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STATE OF THE ART REVIEW ARTICLE
Echocardiographic Epicardial Fat: A Review of
Research and Clinical Applications
Gianluca Iacobellis, MD, PhD and Howard J. Willens, MD, Hamilton, Ontario, Canada; Miami, Florida
Epicardial fat plays a role in cardiovascular diseases. Because of its anatomic and functional proximity to the
myocardium and its intense metabolic activity, some interactions between the heart and its visceral fat depot
have been suggested. Epicardial fat can be visualized and measured using standard two-dimensional echocardiography. Standard parasternal long-axis and short-axis views permit the most accurate measurement of
epicardial fat thickness overlying the right ventricle. Epicardial fat thickness is generally identified as the echofree space between the outer wall of the myocardium and the visceral layer of pericardium and is measured
perpendicularly on the free wall of the right ventricle at end-systole. Echocardiographic epicardial fat thickness
ranges from a minimum of 1 mm to a maximum of almost 23 mm. Echocardiographic epicardial fat thickness
clearly reflects visceral adiposity rather than general obesity. It correlates with metabolic syndrome, insulin resistance, coronary artery disease, and subclinical atherosclerosis, and therefore it might serve as a simple tool
for cardiometabolic risk prediction. Substantial changes in echocardiographic epicardial fat thickness during
weight-loss strategies may also suggest its use as a marker of therapeutic effect. Echocardiographic epicardial fat measurement in both clinical and research scenarios has several advantages, including its low cost,
easy accessibility, rapid applicability, and good reproducibility. However, more evidence is necessary to evaluate whether echocardiographic epicardial fat thickness may become a routine way of assessing cardiovascular risk in a clinical setting. (J Am Soc Echocardiogr 2009;22:1311-9.)
Keywords: Epicardial adipose tissue, Epicardial fat, Echocardiography, Obesity, Metabolic syndrome
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The American Society of Echocardiography is accredited by the Accreditation Council
for Continuing Medical Education to provide continuing medical education for physicians.
The American Society of Echocardiography designates this educational activity for
a maximum of 1 AMA PRA Category 1 CreditÔ. Physicians should only claim credit commensurate with the extent of their participation in the activity.
ARDMS and CCI recognize ASE’s certificates and have agreed to honor the credit hours
toward their registry requirements for sonographers.
The American Society of Echocardiography is committed to ensuring that its educational mission and all sponsored educational programs are not influenced by the special
interests of any corporation or individual, and its mandate is to retain only those authors
whose financial interests can be effectively resolved to maintain the goals and educational integrity of the activity. Although a monetary or professional affiliation with a corporation does not necessarily influence an author’s presentation, the Essential Areas and
policies of the ACCME require that any relationships that could possibly conflict with
the educational value of the activity be resolved prior to publication and disclosed to
the audience. Disclosures of faculty and commercial support relationships, if any,
have been indicated.
Target Audience
This activity is designed for all cardiovascular physicians and cardiac sonographers with
a primary interest and knowledge base in the field of echocardiography; in addition, residents, researchers, clinicians, intensivists, and other medical professionals with a specific interest in cardiac ultrasound will find this activity beneficial.
Objectives
Upon completing the reading of this article, participants will better be able to:
1. Name the postulated roles that epicardial fat might play in cardiac disease.
2. Describe the location of epicardial fat deposits in relation to the coronary arteries and
myocardium.
3. Define the 2-dimensional technique for the measurement of epicardial fat and appreciate characteristics that distinguish it from pericardial fat.
4. Recognize the limitations of echocardiography in the quantification of epicardial fat.
5. Identify the potential utility of echocardiographically-measured epicardial fat in the
diagnosis, prognosis, and therapy of various cardiac diseases.
Author Disclosure
Dr. Iacobellis reported no actual or potential conflicts of interest in relation to this program. Dr. Willens reported that he receives research support from Actelion Pharmaceuticals (Allschwil, Switzerland), Abbott Laboratories (Abbott Park, IL), and GE Healthcare
(Milwaukee, WI).
Estimated Time to Complete This Activity: 1 hour
EPICARDIAL FAT
What Is Epicardial Fat and Where Is It Located?
Epicardial fat is the true visceral fat depot of the heart.1-5 Epicardial
and intra-abdominal fat evolve from brown adipose tissue during
embryogenesis. In the adult human heart, epicardial fat is commonly found in the atrioventricular and interventricular grooves.
Minor foci of fat are also located subepicardially along the free
walls of the atria and around the two appendages. As the amount
of epicardial fat increases, it progressively fills the space between
the ventricles, sometimes covering the entire epicardial surface.
A small amount of adipose tissue also extends from the epicardial
surface into the myocardium, often following the adventitia of
the coronary artery branches. No muscle fascia divides epicardial
fat and myocardium; therefore, the two tissues share the same
microcirculation.1
Why Is Epicardial Fat Important?
A dichotomous role, both unfavorable and protective, has been attributed to epicardial fat,6 but its physiology in animals and humans is not
From the Department of Medicine, Division of Endocrinology, McMaster
University, Hamilton, Ontario, Canada (G.I.); and the Department of Medicine,
Division of Cardiology, University of Miami Miller School of Medicine, Miami,
Florida (H.J.W.).
Reprint requests: Gianluca Iacobellis, MD, PhD, St Joseph’s Hospital, Department
of Medicine, 50 Charlton Avenue East, 5th Fontbonne Building, Hamilton, ON L8N
4A6, Canada (E-mail: [email protected]).
0894-7317/$36.00
Copyright 2009 by the American Society of Echocardiography.
doi:10.1016/j.echo.2009.10.013
1311
1312 Iacobellis and H. J. Willens
completely clear. Epicardial adipose tissue has a smaller adipocyte size
but higher rates of fatty acid uptake and secretion than other visceral
fat depots.7 Under normal physiologic conditions, epicardial fat could
therefore serve several distinct functions: as a buffer, absorbing fatty
acids and protecting the heart against high fatty acids levels; as a local
energy source at times of high demand, channeling fatty acids to the
myocardium7; and perhaps as brown fat to defend the myocardium
against hypothermia.8 Whereas epicardial fat may release factors
that blunt the toxic effects of high fatty acid levels on the myocardium,
it may also release factors that promote harmful coronary artery and
myocardial changes.6 A body of evidence shows that epicardial fat is
an extremely active organ that produces several bioactive adipokines.
It is a source of several proinflammatory and proatherogenic cytokines, as well as tumor necrosis factor–a, monocyte chemoattractant
protein–1, interlukin-6, nerve growth factor, resistin, visfatin, omentin, leptin, plasminogen activator inhibitor–1, and angiotensinogen.9-14 However, epicardial fat also produces anti-inflammatory,
antiatherogenic adipokines, such as adiponectin and adrenomedullin.15-18 Nevertheless, what could influence this equilibrium between
harmful and possible protective effects is still unknown. Because of its
anatomic proximity to the heart and the absence of fascial boundaries,
epicardial adipose tissue may interact locally and modulate the
coronary arteries through the paracrine or vasocrine secretion of
proinflammatory adipokines.1 It is reasonable to postulate that inflammatory signals from the epicardial fat could act reciprocally because
of atherogenic inflammation in the underlying plaques. The regional
ischemia could make the epicardial adipose tissue active toward
oxidant-sensitive inflammatory signals in adjacent adipose stores.
The presence of inflammatory cells in epicardial adipose tissue could
also reflect the response to plaque rupture and lead to the
amplification of vascular inflammation and plaque instability.9 It is
also plausible that the paracrine release of cytokines from periadventitial epicardial fat could traverse the coronary wall by diffusion from
outside to inside and interact with cells in each of its layers. Inflammatory adipokines might be released from epicardial tissue directly into
vasa vasorum and be transported downstream into the arterial wall,
according to a ‘‘vasocrine signaling’’ mechanism.2 The local secretion
of proinflammatory cytokines from the epicardial fat could be predominant and therefore down-regulate the production of protective
and anti-inflammatory cytokines, as well as adiponectin and adrenomedullin in severe and unstable coronary artery disease (CAD).15-18
Epicardial fat secretes adiponectin and adrenomedullin into the coronary circulation.16-18 Adiponectin improves insulin sensitivity and has
anti-inflammatory and antiatherogenic actions, whereas adrenomedullin is a potent vasodilator, anti-inflammatory, and angiogenic
factor. Epicardial fat might exert a protective effect through adiponectin and adrenomedullin secretion in response to local or systemic
metabolic or mechanical insults. Although epicardial fat is a source
of bioactive molecules, it is not clear whether this activity is directly
and simply related to the amount of fat accumulation, particularly
when it is expressed as thickness. A mass-dependent mechanism
could also be evoked to explain higher proinflammatory markers in
combination with higher epicardial fat thickness.
How Is Epicardial Fat Distinguished From Pericardial Fat?
The heart is covered by more or less abundant adipose tissue, particularly on its right side, as astutely noted at the end of 19th century.19
Two different fat depots were described, one located extrinsic to the
pericardium and another directly on the myocardium.19 More
recently, however, whether and how these two fat depots are really
Journal of the American Society of Echocardiography
December 2009
different has been questioned.20 Autopsy and imaging studies seem
be of help in defining and understanding the difference between
epicardial and pericardial fat. Epicardial adipose tissue is the fat located between the myocardium and visceral pericardium, as detected
by autopsy and imaging studies.1,2,21-26 Pericardial adipose tissue is
the fat depot outside the visceral pericardium and on the external surface of the parietal pericardium, as defined by autopsy and imaging
studies.1,2,21-26 Pericardial fat volume is also defined as any adipose
tissue located within the pericardial sac, described as the border
between pericardial and intrathoracic fat.27,28
Epicardial and pericardial fat have different embryologic origins.
Epicardial, mesenteric, and omental fat all share the same origin
from the splanchnopleuric mesoderm.29,30 Pericardial fat originates
from the primitive thoracic mesenchyme, which splits to form the parietal pericardium and the outer thoracic wall.29,30 Local circulation is
also different between the two fat depots. Epicardial fat is supplied by
branches of the coronary arteries, whereas the pericardial fat is supplied by noncoronary sources, such as the pericardiacophrenic branch
of the internal mammary artery.29,30 In addition, although the epicardial fat and the myocardium share the same microcirculation, this is
not true for the pericardial fat. As result of this peculiarity and different
anatomic location, the epicardial fat should be considered the true
visceral fat depot of the heart. To simplify, the adipose tissue of the
heart is divided into two layers: (1) epicardial fat, the visceral layer,
and (2) pericardial fat, situated externally to the parietal layer of the
pericardium. Under physiologic conditions, pericardial adipose tissue
covers 80% of the heart and constitutes between 20% and 50% of its
mass, whereas the epicardial adipose tissue weighs on average 50 g
and represents approximately 20% of the heart’s mass.31
It is seems that it is not just a matter of terminology, but that epicardial fat should be really distinguished from the pericardial fat, because
they are two different cardiac visceral fat depots. However, recent
reports from the Framingham Heart Study do not seem to make
a differentiation between epicardial and pericardial fat, especially
when the authors discuss the biomolecular properties of these two
fat depots.28,32 The Multi-Ethnic Study of Atherosclerosis (MESA)
more generally defined the pericardial fat as the fat around the
heart.33 In these large and well-conducted population studies, pericardial fat volume has been measured using cardiac computed tomography (CT) or multidetector CT (MDCT) and then defined as any
adipose tissue located within the pericardial sac.
A brief summary of the heart’s anatomy may be of help. The pericardial sac consists essentially of two sacs intimately connected with
each other but totally different in structure. The outer sac, known
as the fibrous pericardium, consists of fibrous tissue. The inner sac,
the serous pericardium, is a closed sac that lines the fibrous pericardium and is invaginated by the heart; it therefore consists of a visceral
and a parietal portion. The visceral portion, or epicardium, covers the
heart and the great vessels and from the latter is continuous with the
parietal layer, which lines the fibrous pericardium. It could be therefore assumed that the term pericardial fat is intended to include both
epicardial and pericardial adipose tissues,25 which are actually different fat depots. Conversely, if these large epidemiologic studies really
intended to distinguish between the two fat depots, pericardial fat
should be considered differently, as paracardial fat.34 Reports from
the Framingham Heart Study and others35-41 all agree that the volume
of pericardial fat, as determined on cardiac CT, is significantly associated with the risk for coronary heart disease, coronary artery calcification, metabolic syndrome, diabetes mellitus, and left ventricular (LV)
morphology, independently of traditional anthropometric indicators
such as body mass index and waist circumference. Hence, if it is
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Volume 22 Number 12
Iacobellis and H. J. Willens 1313
unquestionable that pericardial fat volume, as measured using
MDCT, could be an important cardiovascular risk factor, it might
be still questionable if these recent studies really made a differentiation
between the pericardial fat, the outer fat accumulation, and the
epicardial fat, the fat depot immediately adjacent to the heart wall.
In addition, it is worth emphasizing that although the physiologic, biochemical, and biomolecular properties of epicardial adipose tissue
and its possible paracrine interactions with the heart have been
described,1-3 the function and pathophysiologic role of paracardial
fat are still unknown. Conceptually, because its biochemical properties and anatomic proximity to the myocardium and coronary
arteries, epicardial fat thickness might provide a more direct measure
of the cardiac visceral adiposity. However, further studies will be
necessary to clarify this issue.
MEASUREMENT OF EPICARDIAL FAT USING
ECHOCARDIOGRAPHY
Visceral fat deposition has been recognized as an important risk factor
for cardiovascular disease.42,43 The quantification of visceral fat is
a helpful practical diagnostic tool for clinicians who are committed
to managing patients at high risk for cardiovascular disease. In a clinical
setting, visceral fat is typically measured by surrogate markers, such as
waist circumference alone or the ratio of waist circumference to hip
circumference. More direct measurements of visceral fat, including
magnetic resonance imaging (MRI) and/or CT, are certainly precise,
but they are expensive and cumbersome, especially if they are intended to be used in clinical practice. There is therefore a compelling
need and growing interest in less expensive and more reliable imaging
markers of visceral adiposity.44 Although much attention has been
focused on the measurement of intra-abdominal fat, interest in nontraditional visceral fat depots, such as epicardial fat, is relatively recent.
Methodology and Technical Tips
Epicardial fat thickness can be visualized and measured with
two-dimensional (2D) echocardiography using commercially available equipment, as first proposed and validated by Iacobellis
et al.45,46 Standard parasternal long-axis and short-axis views from
2D images permit the most accurate measurement of epicardial fat
thickness on the right ventricle, with optimal cursor beam orientation
in each view. Echocardiographically, epicardial fat is generally identified as the relatively echo-free space between the outer wall of the
myocardium and the visceral layer of pericardium; its thickness is
measured perpendicularly on the free wall of the right ventricle at
end-systole in 3 cardiac cycles (Figure 1). Because it is compressed
during diastole, epicardial fat thickness is best measured at end-systole
at the point on the free wall of the right ventricle at which the ultrasound beam is oriented in a perpendicular manner, using the aortic
annulus as an anatomic landmark.45 Epicardial fat thickness can be
also appear as hyperechoic space, if in large amount (>15 mm). Maximum epicardial fat thickness is measured from 2D parasternal longaxis images at the point on the free wall of the right ventricle along the
midline of the ultrasound beam, perpendicular to the aortic annulus,
used as an anatomic landmark for this view. For midventricular parasternal short-axis assessment, maximum epicardial fat thickness is
measured from 2D images on the right ventricular free wall along
the midline of the ultrasound beam perpendicular to the interventricular septum at midchordal and tip of the papillary muscle level, as anatomic landmarks. The average value of 3 cardiac cycles from each
Figure 1 Echocardiographic epicardial fat thickness. Epicardial
fat thickness (within red dashed shape) is identified as the echofree space between the outer wall of the myocardium and the
visceral layer of pericardium in the parasternal long-axis view.
Epicardial fat thickness is measured during end-systole at the
point on the free wall of the right ventricle along the midline of
the ultrasound beam, with the best effort to be perpendicular
to the aortic annulus, used as an anatomic landmark.
echocardiographic view is determined. The majority of populationbased clinical studies have reported excellent interobserver and intraobserver agreement for epicardial fat thickness measurement.45-49 Intraclass correlation coefficients have ranged from 0.90 to 0.98 and
from 0.93 to 0.98, respectively, indicating good reproducibility and
reliability. Concordance of long-axis and short-axis average epicardial
fat thickness measurement was also excellent at 0.98 (95% confidence interval, 0.97-0.98).46
Echocardiographically, epicardial fat can be distinguished from
pericardial fat. Pericardial fat thickness can be identified as the hypoechoic space anterior to the epicardial fat and parietal pericardium
(Figure 2). Pericardial fat usually does not deform substantially with
cardiac cycles and does not appear hyperechoic. However, fat thickness deformation is not a good way of distinguishing between the two
depots.
A normal upper-limit value for epicardial fat thickness has not been
established yet. Echocardiographic epicardial fat thickness varies from
a minimum of 1 mm to a maximum measured value of almost 23
mm.46 The wide range of epicardial fat thicknesses likely reflects
the substantial variation in abdominal visceral fat distribution. Iacobellis et al46 found median epicardial fat thicknesses of 7 mm in men and
6.5 mm in women in a large population of patients who underwent
transthoracic echocardiography for standard clinical indications.
Jeong et al48 reported a mean epicardial fat thickness of 6.3 mm in
>200 subjects who underwent coronary angiography. Natale et al49
set the normal upper limit to 7 mm, on the basis of the mean value
and distribution of epicardial fat thickness in 50 normal volunteers.
Advantages of Echocardiographic Epicardial Fat Thickness
Echocardiographic epicardial fat measurement may have some
advantages as an index of high cardiometabolic risk: (1) It is a direct
measure of visceral fat rather than an anthropometric measure, such
as waist circumference, that includes muscle and skin layers. The
echocardiographic measurement of epicardial fat provides a more
sensitive and specific measure of true visceral fat content, avoiding
the possible confounding effect of increased subcutaneous
1314 Iacobellis and H. J. Willens
Figure 2 Epicardial versus pericardial fat thickness. Pericardial
fat (within yellow arrows and yellow dashed shape) can be identified as the hypoechoic space anterior to the epicardial fat
(within red arrows and red dashed shape). Pericardial fat usually
does not deform substantially with cardiac cycles and does not
appear as hyperechoic space. Modified parasternal long-axis
view.
abdominal fat. (2) It is an objective, noninvasive, readily available,
and certainly less expensive measure of visceral fat than MRI or
CT. (3) Visceral cardiac fat can be quantified fairly precisely compared with ectopic fat deposition in organs such as the liver, which
can be described only qualitatively unless expensive measurements
are made, such as CT or MRI. (4) Echocardiographic epicardial fat is
a direct measure of ectopic fat deposition, whereas anthropometric
measures can be associated only with ectopic fat deposition. (5) It
can be measured even from echocardiograms that were not specifically performed to optimize the measurement of epicardial fat. (6)
It can be quantified with other echocardiographic parameters, such
LV mass and ejection fraction, traditionally associated with cardiovascular risk. (7) Echocardiographic epicardial fat could be a more
reliable quantitative therapeutic marker during interventions modulating and reducing visceral adiposity.
Limitations of Using Echocardiography to Measure Epicardial
Fat
Echocardiography may be not the optimal technique for the
quantification of epicardial fat. Although the majority of studies
have shown excellent coefficients of interobserver and intraobserver
variability, a single study raised some concerns on the dispersion and
variability in the measurement of epicardial fat thickness.50 A moderate concordance in echocardiographic epicardial fat measurement
and a relatively poor agreement with measurement on MDCT were
reported in this study. Given the small number of patients with
interpretable results on MDCT (n = 55) and the use of end-diastolic
Journal of the American Society of Echocardiography
December 2009
epicardial fat thickness in the study, the actual variability of this measurement is still in question. However, if the echocardiographic
quantification of epicardial fat is performed for cardiometabolic
risk stratification, the reproducibility of this measurement is
undoubtedly a critical issue.
Echocardiographic epicardial fat thickness is a linear measurement at a single location and therefore may not reflect the variability of fat thickness or total epicardial fat volume. Although the
anterior layer of epicardial fat is the one commonly measured by
echocardiography, this region may have the most variability in fat
content as measured using MRI and MDCT. Epicardial fat thickness
is usually smaller in the vicinity of the mid right ventricular free wall
and greater in the distal portion of the right ventricular free wall.
Echocardiographic measurements of epicardial fat thickness in the
atrioventricular groove or interventricular groove areas may give
a more accurate assessment of epicardial fat amount. MDCT is
more sensitive and specific than echocardiography for measuring
fat thickness in deeper epicardial fat layers as well as the thickest
part of the epicardial fat in the atrioventricular grooves.51-53 Epicardial fat has a conspicuous distribution around the heart, and 2D
echocardiographic assessment may not be a completely accurate
estimate of the total amount of fat. Three-dimensional echocardiography could provide a noninvasive and more accurate volumetric
assessment of epicardial fat thickness. Epicardial fat volume, rather
than its thickness, may in fact be the most consistent measure of
risk, as recently suggested.34 Future studies in this direction should
be encouraged.
The variability of echocardiographic measurement techniques has
also resulted in inconsistencies among studies. Epicardial fat thickness
when measured just to the right of the aortic annular plane may
increase in size abruptly compared with thickness measured either at
or just to the left of the aortic annular plane (Figure 3). This abrupt increase in end-systolic epicardial fat thickness is due to the steep downward turn of the free wall of the right ventricle as it approaches the
proximal ascending aorta. In such cases, we recommend measuring
the largest epicardial fat thickness to the left of the annular plane.
When during the cardiac cycle echocardiographic epicardial fat should
be measured has also been a subject of debate. Some echocardiographic studies have measured epicardial fat thickness at end-diastole
rather than end-systole. Although there is no clear consensus yet, we
strongly suggest that maximum epicardial fat thickness is better measured at end-systole, as highlighted before. When scrolling through
the cardiac cycle, in some cases, the largest epicardial fat thickness
may fail to correspond to true end-systole or end-diastole. In these
cases, we recommend measuring epicardial fat thickness at end-systole.
Potential limitations of echocardiography also include difficulties in
differentiating between epicardial fat thickness and pericardial fat, as
well as changes in the velocity of sound in adipose tissue. Although
there are no current data on how and whether the latter might affect
the accuracy of epicardial fat thickness measurement using echocardiography, it would be of interest to evaluate whether it is necessary to
correct for this confounding factor when determining the amount of
epicardial fat.
POTENTIAL USES OF ECHOCARDIOGRAPHIC EPICARDIAL
FAT THICKNESS FOR DIAGNOSIS
The potential role of echocardiographic epicardial fat thickness as
a marker and predictor of cardiometabolic risk has been evaluated.
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Volume 22 Number 12
Figure 3 Large echocardiographic epicardial fat thickness.
Large epicardial fat thickness (within red arrows and red dashed
shape) when measured just to the right of the aortic annular
plane may abruptly increase in size. This abrupt increase in
end-systolic epicardial fat thickness is due to the steep downward turn of the free wall of the right ventricle as it approaches
the proximal ascending aorta. In these cases, it is recommended to measure the largest epicardial fat thickness to the left
of the annular plane.
Different cutoff points of epicardial fat thickness for the prediction of
metabolic syndrome, excess visceral fat accumulation, insulin resistance, subclinical atherosclerosis, and CAD have been proposed
and are summarized in Table 1.
Marker of Visceral Adiposity
It has been established that echocardiographic epicardial fat is a measure of visceral fat, as measured by gold-standard techniques. In fact,
echocardiographic epicardial fat strongly reflects the intra-abdominal
accumulation of visceral fat as measured on MRI and does so better
than waist circumference.45,46 Echocardiographic epicardial fat thickness is therefore an independent predictor of visceral adiposity and
weakly reflects the degree of obesity as measured by body mass
index.45,46 Subjects with higher waist circumferences clearly show
higher epicardial fat thickness, as previously reported.46 Whether
echocardiographic epicardial fat can be associated with intramyocardial and intrahepatic fat accumulation, as measured using magnetic
resonance spectroscopy,54,55 is still unknown but is the object of
current investigations.
Correlation With Cardiometabolic Risk Factors
Several clinical studies have shown the relationship of echocardiographic epicardial fat thickness and traditional and novel cardiovascular risk factors. Metabolic syndrome is a cluster of diseases with
common pathogenic mechanisms, as well as increased visceral fat
accumulation and insulin resistance. Epicardial fat thickness in subjects with metabolic syndrome is significantly higher than that
observed in subjects without metabolic syndrome.46,56 Receiveroperating characteristic curve analysis showed that epicardial fat
thickness values of 9.5 and 7.5 mm maximize the sensitivity and specificity to predict the metabolic syndrome in men and women, respectively.46 Epicardial fat thickness is inversely associated with insulin
sensitivity, as assessed by euglycemic hyperinsulinemic clamp studies
in obese subjects,57 and directly related to surrogate markers of insulin resistance as well as fasting insulin and the homeostatic model
Iacobellis and H. J. Willens 1315
assessment of insulin resistance index in a general population.46 An
epicardial fat thickness of 9.5 mm is associated with clinical parameters of insulin resistance.46 The highest values of epicardial fat were
found in those categories with extremely high intra-abdominal fat
and high insulin resistance.46 Although these cutoff values have
shown good sensitivity and specificity for the prediction of metabolic
syndrome, they have been obtained only in whites and thus may not
be applicable in different ethnic groups.
When other cardiometabolic parameters are considered separately, epicardial fat is also independently associated with blood pressure,56 low-density lipoprotein cholesterol,56 fasting glucose,58 and
inflammatory markers.59,60 In particular, echocardiographic epicardial fat thickness is higher in subjects with impaired fasting glucose,
a prediabetes condition, than in normoglycemic individuals, suggesting its potential role as an additional tool for diabetes-related cardiac
risk stratification.58 Epicardial fat is an endocrine and paracrine source
of cytokines,1 and its echocardiographic thickness is correlated with
several circulating adipokines levels. Epicardial fat thickness is associated with proatherogenic and proinflammatory adipokines, such as
visfatin, plasminogen activator inhibitor–1, monocyte chemoattractant protein–1, and C-reactive protein.59 These correlations remain
significant even after adjusting for visceral adipose tissue, as detected
by CT, and waist-to-hip ratio.59 However, epicardial fat thickness is inversely related to plasma adiponectin levels, an adipokine with specific anti-inflammatory and antiatherogenic properties.56 Lower
plasma adiponectin levels are associated with higher cardiovascular
risk.
Additionally, a higher thickness of epicardial fat is also significantly
associated with higher liver enzymes, surrogate markers of
fatty liver.61 This association seems to be independent of overall
adiposity and rather a function of excess visceral adiposity.
Potential Relevance in CAD
Although its role is still unclear, echocardiographic epicardial fat has
been associated with CAD. Epicardial fat thickness > 7 mm has
been associated with subclinical atherosclerosis49 and CAD, but
only in women.62 However, different and lower epicardial fat thickness cutoff values (>4.5 mm) have shown a good sensitivity and
specificity to detect low coronary flow reserve in women.47 The absence of men may prevent the generalization of these interesting results. Epicardial fat thickness values > 3.0 mm were independently
associated with the presence of CAD in a Korean population of
men and women.60 Ethnic differences and therefore different regional fat distribution could explain, at least partially, this variability.
Epicardial fat thickness seems to be higher in patients with CAD and
in those with unstable angina than in subjects without CAD and in
those with stable angina or atypical chest pain.60 Interestingly, epicardial fat thickness was significantly correlated with the extent
and severity of CAD, as assessed by the Gensini score.60,62 Echocardiographic epicardial fat thickness has been shown to predict coronary flow reserve in women with angiographically normal coronary
arteries.47
Potential Relevance in Atherosclerotic Vascular Disease
The relationship of epicardial fat and atherosclerosis is also of great
interest.63 Carotid intima-media thickness (C-IMT), as measured by
ultrasound, is a well-recognized clinical predictor of subclinical atherosclerosis. Echocardiographic epicardial fat thickness was the best independent predictor of C-IMT in subjects infected with the human
immunodeficiency virus with associated metabolic syndrome.64,65
1316 Iacobellis and H. J. Willens
Journal of the American Society of Echocardiography
December 2009
Table 1 Proposed echocardiographic epicardial fat thickness cutoff values
Outcome
Men (mm)
Women (mm)
Ethnicity
n
Study
Metabolic syndrome*
High abdominal fat†
Extremely high abdominal fat‡
Insulin resistance§
High insulin resistancejj
CAD{
CAD{
CAD{
Low coronary flow reserve#
Subclinical atherosclerosis**
$9.5
$9.5
$13
$9.5
$11
$7
$5.2
$3
—
$7
$7.5
$7.5
$10
$9.5
$11
$7
$5.2
$3
$4.5
$7
European
European
European
European
European
Korean
European
Korean
European
European
246
246
246
246
246
203
150
527
68
459
Iacobellis et al (2008)46
Iacobellis et al (2008)46
Iacobellis et al (2008)46
Iacobellis et al (2008)46
Iacobellis et al (2008)46
Jeong et al (2007)48
Eroglu et al (2009)62
Ahn et al (2008)60
Sade et al (2009)47
Natale et al (2009)49
*As defined by National Cholesterol Education Program Adult Treatment Panel III criteria.
†Waist circumference >88 cm in women and >102 cm in men.
‡Waist circumference >100 cm in women and >120 cm in men.
§Homeostasis model assessment of insulin resistance score of 2.7 to 7.
jj
Homeostasis model assessment of insulin resistance score $ 7.
{Presence of $1 coronary arteries stenosis $50% on coronary angiography.
#
Echocardiographically defined as coronary flow reserve < 2.
**Defined by ultrasonographic C-IMT measurement.
Subjects with metabolic syndrome associated with human immunodeficiency virus infection commonly present with abnormal regional
fat distribution and increased visceral adiposity. Hence, this finding
suggests that the echocardiographic epicardial fat thickness may serve
as independent predictor of subclinical atherosclerosis in subjects with
excess visceral adiposity. Similar results have been recently reported
in a more general high-risk population.49 Interestingly, epicardial fat
thickness was correlated with C-IMT and arterial stiffness better
than waist circumference in hypertensive subjects.49
Correlation With LV Mass and Function
Increased LV mass and LV hypertrophy are independent cardiovascular risk factors. Increased epicardial fat thickness has been associated
with changes in LV mass and diastolic function, as detected by echocardiography.66,67 Echocardiographic findings seem to be in agreement with autopsy studies.31 Although epicardial fat located over
both ventricles normally accounted for about 20% of the total
ventricular mass, left, right, and total epicardial fat weights are significantly greater in hypertrophied hearts.31 LV hypertrophy seems to be
associated with a proportional increase in epicardial fat mass. Echocardiographic LV mass is significantly correlated with the amount of epicardial fat thickness in subjects with a wide range of adiposity,
independent of body mass index and age.66 Because of the relationship between epicardial fat and blood pressure, vascular changes and
the metabolic syndrome, the relationship to LV hypertrophy is in all
likelihood multifactorial. An increase in epicardial fat thickness is
also significantly correlated with enlarged atria and impaired right
ventricular and LV diastolic filling in morbidly obese subjects.68
However, metabolically healthy obesity can be independently associated with these abnormalities.69
POTENTIAL USE OF ECHOCARDIOGRAPHIC EPICARDIAL
FAT FOR MONITORING THERAPY
On the basis of the evidence that epicardial fat reflects visceral adiposity, its echocardiographic measurement has been used as a therapeutic
target in subjects who undergo weight-loss interventions,70 bariatric
surgery,71 exercise programs,72 and hormone-replacement treatment.73 Echocardiographic epicardial fat thickness significantly decreased in all 3 studies that included body weight modulations and
changes. In fact, epicardial fat decreased after very low calorie diet,
bariatric surgery–induced weight loss, and moderate aerobic exercise.
Of great interest, the weight loss intervention study showed that the
decrease in epicardial fat during weight loss was quicker and higher
than the decreases in body mass index, waist circumference, and
body weight, common indices of body fatness.70 We may assume
that epicardial fat reflects the more rapid and massive visceral fat
loss after a very low calorie diet. This finding may open new perspectives in the management of patients with high cardiometabolic risk.
Echocardiographic epicardial fat could become a new target during
pharmaceutical treatments directly or indirectly targeting the fat.74
FUTURE DIRECTIONS
Although several types of evidence have been provided, most published studies might not have large enough sample sizes to draw
definitive conclusions to establish a strong association between echocardiographic epicardial fat thickness and cardiometabolic risk. The
currently available data might not allow a precise estimate of the
relationshipr, might not allow to fully explore the relationship within
various subgroups, and might not allow the calculation of the diagnostic properties of epicardial fat with precision. A larger sample size
would make all of these evaluations possible and therefore make
the results applicable in a general population. Whether this echocardiographic measurement may provide incremental or superior information compared with other more commonly used anthropometric
markers, such as waist circumference, is still not completely established but is currently under evaluation. Ethnic differences in echocardiographic epicardial fat thickness have also been reported recently.75
Several lines of research pointed out the role of ethnicity in cardiovascular disease. Echocardiographic epicardial fat might be a helpful
marker of visceral adiposity in multiethnic population studies. Threshold values of high-risk epicardial fat thickness may therefore vary
among different populations and ethnic groups. It can be also
Journal of the American Society of Echocardiography
Volume 22 Number 12
postulated that the cutoff values could be different if they aimed to
predict metabolic syndrome or CAD. Although the majority of the
studies have found positive relationships between epicardial fat and
cardiovascular risk, a few studies have questioned this association.
Subepicardial adipose tissue on the free wall of the right ventricle
was measured at end-diastole, but it was not associated with the severity of CAD in that study.76 It also has to be proven whether echocardiographic epicardial fat is associated with intramyocardial and
intrahepatic fat accumulation, as measured by magnetic resonance
spectroscopy.55,77 Whether or not echocardiographic epicardial fat
thickness may really have the diagnostic properties to serve as an indicator of cardiovascular risk should be analyzed in large, randomized,
and well-studied multiethnic populations. Finally, the role of epicardial fat as a cardiometabolic risk marker might be stronger in association with other cardiovascular risk factors, considered singly or in
combination.
CONCLUSIONS
Echocardiographic epicardial fat is an inexpensive, reproducible, and
direct measure of visceral fat. It may have an important role in predicting and stratifying cardiovascular risk in both clinical care and the
research setting. However, more robust and convincing evidence is
necessary to evaluate whether echocardiographic epicardial fat thickness may have these diagnostic and predictive properties and really
become a routine way of assessing cardiovascular risk in a clinical setting. Further investigations should be encouraged to confirm or refute
a physiologic mechanism or explanation for a relationship between
epicardial fat and cardiovascular risk. Future studies in these directions
seem to be warranted.
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