**2. Depression**

#### **2.1. Depression and Coronary Heart Disease (CHD)**

Among emotional factors, depression has been most widely studied in recent years. Depressive disorders vary from mild (subclinical) depressive symptoms to classic major depression. According to the Diagnostic and Statistical Manual of Mental Disorders, depression is characterized by low mood and/or anhedonia (lose interest in activities that once were pleasurable) that lasts for two weeks or more and is accompanied by signifi‐ cant functional impairment and somatic complaints (insomnia, excessive sleeping, fati‐ gue, loss of energy, or aches, pains or digestive problems that are resistant to treatment) [2]. Depression is 3 times more common in patients after an acute myocardial infarction than in the general community. In-hospital prevalence of major depression was 15% to 20% of patients with myocardial infarction, and an even more patients showed an elevated level of depressive symptoms [5]. Depression is regarded as an independent risk factor for atherosclerotic deposits in coronary arteries. The pathophysiological background covers hypercortisolaemia related to e.g. insulin resistance, sympathetic vagal dysbalance related to e.g. disturbed regulation of blood pressure, reduced heart rate variability, hypothalamicpituitary-adrenal axis dysfunction, increased plasma platelet factor 4 (suggesting en‐ hanced platelet activation), impaired vascular function, and increased C-reactive protein and fibrinogen levels (suggesting increased inflammatory response) and an unfavourable lifestyle like cigarette smoking, unhealthy diet, and lack of physical activity, medication adherence, as well as social isolation and chronic life stress [1, 5]. Depressive patients have higher risk of non-compliance with medical treatment regimens, therefore reduced chances of successful modifications of other cardiac risk factors and participation in cardiac rehabilitation, and have greatly reduced quality of life [5]. Major depression and elevated depressive symptoms are associated with worse prognosis in patients with CHD: in the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study, a multicen‐ ter, observational, prospective cohort, in healthy, European, middle-aged men were surveyed for the occurrence of first coronary heart disease and stroke events over 10 years. At baseline a questionnaire was used to define the presence of depressive symptoms. Results suggested that, baseline depressive symptoms are associated with an increased risk of coronary heart disease in the short-term and for stroke in the long-term [6]. Barefoot et al. assessed 1250 patients with documented CHD using the Zung Self-Report Depression Scale at the time of diagnostic coronary angiography and followed patients for up to 19.4 years. Results showed that patients with moderate to severe depression were at 69% greater risk for cardiac death and 78% greater risk for all-cause death [7]. Frasure-Smith et al. assessed gender differences in the impact of depression on 1-year cardiac mortality in patients hospitalized for an acute myocardial infarction. Increased depression scores were significantly related to cardiac mortality for both genders (the odds ratio for women was 3.29, for men, the odds ratio was 3.05). Data were controlled for other multivariate predictors of mortality (age, Killip class, the interactions of gender by non-Q wave myocardial infarction, gender by left ventricular ejection fraction, and gender by smok‐ ing) and showed that depression was independent predictor for either gender [8]. Most studies that have examined the relationship between increasing depression severity and cardiac events have shown a dose-response relationship: in a 5-year-follow-up study postmyocardial infarction patients were recruited and assigned to categories based on the severity of depressive symptoms, ranging from no depressive symptoms to moderate to severe depressive symptoms. During follow-up period, a gradient relationship was observed between the magnitude of depressive symptoms and the frequency of deaths, with increased events occurring even in patients with mild depressive symptoms [9]. In the prospective study of Brown et al. elderly adults with significant depressive symp‐ toms at baseline and without a current diagnosis of CHD at baseline were more likely to experience a cardiac event over a 15-year follow-up period. Depressed patients were 1.5 times more likely to suffer a cardiac event (i.e., acute myocardial infarction or cardiac death), even after controlling for demographics and known cardiovascular risk factors. The elevated depressive symptom severity is a predictor of cardiac events among older women and men as well as older white and black adults [10]. Despite methodological differences (sample sizes, sample characteristics, selection of covariates, etc) from study to study, the data from prospective studies with objective outcome measures and validated question‐ naires for depression are remarkably consistent in their results suggesting depression is a risk factor for both the development of and the worsening of CHD [5].

#### **2.2. Depression and CABG**

physiological mechanisms and pathways by which psychosocial factors may influence the outcome after surgery, and discuss some treatment directions likely to be critical to advancing

Among emotional factors, depression has been most widely studied in recent years. Depressive disorders vary from mild (subclinical) depressive symptoms to classic major depression. According to the Diagnostic and Statistical Manual of Mental Disorders, depression is characterized by low mood and/or anhedonia (lose interest in activities that once were pleasurable) that lasts for two weeks or more and is accompanied by signifi‐ cant functional impairment and somatic complaints (insomnia, excessive sleeping, fati‐ gue, loss of energy, or aches, pains or digestive problems that are resistant to treatment) [2]. Depression is 3 times more common in patients after an acute myocardial infarction than in the general community. In-hospital prevalence of major depression was 15% to 20% of patients with myocardial infarction, and an even more patients showed an elevated level of depressive symptoms [5]. Depression is regarded as an independent risk factor for atherosclerotic deposits in coronary arteries. The pathophysiological background covers hypercortisolaemia related to e.g. insulin resistance, sympathetic vagal dysbalance related to e.g. disturbed regulation of blood pressure, reduced heart rate variability, hypothalamicpituitary-adrenal axis dysfunction, increased plasma platelet factor 4 (suggesting en‐ hanced platelet activation), impaired vascular function, and increased C-reactive protein and fibrinogen levels (suggesting increased inflammatory response) and an unfavourable lifestyle like cigarette smoking, unhealthy diet, and lack of physical activity, medication adherence, as well as social isolation and chronic life stress [1, 5]. Depressive patients have higher risk of non-compliance with medical treatment regimens, therefore reduced chances of successful modifications of other cardiac risk factors and participation in cardiac rehabilitation, and have greatly reduced quality of life [5]. Major depression and elevated depressive symptoms are associated with worse prognosis in patients with CHD: in the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study, a multicen‐ ter, observational, prospective cohort, in healthy, European, middle-aged men were surveyed for the occurrence of first coronary heart disease and stroke events over 10 years. At baseline a questionnaire was used to define the presence of depressive symptoms. Results suggested that, baseline depressive symptoms are associated with an increased risk of coronary heart disease in the short-term and for stroke in the long-term [6]. Barefoot et al. assessed 1250 patients with documented CHD using the Zung Self-Report Depression Scale at the time of diagnostic coronary angiography and followed patients for up to 19.4 years. Results showed that patients with moderate to severe depression were at 69% greater risk for cardiac death and 78% greater risk for all-cause death [7]. Frasure-Smith et al. assessed gender differences in the impact of depression on 1-year cardiac mortality in patients hospitalized for an acute myocardial infarction. Increased depression scores were

the field.

464 Artery Bypass

**2. Depression**

**2.1. Depression and Coronary Heart Disease (CHD)**

CABG surgery is a common surgical intervention for CHD patients and prevalence of depression before or after CABG surgery is about 20–25% [4]. The presence of elevated levels of depressive symptoms results in a higher risk of mortality and significantly increased overall risk of major cardiac events following cardiac surgery [11]. In the prospective study of Connerney et al. 309 CABG patients were followed for 1 year after surgery. Compared with non depressed patients, depressed patients were more than twice as likely to have a cardiac event within 12 months after surgery but were not at higher risk for mortality within the first year [4]. In a larger sample of 817 CABG patients followed for up to 12 years, Blumenthal et al. assessed the effect of depression on mortality after CABG surgery. Depression was assessed both at baseline and 6 months after surgery. Results indicated that moderate to severe depression on the day before surgery as well as depression that persisted from baseline to 6 months after surgery were associated with 2-fold to 3-fold increased risk of mortality after adjustment for other risk factors [3]. Readmission following cardiac surgery is a significant burden on the healthcare system. In a prospective study, 226 CABG patients completed baseline self-report measures of depression, anxiety and stress and 222 patients completed these measures after surgery on the hospital ward. In multivariable analyses more than twofold increase in readmission risk was associated with preoperative anxiety and postoperative depression, independent of covariates [12]. When our work group investigated the relation‐ ship between depression, anxiety, education, social isolation and mortality 7.5 years after cardiac surgery, we found that there was a significant difference in depression (measured with Beck Depression Inventory (BDI)) between survivors and non survivors preoperatively, after discharge and in both intervals (Figure 1) [13].

depression had an 84% greater risk 5 to 10 years later and a 72% greater risk after "/> 10 years compared with the nondepressed.

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467

There were 290 patients (133 women) with at least mild to moderate symptoms of depression; 8.3% of the depressed women died of cardiac causes in contrast to 2.7% of the nondepressed. For depressed men, the rate of cardiac death was 7.0% in contrast to 2.4% of the nondepressed. Increased BDI scores were significantly related to cardiac mortality for both genders [the odds ratio for women was 3.29 (95% confidence interval (CI) = 1.02-10.59); for men, the odds ratio was 3.05 (95% CI = 1.29-7.17)]. Control for other multivariate predictors of mortality in the data set (age, Killip class, the interactions of gender by non-Q wave MI, gender by left ventricular ejection fraction, and gender by smoking) did not change the impact of the BDI for either gender.

Significant long-term dose-response relationship between depression symptoms during hospitalization and cardiac mortality was observed. Results remained significant after control for multiple measures of cardiac disease severity. Although 1-year scores were also linked to cardiac mortality, most of that impact was explained by baseline scores. Improvement in depression symptoms was associated with less cardiac mortality only for patients with mild depression. Patients with higher initial scores had worse long-term prognosis regardless of

symptom changes.

Cox proportional hazards models showed that individuals with elevated depressive symptoms were more likely to experience a CHD event, even after adjustment for demographics and comorbid health conditions (relative risk = 1.46, 95% confidence interval: 1.20-1.77). Depression status was also a significant predictor of allcause mortality in adjusted models.

Frasure-Smith N. Gender, depression, and one-year prognosis after myocardial infarction.

Lesperance F. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction

Brown JM. Risk of coronary heart disease events over 15 years among older adults with depressive symptoms

613 men 283 women

infarction.

Beck Depression Inventory (BDI) was used to assess depression symptoms during hospitalization after an acute myocardial

Short and Long Term Effects of Psychosocial Factors on the Outcome of Coronary Artery Bypass Surgery

896 Beck Depression Inventory was administered to

ascertained using Medicare data

2728 Depressive symptom severity at baseline was assessed by the Center for Epidemiologic Studies Depression Scale among primary care practice patients. Data regarding baseline demographic and clinical variables, as well as laboratory evidence of acute MI, were obtained from an electronic medical record system. Allcause mortality and CHD death were determined from the National Death Index

through 2006.

the patients after myocardial infarction during admission and at 1 year. Five-year survival was


ship between depression, anxiety, education, social isolation and mortality 7.5 years after cardiac surgery, we found that there was a significant difference in depression (measured with Beck Depression Inventory (BDI)) between survivors and non survivors preoperatively, after

**Methods Results**

Patients with moderate to severe depression at baseline (adjusted hazard ratio [HR] 2.4, [95% CI 1.4-4.0]; p=0.001) and mild or moderate to severe depression that persisted from baseline to 6 months (adjusted HR 2.2, [1.2-4.2]; p=0.015) had higher rates of death than did

those with no depression.

63 patients (20%) met criteria for major depressive disorder. At 12 months, 17 (27%) of these patients had a cardiac event compared with 25 of 246 (10%) who were not depressed (p<0.0008). In a Cox proportional-hazard model with these five and two other variables of cardiac severity, major depressive disorder (risk ratio 2.3 [95% CI 1.17-4.56]), low ejection fraction (2.3 [1.07-5.03]), and female sex (2.4 [1.24-4.44]) were associated with adverse outcomes. Depression did not predict deaths or

admissions for non-cardiac events.

1.45-4.25).

Depressive symptoms at baseline were associated with coronary heart disease in the first 5 years of follow-up (hazard ratio, 1.43; 1.10-1.87) and with stroke in the second 5 years of follow up (hazard ratio, 1.96; 1.21-3.19) after adjustment. The association was even stronger for ischemic stroke (n=108; hazard ratio, 2.48;

Depression was associated with increased risk of cardiac death (p = 0.002) and total mortality (p < 0.001) after controlling for initial disease severity and treatment. Patients with moderate to severe depression had a 69% greater odds of cardiac death and a 78% greater odds of mortality from all causes than nondepressed patients. Patients with moderate to severe

817 CABG patients completed the Center for

Epidemiological Studies-Depression (CES-D) scale before surgery, 6 months after CABG, and were followed-up for up to 12 years.

CABG patients screened for depression with a structured psychiatric interview (diagnostic interview schedule) and a questionnaire (Beck depression inventory) before discharge. Outcome: cardiac events included angina or heart failure that needed admission to hospital,

myocardial infarction, cardiac arrest, percutaneous transluminal coronary

9601 men The occurrence of first coronary heart disease

1250 Patients with established CAD were assessed for depression with the Zung Self-Rating Depression Scale and followed for subsequent mortality. Follow-up ranged up to 19.4 years.

among healthy men.

angioplasty, repeat CABG, and cardiac mortality. Non-cardiac events consisted of all other reasons for mortality or readmission.

(n=647) and stroke events (n=136) over 10 years

discharge and in both intervals (Figure 1) [13].

**of patients**

207 men and 102 women

**First author and title Number**

Blumenthal JA. Depression as a risk factor for mortality after coronary artery bypass surgery.

466 Artery Bypass

Connerney I. Relation between depression after coronary artery bypass surgery and 12 month outcome: a prospective study.

Majed B. Depressive symptoms, a timedependent risk factor for coronary heart disease and stroke in middle-aged men: the PRIME Study.

Barefoot JC. Depression and long-term mortality risk in patients with coronary artery disease.



Pathophysiological background by which anxiety influences outcome in ischemic heart disease is largely unknown. An increased incidence of ECG QT interval prolongation has been demonstrated among patients with anxiety, which increases the occurrence of ventricular arrhythmia [14]. Patients with anxiety have been shown consistently to have sympathetic nervous system upregulation, with excessive catecholamine production [15]. Furthermore, impaired vagal control, manifest as an impaired baroreflex response and a decrease in heart rate variability has been noted in patients with anxiety. Impairment of the baroreflex response and decreased heart rate variability are each thought to be sensitive markers for abnormalities in autonomic cardiovascular regulation and are independent risk factors for sudden cardiac death [16, 17, 18]. Patients with anxiety and CAD often show an exaggerated systemic response to stress, characterized by an abnormally increased production of catecholamines, which can result in increased myocardial oxygen demand due to elevations in heart rate, blood pressure, and the rate of ventricular contraction [19]. In addition to the biological risks of anxiety, the additive effects of adverse behavioural risk factors (e.g., excessive nicotine and perhaps caffeine) in anxious patients have also be taken into account [20]. Anxiety is very common in patients with myocardial infarction, with an inhospital occurrence rate of 30% to 40% [21]. Studies with coronary patients suggest that anxiety disorders may be associated with greater mortality, particularly sudden cardiac death, and greater cardiovascular morbidity. Higher levels of anxiety have been associated with poorer prognosis and greater recurrence of cardiac events after myocardial infarction [22]. In a cohort study the relative importance of depression, anxiety, anger, and social support in predicting 5-year cardiac-related mortality following a myocardial infarction was investigated. Higher level of anxiety predicted greater cardiacrelated mortality in a sample of nearly 900 patients with myocardial infarction, but this effect was non significant following adjustment for disease severity [23]. The first meta-analysis on the association of anxiety and coronary heart disease showed a consistent association between anxiety and impaired prognosis after myocardial infarction, with a 36% increased risk for mortality (cardiac and all-cause) and for cardiac events. Limitation of the result was the pooled

Short and Long Term Effects of Psychosocial Factors on the Outcome of Coronary Artery Bypass Surgery

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469

odds ratios for cardiac death, because it was based on only four studies [21].

Anxiety is especially high for CABG patients while they are on the waiting list with an unknown surgery date [24]. The patients have fear of dying before, rather than during surgery, and this fear influenced strongly their level of anxiety. Anxiety also manifests as an activator of sympathetic and parasympathetic nervous systems and cardiovascular excitation that can exacerbate CAD symptoms. After surgery, while anxiety may decrease to below pre-operative level, the severity of anxiety does not necessarily remit to below sub-clinical levels and may warrant intervention [25]. In the Post-CABG Trial the presence of anxiety symptoms was significantly associated with a higher incidence rate of death or myocardial infarction after a median follow-up time of 4.3 years following CABG. After controlling for the presence of depressive symptoms and other covariates (age, gender, race, treatment assignment and years since CABG surgery), a significant dose-response relationship persisted between anxiety and mortality. The observed dose-response relationship between level of anxiety and risk of death or myocardial infarction underlines the importance of even lower levels of anxiety. The risk

**3.2. Anxiety and CABG**

**Figure 1.** Figure showes significant difference in depression (BDI points) between survivors and non survivors preoper‐ atively, after discharge and in both intervals.
