ClinicalTrials.gov Identifier: NCT01335737

Principal Investigator:  Richard P. Sloan, Ph.D.

Aerobic exercise is widely recognized to reduce the risk of coronary heart disease, so much so that consensus panels routinely recommend physical activity as part of a cardioprotective regimen for healthy people.  Surprisingly, the physiological or mechanistic basis of this protection is uncertain. One line of investigation has examined the possibility that this cardioprotection derives from the anti-inflammatory effects of exercise, because inflammation occupies a central role in the pathogenesis of atherosclerosis. This application aims to conduct a definitive study to determine whether aerobic exercise exerts a cardioprotective effect by suppressing production of inflammatory mediators and, secondarily, to examine if this suppression is via a mechanism of increasing vagus nerve activity.

Understanding the mechanisms that underlie the beneficial effects of exercise is essential because it will allow development and testing of targeted interventions to produce comparable cardioprotective effects more directly or in cases where aerobic exercise is not possible.  Moreover, it can lead to the therapeutic application of exercise in other diseases characterized by disorders of these underlying mechanisms. Thus, the potential significance of this application is substantial.

A large body of evidence implicates inflammation in atherosclerosis but relatively few clinical studies of exercise and inflammation have been reported, and the conclusions from these studies are tempered by significant shortcomings in study design. Previous investigations generally have measured C-reactive protein (CRP) as the major endpoint.  Although important, CRP, like acute-phase proteins, is at the downstream end of the inflammatory mediator cascade.  Tumor necrosis factor (TNF), more upstream in this cascade, is rarely the focus of exercise studies despite evidence suggesting its role in plaque stability, endothelial dysfunction, and inflammatory damage in the arterial wall.  Additionally, many studies are cross-sectional in nature.  Studies employing training programs typically lack control groups or study only men. 

Our approach to this investigation addresses these shortcomings in several ways.  We propose to conduct a randomized controlled trial of aerobic exercise vs. a wait list control condition to test the impact on cell production of TNF ex vivo, in the whole blood milieu.  Study subjects will be young, healthy sedentary men and women, who are no more than average in fitness as established by the American Heart Association during initial VO2max testing.  Qualifying participants randomized to the exercise group will be studied after 12 weeks of training, and again after 4 weeks of sedentary deconditioning. Participants in the wait list group will be studied after 12 weeks of waiting, and again after another 4 weeks of waiting.  All randomized participants will be assessed for TNF production in blood, aerobic capacity, RR interval variability, and mood at randomization and at these time points.

Marna Freed