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J. Kelly Smith, MD; Rhesa Dykes, BS; John E. Douglas, MD; Guha Krishnaswamy, MD; Steven Berk, MD

JAMA. 1999;281:1722-1727.

Context  Increasing evidence demonstrates that atherosclerosis is an immunologically mediated disease in which the secretion of atherogenic and atheroprotective cytokines, by infiltrating blood mononuclear cells, plays an important role. It is not known whether long-term exercise alters this atherogenic and atheroprotective activity directly.

Objective  To determine the effect of long-term exercise on the atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease.

Design  Before-after trial using a 6-month individualized, supervised exercise program, with an enrollment period from December 1996 to October 1997.

Setting  Hospital-based community wellness center.

Participants  Of 110 persons who responded to a public request for volunteers, 52 met the inclusion criteria (risk ratio for myocardial infarction 1.7 based on serum complement and/or C-reactive protein levels, and normal exercise treadmill test results). Forty-three of the 52 enrollees (25 women [mean age, 49.7 years] and 18 men [mean age, 48.1 years]) completed the study; 9 withdrew for personal reasons. Additional risk factors for ischemic heart disease included hypercholesterolemia (65.1%), a family history of coronary heart disease (62.8%), inactivity (60.5%), hypertension (32.6%), obesity (25.6%), smoking (11.6%), and diabetes mellitus (4.7%).

Main Outcome Measures  Blood levels were compared at baseline and after the exercise program had been completed for the following: spontaneous and phytohemagglutinin-induced production of interleukin 1 , tumor necrosis factor , and interferon gamma (atherogenic cytokines), and interleukin 4, interleukin 10, and transforming growth factor beta 1 (atheroprotective cytokines) by blood mononuclear cells; lymphocyte phenotypes and mitogenic responses to phytohemagglutinin; and serum C-reactive protein levels.

Results  Subjects exercised for a mean of 2.5 (range, 0.3-7.4) hours per week. Mononuclear cell production of atherogenic cytokines fell by 58.3% (P<.001) following the exercise program, whereas the production of atheroprotective cytokines rose by 35.9% (P<.001). Changes in transforming growth factor beta 1 and in phytohemagglutinin-induced atherogenic cytokine production after the exercise program were proportionate to the time subjects spent performing repetitive lower-body motion exercises (P<.02), indicating a dose-response relationship. After the exercise program, changes in cellular function were reflected systemically by a 35% decrease in serum levels of C-reactive protein (P=.12).

Conclusions  Our data suggest that long-term exercise decreases the atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease. This may be a mechanism whereby physical activity protects against ischemic heart disease.

Author Affiliations: Divisions of Immunology (Drs Smith, Krishnaswamy, and Berk, and Ms Dykes) and Cardiology (Dr Douglas), Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City.

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