ENDOCRINE FACTORS AND PATIENT CENTERED OUTCOMES IN CORONARY ARTERY DISEASE

LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY

Viltė Marija Gintauskienė

ENDOCRINE FACTORS AND PATIENT

CENTERED OUTCOMES IN CORONARY

ARTERY DISEASE

Medicine (06B)

Dissertation was prepared at the Institute of Behavioral Medicine, Lithuanian University of Health Sciences, Medical Academy during 2008–2012.

Scientific Supervisor

Dr. Habil. Robertas Bunevičius (Lithuanian University of Health Sciences, Medical Academy, Biomedical Sciences, Medicine – 06B)

Consultant

Dr. Habil. Julija Brožaitienė (Lithuanian University of Health Sciences, Medical Academy, Biomedical Sciences, Medicine – 06B)

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CONTENT

LIST OF ABBREVIATIONS ... 5

INTRODUCTION ... 7

AIM AND OBJECTIVES ... 10

1. REVIEW OF LITERATURE ... 11

1.1. Link between hormone concentrations and Brain natriuretic peptide concentrations in patients with coronary artery disease ... 13

1.1.1. Brain natriuretic peptide marker in patients with coronary artery disease ... 13

1.1.2. B type natriuretic peptide link with thyroid hormone ... 15

1.1.3. B type natriuretic peptide link with cortisol levels ... 18

1.2. Influence of thyroid hormones in patientswith coronary artery disease ... 20

1.3. The role of cortisol in patients with coronary artery disease ... 24

1.4. Depression and thyroid axis function in coronary artery disease .... 26

1.4.1. The prevalence of people with psycho disorders and cardiovascular diseases ... 27

1.4.2. Depression in cardiovascular disease development, course and source ... 28

1.4.3. Anxiety and coronary artery disease ... 31

1.5. Fatigue and depression, also cortisol and thyroid hormones metabolism in patients with CAD ... 32

1.6. Thyroid axis hormones and cortisol associations with health- related quality of life in coronary artery disease patients ... 35

2. MATERIAL AND METHODS ... 37

2.1. Study population ... 37

2.1.1. The subject of study the relationship between thyroid hormone, cortisol and NT-pro BNP levels in patients with CAD ... 40

2.1.2. The subjects of study depression, anxiety symptoms, thyroid axis hormones and NT-proBNP concentrations in CAD patients ... 42

2.1.3. Subjects of study depression, anxiety symptoms and cortisol levels in CAD patients ... 43

2.1.4. Subjects of study association fatigue and physical capacity with thyroid axis hormones and cortisol levels in CAD patients ... 44

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2.1.5. Subjects of study relationship between HRQoL and thyroid axis hormones, cortisol concentrations in CAD

patients ... 45

2.2. Procedure and Instruments ... 46

2.2.1. Objective and subjective methods ... 47

2.2.2. Evaluation of thyroid axis hormone, cortisoland NT-proBNP concentrations ... 49

2.3. Statistical analysis ... 50

3. RESULTS ... 53

3.1. NT-pro BNP concentration in relationship to thyroid hormones and cortisol concentrations in patients with CAD ... 53

3.2. Depression and anxiety symptoms association with the thyroid axis hormones, and NT-proBNP concentrations in patients with CAD ... 56

3.3. Depression and anxiety symptoms relationship with cortisol levels in patients with CAD ... 64

3.4. The relationship between fatigue, exercise capacity and thyroid axis hormones, cortisol levels in patients with CAD ... 67

3.5. Quality of life in relationship to thyroid hormones and cortisol concentrations in patients with coronary artery disease ... 72

4. DISCUSSION ... 77

CONCLUSION ... 88

ACKNOWLEDGEMENTS ... 90

REFERENCE LIST ... 91

PUBLICATIONS OF THE DISSERTATION TOPIC ... 118

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LIST OF ABBREVIATIONS

∆Cortisol ‒ Change in cortisol concentration

ACE ‒ Angiotensin-converting enzyme ACTH ‒ Adrenocorticotropic hormone ANOVA ‒ ANalysis Of VAriance ANP ‒ Atrial natriuretic peptide Anti-TPO ‒ Anti-thyroid peroxidase

Beta, β ‒ Standardised regression coefficient BMI ‒ Body mass index

BNP ‒ Brain natriuretic peptide BP ‒ Blood presure

CAD ‒ Coronary artery disease CFS ‒ Chronic fatigue syndrome CHD ‒ Coronary heart disease CHF ‒ Congestive heart failure CI ‒ Confidence interval CNP ‒ C-type natriuretic peptide CNS ‒ Central nervous system DEFS ‒ Dutch Exertion Fatigue Scale DUFS ‒ Dutch Fatigue Scale

FT3 ‒ Free triiodothyronine FT4 ‒ Free thyroxine

HAD ‒ Hospital Anxiety and Depression HADS ‒ Hospital Anxiety and Depression scale HF ‒ Heart failure

HPA ‒Hypothalamic-pituitary-adrenocortical HRQoL ‒ Health-related quality of life

LV ‒ Left ventricular

MFI-20 ‒ Multidimensional Fatigue Inventory MI ‒ Myocardial infarction

N (n) ‒ Number

NYHA ‒ New York Heart Association NPR ‒ Natriuretic peptidic receptors

NT-proBNP ‒ N-terminal fragment of pro brain (B-type) natriuretic peptide

PTCA ‒ Percutaneous transluminal coronary angioplasty RR ‒ Relative risk

rT3 ‒ Reverse triiodothyronine SD ‒ Standard deviation SES ‒ Sick euthyroid syndrome

6 SF-36 ‒ Short Form Health Survey

SPSS ‒ Statistical Package for the Social Sciences T3 ‒ Triiodothyronine

T4 ‒Thyroxin

TH ‒ Thyroid hormone

TRH ‒ Thyrotropin-releasing hormone TSH ‒ Thyroid stimulating hormone

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INTRODUCTION

According to mortality from cardiovascular diseases in Lithuania is one of the leading places in the Europe, which leads to the disease as much as 54 % all deaths. Psychosocial factors significantly affect the occurrence of ischemic heart disease and development. About 10% of the population suffers more or less lasting state of depression, and mild forms of depression about 25% of the population. Women have a higher risk of developing depression than men. Various studies show that about 15%‒20% of patients with coronary artery disease by the symptoms of severe depression during hospitalization for myocardial infarction, unstable angina after bypass surgery and other cardiac disorders. Mild forms of depression 15%‒25% of patients experiencing.

Anxiety is one of the earliest and most intense psychological responses to coronary artery disease. Approximately 70% of patients with coronary artery disease have higher than normal levels of anxiety. Panic attacks occur in approximately 4% of people in the general population, almost 20% of pa-tients receiving treatment in primary health care facilities, of which approximately 14% of coronary artery disease (CAD) patients. Cardiovas-cular pathology complicates both depression and anxiety. Mechanisms, which explains how depression and anxiety disorders increased mortality among patients with ischemic heart disease patients is still not clearly un-derstood and defined.

It is known that people with depression are activated hypothalamic-pituitary-adrenal axis [185]. Hormonal changes can cause abnormal beha-vior and vice versa, in response to stressful situations, endocrine glands, hormone production often increase [234]. Neuroendocrine and autonomic nervous system dysfunction enhances peripheral receptor sensitivity [234, 304]. Stress is a complex dynamic condition in which the body's normal homeostasis is affected by some form of physical and psychological stresses impact. Response to stressors is the whole complex of adaptive responses in the body. High stress and constant stress of the situation stimulates the hypothalamus, disrupts hormone, especially corticosteroid response. Long-term stress caused by hormonal imbalance, negative effect on the metabo-lism and immune function, causes of sleep disorders. Cortisol is a stress marker, which regulates how the body reacts to stress. Stress increases 10‒15 time's secretion [284]. This hormone performs catabolic function; the increase may weaken the immune system, lower blood pressure, disturbed sleep. The hypothalamus-pituitary-adrenal axis of the initial imbalance of

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cortisol indicates that increase the risk of developing emotional problems and these figures appear before the clinic.

Cortisol levels affect the sympathetic and cardiovascular responses, sti-mulates adrenaline and noradrenalin synthesis increases, leading to coronary artery disease, development and progress. CAD disease the most common cause of depression is a manifestation of fear of death, fear of another cardiac event can be a physical disability, the potential job loss. CAD patients with depression increase mortality risk, reduced heart rate variability, heart rate, increased immune reactivity, deterioration of quality of life, common complaints of angina pain, increased frequency of arrhythmias. Impaired cardiovascular neurohormonal regulation, the body does not respond to normal stimuli. Therefore, heart rate (exertion or hyper-ventilation during orthostatic), increased cardiac output, increase or decrease in vascular tone, blood pressure, peripheral vasoconstriction, vascular and autonomic crisis episode, and others [234]. It should be noted that dep-ression, elevated cortisol levels of women more than men [37]. Cortisol also affects the thyroid hormone fluctuations. Even the normal range of variation of cortisol can cause thyroid hormone changing settings. Cortisol concen-trations increased, decreased thyroid stimulating hormone (TSH), thyroxin (T4), free thyroxin (FT4) and triiodothyronine (T3) and free triiodo-thyronine (FT3) levels. Therefore, the cortisol influence of thyroid hor-mones may affect the metabolism. Thyroid hormone metabolism in an anabolic hyper secretion activates the sympathetic nervous system and in turn, stimulates glucocorticoid [232, 236] secretions.

For people who have persistent stressful situations, sleep disturbance regime, cold sensation, intense physical activity, hunger, and another reported a gradual increase in cortisol and free T4, total T4, total T3 and free T3 decline. Removal of stressful situations in T4 and free T4 concentration levels returned to normal levels within 4 ‒ 5 days, while T3 and free T3 con-centrations remained for a time reduced. If the tense situation lasted for a longer period of time, after five weeks was observed psychological disor-ders and less cardiovascular disorder. Thyroid hormone changes as well as frequent monitoring of patients with cardiovascular disease and depression. Serum NT-proBNP levels are affected by thyroid functions and seem to be a direct stimulatory effect of thyroid hormones.

There is substantial evidence on the relationship between depression and adverse clinical consequences of coronary artery disease. Involved in the pathogenesis of depression associated hypothalamic-pituitary-adrenal (HPA) axis and thyroid hormone changes increase the risk to suffer from ischemic heart disease involve the development, progress and outcomes. Stress negatively affects the metabolism and immune function, causes of

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sleep disorders, chronic diseases triggered by the progress of disease forms the basis for the occurrence of depression can alter the cardiac autonomic regulation. Etiology is the emergence of clinical components of the human body, increases the risk to suffer from CAD and depression occurring simultaneously.

Fatigue is the most distressing health complaint [28] affecting the ma-jority of coronary artery disease patients [88]. It is described as an over-whelming subjective sense of tiredness and lack of energy having a negative effect on physical and mental capacity and not relieved by rest [223]. Nevertheless, the underlying biological mechanisms of fatigue in CAD patients are poorly understood and biological markers of fatigue remain to be identified.

Health related quality of life (HRQoL) depends not only on good physical health, somatic diseases, lack of good cardiovascular adaptations, but also on psycho-emotional state, especially on the presence of depression and anxiety disorders that are largely regulated by the central nervous sys-tem (CNS) and by neuroendocrine syssys-tem.The hypothalamus regulates the activity of internal organs, metabolism, circulation, respiration, digestion, body temperature, glandular activity, sleep and wakefulness, the body's Biorhythms, and parasympathetic sympathetic nervous system activity, etc. Malfunction of the heart and cardiovascular regulation, the body is not adequately responding to conventional stimuli. As a result, pulse rate (exertion or hyperventilation during orthostatic), increased cardiac output, an increase or decrease in vascular tone, blood pressure, peripheral vascular spasm, vascular, and an episode of autonomic crisis and so on. Change in hormone levels can cause abnormal behavior and vice versa, the endocrine glands in response to any stressful situations, often increasing their hormone production. Promoting the hypothalamic-pituitary-adrenal axis, increased corticosteroids, and this affects their regulated cardiovascular function and metabolism.

Lagery, great emphasis on hormonal factors influences prohormone car-diovascular functional status, quality of life in patients with coronary artery disease, and outcomes. Therefore, it is important to complex evaluation of hormonal markers and behavioral factors (depression, anxiety and fatigue) interaction on patients with coronary artery disease for quality of life, di-sease course and outcome. A better understanding of how thyroid hormones affect the brain-thyroid-heart interactions may open up new targets and new markers and myocardial infarction, as well as depression.

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AIM AND OBJECTIVES

The aim of the study – examine the relationship between cortisol and thyroid axis hormone levels with the N-terminal fragment of pro brain (B‒type) natriuretic peptide (NT-proBNP) level and patient oriented out-comes, such as symptoms of depression, fatigue and HRQoL in patients with coronary artery disease.

Tasks of the research:

1. To evaluate the relationship between NT-proBNP concentrations, thyroid hormones and cortisol concentrations in CAD patients.

2. To evaluate the relationship between depressive, anxiety symptoms and thyroid axis hormones and NT-proBNP concentrations in CAD patients. 3. To evaluate the relationship between depressive, anxiety symptoms and

cortisol levels in CAD patients.

4. To evaluate the relationship of fatigue and physical capacity with thyroid axis hormone levels and cortisol levels in CAD patients.

5. To evaluate relationship between HRQoL and thyroid axis hormones in CAD patients.

The study of scientific novelty.

Found that a great importance to the development of CAD must not only be inappropriate lifestyle habits like smoking, over eating, physical immobility and traditional risk factors (obesity, dyslipidemia, diabetes, hypertension), but also non-traditional ‒ how psychosocial stress, persona-lity and neuroendocrine factors. There is more evidence that certain biological mechanisms, such as the thyroid hormones and cortisol also perhaps of interest to the patient-oriented medical condition.

The finding of this study for the first time presented the relationship between thyroid hormone, cortisol and NT-proBNP concentrations in patients with CAD. This study for the first time demonstrates the effects of thyroid axis hormones and cortisol concentration measures on depression, anxiety symptoms, on fatigue and on HRQoL in CAD patients two weeks post-acute cardiac event. Originality of the study is that cortisol con-centrations were measured twice in the morning and evening. So we were able to compare the impact of change of cortisol depression and anxiety. It is important to note that all patients did not have overt thyroid or adrenal disease and all endocrine changes were considered consequence of CAD avoiding these endocrine diseases biases.

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1. REVIEW OF THE LITERATURE

Cardiovascular diseases including coronary CAD are leading causes of mortality [227]. According to mortality from cardiovascular diseases in Lithuania is one of the leading places in the Europe, which leads to the disease as much as 54 % all deaths. Psychosocial factors significantly affect the occurrence of ischemic heart disease and development.

The prevalence of a depression and myocardial infarction is defined as the number of people who have this disease, irrespectively whether newly or previously diagnosed, which has caused at least one contact with health services during the calendar year, expressed per 100,000 population (Table 1.1.).

Table 1.1. The prevalence of depression and myocardial infarction,

ex-pressed per 100 000 population in Lithuania between 2006 and 2011; n (%)

LITHUANIA Indicators 2006 2007 2008 2009 2010 2011 Prevalence of depression, males, age 15+ 527.38 (54) 555.89 (52) (52) 611 622.84 (54) 664.16 (49) 633.84 (45) Prevalence of depression, females, age 15+ 1891.88 (48) 2025.69 (45) 2191 (42) 2225.02 (45) 2283.82 (44) 2313.28 (39) Prevalence of acute

myocardial infarction, age 45‒64

266.38

(55) 250.15 (65) 247.39 (61) 254.42 (49) 284.38 (58) 289.53 (61) Prevalence of acute

myo-cardial infarction, males 251.04 (52) 250.51 (59) 254.81 (62) 262.05 (62) 297.74 (49) 323.22 (62) Prevalence of acute

myo-cardial infarction, females 167.08 (54) 165.39 (55) 162.62 (56) 164.17 (46) 178.19 (58) 195.52 (54) Source: Institute of Hygiene, Health Information Centre, Compulsory Health

Insurance database SVEIDRA, National Mortality Register, Statistics Department.

The prevalence of heart failure increases with age from 0.7% in people aged 55–64 years to 13.0% in those aged 75–84 years. Myocardial in-farction is particularly common between the 65 and the elderly – 7.88/1,000 populations. Men suffering from myocardial infarction 1.7 times more often than women, respectively, 2.99/1.000 population and 1.78/1,000 population. Morbidity among women increase after menopause, when the levels of the female hormone estrogen production. Risk factors: age (men over 45 years, women from 55 years), diabetes, high blood pressure, elevated lipoprotein levels, cigarette smoking (and passive), obesity, stress, alcohol

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tion, excessive low physical activity, women, and oral contraceptive pills (especially at the same time, and smoking). Some data infarction may depend on the circadian rhythm, faster is nine hours morning. The diagnosis of chronic heart failure is often challenging when there are multiple Co morbidities and many other possible causes for dyspnoea, mental diseases, fatigue or peripheral oedema can be present.

The general incidence of myocardial infarction in 2006‒2011 Lithuania has been increasing (Fig. 1.1).

Fig. 1.1. Prevalence of myocardial infarction, in Lithuania

between 2006 and 2011

Source: Institute of Hygiene, Health Information Centre, Compulsory Health Insurance database SVEIDRA, National Mortality Register, Statistics Department.

Lithuania has a very poor mental health indicators. Depression is one of the most commonly diagnosed psychiatric disorders. In recent years the prevalence of depression and rising in Lithuania. In particular, increasing in prevalence of depression in women (Fig. 1.2).

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Depression remains a hot issue. The World Health Organization (WHO) says that in 2020 depression may form 5.7% of all diseases and become one of the major morbidity of cardiovascular causes.

Fig. 1.2. Prevalence of depression and in Lithuania between 2006 and 2011

Source: Institute of Hygiene, Health Information Centre, Compulsory Health Insurance database SVEIDRA, National Mortality Register, Statistics Department. 1.1. Link between thyroid hormone and cortisol concentrations and

Brain Natriuretic peptide concentrations in patients with CAD 1.1.1.Brain Natriuretic peptide marker in patients with CAD

The prevalence of heart failure increases with age from 0.7% in people aged 55‒64 years to 13.0% in those aged 75‒84 years [188]. The diagnosis of chronic heart failure is often challenging when there are multiple co

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morbidity's and many other possible causes for dyspnoea, fatigue or peri-pheral oedema can be present.

The discovery of cardiac hormone production significantly changed the evaluation of the function of the heart, which is rather regarded as a determining factor of the electrolyte and hemodynamic homeostasis coo-perating with other organ systems instead of a mechanical pump. The most important hormones produced by the heart are the natriuretic peptides that have the primary role of protection against volume overload through natriuretic, diuretic, vasodilator and antiproliferative effects. They are integrative markers of the cardiac, vascular and renal functions and marking cardio renal distress. Brain natriuretic peptide and the N-terminal prohor-mone (NT-proBNP) became generally accepted markers of heart failure exceeding traditional pathophysiological significance of those [183].

Brain Natriuretic peptide (BNP) is a strong predictor of morbidity and mortality in heart failure [162]. It has been shown that BNP levels were elevated in heart failure or acute myocardial infarction, and increased BNP levels were related to clinical severity, hemodynamic stress, and myocardial contractility [112, 303]. Brain natriuretic peptide (BNP) is secreted in response to wall stress increase and myocardial hypoxia. We sought to investigate changes in plasma BNP concentration induced by exercise in relation to LV remodeling after MI. BNP level is associated with myocardial electrical instability and functional capacity, while developing of LV remodeling after MI [148].Brain natriuretic peptide level in acute phase of myocardial infarction is strongly associated with the markers of myocardial injury and related to left ventricular geometry changes and remodeling. Brain natriuretic peptide together with troponin I levels in acute phase of myocardial infarction might be useful in predicting subsequent cardiac function [113].

BNP and N-terminal fragment of pro brain (B-type) Natriuretic peptide (NT-proBNP) are produced in a 1:1 ratio when the left ventricle is stretched due to hemodynamic pressure. Elevated levels of either of these peptides are associated with both heart failure and are equally useful as an aide in the diagnosis of congestive heart failure (HF). The NT-proBNP is the inactive degradation product of pro BNP. Recent reports have shown that in the general population, the plasma BNP or NT-proBNP level is affected by many extra cardiac factors including age, obesity, and genetics [224, 290, 291].

Brain Natriuretic peptide is a cardiac neurohormone secreted mainly from both ventricles as a response to volume expansion, pressure overload, and elevated end-diastolic pressure [18]. Cardiac myocytes constitute the

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major source of BNP-related peptides in the circulation. Recently, cardiac fibroblasts have also been shown to produce BNP [276].

The quantitative contribution of this latter source to circulating plasma concentrations is not known. The main stimulus for ANP and BNP peptide synthesis and secretion is cardiac wall stress [174].

In addition in vitro experiments have indicated that other neurohormones may modulate cardiac BNP production in a paracrine and possibly endocrine fashion [122].

Since increased cardiac wall stress is a common denominator of many cardiac diseases, it follows that circulating Natriuretic peptides may serve as clinical biochemical markers of these states. In patients with heart failure, the BNP is elevated in correlation with the degree of cardiac insufficiency [119, 130, 226]. It has potent diuretic, Natriuretic, and vascular smooth muscle relaxing effects and also important central and peripheral sympathoinhibitory effects. Brain Natriuretic peptide inhibits the rennin-angiotensin-aldosterone axis [52, 63, 175, 176]. For patients with left ventricular (LV) dysfunction; increased BNP levels have both diagnostic and prognostic properties. Increased levels have predicted the worst prognosis cardiac death in heart failure patients [58, 104, 142, 160, 277, 293, 308].

1.1.2. B type Natriuretic peptide link with thyroid hormone

The cardiovascular system is very sensitive to thyroid hormones, and a wide spectrum of cardiac changes occurs in overt thyroid dysfunction. In subclinical thyroid dysfunctions similar, but less pronounced cardiac changes are observed.

In addition, thyroid hormones directly increase myocardial gene expression of Natriuretic peptides. Accordingly, previous studies have shown changes in Natriuretic peptide levels in different thyroid function states.

Accordingly, the Christ-Craina M. et al. study evaluated NT-proBNP and mid regional proANP levels in a wide range of thyroid dysfunction, i.e. from overt hypothyroidism through subclinical states to overt hyper-thyroidism. In patients with subclinical hypothyroidism, evaluated Natriu-retic peptide levels before and after restoration of euthyroidism in a double-blind, placebo controlled study taking advantage of stored serum samples [47].

The cardiovascular system is very sensitive to thyroid hormones. Hyper-thyroidism and hypoHyper-thyroidism induce significant changes in cardiac func-tions. The effects of hyperthyroidism on the heart includes hemodynamic

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changes such as decreased systemic vascular resistance as well as increased cardiac output, heart rate, blood volume, blood pressure and impaired cardiac contractility. It may also lead to atrial arrhythmias [294]. These changes result in ventricular stretch and pressure overload, which might cause a concomitant rise in BNP concentrations [277]. Recent attention has been drawn to the relation of BNP and hyperthyroidism. Studies suggest that plasma BNP and NT-proBNP concentrations frequently increase in hyperthyroidism. This increase is partly due to hyperthyroidism induced left ventricular dysfunction, also in vitro animal studies have suggested that T4 and T3 stimulate the BNP release from both cultured atrial and ventricular myocytes [161].

Two small studies suggest a beneficial effect of treatment of subclinical hyperthyroidism on cardiac function [83, 246]. Schultz et al. studied NT‒proBNP levels in different thyroid function states and found that serum levels of NT-proBNP were strongly affected by thyroid function; the higher the thyroid function, the higher the serum levels of NT-proBNP. Likewise the treatment of the destroyed state resulted in a significant increase in NT‒proBNP in both overt and subclinical hypothyroid patients and a de-crease in both overt and subclinical hyperthyroid patients. In order to assess whether those findings were the direct outcome of thyroid hormones or were the results of changes in heart function and structure, they compared NT-proBNP, thyroid function and cardiac output or resting pulse rate in a subgroup of patient work. Cardiac output or resting pulse rate did not have any independent effect on NT-proBNP levels, whereas, thyroid function had a significant effect on NT-proBNP levels [242]. Ertugrul et al. evaluated the serum BNP levels in 18 overt and 47 subclinical hyperthyroid patients together with 39 subclinical and 13 overt hypothyroid patients. BNP levels were more than five times higher in hyperthyroid than euthyroid control subjects. BNP levels were also higher in subclinical hyperthyroidism than euthyroid control subjects. Free T4 and free T3 concentrations were found to be associated with high serum BNP levels. The BNP level in patients with subclinical or overt hypothyroidism was similar to that of the controls [79]. On the other hand, Christ-Crain et al. found that there was no significant difference between NT-proBNP levels of euthyroid and overt hypothyroid, subclinical hypothyroid and subclinical hyperthyroid subjects, and NT-proBNP levels were higher in overt hyperthyroidism compared to other groups [47]. Kohno et al. have found higher BNP levels in untreated hyper-thyroid patients and rats with hyperhyper-thyroidism induced by thyroxine than their normal counterparts. Hypothyroid rats had lower plasma BNP concentration than the euthyroid ones. In vitro effects of T3 and T4 on the release of BNP were investigated in newborn rat atrial and ventricular

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myocytes in primary culture. T3 and T4 stimulated release of BNP from both cultured atrial and ventricular myocytes in a dose-dependent manner [161]. Triiodothyronine also increases BNP gene transcription and amplifies endothelin-dependent BNP gene transcription in rat ventricular myocytes [169]. The effect of hyperthyroidism and subclinical hyperthyroidism on the heart may also cause an increase in the BNP. At the moment, we do not know which one of these mechanisms is actually responsible for alterations in BNP levels in thyroid dysfunction. There is little known about the effects of endogenous subclinical hyperthyroidism on the heart. Faber et al. demonstrated an increase in cardiac output and a reduction in total peri-pheral resistance when treating subclinical hypothyroid subjects with L‒T4, whereas the opposite is seen in treating subclinical hyperthyroidism with radioiodine [83]. Ertugrul et al. studied BNP levels in patients with hyperthyroidism before specific treatment for hyperthyroidism and after euthyroidism was achieved. This study showed that BNP levels were significantly higher in hyperthyroid than euthyroid status of the same patients. It was found that the decrease in BNP levels was positively correlated with the decrease in FT3 and FT4 [80]. Kato et al. measured serum ANP and BNP levels in 130 patients with thyrotoxicosis and correlated them with serum thyroid hormone levels and with the degree of severity of the heart failure. They reported a significant eleva-tion of the BNP and atrial Natriuretic peptide levels which returned to nor-mal values after euthyroididsm was established in patients with thyrotoxicosis. It was concluded that both serum thyroid hormones and cardiovascular dysfunction contribute to the increase of serum BNP levels and atrial fibrillation is an independent contributing factor for the increase of BNP [150]. Shih-Hung Tsai et al. have found elevated BNP levels were mainly found in hyperthyroid patients who had clinical and echocardiography evidence of LV dysfunction, but not in those with normal LV function and normal subjects.Free T4 and free T3 were independently associated with a high se-rum NT-proBNP, whereas cardiac output and resting pulse rate were not. In patients with hyperthyroidism, both NT-proBNP and BNP levels were higher than hypothyroid patients and normal controls; and treatment of thy-roid dysfunctions could result in normalization of NT-proBNP levels in both hypothyroid and hyperthyroid groups [248].

In conclusion, Natriuretic peptide levels are altered in different thyroid states with a more pronounced effect in hyperthyroidism compared to hypothyroidism. This seems to reflect distinct atrial and ventricular cardiac dysfunction in thyroid hormone excess or, alternatively, mirrors a direct effect of thyroid hormones on gene expression of Natriuretic peptides. As hyperthyroidism results in increased serum levels of proANP, NT-proBNP

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and BNP levels as typically seen in mild heart failure, hyperthyroidism should be considered in patients presenting with unclear symptoms and mildly elevated Natriuretic peptide levels [47]. Since the treatment of hyper-thyroidism is quite different from the treatment of heart failure, thyroid hormones should be checked in patients with high levels of BNP. Mild elevations in NT-proBNP levels should therefore always be accom-panied by a thyroid function screening test [79, 80, 169, 242].

Thyroid diseases are known to have an effect on NT-proBNP levels. In hyperthyroidism, NT-proBNP levels reach the levels observed in severe heart failure. Therefore, in patients without severe cardiac dysfunction, ele-vated NT-proBNP level may be suggestive for hyperthyroidism. Although low levels of free triiodothyronine and high levels of the brain Natriuretic peptide have been established as independent predictors of death in chronic heart failure patients, few studies have compared their prognostic values.

Low T3 syndrome is highly prevalent and independently prognostic in cardiovascular patients. The relationship and prognostic impact with the cardiac marker NT-proBNP have not been thoroughly investigated. FT3 and low T3 syndrome are related to NT-proBNP in patients with cardiovascular disease, but are predictors of mortality independently of NT-proBNP and other known cardiovascular risk parameters [211].

Serum NT-proBNP levels are affected by thyroid functions and seem to be a direct stimulatory effect of thyroid hormones.

1.1.3. BNP link with cortisol levels

The level of the inactive NT-proBNP is a strong predictor of mortality among patients with acute coronary syndromes and may be a strong prognostic marker in patients with chronic coronary heart disease as well. Brain Natriuretic peptide, a cardiac peptide has been implicated in the regulation of hypothalamic-pituitary-adrenocortical responses to psycho-logical stressors. In response to academic stress, the plasma cortisol eleva-tion was accompanied by a marked reduceleva-tion in plasma NT-proBNP level. Mental stress entails an interface between the HPA axis and the peripheral Natriuretic peptide system, leading to reciprocating changes in circulating levels of the corresponding hormones [195].

Brain natriuretic peptide (BNP), a cardiac peptide, has been implicated in the regulation of hypothalamic-pituitary-adrenocortical (HPA) responses to psychological stressors. The influence of academic stress on circulating concentration of the N-terminal fragment of BNP precursor (NT-proBNP), and in relation to the stress hormone (cortisol) response was studied in 170 college students undergoing major examinations. Just prior to the

exami-19

nation, measure self-estimated stress level, systolic, and diastolic blood pressure, heart rate, plasma levels of cortisol, and NT-proBNP. These pa-rameters were compared to the participant's baseline measurements, taken at the same hour of a different control day, without a major examination to induce stress. Hemodynamic variables systolic, and diastolic blood pressure and heart rate increased on the examination day compared with baseline values. Circulating cortisol concentration increased before examinations (42%). The response to stress was marked by a significant decrease in plasma NT-proBNP concentration (40%). In response to academic stress, the plasma cortisol elevation was accompanied by a marked reduction in plasma NT-proBNP level. These data may indicate that mental stress entails an interface between the HPA axis and the peripheral natriuretic peptide system, leading to reciprocating changes in circulating levels of the corres-ponding hormones [7].

Natriuretic peptides (ANP, BNP and CNP) comprise a family of struc-turally related peptides, which are derived from three different genes and which shale at 17-amino acid internal ring. Besides their peripheral invol-vement in diuresis and blood pressure regulation these peptides, their bioactive fragments and their corresponding receptors (Natriuretic peptide receptors NPR-A, NPR-B and NPR-C) are found throughout the central nervous sys-tem (CNS): NPR-A and NPR-C is found in neurons anti astrocytes, while NPR-B is located mainly in neurons and partially co localizes with NPR-A. In the CNS of man and rodents NPR-A is found mainly in the cortex and hippocampus, where NPR-B is present in the amygdala and several brain stein regulatory sites. NPR-C is found widely within the CNS i.e. in neocortex, limbic cortex, the hippocampus area and the amygdala. These peptides and their receptors represent an important neuromodulatory system within the CNS, which is involved not only in the regulation of fluid homeostasis, but also directly influences emotional behavior, such as anxiety and arousal, and the sequel of stress hormone release and autonomic nervous system activation. Natriuretic peptides are specifically involved in the regulation of the HPA system: in man and rodents ANP inhibits the HPA system at all regulatory levels, while CNP stimulates the release of cortisol. Complementarily, the anatomic structure of Natriuretic peptide systems within the CNS supports an important role for this in normal and pathologic emotional behavior (e.g. anxiety and panic): in rodents ANP were found to reduce anxiety levels, whereas CNP induced the opposite effect. In patients with panic disorder basal ANP plasma levels are lower in comparison to healthy volunteers, but ANP secretion is faster and more pronounced during experimentally induced panic attacks. The inhibitory potency of ANP could explain the unexpected and so far

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unresolved failure of autonomic and HPA system activation during panic attacks. Moreover, panic anxiety and concomitant ACTH and cortisol secretion elicited by stimulation with the panicogen cholecytokinin-tetrapeptide were also attenuated by ANP infusions in patients as well as in healthy volunteers. Hence, it may be surmised that in man and rodents ANP reduces anxiety and terminates panic attacks and their neuroendocrine sequel [299].

1.2. Influence of thyroid hormones in patients with CAD

The cardiovascular system is the main target organ of thyroid hormone (TH), and TH exerts multiple actions on cardiac function as well as peripheral vascular tone [144, 154, 158, 204, 217]. Overt hypothyroidism decreases myocardial contractility, and diminished myocardial contractility reduces TH metabolism [24, 163, 203]. Subclinical hypothyroidism also exhibits impairment of left ventricular (LV) diastolic function that returns to normal after TH replacement [27].

Over the last decades, several studies have attempted to elucidate the mechanisms underlying the changes on circulating thyroid hormones in non‒thyroidal illness syndrome. Increased inflammatory cytokines, which occurs in response to virtually any illness, has long been speculated to play a role in derangements of deiodinase expression. On the other hand, oxidative stress due to augmented reactive oxygen species generation is characteristic of many diseases that are associated with non-thyroidal illness syndrome. Changes in the intracellular redox state may disrupt deiodinase function by independent mechanisms, which might include depletion of the as yet un-identified endogenous thiol cofactor [287].

Sick euthyroid syndrome (SES) is the entity of change peripheral TH profile in non-thyroidal illness [255, 260]. SES is characterized by decreased total T3 levels and reciprocally increased reverse T3 levels [108]. For pathophysiology of SES, impaired peripheral denomination of T4, decreased thyroid releasing hormone metabolism and reduced TH receptor expression have been suggested [20, 71].

More than 80% of the biologically active hormone triiodothyronine derives from peripheral conversion of prohormone thyroxin secreted by the thyroid gland. Clinical and experimental evidence have shown that T3 plays a major role in modulating heart rate and cardiac contractility as well as arterial peripheral resistance [156, 217]. T3 actions are carried out by bin-ding to specific nuclear receptors that regulate responsive genes encobin-ding

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for structural and functional cardiac proteins; direct, special nuclear, no transcriptional effects have also been reported.

Reverse T3 dominance, functional hypothyroidism also known as Wilson’s Syndrome is a condition that exhibits most hypothyroid symptoms although circulating levels of T3 and T4 are within normal test limits. This is a condition when T4 metabolism produces an excess of reverse T3 in relation to T3, this being a problem with T4 activation rather than a lack of thyroid production. Periods of prolonged stress may cause an increase in cortisol levels as the adrenal glands respond to the stress. Higher cortisol levels suppress the conversion of T4 into T3 thus reducing the active T3 level. The conversion of T4 is then shunted towards the production of the inactive reverse T3. This reverse T3 dominance may persist even after the stress passes and cortisol levels have returned to normal as the reverse T3 itself may also inhibit the conversion of T4 to T3. Reverse triiodothyronine (RT3) has the same molecular structure as T3 however, its three dimen-sional arrangement of atoms is a mirror image of T3 and this fits into the receptor upside down thus preventing or antagonizing the active T3 from binding to the receptor and activating the appropriate response.

The metabolism of T4 into RT3 is in excess when compared to T3 therefore it is a T4 metabolism malfunction rather than a straightforward thyroid deficiency. Periods of prolonged stress may cause an increase in cortisol levels as the adrenal glands respond to the stress. Higher cortisol levels inhibit the 5-deiodinase enzyme and this conversion of T4 into T3 thus reducing the active T3 level. The conversion of T4 is then shunted towards the production of the inactive RT3 via the 5′-deiodinase enzyme. This RT3 dominance may persist even after the stress passes and cortisol levels have returned to normal as the RT3:T3 imbalance it may also inhibit the 5-deiodinase enzyme thus perpetuating the production of the inactive RT3 isomer. There is some argument to this last point with some research suggesting that the elevated RT3 is only temporary and not a permanent condition and in most healthy people this may well be the case. We have however found that in many patients suffering from a range of hypothyroid symptoms do indeed have prolonged elevated RT3 levels which respond favorably to this treatment. Many medical practitioners do not accept RT3 dominance theory and this many doctors will refuse to treat this condition, despite the fact many suffer have been successfully treated.

Triiodothyronine, the biologically active form of thyroid hormone derived predominantly from the peripheral conversion of the precursor thyroxine, exerts a wide range of functions in several organs, including the heart. Abnormal thyroid hormone metabolism may contribute to different forms of heart disease and hypothyroidism, in particular, is a well known

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cause of accelerated coronary atherosclerosis. In recent years, attention has shifted towards milder forms of thyroid disease, such as the so called low T3 syndrome, which is characterized by an isolated reduction in circulating levels of the biologically active form of thyroid hormone, triiodothyronine. Furthermore, variations of T3 within the physiological range have been linked to coronary artery disease, one of the leading causes of morbidity and mortality worldwide [55].

Low T3 syndrome, being characterized by reduced serum levels of both total and free T3 with normal TSH and FT4 levels, and once believed to be a beneficial adaptive mechanism under conditions of stress, has emerged as a strong prognostic determinant in chronic, systolic heart failure. Increased mortality among patients with the low T3 syndrome has also been observed in acute myocardial infarction, a common precursor of chronic heart failure of ischemic origin. However, whether variations in FT3 levels, not only in the context of the low T3 syndrome, but also within the physiological range, are related CAD per se remains unclear.

A typical pattern of altered thyroid hormone metabolism characterized by low T3 circulating levels has been described in patients with acute myocardial infarction [94, 299] and heart failure. The principal pathophy-siological mechanism underlying low circulating T3 is the reduced enzyme activity of 5′ monodeiodinase responsible for converting T4 into T3 in peripheral tissues [279].

Experimental and clinical findings strongly support the concept that thyroid hormone (TH) plays a fundamental role in the cardiovascular (CV) homeostasis. CV diseases represent a major public health care and economic problem being one of the principal causes of morbidity, mortality and hospitalization. TH derangement may have a key role in the evolution process of HF. In HF, the main and earlier alteration of the thyroid function is referred to as “low T3” syndrome characterized by the reduction in serum total T3 and free T3 with normal levels of thyroxine (T4) and thyrotropin (TSH). This syndrome may affect till one-third of advanced HF patients [132].

Low thyroid hormone concentrations, in particular low serum T3 con-centrations, are a common finding in patients with nonthyroidal illnesses, including cardiac disorders. Its pathophysiological role is not well under-stood, although the common belief is in favor of an adaptive mechanism to preserve energy [217, 279]. Nonetheless, based on the knowledge of the fundamental actions of T3 on both the heart and vessels, a direct relationship between low circulating levels of T3 and adverse prognosis of cardiac patients has represented an attractive hypothesis in the last few years [156]. This respect has been postulated that the low T3 state may produce a

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hypothyroid ‒ like syndrome that contributes to the worsening or exa-cerbation of the intrinsic cardiac disease [155]. Low FT3 serum concen-tration represents a negative prognostic index it is likely that impairment of T3 production and enhanced inflammation represent pathogenic mecha-nisms linked to HF progression [170].

There is increasing evidence that altered TH status in SES may have an influence on clinical outcome and cardiac function [11, 46, 103, 157, 177]. It has been demonstrated that the degree of thyroid dysfunction was asso-ciated with severity of diseases, and low levels of biologically active TH predicted a poor prognosis in several diseases [118, 180, 208]. Previous studies have reported that low total T3 levels were associated with increased mortality and impaired cardiac function and were strong prognostic predict-tors of death in heart disease [131, 205, 214].

Acute myocardial infarction (MI) may be associated with a number of endocrine alterations, including those of thenon-thyroidal illness syndrome NTIS which reflect the acute hormonal response to stress and trauma. A transient decrease in T3 and increase in reverse RT3 occurs within the first 24 h, reaching the highest degree on the third day after the attack. The de-creased nutrition during the first days of the myocardial infarct, the in-creased levels of serum cortisol and circulating free fatty acids or free ra-dicals are some of the factors which may contribute to the monodeiodinase inhibition. Less prominent are the alterations of T4 and TSH which appear to be non-significantly changed in most of the patients with acute myo-cardial infarct [149].

Thyroid hormone levels begin to decline at a very early stage of heart failure, and this decrease is seen even in asymptomatic or mildly symptom-matic patients with idiopathic LV dysfunction [214]. These observations indicate that there is a reduction in the conversion of FT4 into FT3, despite the finding of a normal range of FT3 levels in the very early stages of heart failure. Patients who have decreased FT3 levels may also have increased plasma rennin activity and increased aldosterone, noradrenalin, BNP, and atrial Natriuretic peptide levels [214]. Low FT3 levels can indicate higher activity of the neuroendocrine and proinflammatory systems, they contribute to a poor prognosis. Indeed, low T3 syndrome has been found to be a strong and independent predictor of death in heart failure patients [44, 131, 177]. FT3 serum level < 2.1 pg/ml with normal thyrotropin (low T3 syndrome) showed an independent and incremental prognostic value, and were associated with an increase in the rate of cardiac events of 41% [238].

Dobutamine infusion in low T3 syndrome patient group evoked a statistically significant cardiac index increase, pulmonary capillary arterial wedge pressure, and right atrial pressure decrease with left ventricle

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diastolic dysfunction recovery; the hemodynamic and clinical improvement were associated with brain natriuretic peptide reduction and increased FT3 levels [59].

A recent randomized controlled trial suggests that hypothyroid subjects may find levothyroxine (l-T4) and levotriiodothyronine combination therapy to be superior to l-T4 monotherapy in terms of quality of life, suggesting that the brain registered increased T3 availability during the combination therapy [240].

The aberration is characterized by decreased circulating levels of the biologically active form of T3 and by increased levels of reverse T3 in se-rum as a result of impaired conversion of sese-rum T4 to T3 in peripheral tissues, despite the presence of normal TSH and T4 levels [11, 70, 131, 214]. This syndrome occurs in approximately 30% of patients with advanced chronic heart failure. The presence of low T3 levels has been found to be an independent predictor of poor prognosis; indeed it can be used as a predictor of death in chronic heart failure patients [118, 214].

The cardiovascular system is one of the most important targets on which thyroid hormones act [296]. Higher TSH levels within the normal range are associated with an increased risk of myocardial infarction, in patients with the clinical manifest vascular disease

Progression of chronic heart failure is mediated largely via persistent activation of various neuroendocrine systems [200].

1.3. The role of cortisol in patients with CAD

Cortisol has been implicated in the etiology of SES [108, 118]. Cortisol levels may be involved in the pathophysiology of SES in stress. There is in-creasing evidence that cortisol may interfere directly with the pathological processes that led to heart failure progression by binding to and activating cardiac mineralocorticoid receptor [6, 100]. According to a hypothesis pro-posed by J.W. Founder, cortisol may be the dominant agonist that activates cardiac and vascular mineralocorticoid receptor under conditions of chronic heart failure [102, 309].

The derangement of neuroendocrine control of circulation influences both disease evolution and response to treatment in patients with heart failure, but little data are available about the complex relationships between the degree of neurohormonal activation and clinical severity [184].

Typically, concentrations of cortisol in the bloodstream are subject to diurnal variability. Normally, cortisol concentrations peak in the morning and subside in the evening, with the lowest concentrations occurring around

25

midnight [53, 306]. Plasma concentrations of cortisol were characterized by distinct circadian rhythms, which were equally observed during conditions of regular sleep and 24-hour wakefulness. Cortisol concentrations showed a minimum approximately 00:30 h and a maximum around the time of morning awakening approximately 08:00 h [266].

Cortisol usually acts as a brain mineralocorticoid receptor antagonist in the kidney and the heart [109, 221]. If an intracellular redox state change with tissue damage and the generation of reactive oxygen species in HF, cortisol may act as MR agonists like ALD [100, 101, 191].

However, the usefulness of predicting cardiac events based on cortisol levels, which may also bind and activate the MR, remains unclear. Güder et al. [114]reported that higher serum levels of both cortisol and ALD were in-dependent predictors of increased mortality risk in patients with HF. However, they did not evaluate BNP, adrenocorticotropic hormone (ACTH), and a biomarker of oxidative stress [307].

The accumulating evidence that stress-related factors contribute to the development of CAD has stimulated research into the underlying pathways involved [229]. Psychophysiological stress testing can be used to better understand the mechanisms underlying the association between mental stress and CAD [69]. Abnormalities in HPA function have been described in several chronic inflammatory disorders, and may be possible mechanisms through which psychosocial stress influences the risk of CAD [116, 297]. Prolonged hypothalamic pituitary adrenal axis activation may interfere with exercise-related improvements in memory in CAD [237].

The term “stressˮ describes the state of the organism under the influence of external or internal forces, or “stressorsˮ, which threaten to alter it's dynamic equilibrium or homeostasis. The adaptive changes occurring in response to stresses are both behavioral and physical. Once a certain threshold has been exceeded, a systemic reaction takes place that involves the “stress systemˮ in the brain along with its peripheral components, the HPA axis, and the autonomic sympathetic system.

A variety of secondary changes occur when heart failure becomes chronic (i.e., after 3 or 6 months). These secondary changes are primarily a response to the impaired cardiac function, although some of these varieties may develop consequent to the drugs used in the treatment of heart failure. These secondary changes include general neurohormonal activation with stimulation of the sympathetic nervous system, the rennin-angiotensin-aldosterone axis, and the Natriuretic peptide system. Initially, these systems are thought to be beneficial, but eventually they contribute to increased vascular resistance and after load, and ventricular enlargement and remodeling [92]. The neurohormonal hypothesis [200]postulates that heart

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failure progresses because the activated endogenous neurohormonal systems exert a deleterious effect on the heart and circulation. Several studies have found neurohormonal activation to be strongly related to mortality [56, 93, 269], but different hormones correlate only weakly with each other.

The pathophysiological mechanisms underlying emotional triggering of acute cardiac events are poorly understood. Atherosclerosis is a chronic inflammatory process involving the progressive recruitment and activation of leukocytes, lipid, platelets, and smooth muscle cells in the endothelial lining of coronary arteries, resulting in the formation of a fibrous plaque that protrudes into the arterial lumen. Atherosclerosis occur when there is a rupture of vulnerable plaque and consequent activation and aggregation of platelets, leading to the formation of a blood clot (thrombus) that occludes the artery and prevents blood flow to the heart [121].

Emotional stress activates the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, resulting in respective increases in blood pressure and circulating levels of catecholamine's and glucocorticoids (cortisol) [26].

Acute elevations in blood pressure can provoke plaque rupture by disrupting blood flow across the diseased vessel and increasing endothelial stress [262], and glucocorticoids regulate a number of processes involved in plaque stability including vascular endothelial function and inflammation [107]. Circulating levels of inflammatory cytokines are also up-regulated during stress, and these molecules play a pivotal role in plaque rupture and thrombosis [262, 263].

There is considerable evidence that healthy hostile individuals have heightened or prolonged cardiovascular and neuroendocrine responses to acute emotional stress [254].

However, studies relating hostility and inflammatory stress responses are sparse. Furthermore, little is known about the role of hostility in acute stress responses in patients with advanced cardiovascular disease. We set out to address these issues by investigating the relationship between trait hostility and physiological responses to laboratory stress in a sample of patients who had recently survived an atherosclerosis. We predicted that patients with elevated hostility scores would be more responsive to stress.

1.4. Depression and thyroid axis function in coronary artery disease Depression to cardiovascular disease may be connected in various ways: 1. There is epidemiological evidence that a depressive symptom in male and female patients is associated with an increased risk of myocardial

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infarction and increased mortality after acute cardiac cases. In addition, patients with depression often occur after myocardial infarction.

2. Patients with chronic heart failure and depression as well as a worse cardiac functional status and more frequent and severe chest pain, more physical limitations, poorer quality of life.

3. More frequent complication in patients with cardiovascular disease in people with depression is not fully elucidated, but it may be associated with an increased adrenergic stimulation sympathies and increased platelet aggregation.

1.4.1. The prevalence of people with psycho disorders and cardiovascular diseases

Depression is a common psychiatric disorder in patients with CAD. Some authors, the incidence of myocardial infarction, major depression affects 15% to 20% [22], and develops to 50% of patients is develop mild symptoms of depression. Other ‒ within 12 months after acute myocardial infarction at least 30% of patients may develop severe and 30% for mild depression [120]. Thus, patients who experienced acute MI symptoms of depression within 12 months after the event can occur in up to 60% [96].

Another study reported the occurrence of depression in patients with coronary artery disease is disproportionately large compared with the general population, even 4%‒7%. And as much as 14%‒47% of CAD patients with unstable angina or in patients awaiting coronary artery bypass graft surgery [12, 261].

Due to the high prevalence of depression among patients with coronary artery disease to determine how depression may contribute to the deve-lopment of coronary artery disease and depression with individuals more prone to coronary artery disease and the influence of disease complications. Depression is a significant risk factor leading to heart disease and mortality in patients with coronary artery disease. This risk increases from the initial diagnosis of clinical symptoms and angiography data before acute myo-cardial infarction (MI) or unstable angina episode. More than 20 studies have indicated that depression after acute MI increases to more than double the risk of mortality within one month after the event [16].

Negative emotions have an impact on health status. Even in 1628 by William Harvey noted that mental disorders can affect the cardiovascular system and impair its function. However, only in the last few decades, proved methodologically based on epidemiological research, which pro-vided a compelling connection between emotions and cardiovascular disea-ses, emotions regarded as a risk factor like smoking, obesity and others.

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There is growing evidence that negative emotions accumulates and even-tually may lead to adverse effects on the cardiovascular system. This ex-plains the neurohormonal regulatory mechanisms [82, 165, 231].

One of the most famous INTERHEART case control studies (29.972 patients from 52 countries), the effect on the nine conventional risk factors causing acute myocardial infarction (MI). Psychosocial distress is caused by a higher risk of acute MI, neither hypertension, obesity, diabetes and many other traditional risk factors. High levels of psychosocial distress increased the risk of MI more than 2.5‒fold. Psychological stress had a greater MI risk in men, but depression was most significant among women [310]. Perceived stress and depression were shown to be important risk factors, which

together accounted for 32.5% of the population attributable risk for CAD.

A rate of major depressive disorder by around 15% has been reported in patients after myocardial infarction (MI) or coronary artery bypass grafts. If milder forms of depression are included, a prevalence of greater than 40% has been documented. Recently, the EUROASPIRE III study investigated 8580 patients after hospitalization for CHD. The proportion of patients with depression, measured by the Hospital Anxiety and Depression Scale, varied from 8.2% to 35.7% in men and 10.3% to 62.5% in women.

Nicholson et al. found that for people with CAD and co morbid de-pression, the relative risk (RR) of death is increased (RR, 1.80 [95% CI, 1.50–2.15]), independent of standard risk factors for secondary prevention. Co morbid depression also leads to a higher risk of other adverse outcomes in patients with CAD, such as a lower likelihood of return to work, poor exercise tolerance, fewer adherences to therapy, greater disability, poorer quality of life, cognitive decline and earlier dependency. Individuals with CAD and co morbid depression often have less access to interventions for CAD, despite being in a higher risk group [193]. Mild depression may resolve spontaneously; however, for most individuals with CHD, depression remains long-term [60].

1.4.2. Depression in cardiovascular disease development, course and source

As a negative emotion is the development of ischemic heart disease? Negative emotions can cause a direct physiological effect on the growth of CAD through the reuse of the sympathetic nervous system and HPA axis activation, dysregulation of the immune system and inflammation. Negative emotions may indirectly affect CAD through behavioral motivation to harm health. For example, individuals who experienced high anxiety are more likely to smoke and more likely to be less physical activity. Thus, negative

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emotions can accelerate the progression of the disease or reduce the survival as direct or indirect physiological effects ‒ without complying with the recommended regimen [151]. HPA axis hyperactivity is implicated as a potential mechanism through which depression can increase the risk for physical disease and early mortality. Among depressed individuals, cortisol secretion was associated prospectively and positively with risk for death from cardiovascular disease [265].

Mechanisms of influencing negative emotions and cardiovascular system, to this day coincides with the findings from the INTERHEART study [310]. This study is based on the etiological relationship between the three negative emotions ‒ anger, anxiety and depression ‒ and the deve-lopment of CAD. Numerous prospective studies that examined a wide range of CAD risk factors do not deny the positive relationship between these three emotions and the occurrence of CAD.

Much of the research deals with depression as a manifestation of negative emotions and CAD. In 2002, 11 published studies have shown a strong positive association between depression and CAD events with RR 2.69 (95% CI: 1.63‒4.43) for individuals with clinically significant depression, and RR 1.49 (95% CI: 1.16‒1.92) for individuals with depressive symptoms [234]. After a further 10 additional studies, have confirmed a significant association between depression and coronary artery disease development [73, 77, 78, 230, 268]. This risk is increased not only clinically significant depression, but also symptoms of depression [302, 305]. A similar risk was found with anger and anxiety [147, 179, 274]. Post-traumatic stress disorder is closely associated with anxiety and depression, while the progression of coronary artery disease and outcome. A large number of trials to measure depressive symptoms in patients with cardiovascular disease, using clinical interviews and/or questionnaires and followed over time, assess the extent to which depression affects clinical outcomes. Table 1.4.2.1. summarizes the relationship between depression and clinical signs, such as death or MI [123].

Depression is a chronic, disabling mental disease worsening the course of several somatic disorders, including heart disease [41]. Increased rates of depression are reported in CAD [125, 233], after myocardial infarction [239] and in heart failure [111, 143]. In heart disease depression increases disability [2], reduces quality of life [19], and increases mortality [16].

The mechanisms by which depression may increase the morbidity and mortality associated with CAD are not fully understood. Several factors associated with depression may be implicated: increased inflammatory activity [206]; increased adrenergic activity [10, 29];and dysregulation of autonomic function [110, 164].

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Table 1.4.2.1. Impact assessment of depression in patients with

cardiovas-cular disease

Author Sample Patients Period Manifestation _{of disease} Relative _risks

Carney

et al. 52/22 death CAD 12 months MI and death RR = 2.2 Barefoot

et al. 1250/197 death CAD 0 –19.4 years heart diseaseDeath from RR = 1.7 Murberg

et al. 119/22 death HF 2 years heart diseaseDeath from RR = 1.9 Frasure-Smith

et al. 222/12 death MI 6 months heart diseaseDeath from RR 4.29 Frasure-Smith

et al. 896/39 death MI 1 year heart diseaseDeath from RR = 3.05; Men Women RR = 3.29 Frasure-Smith

et al. 896/155 death MI 5 years heart diseaseDeath from RR = 3.13 –3.17 Welin

et al. 275/167 death MI 10 years heart diseaseDeath from RR = 3.16 Bush

et al. 144/17 death MI 4 months heart diseaseDeath from RR = 3.5 Horsten

et al. 292/81 death event (MI or Acute CAD Angina)

5 years Death from

heart disease RR = 1.9 Despite increasing information about links between depression and heart disease there is no accepted model that accommodates all the mechanisms that may be involved. Moreover, some potentially important factors have only begun to be studied. Dysfunction of the thyroid axis is such a factor.

Thyroid hormones have profound effects on the cardiovascular system [157] and brain [220]. The majority of the biologically active thyroid hormone, triiodothyronine (T3), results from the peripheral conversion of the pro-hormone thyroxin (T4) secreted by the thyroid gland [212]. A reduced concentration of serum T3, called the low T3 syndrome, is the most often reported thyroid function abnormality in serious physical and mental diseases and during starvation. The principal mechanism underlying the low T3 syndrome in non-thyroid illnesses is an alteration in the activity of peripheral deiodinase enzymes [279]. A decline in T3 concentration paral-lels an increase in the concentration of reverse T3, which is metabolically

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inactive, and this has been interpreted as a compensatory mechanism that ensures energy conservation. However, this interpretation has been ques-tioned in several diseases, including cardiovascular disease, as noted below. Serum T3 concentration declines after myocardial infarction [98], cardiac surgery [159], in congestive heart failure [118] and is a strong predictor of early death in patients with heart disease [131, 214]. It is related to decrease functional capacity of the heart [11] and to increase Natriuretic of the B-type natriuretic peptide [76], a cardiac neurohormone secreted mainly from the ventricles of the heart in response to cardiac dysfunction [18].

An association between mood disorders and thyroid immunity has been demonstrated in different studies [220]. Even fluctuations in thyroid hor-mone concentration within the normal range may affect mental functioning. Thus, for example, subclinical hypothyroidism may be a risk factor for depression [115], and patients with treated Grave's disease, even though euthyroid, exhibit a high prevalence of affective disorders [38]. The low T3 syndrome is reported to occur in 8 to 21% of depressed patients [85, 289].

1.4.3. Anxiety and coronary artery disease

The relationship between HF and anxiety disorders has also been studied. The anxiety syndromes of primary interest have been generalized anxiety, panic with or without agoraphobia, and acute and post trauma tic stress disorders [42].

Although anxiety is more common in CAD and post MI patients than depression, evidence on the exact role in cardiovascular prognosis or effective and safe anxiolytic medications is very limited. Only recent studies suggest that anxiety following MI independently predicts the risk of in hospital adverse events and long-term clinical outcomes [126, 187].

Chronic anxiety increases the risk of coronary artery disease suffers from 1.5 to 7 times, depending on the type of anxiety [3, 72, 274].

The highest level of anxiety caused by fear of a lethal ischemic episode (relative risk (RR) of 3.77, 95% confidence interval (CI): 1.64 ‒ 8.64) com-pared with men without anxiety, assessment of other known coronary risk factors. Other studies found that anxiety as much as 60% higher risk to suffer from CAD for men and women, regardless of other risk factors [274].

Anxiety disorders are prevalent and associated with poor prognosis in patients with coronary artery disease (CAD). However, studies examining screening of anxiety disorders in CAD patients are lacking [33].

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1.5. Fatigue and depression, also cortisol and thyroid hormone metabolism in patients with CAD

Fatigue is an ambiguous concept, which especially relates to the reaction to physical and psychological workloads, but it may also include many different experiences and states of mind, e.g., the experience of exhaustion, impaired energy and vitality, and the need to sleep. Further, fatigue is the normal physiological reaction in an organism, a part of the body, or an organ, which has reached the limits of its capacity after heavy strain. Fatigue is a general reaction many biological processes after intensive and/or long-lasting work because metabolic demands cannot be satisfied. This may occur outside the central nervous system, e.g., in muscles, after heavy and intensive stimulation, as feedback from joints, muscles, and tendons [273]. Centrally conditioned fatigue is complex, and entails both chemical and hormonal factors in nerve cells and their synapses, e.g., as changes in neurotransmitter levels in various brain structures, but also psychological factors such as endurance, motivation, mood, and expectation of task difficulty. Fatigue may be acute or chronic: acute fatigue has a rapid onset and a short duration, and generally does not affect a person’s quality of life.

Feeling very tired is a human experience often referred to as fatigue, decreased energy, loss of vitality, energy, exhaustion, tiredness, weakness, and lethargy.

General fatigue is one of the symptoms of depression, and the feeling of fatigue is this included in several measures of depressive symptoms [197]. It is well known that depression is related to changes in the central nervous system, but also that these associations are bidirectional. Depression may lead to changes in both central (cognition, behavior, and affect) as well as peripheral functions (physiological and immunological responses), and vice versa, i.e., changes in cognition may have depression. A hypothetical model of fatigue in aging proposes that psychosocial factors (e.g., stress and depression) plus individual differences (e.g., personality and neuroticism) can lead to fatigue directly or indirectly through inflammation. Both fatigue and inflammation interact with, and potentially modify, disease. It is so very plausible that depressive symptoms explain some of the associations bet-ween fatigue and outcomes.

Several studies have shown strong associations between fatigue and depressive symptoms among younger general populations, primary care patients, and in patients with a specific condition, such as cancer or chronic pulmonary disease.

The observed associations between fatigue and depressive symptoms have given rise to discussions on the nature of the relationship, which may