Hypothesis 4. Depression is associated with other physical precipitants of heart disease.

Lespérance F, Frasure-Smith N, Théroux P, Irwin M: The association between major depression and levels of soluble intercellular adhesion molecule 1, interleukin-6, and C-reactive protein in patients with recent acute coronary syndromes. Am J Psychiatry 161:271–277,2004

Investigators are avidly seeking pathophysiological (or biological) links between depression and coronary heart disease (CHD). Such data would further the status of depression as a modifiable CHD risk factor.

In this study, Lespérance et al. determined whether depressed patients with established CHD have higher levels of inflammatory markers following an acute coronary event when judged against comparable nondepressed patients. The development of thrombi from an atherosclerotic plaque leads to a release of cytokines (including interleukin-6 [IL-6]), elevation of serum proteins known as acute-phase reactants (such as C-reactive protein), and the expression and endothelial shedding of soluble intercellular adhesion molecules (such as sICAM-1). These markers tend to be elevated following an acute coronary event, and higher levels predict a worse prognosis.³⁶ The authors wondered whether depression further elevates these markers in patients with recent acute coronary syndromes,thereby increasing the risk for subsequent cardiac events and cardiac-related mortality.

Four hundred eighty-one patients from the Montreal Heart Institute referred for a coronary angiogram following a myocardial infarction (MI) or because of unstable angina were assessed for depression. The patients then provided blood samples for measurement of IL-6, sICAM-1, and C-reactive protein. sICAM-1, but not IL-6 or C-reactive protein, was found to differ between depressed and nondepressed patients. The results suggested to the authors that, in patients with a recent acute coronary syndrome, depression is associated with higher degrees of endothelial dysfunction. This relationship remained significant even after adjusting for possible confounders, including the presence of the metabolic syndrome.

The authors describe a number of limitations of the study. They had a refusal rate of about 50%, and blood draws occurred at various times relative to the time of the acute MI or episode of unstable angina. However, despite these limitations, the study has identified another marker associated with depression that may increase the risk for incident CHD, as well as for cardiac events, in patients with established CHD.

Diabetes is a major risk factor for incident CHD. Depression is common in patients with diabetes, as well as in patients with CHD.³⁷

Depression has been shown to predict incident cardiac disease in patients without clinical evidence of heart disease at the beginning of a longitudinal study and clinical cardiac events in patients with established CHD. For example, in a 12-year prospective study, high levels of depressive symptoms were associated with a 1.5-fold increase in the risk of fatal ischemic events in a group of community residents.³⁸ This effect was independent of demographic (age, sex, race, marital status, socioeconomic status) and cardiovascular risk factors (smoking, alcohol use, physical activity, blood pressure, cholesterol).

Likewise, in a recent study from the Women's Health Initiative, depression predicted CHD in 93,000 women followed for an average of 4.1 years.³⁹ Among those with no history of cardiovascular disease,depressed subjects had a relative risk (RR) of death due to cardiovascular causes of 1.5 after adjustment for age, race, education, and income, as well as diabetes, hypertension, smoking, high cholesterol, body mass index, and physical activity level.

Two meta-analyses of this literature were published recently. Using conservative inclusion criteria, Rugulies⁴⁰ identified 11 studies of depression or depressed mood in initially healthy subjects, with MI or cardiac-related death as the outcome variables. He found that the overall RR for developing CHD in depressed individuals was 1.6 (95% CI, 1.3–2.1). He also reported that clinical depression (RR = 2.7) was associated with a higher RR than was subclinical elevation in depressive symptoms (RR =1.5).

Using slightly different criteria but including some of the same studies,Wulsin and Singal⁴¹ identified 10 studies for their meta-analysis after reviewing 500 articles. They also found that depression imposed an RR of 1.6 for incident CHD.

In addition to being a risk factor for developing cardiovascular disease,depression, like diabetes, is a risk factor for cardiac events in patients with established CHD. This has been documented in patients following diagnostic cardiac catheterization, bypass surgery, or an episode of unstable angina. Depression is a particularly significant risk factor for morbidity and mortality following acute MI. After adjusting for the severity of the infarction, one study found the risk of death to be more than four times higher in the following 6 months among depressed than among nondepressed patients.⁴²

At the present time, it is not known how depression increases a patient's risk for incident CHD and cardiac events. Many studies have attempted to identify plausible biological or behavioral pathways that might link depression to medical outcomes. One such pathway includes dysregulation of the autonomic nervous system and hypothalamic-pituitary-adrenal axis, manifested by elevated plasma and urinary catecholamine and cortisol levels,abnormalities that have been detected in medically well patients with major depressive disorder. Neurohormonal and autonomic nervous system dys-regulation may induce proarrhythmic, procoagulant, and proinflammatory processes, thereby increasing the risk of sudden cardiac death, coronary thrombosis, and other cardiac events.

CHD generally is seen as a chronic inflammatory process involving immune response to injuries of the vascular endothelium. Inflammatory markers are elevated in patients with acute coronary syndromes, and, in fact, inflammatory processes are believed to underlie the development of atherosclerosis and to contribute to the evolution of thrombotic cardiac events. A number of studies in depressed patients without medical illness have shown that depression is accompanied by higher circulating levels of the inflammatory markers IL-6,C-reactive protein, and tumor necrosis factor-α. Whether these elevated inflammatory markers reflect comorbid CHD or another inflammatory process linked to depression remains unclear. However, some previous studies have involved young, healthy, depressed subjects who are unlikely to have atherosclerosis. Depression could lead to increased levels of inflammatory markers as a result of increased sympathetic activity associated with the affective illness.

The report by Lespérance et al. now links depression in CHD patients with sICAM-1, a marker of endothelial dysfunction. Endothelial dysfunction previously had been found in medically well depressed patients, even those without other cardiovascular risk factors. The types of endothelial markers that have been measured suggest atherosclerotic involvement of both cranial and coronary arteries, and some have speculated that cranial atherosclerosis may actually have a causative role in depression.⁴²

The Lespérance study provides further support for a relationship of depression with the basic mechanisms of atherosclerosis, but it is surprising that the authors found no differences between groups in IL-6 and C-reactive protein levels given the previous results in medically well depressed patients. However, differences in C-reactive protein levels between depressed and nondepressed patients were found in the subset that was not taking cholesterol-reducing statin agents, drugs that also reduce inflammatory markers. It is possible that any inflammation-reducing approach in depressed patients may decrease depression-related risks for cardiac events. This intriguing possibility may explain failure to detect a relationship between depression and mortality following acute MI in two recent studies,^43,44 as statin agents have become widely used in the treatment of CHD.

It is not known whether treating depression alone will reduce cardiac events in patients with established CHD. The recently completed Enhancing Recovery in Coronary Heart Disease clinical trial was designed to determine whether treating depression and social isolation will improve survival following acute MI.⁴⁵ The trial failed to find a significant difference in survival between the intervention and control arms, but there was only a small difference between groups in depression scores after the intervention. A more robust difference in levels of depression between the intervention and control groups may have led to improved survival in the actively treated patients.

Clearly, more work is needed to determine the effects of treatment of depression on medical outcomes. However, the presence of depression in patients with or at risk for heart disease should encourage aggressive treatment of other cardiac risk factors. At a minimum, depression treatment should improve a patient's quality of life.