Electronic Journal of Biology

Keywords

Anxiety; Depression; Coronary heart disease and acute myocardial infarction.

Introduction

In the United States (US), the prevalence of Coronary Heart Disease (CHD) is 6.3% in adults greater than 20 years of age [1]. In 2012, approximately 9 million Americans visited physician for CHD [1]. Over a 4 years period from the beginning of 2011 to the end of 2014, an estimated 16.5 million Americans greater than 20 years of age had CHD [1]. Among all Americans less than 55 years old, CHD mortality did not decline between 1990 to 2011 [1]. In males and females less than 75 years of age, CHD makes up more than half of all cardiovascular events [2].

Approximately every 40 s, an American will have an acute myocardial infarction (AMI) due to CHD [1]. Coronary Heart Disease was an underlying cause of death in ≈ 1 of every 7 deaths in the US in 2014 with an overall age-adjusted death rate 98.8 per 100,000 [3]. Coronary Heart disease is prevalent in developing countries as well. For instant, In Jordan, a developing low income country; where this study was conducted, CHD caused approximately 19% of the total deaths and the rate per 100,000 is 131 leaving Jordan in the rank of 46 worldwide [4]. Acute myocardial infarction due to CHD was found to have a significant prevalence in Jordan according to the Jordan Ministry of Health statistics [5].

Anxiety and depression are the most common prevalent psychiatric disorders among patients with CHD [6]. In patients diagnosed with CHD who have not experienced an AMI event or required an intervention, the prevalence of anxiety is about 20% to 25% [7]. In patients with cardiac diseases, the prevalence of depression is approximately 10% [8]. Fifteen to 20% of patients with AMI due to CHD meet Diagnostic and Statistical Manual of Mental Disorders of depression [8]. Depressive symptoms are much higher among people with CHD living in the society as compared with individuals without CHD [8,9]. For instance, in a meta-analysis of 23 studies about depression in coronary CHD in China, it was found that the prevalence of depression is 51%. This rate ranged between 34.6% to 45.8%, in community participants without CHD [10].

Previous literature reported two major types of studies about the relationship between anxiety/ depression and CHD. Firstly, studies that followed healthy persons to detect the occurrence of CHD (i.e., incident CHD). Second: Studies among patients with pre-existing CHD followed up to detect the occurrence of new events related to the CHD (i.e., cardiac mortality, non-fatal AMI).

With regard to anxiety and CHD, a meta-analysis investigated anxiety and risk of incident of CHD between the years 1980 and 2009 [11]. The study examined twenty prospective studies on 249,846 persons who were followed for an average of 11.2 years with a range from 2.0 to 20.9 years. Results showed that anxious persons were at risk of CHD (hazard ratio: 1.26; 95% confidence interval: 1.15 to 1.38; p<0.0001) after controlling for their demographic variables, biological risk factors, and health behaviors. Five studies [12-16] in a metaanalysis about cardiac mortality and AMI, found that anxiety was significantly associated with cardiac mortality, among which three remained significant after controlling for the covariates [12,15,16]. The pooled hazard ratio for cardiac mortality was 1.48 (95% CI: 1.14 to 1.92; p=0.003). In patients with preexisting CHD, five studies used non-fatal AMI as an end-point. Two of them [17,18], found a significant association between general anxiety and AMI, among which one did not adjust for confounders [18] and excluded from the analysis. The hazard ratio was 1.23 (95% CI: 0.74 to 2.05; p=0.416).

A large Swedish survey on 49,321 young men investigated the long term association (over 37 years) between anxiety and subsequent CHD and development of AMI. The results showed that the multi adjusted hazard ratios were 2.17 (95% CI: 1.28 to 3.67) and 2.51 (95% CI: 1.38 to 4.55) for CHD and for AMI, respectively [19]. This indicates that anxiety independently predicted subsequent CHD events. A contradicting result was reported by other studies [20-22] which showed no relationship between anxiety and CHD.

With regard to depression and CHD, different prospective studies found that there is a moderately strong association between depression and the incidence of CHD [23-30]. Moreover, other studies found that there is a dose-response relationship between the severity of depression and the earlier and more severe cardiac events [31,32]. In a prospective study of 314 patients (age range, 19-79 years) who had presented with chest pain, every 1-point increase in the depression score was associated with an average of 6% increase in coronary artery stenosis, after controlling for sex differences and other confounding variables [20]. In a meta-analysis about the impact of depression on the development of CHD in initially healthy subjects, 11 studies met the inclusion criteria. It was found that the overall relative risk for the development of CHD in depressed subjects was 1.64 (95% CI=1.29-2.08, p<0.001) [33].

Previous literature found that there is an association between base line depression and the development of CHD events. A meta-analysis of 21 prospective studies on 124,509 participants was conducted. The meta-analysis examined the relationship between depression and development of CHD events. In 11 studies which adjusted for cardiac risk factors, relative risk was 1.90 (95% CI: 1.49-2.42) [23]. In another meta-analysis quantifying the impact of depressive symptoms on cardiac mortality in healthy people, depressed patients were two times higher than non-depressed for developing cardiac mortality [31].

In a recent study conducted in Brazil, an uppermiddle- income country, major depressive disorder was associated with a two-fold increase in CHD after full adjustment for covariates [34]. However, other studies failed to find an association between depression and CHD. For instance, in a Swedish survey [19] depression did not predict subsequent CHD events. Another study conducted in Netherlands on 2807 patients concluded that no associations were found for persons with depressive disorders and increased prevalence of CHD [35].

Most of the previous research has been restricted to high-income developed countries including Australia, Canada, Denmark, Finland, Netherlands, UK and US stressing the need for research in low to middle- income countries. This need was also highlighted by the authors of a meta-analysis [36] of prospective studies about depression and risk of CHD who recommended that results should not be extended to developing countries. Furthermore, they concluded that in order to generalize the findings to other populations, additional studies should be conducted in other populations from Asia, Africa and South America. Therefore, the purpose of this study was to examine if there is an association between anxiety and depression with CHD in Jordan.

Materials and Methods

Research hypotheses

After controlling for sociodemographics and clinical variables (i.e., age, gender, history of diabetes, history of hypertension, smoking history, hypercholesterolemia, family history of CHD, and body mass index (BMI)); 1) Anxiety and depression scores will be independent predictors for the development of AMI, and 2) Anxiety and depression scores will be independent predictors for the percentage of coronary artery stenosis.

Design, sample and setting

A prospective observational design was used in patients with a pre-existing diagnosis of CHD. One thousand three hundred fifty patients were approached when they visited out patients' clinics for treatment or follow up from three private and two governmental hospitals in Amman, Jordan. Among them, 1000 agreed to participate and filled in the questionnaires. Those 1000 patients composed the sample and were followed up for two years or until the development of any AMI event.

A total of 157 patients developed AMI events and met the following criteria were included in the final analyses. a) signed an informed consent, b) greater than 18 years old, c) can read and write Arabic, d) not on anti-anxiety or anti-depressant treatment and e) did not have a previous AMI event or heart failure due to myocardial infarction. To make sure that the sample size is sufficient, a-priori Sample Size Calculator for Multiple Regression was used [37]. The assumptions were: number of predictors was 9, a power of 0.9, an alpha of 0.05, and a small effect size of 0.15. Accordingly, the needed sample size was 141 participants. Therefore, 157 participants were considered enough to perform the analyses and reach a statistical significant result.

Ethical consideration

The institutional review board (IRB) committee at the Applied Science Private University, Amman, Jordan granted the approval for this study (faculty 005B). The principal investigator presented the study proposal to the medical and nursing directors of the previously mentioned hospitals, and submitted the IRB approval letter. These hospitals accepted the IRB approval from the Applied Science Private University. Then, permissions to conduct the study within these hospitals were issued to the principal investigator by the medical directors.

Procedure

Five research assistants were trained to collect data (one for each selected hospital) and authorized to work in the settings in the current study. Regular meetings were held between the principal investigator and research assistants to reduce recruitment bias and to answer their questions. They all agreed on a recruitment script in order to recruit participants identically.

The study was explained by research assistants to the participants. They guaranteed the participants that their participation was voluntary and they could withdraw from the study at any time. Participants then signed an informed consent if they agreed to participate including an approval to review their medical record if they were admitted to the hospital due to an AMI event. An initial interview with those who agreed to participate was held, during which the participants completed the required questionnaires. Then, patients were followed for 2 years or until they developed an AMI event. Patients and other family members were asked to contact the principal investigator/research assistant after they were discharged from an admission for an AMI event. Since it is difficult that all patients and family members would remember to call, patients were followed-up at 3, 6, 12 and 24 months by phone calls. During these phone calls, patients were queried about whether they experienced any hospital admissions. If any of them have been hospitalized for an AMI event, the medical records were obtained and reviewed by principal investigator/research assistant to collect data about the results of the cardiac catheterization.

Measurement of variables

Sociodemographics and clinical characteristics

Data were obtained either during the interview or from medical record review including: age, gender, history of diabetes, history of hypertension, smoking history, hypercholesterolemia, family history of CHD, BMI, which coronary artery disease was stenosed and the percentage of the stenosis.

Anxiety and depression

The Arabic version of Hospital Anxiety and Depression Sale (HADS) was used to measure anxiety and depression. The psychometric proprieties of this version have been checked in previous studies [38-42]. The Cronbach's alpha was 0.78 for anxiety subscale and 0.87 for depression subscale. Each subscale has seven items that were rated by patients on a 0-3 scale, with 3 indicating higher symptom frequency and severity. Each subscale score ranges from 0-21. Patients were considered normal if the anxiety/depression scores were between 0 and 7; mildly anxious/depressed if the scores were between 8 and 10; moderately anxious/depressed if the scores were between 11 and 14; and severely anxious/depressed if the scores were between 15 and 21 [38-42].

Data analysis

Data were analyzed using SPSS software version 21.0 (SPSS Inc., Chicago, Illinois). Statistical significance was defined as p<0.05. The socio demographics and clinical characteristics of the sample were described using descriptive statistics with frequencies and percentages or mean ± standard deviation (SD).

The first hypothesis of the study was tested by three different logistic regression analyses, each included three blocks. Variables entered in the first and second block in each analysis were the followings: In the first block, age and gender were entered; in the second block, BMI, history of hypertension, history of diabetes, smoking history, hypercholesterolemia, and family history of CHD were entered. The third block is different in the three analyses. In the first analysis, anxiety scores formed the third block, in the second analysis, depression scores were entered as the third block, in the third analysis, depression and anxiety scores together were entered as the third block. To check if anxiety and depression scores were independent predictors of coronary artery stenosis (i.e., the second hypothesis); first a serial bivariate correlation between (anxiety, depression) scores and the percentage of the coronary artery stenosis was done. Then, three different stepwise regression analyses were done in the same method done in the logistic regression.

Results

One thousand three hundred fifty patients were asked to participate in the study among which 1000 agreed to participate. The final analysis included only 157 patients who had AMI event during the follow up period. Sociodemographics and clinical characteristics of the patients are presented in Table 1. Approximately 70% of the patients were males, more than three-quarters of the sample had hypertension, and more than one-third of the patients were diabetic. Patients were mildly anxious and depressed based on a mean ± (SD) for the HADS.

Table 1: Sociodemographics and clinical characteristics of the patients.

As shown in Table 2, anxiety levels, depression levels, hypercholesterolemia, and male gender were independent predictors of AMI events. Both anxiety and depression have a strong positive significant correlation with the percentage of coronary artery stenosis; r=0.72, p<0.001 and 0.69, p<0.001, respectively. Tables 3 and 4 show the results of the stepwise regression. Male gender was an independent predictor in all models. Anxiety and depression levels also were independent predictors for stenosis. Hypercholesterolemia was an independent predictor in the anxiety model, anxiety and depression model but not in the depression model.

Table 2: Independent predictors of myocardial infarction anxiety model, depression model, depression and anxiety model respectively.

Table 3: Predictors of coronary artery stenosis when anxiety scores alone were entered in the third block, then when depression scores entered alone in the third block respectively.

Table 4: Predictors of coronary artery stenosis when anxiety and depression scores were entered together in the third block.

Discussion

This was the first study to examine the relationship between anxiety, depression and the development of AMI events in patients with pre-existing CHD in Jordan. The major findings of this study were that anxiety and depression independently predicted the occurrence of AMI and increased the risk for coronary artery stenosis after adjusting for covariates. Moreover, the results indicated that depression was stronger than anxiety in this relationship. Male gender and hypercholesterolemia also were independent predictors.

This study was conducted in a low-income Arabic developing country to duplicate or counter the findings from developed countries. The results of the current study are fairly comparable to those in developed countries, suggesting that anxiety and depression are predictors of an AMI events and important risk factors for coronary artery stenosis across a broad diversity of cultures.

The results of this study are consistent with previous studies checking the effect anxiety and depression on CHD patients [12,15,16,23-30]. It has been suggested that anxiety and depression are as important as other traditional risk factors (i.e., age, gender, smoking, and family history) in the development of CHD and increasing risk of cardiac events among patients diagnosed with CHD [6,19]. Anxiety and depression may affect the heart in biological and behavioral pathways. Biologically, anxiety and depression stimulate the sympatric nervous system (SNS) and decrease heart rate variability due to higher epinephrine and nor-epinephrine levels [43-45]. Moreover, anxiety and depression are associated with hypercoagulation due to increased plasma platelet factor 4 and thromboglobulin (suggesting enhanced platelet activation) [46,47]. Furthermore, anxiety and depression are associated with hyperlipidemia [48] and immune suppression [48]. In addition, depression was associated with low levels of omega-3 fatty acid [49] and enhancing inflammatory processes [50,51]. Behaviorally, anxiety and depression might negatively affect adherence to specific diet and medication [43,52,53] decrease physical activity [43,54] and enhance (smoking [55], social isolation and chronic life stress) [56].

Different explanations have been made why anxiety and depression did not predict AMI events or coronary artery stenosis in previous studies. First, uncertainty concerning causal inferences [19]. Second, concerns about reverse causation (the possibility that both depression and subsequent CHD are caused by subclinical manifestations of cardiovascular disease) [19,57] which means that, when a prospective clinical study includes individuals free from clinical heart disease, they might not be free from atherosclerosis which may assist depressive symptoms even before generating cardiac ischemia creating a fake association between depression and atherosclerosis [57]. Third, incomplete adjustment to CHD risk supply factors and publication bias [23]. Fourth, instruments used included a broad depressive symptom band, such as sleep problems, being short of energy and troubled appetite [25]. These symptoms significantly go beyond with symptoms of common physical illnesses, including subclinical coronary artery disease [25,57].

The instrument which has been chosen in this study (HADS) was initially intended to detect anxiety and depression in patients with physical illness. Therefore, it methodically excludes somatic symptoms which can imitate heart disease [58]. For this reason, our study is the first study in a low-income country to link core psychological and cognitive symptoms of anxiety and depression to increased AMI risk. Yet, using this style, some patients with mostly somatic symptoms of depression might go invisible. Consequently, we are more likely to have underestimated, rather than overestimated, the association between depression and AMI in our study. Anxiety and depression can be treated effectively with different management strategies [59]. Unluckily, a lot of patients do not receive sufficient treatment [59]. In addition to the effect that anxiety/depression has on disability and decreased quality of life, clinicians must be alert about the association between anxiety/depression with incident CHD. Future randomized control trials checking whether the treatment of anxiety/ depression has a significant beneficial effect on the incidence CHD is warranted.

Conclusion

Anxiety and depression independently predict the occurrence of AMI events and coronary artery stenosis among patients with pre-existing CHD in a low-income Arabic developing country. These results are comparable with those from developed countries, indicating that anxiety and depression are important global risk factors to develop AMI events in patients with pre-existing CHD. Interventional studies to control the effect of anxiety and depression in this population are needed.

Acknowledgment

The authors are grateful to the Applied Science Private University, Amman, Jordan, for the partial financial support granted to this research project and the financial support granted to cover the publication fees of this research article.

References

1. Benjamin EJ, Blaha MJ, Chiuve SE, et al. (2017). Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation. 135: 146-603.
2. Safford MM, Brown TM, Muntner PM, et al. (2012). Association of race and sex with risk of incident acute coronary heart disease events. JAMA. 308: 1768-1774.
3. Statistics. NCfH. Mortality multiple cause micro-data files, 2014: Public-use data file and documentation: NHLBI tabulations. (2007) [cited 2017 13 oct]; Available from: https://www.cdc.gov/nchs/data_access/Vitalstatsonline.htm#Mortality_Multiple.
4. WHO. Jordan: WHO statistical profile. Country statistics and global health estimates by WHO and UN partner. (2015) [cited 2015 10/5/2016]; Available from:  https://www.who.int/countries/jor/en/.
5. Jordanian Ministry of Health DoIaR. Information and Research Newsletter: mortality data in Jordan 2007. (2007) [cited 2017 Aug 12]; Available from: https://www.moh.gov.jo.
6. Abed MA, Kloub MI, Moser DK. (2014). Anxiety and adverse health outcomes among cardiac patients: a biobehavioral model. J Cardiovasc Nurs. 29: 354-363.
7. Moser DK. (2007). "The rust of life": Impact of anxiety on cardiac patients. Am J Crit Care. 16: 361-9.
8. Lichtman JH, Bigger JT Jr, Blumenthal JA, et al. (2008). Depression and coronary heart disease: Recommendations for screening, referral and treatment: A science advisory from the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research: Endorsed by the American Psychiatric Association. Circulation. 118: 1768-1775.
9. Thombs BD, Bass EB, Ford DE, et al. (2006). Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med. 21: 30-38.
10. Ren Y, Yang H, Browning C, et al. (2014). Prevalence of depression in coronary heart disease in China: a systematic review and meta-analysis. Chin Med J (Engl). 127: 2991-2998.
11. Roest AM, Martens EJ, de Jonge P, et al. (2010). Anxiety and risk of incident coronary heart disease: a meta-analysis. J Am Coll Cardiol. 56: 38-46.
12. Kawachi I, Colditz GA, Ascherio A, et al. (1994). Prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation. 89: 1992-1997.
13. Phillips AC, Batty GD, Gale CR, et al. (2009). Generalized anxiety disorder, major depressive disorder and their comorbidity as predictors of all-cause and cardiovascular mortality: The Vietnam experience study. Psychosom Med. 71: 395-403.
14. Albert CM, Chae CU, Rexrode KM, et al. (2005). Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women. Circulation. 111: 480-487.
15. Denollet J, Maas K, Knottnerus A, et al. (2009). Anxiety predicted premature all-cause and cardiovascular death in a 10-year follow-up of middle-aged women. J Clin Epidemiol. 62: 452-456.
16. Rosengren A, Tibblin G, Wilhelmsen L. (1991). Self-perceived psychological stress and incidence of coronary artery disease in middle-aged men. Am J Cardiol. 68: 1171-1175.
17. Kubzansky LD, Cole SR, Kawachi I, et al. (2006). Shared and unique contributions of anger, anxiety, and depression to coronary heart disease: A prospective study in the normative aging study. Ann Behav Med. 31: 21-29.
18. Gafarov VV, Gromova HA, Gagulin IV, et al. (2007). Arterial hypertension, myocardial infarction and stroke: risk of development and psychosocial factors. Alaska Med. 49: 117-119.
19. Janszky I, Ahnve S, Lundberg I, et al. (2010). Early-onset depression, anxiety and risk of subsequent coronary heart disease: 37 year follow-up of 49,321 young Swedish men. J Am Coll Cardiol. 56: 31-37.
20. Vural M, Satiroglu O, Akbas B, et al. (2009). Coronary artery disease in association with depression or anxiety among patients undergoing angiography to investigate chest pain. Tex Heart Inst J. 36: 17-23.
21. Mykletun A, Bjerkeset O, Dewey M, et al. (2007). Anxiety, depression and cause-specific mortality: the HUNT study. Psychosom Med. 69: 323-331.
22. Martin RL, Cloninger CR, Guze SB, et al. (1985). Mortality in a follow-up of 500 psychiatric outpatients. II. Cause-specific mortality. Arch Gen Psychiatry. 42: 58-66.
23. Nicholson A, Kuper H, Hemingway H. (2006). Depression as an aetiologic and prognostic factor in coronary heart disease: A meta-analysis of 6362 events among 146 538 participants in 54 observational studies. Eur Heart J. 27: 2763-2774.
24. Rafanelli C, Roncuzzi R, Ottolini F, et al. (2007). Psychological factors affecting cardiologic conditions. Adv Psychosom Med. 28: 72-108.
25. Carney RM, Freedland KE. (2003). Depression, mortality and medical morbidity in patients with coronary heart disease. Biol Psychiatry. 54: 241-7.
26. Charlson M, Peterson JC. (2002). Medical comorbidity and late life depression: what is known and what are the unmet needs? Biol Psychiatry. 52: 226-35.
27. Janszky I, Ahlbom A, Hallqvist J, et al. (2007). Hospitalization for depression is associated with an increased risk for myocardial infarction not explained by lifestyle, lipids, coagulation and inflammation: The SHEEP study. Biol Psychiatry. 62: 25-32.
28. Alboni P, Favaron E, Paparella N, et al. (2008). Is there an association between depression and cardiovascular mortality or sudden death? J Cardiovasc Med (Hagerstown). 9: 356-362.
29. Rudisch B, Nemeroff CB. (2003). Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry. 54: 227-240.
30. Strike PC, Steptoe A. (2004). Psychosocial factors in the development of coronary artery disease. Prog Cardiovasc Dis. 46: 337-347.
31. Rugulies R. (2002). Depression as a predictor for coronary heart disease: A review and meta-analysis. Am J Prev Med. 23: 51-61.
32. Frasure-Smith N and Lesperance F. (2005). Reflections on depression as a cardiac risk factor. Psychosom Med. 67: S19-25.
33. Barth J, Schumacher M, Herrmann-Lingen C. (2004). Depression as a risk factor for mortality in patients with coronary heart disease: A meta-analysis. Psychosom Med. 66: 802-813.
34. Kemp AH, Brunoni AR, Nunes MA, et al. (2015). The association between mood and anxiety disorders,and coronary heart disease in Brazil: Across-sectional analysis on the Brazilian longitudinal study of adult health (ELSA-Brasil). Front Pyschol. 6: 1-9.
35. Vogelzangs N, Seldenrijk A, Beekman AT, et al. (2010). Cardiovascular disease in persons with depressive and anxiety disorders. J Affect Disord. 125: 241-248.
36. Gan Y, Gong Y, Tong X, et al. (2014). Depression and the risk of coronary heart disease: A meta-analysis of prospective cohort studies. BMC Psychiatry. 14: 371.
37. A-priori Sample Size Calculator for Multiple Regression. [cited 2017 13 Oct]; Available from: https://www.danielsoper.com/statcalc/calculator.aspx?id=1.
38. el-Rufaie OE, Absood GH. (1995). Retesting the validity of the Arabic version of the Hospital Anxiety and Depression (HAD) scale in primary health care. Soc Psychiatry Psychiatr Epidemiol. 30: 26-31.
39. el-Rufaie OE, Albar AA, Al-Dabal BK. (1988). Identifying anxiety and depressive disorders among primary care patients: a pilot study. Acta Psychiatr Scand. 77: 280-282.
40. el-Rufaie OE, Absood G. (1987). Validity study of the hospital anxiety and depression scale among a group of Saudi patients. Br J Psychiatry. 151: 687-688.
41. Bjelland I, Dahl AA, Haug TT, et al. (2002). The validity of the hospital anxiety and depression scale. An updated literature review. J Psychosom Res. 52: 69-77.
42. Malasi TH, Mirza IA, el-Islam MF. (1991). Validation of the hospital anxiety and depression scale in Arab patients. Acta Psychiatr Scand. 84: 323-326.
43. Whooley MA, de Jonge P, Vittinghoff E, et al. (2008). Depressive symptoms, health behaviors and risk of cardiovascular events in patients with coronary heart disease. JAMA. 300: 2379-2388.
44. Otte C, Marmar CR, Pipkin SS, et al. (2004). Depression and 24 h urinary cortisol in medical outpatients with coronary heart disease: The Heart and Soul Study. Biol Psychiatry. 56: 241-247.
45. Otte C, Neylan TC, Pipkin SS, et al. (2005). Depressive symptoms and 24 h urinary norepinephrine excretion levels in patients with coronary disease: Findings from the Heart and Soul Study. Am J Psychiatry. 162: 2139-2145.
46. Pollock BG, Laghrissi-Thode F, Wagner WR. (2000). Evaluation of platelet activation in depressed patients with ischemic heart disease after paroxetine or nortriptyline treatment. J Clin Psychopharmacol. 20: 137-140.
47. Serebruany VL, Glassman AH, Malinin AI, et al. (2003). Enhanced platelet/endothelial activation in depressed patients with acute coronary syndromes: Evidence from recent clinical trials. Blood Coagul Fibrinolysis. 14: 563-567.
48. Shang YX, Ding WQ, Qiu HY, et al. (2014). Association of depression with inflammation in hospitalized patients of myocardial infarction. Pak J Med Sci. 30: 692-697.
49. Frasure-Smith N, Lesperance F, Julien P. (2004). Major depression is associated with lower omega-3 fatty acid levels in patients with recent acute coronary syndromes. Biol Psychiatry. 55: 891-896.
50. Lesperance F, Frasure-Smith N, Theroux P, et al. (2004). 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.
51. Empana JP, Sykes DH, Luc G, et al. (2005). Contributions of depressive mood and circulating inflammatory markers to coronary heart disease in healthy European men: The Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation. 111: 2299-2305.
52. Ziegelstein RC, Fauerbach JA, Stevens SS, et al. (2000). Patients with depression are less likely to follow recommendations to reduce cardiac risk during recovery from a myocardial infarction. Arch Intern Med. 160: 1818-1823.
53. Gehi A, Haas D, Pipkin S, Whooley MA. (2005). Depression and medication adherence in outpatients with coronary heart disease: findings from the Heart and Soul Study. Arch Intern Med. 165: 2508-2513.
54. Ruo B, Rumsfeld JS, Pipkin S, Whooley MA. (2004). Relation between depressive symptoms and treadmill exercise capacity in the Heart and Soul Study. Am J Cardiol. 94: 96-99.
55. Weinberger AH, Kashan RS, Shpigel DM, et al. (2017). Depression and cigarette smoking behavior: A critical review of population-based studies. Am J Drug Alcohol Abuse. 43: 416-431.
56. Everson-Rose SA, Lewis TT. (2005). Psychosocial factors and cardiovascular diseases. Annu Rev Public Health. 26: 469-500.
57. Gustad LT, Laugsand LE, Janszky I, et al. (2014). Symptoms of anxiety and depression and risk of acute myocardial infarction: The HUNT 2 study. Eur Heart J. 35: 1394-403.
58. Zigmond AS and Snaith RP. (1983). The hospital anxiety and depression scale. Acta Psychiatr Scand. 67: 361-70.
59. Davidson JR. (2009). First-line pharmacotherapy approaches for generalized anxiety disorder. J Clin Psychiatry. 70: 25-31.