cardiovascular disease was related primarily to traditional risk factors such as serum lipid levels, blood pressure, and smoking. Although these risk factors are clearly important contributors to this process, inflammation is being increasingly recognized as an important modulator of atherosclerosis.1, 2 Early atherosclerotic lesions contain activated immune cells, including T cells, monocytes, macrophages, and endothelial cells. These cells produce a variety of cytokines identified in atherosclerotic lesions, including tumor necrosis factor-α, interleukin (IL)-1, 2, 4, 6, and 10, interferon-γ, and transforming growth factor β. What initiates this immune response is unclear; possible candidates are infectious agents,3, 4 heat-shock proteins,5 or oxidized low-density lipoprotein.6 In transplanted human hearts, coronary endothelial cell activation, a manifestation of heightened inflammatory activity, predicts future development of coronary atherosclerosis.7 The proinflammatory cytokines produced in active atherosclerotic plaque increase systemic markers of inflammation such as C-reactive protein (CRP), fibrinogen, and leucocyte count. Clinically, numerous studies have documented an association between higher blood levels of these acute phase reactants and the risk of future coronary events.8-12 Of these inflammatory markers, the most widely studied is CRP, produced in the liver from IL-6. In multiple, large cohort studies, elevated circulating CRP levels have been associated with increased risk of cardiac events or death in apparently healthy persons,9, 10 patients with stable angina pectoris,11 and those with acute coronary syndromes.11, 12 Elevated serum levels of CRP have been positively associated with several coronary risk factors.13, 14 Conversely, the potent cholesterol-lowering statin drugs are known to reduce circulating CRP levels.15 Thus, some of the atherosclerotic effects of these traditional risk factors may be mediated by their proinflammatory effects. Several cross-sectional studies have demonstrated an inverse relationship between levels of physical activity and inflammatory markers. Among 13,748 adult participants in the third National Health and Nutrition Examination Survey (NHANES III) (1988–1994), Ford et al.16 found odds ratios for elevated serum CRP of 0.98, 0.85, and 0.53 for individuals who engaged in light, moderate, or vigorous physical activity, respectively, during the prior month compared with totally sedentary persons. In addition, leisure-time physical activity was inversely correlated with log-transformed plasma fibrinogen level and leucocyte count. More recently, strong inverse correlations were found between CRP levels and body mass index (BMI) in 2846 children aged 3–17 years.17 Although physical activity was not measured in these children, it is likely that higher BMI was a marker for lower activity levels. In 5888 adults ≥65 years or older from the Cardiovascular Health Study, persons in the highest quartile of physical activity had 19%, 6%, 4%, and 3% lower CRP (Figure 1), leucocyte count, fibrinogen activity, and Factor VIII activity, respectively, compared with those in the lowest quartile after adjustment for age, gender, race, and cardiovascular risk factors.18 Multiple regression models suggested that the association of higher physical activity levels with lower levels of inflammatory markers was mediated by BMI and fasting glucose. Similar inverse relationships between serum CRP and physical activity have been observed in several other studies.19-21 Among 2833 participants in the multicenter community-based Pravastatin Inflammation/CRP Evaluation (PRINCE) study,19 CRP varied inversely with the frequency of strenuous aerobic activity in men, both before and after adjustment for BMI and traditional coronary risk factors. No such relationship, however, was observed in women. Faster times on a 6-meter walk were associated with lower CRP and IL-6 levels in a cohort of healthy 70–79 year olds in the MacArthur Study of Successful Aging.21 Adjusted mean C-reactive protein (CRP) levels by physical activity quartile in the Cardiovascular Health Study. Values were adjusted for age, gender, race, body mass index, smoking status, and the presence or absence of hypertension, diabetes, and cardiovascular disease. Reproduced with permission from Am J Epidemiol. 2001;153:242–250.18 Although cross-sectional studies have established an association between circulating inflammatory markers and physical activity, these studies cannot determine whether physical activity plays a causal role in this relationship. Recent data from longitudinal training studies do provide such a link. Among 43 asymptomatic middle aged adults with elevated serum complement or CRP, a 6-month supervised exercise program resulted in a 35% decline in CRP and attenuated production of interferon-γ, tumor necrosis factor-α and IL-1 by blood mononuclear cells.22 Overall production of atherogenic cytokines declined 58% after the exercise program. Decreases in cytokine production were proportionate to the time spent performing lower body motion exercises, suggesting a dose-response relationship. The effect of a formal 3-month phase II cardiac rehabilitation program on serum CRP levels was assessed recently in 235 patients after coronary revascularization and/or myocardial infarction.23 An additional 42 patients who entered rehabilitation but dropped out before starting active participation served as controls. In the exercising group, median CRP levels declined 41% from 3.4 to 2.0 mg/L, but was unchanged in controls. BMI did not change in either group. Furthermore, the magnitude of the CRP decline in the exercisers was similar regardless of whether they gained or lost weight (Figure 2) and whether they received statin drugs or not.23 Change in high-sensitivity C-reactive protein (HSCRP) after exercise training in patients who lost weight (n=121) vs. those who gained weight (n=100). Reproduced with permission from J Am Coll Cardiol. 2004;43:1056–1061.23 Finally, Gielen, et al.24 demonstrated increased local expression of tumor necrosis factor-α, IL-1 β, and IL-6 in skeletal muscle biopsies from patients with chronic heart failure. After 6 months of home exercise training on a cycle ergometer, local expression of these inflammatory cytokines decreased 36%–52% in vastus lateralis muscle biopsy specimens, although serum levels were unaffected by training. Given the adverse prognosis associated with elevations of these inflammatory markers in chronic heart failure, such training-induced reductions may have clinical relevance. Although it is unclear how physical activity levels might influence inflammatory activity, there are several possibilities. For example, an exercise-induced reduction in BMI can reduce IL-6 production from adiposites; IL-6 is a precursor to CRP. In addition, physical activity might reduce inflammation by improving insulin resistance, given that inflammatory markers are typically elevated in insulin-resistant individuals.13 By improving endothelial function, physical activity might reduce endothelial cell secretion of IL-1 and IL-6, both inducers of an acute phase inflammatory response. In heart failure patients, exercise training may augment the capacity of skeletal muscle to buffer the increased reactive oxygen species generated during exercise.25, 26 Among the many physiological benefits of physical activity is its anti-inflammatory effect. Both cross-sectional and longitudinal studies support an inverse relationship between inflammatory cytokines and physical activity levels in both healthy individuals and those with established cardiovascular disease. These anti-inflammatory effects may contribute, at least in part, to the protective effects of high physical activity levels on the development of future cardiovascular events. Prospective studies examining the effects of exercise training and other lifestyle interventions on cardiovascular risk factors and clinical events should include serial measurements of inflammatory markers to further elucidate their response to such interventions and their role in predicting adverse outcomes.