Depression and heart disease: What do we know, and where are we headed?
ABSTRACTDepression and heart disease have an intricate association and perhaps a causal relationship. We review the current status of depression and heart disease and provide an algorithm for diagnosing and treating depression in cardiac patients that internists and cardiologists can use in their daily patient encounters.
KEY POINTS
- Depression is a risk factor for new cardiac disease and has a detrimental impact in established cardiac disease.
- Numerous mechanistic pathways have been implicated.
- In clinical trials, drug therapy and psychotherapy have not clearly decreased the rate of cardiac death in depressed cardiac patients, but they did improve depression, adherence to drug therapy, and quality of life.
- Clinicians should routinely screen for depression in cardiac patients and should not hesitate to treat it.
- Eligible patients should routinely be referred to cardiac rehabilitation programs.
MEDICAL ILLNESS CAN PREDISPOSE TO DEPRESSION, AND VICE VERSA
Medical illnesses can predispose a patient to develop depression. Specifically, compared with healthy people, cardiac patients appear to be at greater risk of developing depression for many years after the initial medical diagnosis is made.41
Katon et al42 reviewed 31 studies involving 16,922 patients, that assessed the impact of depression and anxiety in chronic medical illnesses such as heart disease, diabetes, pulmonary disease, and arthritis. After the severity of the medical disorder was controlled for, patients with depression and anxiety reported a higher number of medical symptoms.
DEPRESSION WORSENS QUALITY OF LIFE AND ADHERENCE TO TREATMENT
Depressed patients perceive their health status and quality of life negatively. In the Heart and Soul study,43 depressive symptoms and low exercise capacity—but not low ejection fraction or ischemia—were significantly associated with perceived deterioration of health in patients with coronary artery disease.
After an MI, patients who take their cardiac drugs properly have a better chance of survival.44,45 Clinical depression can worsen compliance with cardiac medication regimens,46 and reducing depression increases medication adherence overall.47 Not surprisingly, depressed patients also adhere less well to other recommendations,48 including modifying the diet, exercising, stopping smoking, and attending cardiac rehabilitation programs. 49
PLAUSIBLE MECHANISMS LINK DEPRESSION AND HEART DISEASE
Traditional cardiac risk factors such as smoking, high cholesterol, hypertension, diabetes, and obesity tend to cluster in depressed patients. 50 Other mechanisms linking depression and heart disease are reviewed below.51,52
Autonomic imbalance
Excessive sympathetic stimulation or diminished vagal stimulation or both are associated with higher rates of morbidity and death.53
Lack of variability in the heart rate reflects a sympathetic-vagal imbalance and is a risk factor for ventricular arrhythmias and sudden cardiac death in patients with cardiovascular disease.54 Carney et al55 reported that patients with coronary artery disease and depression had significantly less heart rate variability than nondepressed cardiac patients. Similarly, after an MI, depressed patients had significantly less heart rate variability than nondepressed patients,56 implying that low heart rate variability may mediate the adverse effect of depression on survival after an MI.57
In the Heart and Soul study, Gehi et al58 found no distinct relationship between heart rate variability and depression. However, in the same study, de Jong et al59 did find specific somatic symptoms of depression to be associated with lower heart rate variability, although cognitive symptoms were not.
Platelet activation, endothelial dysfunction
Depressed patients have been found to have exaggerated platelet reactivity.60 Plasma levels of platelet factor IV and beta-thromboglobulin, markers of platelet activation, are higher in depressed patients with ischemic heart disease than in nondepressed patients with ischemic heart disease and in control patients.61 This activation of platelets can lead to vascular damage and thrombosis.
In a subset study of the Sertraline Anti-Depressant Heart Attack Randomized Trial (SADHART), depressed MI patients were treated with sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), and had substantially less platelet and endothelial biomarker release.62
Depressed cardiac patients also have impaired flow-mediated dilation of the brachial artery, a sign of endothelial dysfunction.63 Although a recent study did not find coronary endothelial dysfunction in depressed patients who did not have cardiac disease, these patients had more clustering of other cardiac risk factors.64
Hypothalamic-pituitary-adrenocortical and sympathetic adrenal medullary activation
High cortisol levels can accelerate the development of hypertension and atherosclerosis and result in endothelial vascular injury. Sympathoadrenal activation in turn can lead to higher levels of catecholamines, predisposing to vasoconstriction, a rapid heart rate, and platelet activation. Depressed patients have more activation of the hypothalamic-pituitary-adrenocortical and sympathetic adrenal medullary systems,51,65 yet another plausible mechanism for worse clinical outcomes in depressed cardiac patients.
Sudden emotional stress can cause transient left ventricular dysfunction, even in people without coronary disease, an effect that may be mediated by elevated plasma catecholamine levels.66
Inflammatory cytokines
Inflammatory cytokines play a key role in the development of atherosclerosis.67 C-reactive protein, an acute-phase reactant produced in hepatocytes, can be induced by cytokines such as interleukin 6. Damage to endothelial tissues leads to the release of inflammatory cytokines, including interleukin 1, interleukin 6, and tumor tumor necrosis factor alpha.
Depressed patients have higher levels of these inflammatory markers.68,69 A prospective study reported direct correlations between depression scores and C-reactive protein levels in post-MI patients.70 The Heart and Soul study, however, did not confirm that coronary patients have more inflammation if they have depression,71 indicating that the relationship is complex and is perhaps more evident in specific types of depression.72
Anticholinergic inflammatory pathway
Tracey73 proposed a theory that vagal tone inhibits the release of inflammatory cytokines. This has important implications for treatment, as exercise, biofeedback, and meditation can stimulate the vagus nerve and therefore have beneficial anti-inflammatory effects.74
Polymorphism in the serotonin transport promoter region gene
Research is focusing on the serotonin transport promoter region gene (5-HTTLPR).75 The gene exists in two forms, a long one and a less-effective short one that appears to predispose to depression.76
Nakatani et al77 showed that MI patients were more likely to become depressed and to have subsequent cardiac events if one or both of their alleles of this gene were short. Otte et al,78 using Heart and Soul study data, found that patients with a short allele had a higher likelihood of depression, higher perceived levels of stress, and higher urinary norepinephrine secretion. However, the long allele genotype may be associated with a higher risk of developing an MI.79
Our knowledge of the genetic interplay of depression and cardiovascular disease is still in its infancy, and further studies are needed to clarify these findings.
