Despite recent advances in prevention, diagnosis, and treatment, coronary artery disease (CAD) claims the lives of more than 500 000 women every year—about 1 death every minute—a number greater than the next 7 causes of death combined.¹ Although CAD mortality has declined among men over the past decade, there continues to be an unexplained increase in CAD mortality rates among women.

Coronary artery bypass graft (CABG) surgery is a common procedure for the treatment of CAD for both men and women in the United States. Women undergo approximately 28% of the total number of CABG procedures annually, or about 180 000 surgeries per year.¹ Because CABG surgery yields only a small benefit in absolute survival compared with medical treatment,² the primary goal of the surgery is to improve symptom burden, functional status, and quality-of-life outcomes. More than one third of patients continue to be symptomatic with angina, however, and have physical limitations after CABG surgery.^3,4 Thus, there is a large interindividual variation in the symptomatic and functional benefits associated with CABG surgery. The reasons for this variation in outcomes are poorly understood and not entirely explained by conventional risk factors and treatments. Alternative explanations must therefore be sought.

Women may be uniquely susceptible to adverse outcomes, or lack of benefits, after CABG surgery. In a follow-up study of patients who had received CABG surgery, we found that women had a more difficult recovery than men at 6 weeks after the surgery, and their physical and mental health was substantially worse than men’s at 6 months.^5,6 Although both men and women demonstrated, on average, a significant improvement in physical function and mental health, the proportion of patients whose scores improved was twice as large for men as for women; conversely, the proportion of patients who worsened was twice as large for women as for men. The sex disparity in outcome after CABG surgery was not ex­plained by disease severity, health status before surgery, or other patient characteristics. Thus, it is important to identify factors that influence functional outcomes after CABG surgery, especially in women, and special efforts should be directed toward understanding the underlying reasons for these differences in future studies.

Depression and outcomes after CABG surgery
In recent years, evidence has accumulated on the effects of mind–body interactions on health, particularly on the link between depression and CAD.^7-10 Depression is a highly prevalent condition among CABG pa­tients.¹¹ Of patients undergoing CABG sur­gery, 20% to 25% have depression during hospitalization, suggesting that a typical cardiologist doing rounds in a 25-bed hospital unit sees about 5 patients per day with this disorder. Women have a higher prevalence of depressive symptoms than men, as well as more severe depressive symptoms after CABG surgery.¹²

For cardiac patients, depressive symptoms predict mortality¹³ and hospital readmission,^14,15 and increase the frequency of cardiac events independent of traditional risk factors after CABG surgery.^16,17 The adverse effect of depression on outcomes after CABG surgery is consistent with its effect on other CAD patient populations, such as patients with stable cor­onary disease,¹⁸ acute coronary syn-d­romes,¹⁹ and congestive heart failure.²⁰ Depressive symptoms after CABG surgery also diminish the ability of patients to return to presurgical activity levels¹⁵ and to return to work,²¹ and they worsen cardiac-related symptoms^15,22 and sleep problems.²²

Our team examined the effects of depression on a global measure of functional status after CABG surgery among 963 CABG surgery patients.¹² We evaluated depressive symptoms using the Geriatric Depression Scale and physical function using the Short Form-36 Physical Component Scale at baseline and at 6 months after CABG surgery. At 6 months, we found a strong and graded association between the number of depressive symptoms at baseline and improvement in physical function. After adjusting for baseline physical function and other known factors that influence outcome after CABG surgery (ie, sociodemographic factors, social support, current smoking, number of hospitalizations in the year before admission, severity of CAD, angina class, and medical history), increasing levels of depressive symptoms retained a strong and significant trend toward less improvement in functional status. In fact, depressive symptoms tended to be a stronger inverse risk factor for functional im­provement after CABG sur­gery than traditional measures of disease severity, such as previous myo­cardial infarction (MI), heart failure on admission, history of diabetes, and even left ventricular ejection fraction, which was not associated with functional improvement. These findings show that depressive symptoms are at least as important as traditional measures of cardiac function in predicting functional outcomes after CABG surgery.

Sex and adverse events after CABG surgery
Although several studies have shown that depression is a strong and independent risk factor of outcome after CABG surgery, there is little information available on the unique effects of depression on women’s prognosis and how it compares with men’s after CABG surgery, perhaps because of the small number of wom­en included in several of these studies. Our data suggest that depressive symptoms are more strongly related to lack of improvement in functional status in women than in men after CABG surgery.¹² After adjusting for more than 20 common clinical variables, the likelihood of improved function was 75% lower for women if they had more depressive symptoms compared with women with fewer depressive symptoms. For men, the corresponding figure was 30% (P = .03 for the interaction between depression category and sex). These findings suggest that women might have greater vulnerability than men to the adverse effects of depression on the cardiovascular system. The higher prevalence of depression in women as well as a more negative influence of depression on post-CABG surgery outcomes in this group could explain why women derive less functional benefit from CABG surgery than men. Surprisingly, this question has not been systematically addressed. However, these results identify a unique feature of women undergoing CABG surgery and highlight the crucial importance of prompt identification and treatment of depression to improve outcomes in this group.

It is not surprising that depression is associated with a more adverse outcome in women compared with men. Women and men with CAD differ in a number of psychobehavioral dimensions that may impair functional outcomes. For example, marital stress increases the risk of recurrent cardiac events and death in women, whereas work stress is associated with in­creased CAD incidence and cardiac death in men.^23,24 There are also significant sex differences in coping strategies as well as social support networks that may influence recovery after a coronary event.²⁵

Our results are consistent with our previous studies showing that depressive symptoms predict congestive heart failure and incident CAD events in women but not in men,^26,27 although this may not apply to MI patients. In a study by Frasure-Smith and colleagues, depression was found to be a significant independent predictor of 1-year cardiac mortality for both wom­en and men hospitalized with MI, with a similar magnitude of effect by sex.²⁸ Future prospective multicenter studies are needed to evaluate the sex differences in the effect of depression in different coronary populations.

Potential mechanisms
Depression is associated with several pathophysiologic and behavioral mechanisms that could contribute to adverse cardiac outcomes in CAD patients. Patients with de­pression are in a constant state of perceived stress, which may be ac­companied by in­creased autonomic dysfunction and dysregulation of the hypothalamic-pituitary-adrenocortical axis.^29-31 De­pres­sion may increase platelet aggregability and immune activation, leading to worse outcomes.³² Al­though these may be po­tential mechanisms by which de­pres­sion could mediate increased mor­-tality, little is known about the mechanisms through which depression is associated specifically with functional status. In addition to biological mechanisms, some behavioral factors may in part link depression to lower functional status in cardiac patients.³³ Depressed patients are less likely than nondepressed patients to be compliant with medications or other treatment regimens, to follow recommendations regarding smoking cessation or exercise, or to practice self-management (eg, monitoring weight, participating in cardiac rehabilitation, or following up with their providers).³³ It is possible that similar mechanisms may be underlying the association between depression and lower functional benefits after CABG surgery. Clarification of these mechanisms should help to develop effective interventions aimed at preventing adverse outcomes in both male and female CAD patients with depression.

Conclusion
Depressive symptoms at the time of CABG surgery, particularly if se­vere, are associated with a lack of functional benefits at 6 months post-CABG surgery. The negative effects of depressive symptoms on functional outcomes after CABG surgery appear to be stronger in women than in men. Treatment trials are needed to evaluate whether the treatment of depression after CABG surgery can improve outcomes. In the meantime, current American College of Cardiology/American Heart Associa­tion guidelines for CABG surgery recommend evaluation of symptoms ­of depression and consideration of treatment of depression for both men and women.

Acknowledgement
This study was supported by grants from the Ethel F. Donaghue Women’s Health Investigator Pro­gram, New Haven, Connecticut and the Quality Care Research Fund, Aetna Foun­dation, Hartford, Con­necticut; and the Emory University Gen­eral Clinical Research Center MO1-RR00039. Dr Mallik is supported by grant K12RR17643 and Ameri­can Heart Association Scientist De­velop­ment Award 0630084N and Dr Vaccarino by grants K24HL077506, R01-HL68630, and R01 AG026255 from the National Institutes of Health.

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