Alterations in autonomic nervous system activity, as demonstrated by exaggerated responses in heart rate to orthostatic challenge or reduction in HRV, represent yet another mechanism that potentially contributes to the diminished survival of depressed patients with CVD. The beat-to-beat fluctuations in hemodynamic parameters are thought to reflect the dynamic response of cardiovascular control systems to a myriad of naturally occurring physiologic perturbations, such as fluctuations in heart rate associated with respiration. Therefore, HRV may provide a sensitive measure of the functioning of the rapidly reacting sympathetic, parasympathetic, and renin-angiotensin systems. Cardiovascular homeostasis is maintained by the parasympathetic and sympathetic nervous systems through afferent pressor receptors and chemoreceptors and efferents that alter heart rate, atrioventricular conduction, and contractility and impinge on the peripheral vasculature, altering arterial and venous vasomotor tone. HRV is the standard deviation of successive R-R intervals in sinus rhythm and reflects the interplay and balance between sympathetic and parasympathetic input on the cardiac pacemaker. Peripheral control of HRV occurs mainly through the parasympathetic cholinergic vagus nerve. Central generation and control of heart rate are regulated by the hypothalamus, the limbic system, and the brainstem. Numerous CNS neurotransmitters are involved in modulating HRV, including acetylcholine, NE, 5-HT, and dopamine.

A high degree of HRV is observed in normal hearts with good cardiac function, whereas HRV can be decreased significantly in patients with severe CAD or heart failure. Moreover, the relative risk of sudden death after an acute MI is significantly higher in patients with decreased HRV. Heart rate variability is one of many prognostic factors after an infarction [e.g., age, left ventricular ejection fraction (LVEF), and frequency of arrythmias]. Its positive predictive power, like that of other factors after an MI, is relatively modest when considered in isolation. Although positive predictive accuracy is not high when HRV is considered alone, in combination with other prognostic factors, clinically useful levels of negative predictive accuracy can be achieved. Among the many arrhythmogenic factors, autonomic tone is the most difficult to measure, and, therefore, interest in HRV continues. Power spectral analysis measurements of HRV often are used because certain frequency bands of the heart period power spectrum have been associated with autonomic nervous system control of the sinus node. The low-frequency power of the heart period power spectrum reflects modulation of sympathetic and vagal tone by baroreflex activity, while high-frequency power reflects modulation of vagal tone, primarily by respiratory frequency and depth (i.e., respiratory sinus arrhythmia). The physiologic mechanisms that contribute to ultralow-frequency and very low frequency power of the heart period spectrum (which account for more than 90 percent of the total power in a 24-h period) remain obscure. In a study of 715 patients after MI, certain frequency bands (total, ultralow, and very low frequencies) of the heart period power spectrum were strongly associated with mortality during 4 years of follow-up, even after adjustment for other major risk factors. Indeed, very-low-frequency power was most strongly associated with death secondary to arrhythmia.

Reduced high-frequency HRV has been observed in depressed patients in comparison with nondepressed groups, although discrepant reports exist. In patients with angiographically confirmed CAD, diminished HRV during 24-h Holter monitoring was significantly more common in depressed patients than in matched nondepressed patients. Diminished high-frequency HRV is thought to reflect decreased parasympathetic tone, possibly predisposing patients to ventricular arrhythmias and perhaps to the excessive cardiovascular mortality found in CVD patients with a comorbid major depressive disorder. Diminished HRV in patients with major depression also may be contributed to by a deficiency of omega-3 fatty acids in this patient population. Not only have multiple studies documented a deficiency of omega-3 fatty acids in patients with major depression, these polyunsaturated lipids possess antiarrhythmic properties and reduce the risk of ventricular arrhythmias.

Few studies have documented improvement of reduced HRV after effective depression treatment, either antidepressant or cognitive behavioral psychotherapy. Nevertheless, the complexity and chaos of HRV of depressed patients is increasingly characterized using nonlinear techniques, though the physiologic significance of such nontraditional methods requires further examination. Nevertheless, the prognostic importance of improvement in diminished HRV in depressed patients remains an intriguing area of research. Subsequent investigations will also seek to determine the processes that underlie ultralow and very-low-frequency bands of the heart power spectrum; whether these bands are altered in depressed patients (with or without CVD) remains obscure.