Depression and cardiovascular disease: mechanisms of interaction

Depression and Cardiovascular Disease: Mechanisms of Interaction Karen E. Joynt, David J. Whellan, and Christopher M. O’Connor This article explores the relationship between depression and cardiovascular disease from a mechanistic standpoint. Depression and cardiovascular disease are two of the most prevalent health problems in the United States and are the two leading causes of disability both in the United States and worldwide. Although depression is a known risk factor for the development of cardiovascular disease, as well as an independent predictor of poor prognosis following a cardiac event, the mechanistic relationship between the two remains unclear. Depression is associated with changes in an individual’s health status that may influence the development and course of cardiovascular disease, including noncompliance with medical recommendations, as well as the presence of cardiovascular risk factors such as smoking and hypertension. In addition, depression is associated with physiologic changes, including nervous system activation, cardiac rhythm disturbances, systemic and localized inflammation, and hypercoagulability, that negatively influence the cardiovascular system. Further, stress may be an underlying trigger that leads to the development of both depression and cardiovascular disease. This article reviews seven potential mechanisms for the relationship between depression and cardiovascular disease and presents the available evidence surrounding each mechanism. Finally, future directions for research are discussed. Biol Psychiatry 2003;54:248 –261 © 2003 Society of Biological Psychiatry Key Words: Depression, cardiovascular disease, autonomic nervous system, heart rate variability, inflammation, platelets

Introduction

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ardiovascular disease (CVD) and depression are two of the nation’s most prevalent health problems. Cardiovascular disease is the leading cause of death and hospitalization in the United States and was responsible for 945,836 deaths, more than 6 million hospital dis-

From the Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina. Address reprint requests to David J. Whellan, M.D., Duke Clinical Research Institute, PO Box 17969, Room 7442 North Pavilion, Durham, NC 27715. Received January 10, 2003; revised March 17, 2003; accepted May 29, 2003.

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charges, and $350 billion in spending in 2000 (American Heart Association 2002). Depression, affecting 17 million Americans annually, accounts for direct and indirect costs approaching $43 billion per year (American Psychiatric Association 1998) and is the leading cause of disability worldwide (Murray 1996). Patients with depression have a twofold to fourfold increased risk of developing cardiovascular disease (Anda et al 1993; Ariyo et al 2000; Barefoot and Schroll 1996; Ford et al 1998; Penninx et al 2001; Pratt et al 1996) and a twofold to fourfold risk of mortality after experiencing a cardiac event (Frasure-Smith et al 1993, 1995; Barefoot et al 1996; Kaufmann et al 1999; Jiang et al 2001; Lesperance et al 2002; Penninx et al 2001). Recent review articles (Musselman et al 1998; Rozanski et al 1999; O’Connor et al 2000; Smith and Ruiz 2002) have concluded that symptoms of depression predict future coronary events for initially healthy individuals, as well as a poor prognosis for those who suffer from established CVD (see also Carney and Freedland, this journal). Despite the evidence that heart disease and depression are epidemiologically linked, the mechanistic correlation between the two is not well understood. It is difficult to compare data between studies because of the many different scales, instruments, and cutoffs used to detect depression, and it is not clear which symptoms of depression are predictive of poor outcomes in the setting of medical illness (see Carney and Freedland, this journal). Therefore, studies of depression and its interaction with CVD are necessarily complex; however, there are a number of mechanistic considerations that are important to explore as we continue to seek ways to improve prognosis for individuals suffering from depression, cardiovascular disease, or both. For example, depression is associated with changes in an individual’s health status that may influence the development and course of cardiovascular disease, including noncompliance with medical recommendations, as well as the presence of cardiovascular risk factors such as smoking and hypertension. In addition, depression is associated with physiologic changes, including nervous system activation, cardiac rhythm disturbances, systemic and localized inflammation, and hypercoagulability, that negatively influence the cardiovascular system. Further, 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00568-7

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know to be associated with poor prognosis (Ziegelstein et al 1998).

Depression, Health Status, and CVD: Risk Factor Clustering

Figure 1. Diagram of potential mechanisms for the relationship between depression and cardiovascular disease. Mechanisms could include causation via health status, causation via physiologic change, or the presence of an underlying factor that causes both depression and cardiovascular disease.

stress may be an underlying trigger that leads to the development of both depression and cardiovascular disease. This article reviews potential mechanisms for the relationship between depression and cardiovascular disease (Figure 1); future directions for research are also discussed.

Depression, Health Status, and CVD: Noncompliance Noncompliance with a medical regimen has been shown to worsen prognosis in CVD. Two large studies in the early 1990s suggested a twofold to threefold increased risk of mortality for noncompliant patients in the year following myocardial infarction (MI) (Horwitz et al 1990; Gallagher et al 1993). Depressed patients are more likely to be noncompliant, according to studies of CVD patients, as well as patients with other medical illnesses such as acquired immunodeficiency syndrome (AIDS) and asthma (Wang et al 2002). Carney et al (1995) found that depressed CVD patients were less likely to comply with a recommendation for daily aspirin therapy than nondepressed patients (45% vs. 69%); a study of 496 patients being treated for hypertension found depression to be the only variable independently associated with higher odds of noncompliance (Wang et al 2002). Patients who are depressed are also less likely to adhere to cardiac rehabilitation programs after MI (Ades et al 1992; Blumenthal et al 1982; Glazer et al 2002). However, it may be noncompliance itself, rather than noncompliance with a specific medical regimen, that is detrimental to prognosis. A meta-analysis by McDermott et al (1997) found that patients’ noncompliance to placebo was associated with a higher risk of morbidity and mortality. Noncompliance may be a marker of poor health behaviors that are detrimental to prognosis; alternatively, noncompliance may be a marker of depression, which we

A number of factors increase an individual’s risk for cardiovascular disease, including smoking, hypertension, diabetes, hypercholesterolemia, and obesity (Fuster et al 1996; Wilson et al 1998). In addition, “novel” risk factors such as homocysteine have been identified (Severus et al 2001). Depressed individuals may be more likely than nondepressed individuals to have one or more of these risk factors, and therefore the link between depression and CVD may be, in part, due to risk factor clustering. Although most studies examining this link have controlled for risk factors, the sum of the parts may be greater than the whole; that is, the presence of multiple risk factors may be inadequately controlled for because of the robustness of its effect. Cigarette smoking is associated with an increased risk of cardiovascular disease; the relative risk of CVD mortality associated with each additional pack of cigarettes smoked per day is approximately 1.39 (Multiple Risk Factor Intervention Trial Research Group 1986). In the US, 49% of individuals with depression smoke, whereas only 20% to 30% of the general population does so (Quattrocki et al 2000). A 1996 study suggested that a history of major depression conferred a threefold increased risk of becoming a smoker and that daily smokers had a twofold increased risk of developing major depression (Breslau et al 1998). Lifetime prevalence rates of depression for smokers are 30% to 45%, significantly higher than the 5% to 10% seen in the general population (Anda et al 1990; Hall et al 1993). Depressed smokers have repeatedly been shown to be less likely to successfully quit and more likely to experience withdrawal symptoms during their efforts at abstinence (Hall et al 1993; Anda et al 1990; Quattrocki et al 2000). All these factors combine to make smoking more prevalent within the depressed population than the nondepressed population. Patients with hypertension are significantly more likely to develop cardiovascular disease; a prolonged increase of 10 mm Hg above normal in diastolic pressure is associated with a 37% increased risk of CVD (Wilson et al 1998). A number of studies have investigated the relationship of depression and blood pressure, theorizing that the autonomic hyperactivity seen in patients with anxiety or depression (see later) has a pressor effect on the cardiovascular system, but prospective studies have yielded mixed results. Shinn et al (2001), following 508 adults for 4 years, found no association between either anxiety or

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depression and blood pressure; however, Jonas and Lando (2000) followed 3310 initially normotensive patients in the National Health and Nutritional Examination Survey (NHANES) I study and found that symptoms of depression and anxiety at baseline were associated with a higher risk of developing hypertension over 20 years of follow-up (relative risk [RR] white women ⫽ 1.73, RR black women ⫽ 3.12, RR all men ⫽ 1.56), controlling for demographic and behavioral risk factors for hypertension such as age, smoking status, and body mass index (BMI). Davidson et al (2000) followed 3340 individuals in the Coronary Artery Risk Development in Young Adults (CARDIA) Study and found that those with Center for Epidemiologic Studies-Depression (CES-D) scores ⱖ16 were significantly more likely to develop hypertension during 5 years of follow-up, again controlling for demographic and behavioral factors. The effect was particularly robust in black study subjects (odds radio [OR] ⫽ 2.70; 95% confidence interval [CI], 1.49-4.92). Diabetes is associated with a threefold to fourfold increased risk of cardiovascular disease and cardiovascular mortality (Garcia et al 1974). Depression is more prevalent in individuals with diabetes than in the general population; a recent meta-analysis examining 39 studies of depression and diabetes found a composite odds ratio for depression of 2.0 (95% CI, 1.8-2.2) (Anderson et al 2001). Data from the Epidemiologic Catchment Area study suggested a relative risk of 2.23 for development of diabetes over a 13-year follow-up for otherwise healthy individuals with depression compared with controls, but the data were found to be statistically nonsignificant (p ⫽ .11; 95% CI, .90-5.55) (Eaton et al 1996). Depression has been shown to negatively influence glycemic control in diabetic patients (Lustman et al 2000), as well as to increase the risk of complications including nephropathy, neuropathy, and retinopathy (de Groot et al 2001). Hypercholesterolemia is also an established risk factor for cardiovascular disease. Cardiovascular disease mortality increases 9% for each 10 mg/dL increase in plasma cholesterol (Anderson et al 1987), and individuals in the highest quartile of plasma cholesterol levels are 3 times more likely to die of CVD than those in the lowest quartile (Multiple Risk Factor Intervention Trial Research Group 1986); however, a link has been noted not between high cholesterol levels and depression but rather between low cholesterol levels and depression (Horsten et al 1997; Olusi and Fido 1996; Steegmans et al 1996, 2000), and cholesterol-lowering agents have been reported to cause depressive symptoms (Hyyppa et al 2003). A recent study by Steegmans et al (2000) replicated previous smaller trials, and found that men with chronically low cholesterol levels were more likely to experience depressive symptoms than controls, even after adjusting for potential

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confounders, including age, alcohol use, and chronic disease (RR ⫽ 7.0; 95% CI, 1.7-29.5) (Steegmans et al 2000). Olusi and Fido (1996) showed that clinical recovery from depression was associated with an increase in serum cholesterol to normal levels. One possible explanation for these findings is an alteration of serotonin metabolism: fatty acids compete with tryptophan, a serotonin precursor, for binding to albumin; fewer free fatty acids in the blood leaves more albumin available to bind to tryptophan, thereby decreasing the amount of free tryptophan available for conversion to serotonin in the brain (Steegmans et al 1996). Supporting this hypothesis, decreased plasma serotonin was associated with low cholesterol levels in a study of 100 individuals (Steegmans et al 1996). Interestingly, data from the Framingham study suggested that falling cholesterol levels over the first 14 years of observation, found in 14% of men and 20% of women, were associated with an increased risk of CVD death over the subsequent 18 years, although no data on depression is available from this study (Anderson et al 1987). Obesity is another known risk factor for cardiovascular disease. A recent examination of Framingham data showed that overweight (BMI 25.0-29.9) and obesity (BMI ⱖ30) were associated with relative risks of CVD of 1.2 and 1.64, respectively, in comparison to normal weight subjects (BMI 18.5-24.9) (Wilson et al 2002). There may be gender differences in the relationship between depression and obesity; a study of 2853 NHANES I subjects showed that obesity was associated with an increased risk of depression among women (OR ⫽ 1.38; 95% CI, 1.07-1.69) but not among men (Istvan et al 1992). More than 42,000 subjects were included in a study by Carpenter et al (2000), who demonstrated that obesity was associated with an increased risk of depression among women (OR ⫽ 1.37; 95% CI, 1.09-1.73) but a reduced risk of depression among men (OR ⫽ .63; 95% CI, .60-.67) Elevated plasma homocysteine is a novel cardiovascular risk factor; a recent meta-analysis found that a 25% lower homocysteine level was associated with an 11% lower risk of CVD (Homocysteine Studies Collaboration 2002), and reduction of homocysteine levels with B-vitamin supplementation has been shown to reduce vascular event rates after percutaneous coronary intervention (Schnyder et al 2002). A genetic polymorphism causing elevations in plasma homocysteine was also recently shown to be linked to CVD (Klerk et al 2002). Homocysteine levels are higher in depressed patients than in healthy controls, with 20% to 50% of depressed patients exhibiting homocysteine levels that would, based on studies of CVD patients, confer an increased risk of CVD mortality (Severus et al 2001). Further, folate supplementation, known to lower plasma homocysteine levels, may augment the antidepressant

Depression and CVD: Mechanisms

effects of fluoxetine in women (Coppen and Bailey 2000), and folate alone was found to have antidepressant properties in a small trial of elderly patients (Guaraldi et al 1993).

The Physiologic Impact of Depression on CVD: HPA and SA Activation Activation of the hypothalamic-pituitary-adrenocortical (HPA) axis can speed the development of CVD. Elevated cortisol promotes the development of atherosclerosis and hypertension and accelerates injury of vascular endothelial cells (Colao et al 1999; Troxler et al 1977). Hypothalamicpituitary-adrenocortical hyperactivity, in turn, augments sympathoadrenal (SA) hyperactivity via central regulatory pathways. The resulting increase in plasma catecholamines leads to vasoconstriction, platelet activation, and elevated heart rate, all of which are damaging to the cardiovascular system (Remme 1998). Matthews et al (1998) showed that the magnitude of stress-induced pulse pressure change predicted the appearance of carotid atherosclerosis in 254 initially healthy women, further evidence that sympathetic hyperresponsiveness might impact the development and progression of cardiovascular disease. Studies have consistently documented HPA hyperactivity in depressed patients, as reflected by elevated corticotropinreleasing factor (CRF) in cerebrospinal fluid, decreased adrenocorticotropic hormone (ACTH) response to CRF challenge, nonsuppression of cortisol secretion in response to dexamethasone, hypercortisolemia, and pituitary and adrenal gland enlargement (for review, see Plotsky et al 1998; Arborelius et al 1999; Ehlert et al 2001). Sympathoadrenal hyperactivity has also been demonstrated in depressed patients, manifest by elevated plasma norepinephrine as well as a hypersecretory catecholamine response to orthostatic challenge (Gold et al 2000; Maas et al 1994), although not all studies have found this association (Carney et al 1999). Therefore, HPA and SA hyperactivity may speed the development of CVD and worsen prognosis for patients with underlying CVD. Although these relationships remain largely unquantified, it is likely that they play a significant role in the effect of depression on the development and prognosis of cardiovascular disease.

The Physiologic Impact of Depression on CVD: Rhythm Disturbances Rhythm disturbances are associated with a poor prognosis in patients with cardiovascular disease. Sudden cardiac death accounts for 50% of deaths in patients with CVD (Buxton et al 2002; Goldstein et al 1984; Rouleau et al 1996), and a majority of sudden deaths in patients with CVD result from ventricular arrhythmias (Bayes et al 1989; Pires et al 1999). Decreased heart rate variability

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(HRV), which reflects sympathovagal imbalance (either heightened sympathetic activity, decreased parasympathetic regulation, or both), is a known risk factor for sudden death and ventricular arrhythmias in patients with CVD (for review, see Curtis and O’Keefe 2002; Huikuri and Makikallio 2001). For example, Kleiger et al (1987) found that CVD patients with low HRV, defined as a standard deviation (SD) of normal R-R intervals (SDNN) ⬍50 ms, were 5.3 times as likely to die in 31 months of follow-up as the group with normal HR variability (SDNN ⬎100 ms) and La Rovere et al (1998) found that SDNN ⬍70 ms carried a relative risk of cardiac mortality of 3.2 in a group of 1284 post-MI patients. Additionally, La Rovere et al (1998) showed that low baroreflex sensitivity (⬍3.0 ms/mm Hg), a measure of the body’s ability to vary heart rate in response to blood pressure change, was associated with a relative risk of cardiac mortality of 2.8. Depressed patients may have rhythm disturbances that predispose them to cardiac death. Carney et al (1993) showed that CVD patients with depression were significantly more likely to exhibit episodes of ventricular tachycardia during ambulatory monitoring than those without depression; Carney et al (2001) also monitored over 700 post-MI patients and found that depressed patients had significantly decreased HRV on four HRV indices, as compared to controls. Watkins and Grossman (1999) showed that depressive symptoms were associated with a 30% reduction in baroreflex sensitivity. Similarly, Yeragani et al (2000) showed that depressed patients had higher QT variability than controls, and Nahshoni et al (2000) demonstrated increased QT dispersion in patients with depression compared to controls. Rhythm disturbances might have a major impact on mortality for depressed patients with CVD; Frasure-Smith et al (1995), following over 200 patients after MI, found that while depressed patients had an odds ratio for mortality of 6.64 compared with nondepressed patients, depressed patients with a high frequency of premature ventricular contractions had an odds ratio for mortality of 29.1 (Figure 2). Much of the increased risk of mortality was a result of sudden death; the authors hypothesized that this increase might be a result of decreased HRV in the depressed patients in their sample (Frasure-Smith et al 1995). Patients with major depression have elevated sympathetic nervous system activity, as well as dysregulation of the HPA axis (see above); this combination of decreased parasympathetic control and increased sympathetic stimulation may explain the decreased HRV and high risk of fatal arrhythmias seen in depressed post-MI patients. Based on the available evidence, it seems feasible that depression may impact prognosis in CVD via its influence on rhythm.

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Figure 2. Bar graph of 18-month cardiac mortality in relation to premature ventricular contractions (PVCs) and Beck Depression Inventory (BDI) scores in the hospital after myocardial infarction. (Reproduced from Frasure-Smith et al 1995 with permission from Lippincott Williams & Wilkins.)

The Physiologic Impact of Depression on CVD: Inflammation Proinflammatory cytokines have been implicated in the pathogenesis of atherosclerosis and consequent cardiovascular disease (for review, see Koenig 2001; Mulvihill and Foley 2002; Robbins and Topol 2002). Damage to the endothelium of coronary vessels leads to the release of proinflammatory cytokines, such as interleukin (IL)-1, IL-6, and tissue necrosis factor alpha (TNF-␣). These cytokines induce leukocyte chemoattraction, while exposure of adhesion molecules causes inflammatory cells to adhere to the endothelium (Thompson et al 1995). Macrophages and T-cells then invade the vascular wall and further activate cytokine cascades and growth factor release. In response, intimal smooth muscle cells proliferate and atherosclerosis accelerates. Continued degradation of the plaque matrix by macrophages can cause plaques to become unstable, promoting thrombus formation and consequent vascular occlusion (Koenig 2001; Mulvihill and Foley 2002). The magnitude of the proinflammatory response to endothelial damage may predict progression and prognosis of coronary disease. Elevated plasma concentrations of C-reactive protein (CRP), a surrogate action marker for IL-6 (Papanicolaou et al 1998), have been reported in patients with acute ischemia and/or MI and predict recurrent ischemia and MI among patients with unstable angina (Liuzzo et al 1994; Thompson et al 1995; Ridker et al 1997). Ridker et al (1997) showed that initially healthy men who had elevated baseline levels of CRP were at greater risk for MI and stroke than those with normal levels; men in the highest CRP quartile had 3 times the risk of MI of those in the lowest quartile over 8 years of

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follow-up. Furthermore, aspirin, an anti-inflammatory drug, had its greatest effects in reducing the risk of MI in men with the highest levels of CRP (Ridker et al 1997). These data suggest that the degree of baseline inflammation for any individual may impact the body’s response to the initiation of the atherosclerotic process. Depressed patients both with and without cardiovascular disease have been shown to have elevated plasma levels of inflammatory markers (Maes et al 1993; Kop et al 2002; Appels et al 2000). Kop et al (2002) found that depression was associated with elevated CRP and fibrinogen in a sample of 4268 individuals without cardiovascular disease, while Appels et al (2000) found that depression was associated with elevated IL-1 in angioplasty patients and Musselman et al (2001) found that depression was associated with elevated IL-6 in cancer patients. Interleukin-6 is secreted in response to stress, probably through a ␤-adrenergic receptor mechanism, and is one of the most potent stimulators of the HPA axis (see previous), as well as of the release of other inflammatory cytokines (Maes et al 1993; Papanicolaou et al 1998); the increased levels of inflammatory molecules seen in depressed patients may therefore represent a response to chronic psychological distress (Leonard 2001). An augmented inflammatory response to endothelial damage and consequent accelerated progression of atherosclerosis and plaque rupture might explain the link between depression and CVD. Alternatively, inflammation might actually cause depression. Inflammatory hyperresponsiveness has been postulated to play a role in endothelial damage of the cerebral vasculature and thus contribute to the development of a specific subtype of depression known as vascular depression. Vascular depression is characterized by apathy, psychomotor changes, and cognitive impairment; it is more common in the elderly and less often associated with a family history of depression (Manolio et al 1994; Krishnan et al 1997; Steffens et al 2002). In both population studies and focused studies of depressed individuals, vascular changes, defined by lesions visualized on magnetic resonance imaging (MRI), are associated with worse depressive symptoms (Krishnan et al 1997; Steffens et al 2002). Further, these vascular changes correlate with the degree of atherosclerosis present, supporting the likelihood of a common underlying process (Manolio et al 1994). Steffens et al (2002) recently conducted a prospective study, showing that cerebrovascular disease at baseline predicted the worsening of symptoms of depression. Thomas et al (2000) showed that expression of intercellular adhesion molecule-1, a marker of ischemia-induced inflammation, is higher in the dorsolateral prefrontal cortex in depressed patients. These findings suggest that cerebrovascular disease and resulting ischemia can lead to

Depression and CVD: Mechanisms

inflammatory damage in brain areas implicated in depression (Thomas et al 2000). Currently, there is no evidence to suggest that vascular depression is more common in patients with CVD than without; a correlation would lend further support to the idea that inflammation-accelerated atherosclerosis is the common underlying pathology in depression and CVD that could explain their association. It is also possible that interleukins and other cytokines might affect the onset and progression of depression via systemic effects rather than via local endothelial damage and ischemia (Leonard 2001). Patients treated with IL-1 or interferon alpha for cancer or chronic viral infection, for example, tend to develop a syndrome of depressive symptoms such as anorexia and decreased social interaction (Maes et al 1993; Dantzer et al 1998; Capuron et al 2002); however, little other data exist to support cytokines as a causative agent for depression at the present time. Although it seems likely that inflammation impacts the progression of cardiovascular disease, it remains unclear whether the inflammation seen in depressed patients is a result of the stress response or whether inflammation contributes to the pathogenesis of depression. Further research will undoubtedly help to clarify these relationships.

The Physiologic Impact of Depression on CVD: Hypercoagulability Four components of hemostasis (blood coagulation, anticoagulation, fibrinolysis, and platelet activity) are crucial in the development and prognosis of CVD (Fuster et al 1992a, 1992b). When these components are dysregulated, a hypercoagulable state can result. The consequent promotion of fibrin deposition in the vasculature augments progression of CVD; increased levels of coagulationpromoting entities (including fibrinogen, Factor VII activity, Factor VIII activity, von Willebrand Factor antigen, tissue-type plasminogen activator antigen, type 1 tissuetype plasminogen activator inhibitor antigen, D-dimer, and plasmin-␣2 antiplasmin complex) have been shown to predict coronary syndromes, such as unstable angina, MI, and sudden cardiac death, in patients with CVD as well as healthy individuals (Davies 1996). The importance of hypercoagulability in prognosis for CVD patients is further supported by the therapeutic benefits of anticoagulant and fibrinolytic therapy in treating patients with both acute and chronic coronary syndromes (Braunwald et al 2003; Gibbons et al 2003). Platelet activation also clearly plays a role in ischemic heart disease, as demonstrated by the ability of antiplatelet therapies, such as aspirin and glycoprotein IIb/IIIa inhibitors, to improve long-term survival in patients with evolving MI or unstable angina (Antithrombotic Trialists’

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Collaboration 2002). Patients with thoracic aortic atherosclerotic disease have been shown to have elevated platelet activation relative to both normal controls and dialysis patients (Musselman et al 2002). A small number of studies investigating procoagulant factors in depression have found evidence of hypercoagulability in depressed individuals (for review, see von Kanel et al 2001). The Coronary Artery Risk Development in Young Adults Study suggested that fibrinogen levels were positively associated with the presence of depressive symptoms, although the degree of increase was small (Folsom et al 1993). Kop et al (2002), in a study including 4268 subjects free of CVD, found that depressed individuals exhibited elevated fibrinogen and factor VIIc, but these associations disappeared when statistical adjustments for risk factors and physical measures of frailty were added. The relationship of procoagulant factors to depression may be mediated by HPA or SA hyperactivity, as both have been shown to stimulate blood coagulation; hypercortisolism is associated with increases in factor VIII and von Willebrand Factor, as well as a decrease in fibrinolytic activity, while elevated norepinephrine is associated with concurrent increases in both coagulation and fibrinolysis (von Kanel et al 2001). While the data for procoagulant factors are equivocal, a number of studies have shown that untreated depressed patients have a variety of abnormalities in platelet function that lead to platelet activation (for review, see Markovitz and Matthews 1991; Nair et al 1999; Nemeroff and Musselman 2000). Platelet reactivity up to 40% greater than controls, as measured by ␤-thromboglobulin (␤-TG), platelet factor 4 (PF4), and antiligand-induced binding site (LIBS) antibody plasma levels, has been demonstrated in studies of depressed patients (Kuijpers et al 2002; Laghrissi-Thode et al 1997; Musselman et al 1996); the degree of activation is similar to that seen in patients with large-vessel atherosclerotic disease (Musselman et al 2002; (Table 3); however, studies of depressed patients’ platelet aggregation in response to thrombin, adenosine diphosphate, and collagen have shown mixed results (Lederbogen et al 2001; Maes et al 1996). Depression has been found to be associated with abnormalities in platelet serotonin 5-HT2A receptors (for review, see Mendelson 2000), including receptor upregulation (Hrdina et al 1995; Neuger et al 1999; Sheline et al 1995); these findings are of particular interest given the implication of serotonin abnormalities in the pathophysiology of depression (Leonard 2000). Many studies have reported that depressed patients demonstrate decreased platelet aggregation in response to serotonin (for review, see Mendelson 2000); however, Shimbo et al (2002) recently reported that platelet reactivity to serotonin was significantly increased in depressed patients, while reactivity to

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of paroxetine treatment. Serebruany et al (unpublished data) found that sertraline administration significantly decreased platelet activation compared to placebo, even with concomitant administration of aspirin and clopidogrel; however, it is still unknown whether the normalization of platelet function after SSRI treatment is the result of a decrease in depressive symptoms or a direct effect on platelets (Musselman et al 2000). Although more research is needed to elucidate the relationship between platelet activation and clinical outcomes, platelet activation may play an important role in the link between depression and the development and progression of CVD.

Figure 3. Platelet anti-LIBS binding of patients with major depression in comparison to normal controls, patients with aortic atherosclerosis, and dialysis-dependent patients. Anti-LIBS platelet binding levels were different among the four study groups by the overall Kruskal-Wallis analysis of variance (ANOVA) test (␹2 ⫽ 15.74, df ⫽ 3, p ⫽ .0012). The patients with depression had higher mean values of anti-LIBS than the normal comparison subjects (p ⫽ .02). The vertical lines are SD bars with a mean ⫾ of 1 SD. (Reproduced from Musselman et al 2002 with permission from John Wiley & Sons Inc.)

adenosine diphosphate was identical between depressed patients and matched controls. Whyte et al (2001) showed that depressed patients with the serotonin-transporterlinked promoter region l/L genotype (associated with a greater number of serotonin transporters) had increased platelet activation relative to both nondepressed controls and depressed patients without the l/L genotype, suggesting that genetic differences may influence the effect of serotonin dysregulation on platelet activation. Further supporting the theory that serotonin plays a role in platelet activation in depressed patients, an in vitro study of the selective serotonin reuptake inhibitor (SSRI) sertraline and its metabolite N-desmethylsertraline found both to inhibit platelets in a dose-dependent and significant fashion (Serebruany et al 2001a). Serebruany et al (2001b), in a study of 126 CVD patients presenting for revascularization, found that patients with antecedent SSRI therapy had significantly lower baseline platelet activation by a broad range of measures than those not using SSRIs. Pollock et al (2000) demonstrated that the administration of the SSRI paroxetine to depressed patients with ischemic heart disease and elevated PF4/␤-TG caused a significant reduction in PF4 and ␤-TG, while nortriptyline failed to impact platelet measures; Musselman et al (2000) similarly found that platelet activation was reduced to levels comparable to controls after 6 weeks

Common Underlying Cause: Stress, CVD, and Depression Stress has been implicated in the development and prognosis of cardiovascular disease. Although the biological definition of stress suggests that it is “a state of threatened homeostasis provoked by a psychological, environmental, or physiologic stressor” (Black and Garbutt 2002), many studies use self-reported “stress,” a much less precise measure, to evaluate the effect of stress on CVD. For example, a prospective study of 73,424 men and women in Japan found that women with self-reported high stress had a relative risk of 2.58 (95% CI, 1.21-5.47) for MI and 2.28 (95% CI, 1.17-4.43) for coronary artery disease, even after adjusting for demographic, medical, and psychological factors; the associations for men were not significant (Iso et al 2002). A study of 7000 men in Sweden suggested a relative risk of 1.5 for CVD among men reporting high stress but found no association between stress and CVD in a smaller subsequent sample (Rosengren et al 1991). A prospective study by Tennant et al (1994) of post-MI patients suggested that acute and chronic stress were associated with relative risks of reinfarction of 2.5 and 2.3, repectively, while two other studies found no relationship between life stress level and mortality after MI (Jenkinson et al 1993; Welin et al 2000). There are many ways in which stress may affect cardiovascular health (for review, see Bairey Merz et al 2002; Black and Garbutt 2002; Chrousos and Gold 1992; Esch et al 2002). Mental stress-induced myocardial ischemia might contribute; mental arithmetic under stressful conditions has been shown to cause paradoxical coronary artery constriction in patients with atherosclerotic disease, whereas healthy controls respond with dilation (Yeung et al 1991). Blumenthal et al (1995) and Jiang et al (1996) performed 48-hour ambulatory Holter monitoring on a sample of 132 subjects with documented CVD and subsequently performed radionuclide ventriculography during mentally stressful tasks (public speaking, mathematical

Depression and CVD: Mechanisms

Figure 4. Probability of event-free survival as a function of mental stress-induced left ventricular ejection fraction (LVEF) change plotted at 2 prototypical values, 1 SD below (LVEF change ⫽ ⫺12.40%) and 1 SD above (LVEF change ⫽ ⫹1.05%) the mean of the entire sample (LVEF change ⫽ ⫺6.73%). Curves are adjusted for baseline LVEF, history of myocardial infarction, and age. The risk ratio associated with the lower curve compared with the higher curve is 2.40 (p ⫽ .02). (Reproduced from Jiang et al 1996 with permission from the American Medical Association. Copyright © 1996, American Medical Association. All rights reserved.)

calculations, mirror tracing) and exercise testing. Fiveyear follow-up suggested that patients who had tested “positive” for mental stress-induced ischemia (new wall motion abnormality or reduction in ejection fraction ⬎5%) were more likely to experience a cardiac event (death, MI, or revascularization), even after adjusting for age, history of MI, and baseline ejection fraction (OR ⫽ 2.8; 95% CI, 1.0-7.7); transforming reduction in ejection fraction into a continuous variable yielded a standardized risk ratio for cardiac events of 2.4 (Jiang et al 1996) (Figure 4). Sheps et al (2002) assessed response to mental stress (a public speaking task) using radionuclide ventriculography in 196 patients with known CVD and found that the presence of new wall motion abnormalities during mental stress testing was associated with a relative risk of 2.95 for mortality over 5 years of follow-up; however, patients who demonstrated ischemia during ambulatory Holter monitoring were not at increased risk for events in either study, suggesting that the presence of stress-induced ischemia might be a marker for poor outcomes not because of chronic ischemia but rather via a different mechanism, such as autonomic hyperresponsiveness, an augmented neurohormonal response, or changes in other biological correlates of psychological stress that would impact cardiac outcomes (Jiang et al 1996). Autonomic function and inflammation, two systems discussed previously, may also account for the effect of

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stress on the cardiovascular system. The stress response is regulated by the HPA axis and the sympathetic nervous system, suggesting that many of the deleterious effects that hyperactivity of these systems can have on the cardiovascular system (see previous) might be triggered or augmented by stress (Black and Garbutt 2002; McEwen 2000). Similarly, several studies have proposed that inflammation is the intermediary factor; mental stress has been shown to induce cytokine production (Song et al 1999; Uchakin et al 2001), and cytokine production may have a negative impact on cardiovascular health (see previous). Although the definition of stress is somewhat less precise when moving from controlled laboratory experiments to real-life observations, evidence suggests that stress in daily life might influence the onset and course of depression (for review, see Brown and Harris 1978; Harris 2001; Kessler 1997). In community and clinic samples, stressful life experiences have been shown to correlate with the onset and course of depressive disorders (Lora and Fava 1992; Monroe et al 1983; Monroe et al 2001; Ravindran et al 1995). A longitudinal study of 680 pairs of twins investigating genetic, life event, and temperament variables found that a stressful event in the preceding year was the most powerful risk factor for depression (Kendler et al 1993). Stressful work environment has been shown to correlate with depressive symptoms (Chevalier et al 1996), as well as to predict a longitudinal increase in depressive symptoms (Paterniti et al 2002). Bosworth et al (2000) evaluated 335 inpatients with coronary artery disease and found that self-reported “negative life events” were predictive of depression (OR ⫽ 4.30; 95% CI, 1.39-13.27), even after controlling for demographic factors; however, much of the data driving the literature in this area is observational, making conclusions somewhat difficult to draw (Kessler 1997). In summary, patients who experience life stress may be at risk for adverse cardiovascular outcomes, as well as at increased risk for depression; CVD and depression might be two outcomes of the same causative agent.

Future Directions for Research Large-scale treatment studies, with collection of both physiologic and outcomes data, are needed as we attempt to put together the pieces of the puzzle linking depression and cardiovascular disease. Stress management and other nonpharmacologic interventions have shown mixed results in their ability to impact morbidity and mortality for depressed CVD patients. Frasure-Smith and Prince (1989) found that post-MI patients receiving stress-reducing interventions had a 50% decrease in cardiac mortality (4.5% vs. 9%), although no change was found in readmission

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rates. Blumenthal et al (1997) showed that post-MI patients in a stress management program had a relative risk for cardiac events of .26 compared to controls; however, the patient population was not assessed for depression. The Montreal Heart Attack Readjustment Trial (MHART), on the other hand, found that women receiving nonpharmacologic anxiety-reducing intervention after MI were actually more likely to die (RR ⫽ 1.39), with the increased mortality primarily related to sudden death caused by arrhythmias (Frasure-Smith et al 1997). The recent Enhancing Recovery in Coronary Heart Disease (ENRICHD) study failed to find evidence that psychotherapy for depression had any impact on survival in post-MI patients (Sheps 2003). Historical efficacy data are relatively sparse for pharmacologic interventions in CVD because of the cardiotoxicity of older antidepressants (Carney and Jaffe 2002); however, a recent study of sertraline for the treatment of depression in the post-MI population found sertraline to be safe and efficacious (Glassman et al 2002). Further, the treatment group had fewer cardiovascular events than the control group (14.5% vs. 22.4%), although the difference did not reach statistical significance (Glassman et al 2002); these results raise the possibility that appropriate treatment of depression, when concomitantly present, may reduce the morbidity and mortality associated with ischemic heart disease. The Myocardial Infarction and Depression-Intervention Trial (MIND-IT), currently underway in the Netherlands, will examine mirtazapine, citalopram, and placebo in depressed post-MI patients and may help clarify this issue (van den Brink et al 2002). Teasing out causative factors from factors that are simply coincidental, when a multitude of biologic and psychologic variables differ between each individual, is extremely difficult. Data collected specifically for the purpose of investigating mechanisms might help to shed light on this problem; for example, if an intervention causes a reduction in mortality for depressed patients with CVD, it would be useful to know whether heart rate variability concomitantly increases, or whether platelet activation decreases, or whether inflammatory mediators decrease. Any one of the physiologic changes associated with depression may or may not contribute significantly to the development and progression of CVD, and treatment studies are the best way to correlate those changes with outcomes. Finally, in the era of genetics and genomics, it will become increasingly common to investigate potential genetic causes for the linkage between symptoms, syndromes, and diseases. Although no conclusive research has of yet emerged regarding the genetics of the relationship between cardiovascular disease and depression, genetic links are certainly possible. Research regarding the

genetic basis of depression has identified candidate regions on chromosomes 4, 5, 11, 12, 18, 21, and X, although no single region has been shown to consistently predict depression (Souery et al 2001). A genetic predisposition for any of the pathophysiologic mechanisms listed above could be responsible for the development of both depression and CVD in an individual. For example, a genetic polymorphism causing elevations in plasma homocysteine has been linked to CVD (Klerk et al 2002), and a serotonin transporter polymorphism predicts increased cardiovascular reactivity to stress (Williams et al 2001). Alternatively, factors that are unrelated biologically but linked genetically may be creating a link that exists only at the most basic level. Ultimately, genetic and genomic discovery may allow us to better understand the linkages between depression and CVD.

Aspects of this work were presented at the conference, “The Diagnosis and Treatment of Mood Disorders in the Medically Ill,” November 12–13, 2002 in Washington, DC. The conference was sponsored by the Depression and Bipolar Support Alliance through unrestricted educational grants provided by Abbott Laboratories, Bristol-Myers Squibb Company, Cyberonics, Inc., Eli Lilly and Company, Forest Laboratories, Inc., GlaxoSmithKline, Janssen Pharmaceutica Products, Organon Inc., Pfizer Inc, and Wyeth Pharmaceuticals.

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