Epicardial Fat in Coronary Artery Disease

Study Overview
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Brief Summary
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We hypothesize that human epicardial fat plays a thermogenic role to the myocardium. We hypothesize that epicardial fat may express genes of brown fat and thyroid function that are down-regulated by the presence of coronary artery disease. Because the postulated metabolic role of the epicardial fat, we also hypothesize that the gene expression of these regulatory thermogenic factors is higher in epicardial than subcutaneous fat This will be a cross-sectional study conducted over a one-year period in patients with or without coronary artery disease who require elective cardiac surgery regardless their participation in the study. Study group will be formed by 50 patients with clinically and angiographically established CAD who will undergo coronary artery bypass graft, as part of their standard medical care. Control group will be formed by 10 subjects, randomly selected, who will undergo cardiac surgery for aortic or mitral valve replacement as part of their standard medical care (these patients have no history, clinical signs of CAD, and show normal coronary arteries on coronary angiography). This will be a cross-sectional study conducted over a one-year period in patients with or without coronary artery disease who require elective cardiac surgery regardless their participation in the study. Adipose tissue will be collected during the cardiac surgery.

Detailed Description
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Our previous studies indicate that epicardial fat, the visceral fat depot of the heart, plays a role in modulating the heart morphology and its function (Iacobellis et al 2005). Notably, no muscle fascia divides the epicardial fat and the myocardium and the two tissues share the same microcirculation (Iacobellis et al 2005). Epicardial fat has peculiar biochemical properties and is actively involved in lipid and energy homeostasis. Epicardial fat is also a source of several bioactive molecules that might directly influence the myocardium and coronary arteries (Iacobellis et al, 2005,). Because of its anatomic proximity to the myocardium and its intense paracrine and metabolic activity, it is suggested that epicardial fat cytokines reach the myocardium through paracrine or vasocrine pathways and consequently modify its function. Given all these effects and properties, epicardial fat is pathophysiologically and clinically related to development and progression of coronary artery disease and atherosclerosis, regardless of obesity (Iacobellis 2010). Additionally, epicardial fat directly correlates with the intramyocardial lipid content, as we recently described (Malavazos 2010), suggesting a real interaction between the two tissues. However, a dichotomous role has been actually attributed to the epicardial fat. In fact, under physiological conditions epicardial fat displays cardioprotective effects (Iacobellis 2009) and potentially energetic and thermogenic properties, as brown fat (Sacks 2009). Although the interpretation of this finding is still unclear, expression of uncoupling protein1 (UCP1), a marker of brown fat, has been found in human epicardial fat and significantly higher than in subcutaneous fat. We know that brown fat generates heat in response to cold temperatures and activation of the autonomic nervous system under the direct control of thyroid hormones (Bianco 2011). Although the interest in brown fat in humans is growing, our understanding of its actual role in humans is still unclear. The heart is a highly demand organ, under the metabolic control of the thyroid and possibly the epicardial fat. Interestingly experimental models show that hypoxia induces type 3 deiodinase (D3) overexpression in the myocardium that inactivates T3 during ischemia, to protectively decrease cardiomyocytes metabolism and energy expenditure (Simonides et al 2008). Epicardial fat may function like brown fat and thyroid target tissue to protect and defend the myocardium and coronary artery against hypothermia and chronic hypoxia. Nevertheless, whether epicardial fat may have this role and whether this may be affected by the presence of coronary artery disease is currently unknown. We therefore hypothesize that human epicardial fat plays a thermogenic role to the myocardium. We hypothesize that epicardial fat may express genes of brown fat and thyroid function that are downregulated by the presence of coronary artery disease. Because the postulated metabolic role of the epicardial fat, we also hypothesize that the gene expression of these regulatory thermogenic factors is higher in epicardial than subcutaneous fat. These hypotheses will be tested as follows:Specific Aims Ia)Does human epicardial fat express makers of brown adipose tissue, such UCP1 and brown adipocyte differentiation transcription factors in subjects with and without coronary artery disease?b)Does human epicardial fat express type 2 and type 3 deiodinase, thyroid hormones and 3 adrenergic receptors in subjects with and without coronary artery disease?c)Is the thermoregulatory function of the human epicardial fat correlated to the presence and severity of coronary artery disease? Specific Aims IIa)Does the expression of brown fat and thyroid markers gene expression is higher in epicardial than subcutaneous fat?b)Does epicardial fat thickness, as measured by echocardiography, correlate with the gene expression of brown adipose tissue and thyroid markers?c)Does epicardial fat thickness, as measured by echocardiography, correlate with the presence and severity of coronary artery disease?

Official Title
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Epicardial Fat as Brown Fat in Coronary Artery Disease

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Procedure: Coronary artery bypass grafting (CABG)
* Procedure: Valve replacement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with clinically and angiographically established CAD Controls: subjects with have no history, clinical signs of CAD, and show normal coronary arteries on coronary angiography, who will undergo cardiac surgery for aortic or mitral valve replacement as part of their standard medical care Exclusion Criteria: Patients with heart failure, kidney failure or liver failure, infective disease or cancer will be excluded from the study. Subjects taking glucocorticoids or estrogens or patients currently smoking will be excluded from the study. Patients with mental disorders will also not be included

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Coronary Artery Disease (CAD)<br>Patients with clinically and angiographically established coronary artery disease (CAD) who require CABG, as part of the standard medical care. | Procedure: Coronary artery bypass grafting (CABG)<br>* CABG, as part of the standard medical care<br>|
| controls<br>Control group will be formed by subjects, randomly selected, who will undergo cardiac surgery for aortic or mitral valve replacement as part of their standard medical care (these patients have no history, clinical signs of CAD, and show normal coronary arteries on coronary angiography). | Procedure: Valve replacement<br>* cardiac surgery for aortic or mitral valve replacement as part of their standard medical care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EAT thermoregulatory genes | Does human epicardial fat express makers of brown adipose tissue, such UCP-1 and brown adipocyte differentiation transcription factors in subjects with and without coronary artery disease? Does human epicardial fat express type 2 and type 3 deiodinase, thyroid hormones and β-3 adrenergic receptors in subjects with and without coronary artery disease? Is the thermoregulatory function of the human epicardial fat correlated to the presence and severity of coronary artery disease? | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subcutaneous fat genes | Does the expression of brown fat and thyroid markers gene expression is higher in epicardial than subcutaneous fat? | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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epicardial fat