Epicardial Fat in Coronary Artery Disease

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?

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