Increased Secretion of Proinflammatory Cytokines

Inflammation and associated secretion of proinflammatory cytokines may mediate the association of depression and atherosclerostic progression. During inflammation, infection, and other conditions, intercellular signaling polypeptides known as cytokines are secreted by activated cells such as endothelial cells, fibroblasts, macrophages, and monocytes. Though cytokines exert a variety of effects in the acute-phase response, the proinflammatory cytokines, interleukin (IL)-1, IL-6, and tumor necrosis factor- (TNF-), stimulate production of hepatic-derived acute-phase proteins, such as C-reactive protein and fibrinogen, and also induce "sickness" behavior. Sickness behavior, a constellation of nonspecific signs and symptoms that accompanies the physiologic response to infection and inflammation, includes fatigue, anorexia, anhedonia, decreased psychomotor activity, and disappearance of body-care activities, which overlap with the symptoms of major depression. Perhaps not surprisingly, IL-6 is elevated in many patients with major depression, along with elevations of acute phase reactants, including fibrinogen.

Given reports linking increased secretion of proinflammatory cytyokines to symptoms of exhaustion in clinical samples, and elevations of fibrinogen in depressed individuals in large-scale, prospective, community-based, epidemiologic studies, future studies will ascertain whether inflammatory markers mediate the increased incidence of CVD and cardiac-related mortality in patients with depressive syndromes.

Myocardial Ischemia and Ventricular Instability in Reaction to Mental Stress

The combination of a vulnerable myocardium after MI, acute ischemia, and negative emotional arousal has long been thought to trigger fatal ventricular arrythmias. Indeed, Jiang and colleagues longitudinally assessed 126 patients with CAD over a 5-year period. Mental stress-induced myocardial ischemia at baseline in CAD patients was associated with significantly higher rates of subsequent fatal and nonfatal cardiac events independently of age, baseline LVEF, and previous MI. This study proposed that the relation between psychological stress and adverse cardiac events is mediated by myocardial ischemia. Although myocardial ischemia probably is the most significant factor in predisposition to ventricular instability, other factors also contribute. CNS control mechanisms can significantly decrease the threshold for ventricular fibrillation. Ventricular fibrillation is believed to be the mechanism underlying sudden cardiac death, the most common cause of fatality among patients with CAD. Indeed, psychological stress predisposes to abnormal ventricular activity by lowering the ventricular vulnerable-period threshold even to the point of fibrillation. The vagus nerve, however, exerts antiarrthymic activity through a direct action on the ventricular myocardium and interference with sympathetic activity. Increased parasympathetic activity has a protective effect on myocardium electrically destabilized by increased adrenergic tone.