Autonomic Nervous System Dysfunction and Inflammation Contribute to the Increased Cardiovascular Mortality Risk Associated With Depression

Objective: To investigate prospectively whether autonomic nervous system (ANS) dysfunction and inflammation play a role in the increased cardiovascular disease (CVD)-related mortality risk associated with depression. Methods: Participants in the Cardiovascular Health Study (n = 907; mean age, 71.3 ± 4.6 years; 59.1% women) were evaluated for ANS indices derived from heart rate variability (HRV) analysis (frequency and time domain HRV, and nonlinear indices, including detrended fluctuation analysis (DFA1) and heart rate turbulence). Inflammation markers included C-reactive protein, interleukin-6, fibrinogen, and white blood cell count). Depressive symptoms were assessed, using the 10-item Centers for Epidemiological Studies Depression scale. Cox proportional hazards models were used to investigate the mortality risk associated with depression, ANS, and inflammation markers, adjusting for demographic and clinical covariates. Results: Depression was associated with ANS dysfunction (DFA1, p = .018), and increased inflammation markers (white blood cell count, p = .012, fibrinogen p = .043) adjusting for covariates. CVD-related mortality occurred in 121 participants during a median follow-up of 13.3 years. Depression was associated with an increased CVD mortality risk (hazard ratio, 1.88; 95% confidence interval, 1.23–2.86). Multivariable analyses showed that depression was an independent predictor of CVD mortality (hazard ratio, 1.72; 95% confidence interval, 1.05–2.83) when adjusting for independent HRV and inflammation predictors (DFA1, heart rate turbulence, interleukin-6), attenuating the depression-CVD mortality association by 12.7% (p < .001). Conclusion: Autonomic dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression, but a large portion of the predictive value of depression remains unexplained by these neuroimmunological measures. ANS = autonomic nervous system; LF = low frequency; CI = confidence interval; PNN50 = percent of successive RR interval differences >50 ms; CRP = C-reactive protein; CES-D = Centers for Epidemiological Studies Depression scale; PVC = premature ventricular complex; RMSSD = root mean square successive difference of RR intervals; CHS = Cardiovascular Health Study; CVD = cardiovascular disease; SD = standard deviation; DFA1 = detrended fluctuation analysis; SDNN = standard deviation of the NN intervals; HF = high frequency; HR = hazard ratio; HRT = heart rate turbulence; TO = turbulence onset; HRV = heart rate variability; TS = turbulence slope; VLF = very low frequency; IL-6 = interleukin-6; WBC = white blood cell count.