The Inverse Association Between Cardiorespiratory Fitness and C-reactive Protein is Mediated by Autonomic Function: a Possible Role of the Cholinergic Antiinflammatory Pathway

Although studies have shown an inverse association between cardiorespiratory fitness (CRF) and C-reactive protein (CRP) levels, the underlying mechanisms are not fully understood. There is emerging evidence that autonomic nervous system function is related to CRP levels. Because high CRF is related to improved autonomic function, we hypothesized that the association between high CRF and low CRP levels would be affected by autonomic nervous system function. Cross-sectional analyses were conducted on 2,456 asymptomatic men who participated in a medical screening program. Fasting blood samples for cardiovascular disease risk factors were analyzed, and CRF was measured by maximal exercise treadmill test with expired gas analysis. We used an index of cardiac autonomic imbalance defined as the ratio of resting heart rate to 1 min of heart rate recovery after exercise (RHR/HRR). CRF was significantly correlated with CRP (r = -0.16, P < 0.05), and RHR/HRR (r = -0.48, P < 0.05), while RHR/HRR was significantly correlated with CRP (r = 0.25, P < 0.05). In multivariable linear regression models that adjusted for age, body mass index, smoking, disease status, medications, lipid profiles, glucose, and systolic blood pressure, CRF was inversely associated with CRP (beta = -0.09, P < 0.05). However, this relationship was no longer significant after adjusting for RHR/HRR in a multivariable linear regression model (beta = -0.03, P = 0.29). These results suggest that autonomic nervous system function significantly affects the relationship between CRF and inflammation in middle-aged men. Thus, physical activity or exercise training may favorably affect the cholinergic antiinflammatory pathway, but additional research is needed to confirm this finding.