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Stimulated Production of Proinflammatory Cytokines Covaries Inversely With Heart Rate Variability

From the Behavioral Immunology Laboratory (A.L.M., A.A.P.), Department of Psychology, University of Pittsburgh; Department of Psychiatry (P.J.G., J.R.J.), University of Pittsburgh School of Medicine, Departments of Psychiatry and Behavioral Sciences and Psychology (S.A.N.), Eastern Virginia Medical School, Behavioral Physiology Laboratory (S.B.M.), Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Address correspondence and reprint requests to Anna L. Marsland, Behavioral Immunology Laboratory, Department of Psychology, 3943 O'Hara Street, Pittsburgh, PA 15260. E-mail: marsland{at}pitt.edu

Objective: To examine whether high-frequency heart rate variability, an indirect measure of parasympathetic (vagal) control over variations in heart rate, is associated with immune reactivity to an in vitro inflammatory challenge. Convergent evidence from the animal literature shows that the autonomic nervous system plays a key role in regulating the magnitude of immune responses to inflammatory stimuli. Signaling by the parasympathetic system inhibits the production of proinflammatory cytokines by activated monocytes/macrophages and thus decreases local and systemic inflammation. As yet, no direct human evidence links parasympathetic activity to inflammatory competence.

Methods: We examined the relationship of variations in heart rate, recorded during paced respiration, to lipopolysaccharide-induced production of the inflammatory cytokines interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-, and IL-10 among a community sample of 183 healthy adults (mean age = 45 years; 59% male; 92% White, 7% African-American).

Results: Consistent with animal findings, higher derived estimates of vagal activity measured during paced respiration were associated with lower production of the proinflammatory cytokines TNF- and IL-6 (r = –.18 to –.30), but were not related to production of the anti-inflammatory cytokine IL-10. These associations persisted after controlling for demographic and health characteristics, including age, gender, race, years of education, smoking, hypertension, and white blood cell count.

Conclusions: These data provide initial human evidence that vagal activity is inversely related to inflammatory competence, raising the possibility that vagal regulation of immune reactivity may represent a pathway linking psychosocial factors to risk for inflammatory disease.

Key Words: proinflammatory cytokines • heart rate variability • inflammation • autonomic nervous system • parasympathetic system

Abbreviations: ANS = autonomic nervous system; HRV = heart rate variability; HF = high frequency; LF = low frequency; rMSSD = root mean square of successive differences; IL = interleukin; TNF = tumor necrosis factor; LPS = lipopolysaccharide; WBC = white blood count; BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic blood pressure.