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.
Psychological and physical events can elicit a stress response, which usually is defined as the reaction of an organism to deleterious forces that disturb physiologic homeostasis. Psychological stress in humans with CAD increases ventricular ectopic activity and increases the risk of ventricular fibrillation. There are several similarities between the stress response and major depression: both can be characterized by increased blood pressure and heart rate as well as increased arousal and increased mobilization of energy stores. Particularly relevant to both the stress response and depression are the critical brain structures-the locus coeruleus and the central nucleus of the amygdala-which both are innervated by CRF-containing nerve terminals. The stress response and major depression differ in some respects, however. In depression, some aspects of the normal stress response seem to escalate to a pathologic state that fails to respond appropriately to usual counterregulatory responses, resulting in a sustained version of a usually transient phenomenon (i.e., hyperactivity of the HPA axis or the sympathoadrenal system). Although many studies have linked stressful life events to the onset of major depression, some depressions are clearly “endogenous” (i.e., they have no obvious environmental precipitant).
Frasure-Smith and colleagues proposed that depression worsens the prognosis after an MI through another mechanism: PVCs. The risk of sudden cardiac death associated with significant depressive symptoms (Beck Depression Inventory score >10) was greatest among patients with 10 or more PVCs per hour (60 percent of these patients died within 18 months), suggesting arrythymia as the link between depression and sudden cardiac death. Depressed patients with CAD are not more likely to have arrhythmias than are nondepressed patients with CAD, but the risk associated with depression is confined largely to patients with PVCs. Patients who were not depressed experienced little increase in risk associated with PVCs even in the presence of a low LVEF. Thus, the prognostic impact of PVCs may be related more to depression than to PVCs per se. In the Cardiac Arrhythmia Suppression Trial (CAST), suppression of PVC frequency in post-MI patients did not reduce but actually increased mortality even though PVCs are associated with increased mortality after an MI. Thus, treatment of depression may be necessary to improve survival in depressed patients with PVCs.
Depression and Comorbid Medical Illness
Depression and Cardiovascular Disease: Clinical Samples
Anxiety Disorders and Cardiovascular Disease
Diminished Heart Rate Variability
Hypothalamic - Pituitary - Adrenocortical and Sympathomedullary Hyperactivity
Alterations in Platelet Receptors and/or Reactivity
Pathophysiology of Anxiety
Treatment of Major Depression and Anxiety Disorders in Patients with Cardiovascular Disease
Effects of Mood and Anxiety Disorders: Future Directions for Research
Revision date: July 3, 2011
Last revised: by Andrew G. Epstein, M.D.