1

REVIEW

Ectopic fat deposition and global cardiometabolic risk :

New paradigm in cardiovascular medicine
1,2 3 3 3
Michio Shimabukuro , Chisayo Kozuka , Shin-ichiro Taira , Koichi Yabiku ,
5 2 2
Munkhbaatar Dagvasumberel , Masayoshi Ishida , Sachiko Matsumoto ,
2 1,2 4 4 2
Shusuke Yagi , Daiju Fukuda , Ken Yamakawa , Moritake Higa , Takeshi Soeki ,
5 3 2
Hisashi Yoshida , Hiroaki Masuzaki , and Masataka Sata
1
Department of Cardio-Diabetes Medicine, 2Department of Cardiovascular Medicine, the University
of Tokushima Graduate School of Health Biosciences, Tokushima, Japan ; 3Division of Endocrinology,
Diabetes and Metabolism, Hematology, Rheumatology, Second Department of Internal Medicine,
University of the Ryukyus School of Medicine Graduate School of Medicine, Okinawa, Japan ; 4Diabetes
and Lifestyle-Related Disease Center, Tomishiro Central Hospital, Okinawa, Japan ; 5Cardiovascular
Division, Shonan Hospital, Okinawa, Japan

Abstract : The obesity epidemic is a global public health concern that increases the likeli-
hood of morbidity and mortality of metabolic and cardiovascular disease (CVD) and threat-
ens to reduce life expectancy around the world. The concept of the metabolic syndrome
(MetS) takes into account that visceral fat plays an essential role in the development of
metabolic and cardiovascular diseases. However, MetS cannot be used to assess global CVD
risk but is at best one more modifiable CVD risk factor. Thus, global cardiometabolic risk
(the global risk of cardiovascular disease resulting from traditional risk factors combined
with the additional contribution of the metabolic syndrome and/or insulin resistance)
should be considered individually. There is solid evidence supporting the notion that ex-
cess abdominal fat is predictive of insulin resistance and the presence of related metabolic
abnormalities currently referred to as MetS. Despite the fact that abdominal obesity is a
highly prevalent feature of MetS, the mechanisms by which abdominal obesity is causally
related to MetS are not fully elucidated. Besides visceral fat accumulation, ectopic lipid
deposition, especially in liver and skeletal muscle, has been implicated in the pathophysiol-
ogy of diabetes, insulin resistance and obesity-related disorders. Also, ectopic fat deposi-
tion could be deteriorated in the heart components such as (1) circulatory and locally re-
cruited fat, (2) intra- and extra-myocellular fat, (3) perivascular fat, and (4) pericardial fat.
In this review, the contribution of ectopic lipid deposition to global cardiometabolic risk
is reviewed and also discussed are potential underlying mechanisms including adipocy-
tokine, insulin resistance and lipotoxicity. J. Med. Invest. 60 : 1-14, February, 2013

Keywords : obesity, insulin resistance, cardiovascular disease, diabetes mellitus

Abbreviations : CVD : cardiovascular disease ; T2DM : type 2 dia- Received for publication January 4, 2013 ; accepted February 14,
betes mellitus ; BMI : body mass index ; AMI : acute myocardial 2013.
infarction ; CHD : coronary heart diseases ; FFA : free fatty acids ;
ROS : reactive oxygen species ; eNOS : endothelial nitric oxide Address correspondence and reprint requests to Michio
synthase ; NO : nitric oxide ; TG : triglycerides ; lipoprotein- Shimabukuro, MD, Departments of Cardio-Diabetes Medicine,
cholesterol ; HDL-C : high-density lipoprotein-cholesterol. the University of Tokushima Graduate School of Health Bi-
osciences, 3-18-15 Kuramoto, Tokushima 770-8503, Japan and
Fax : + 81 -88 -633 -7894.

The Journal of Medical Investigation Vol. 60 2013

 2 M. Shimabukuro, et al. Ectopic fat and cardiometabolic risk

INTRODUCTION and its potential underlying mechanisms are re-

viewed.
The obesity epidemic is a global public health
concern that increases the likelihood of morbidity
and mortality of metabolic and cardiovascular dis- 1. CONTRIBUTION OF ECTOPIC FAT
ease (CVD) and threatens to reduce life expectancy
DESPOSION TO CARDIOVASCULAR DIS-
around the world (1-2). The concept of the meta-
EASE
bolic syndrome (MetS) takes into account that vis-
ceral fat plays an essential role in the development The amount of adipose tissue, as well as its dis-
of metabolic and cardiovascular diseases (3-5). tribution, is of special importance in the pathogene-
MetS is merely a modifiable CVD risk factor as well sis of insulin resistance and type 2 diabetes. Visceral
as traditional risk factors such as LDL-cholesterol, adipose tissue is metabolically highly active (3-5)
diabetes, hypertension and smoking, but accounts and its major role in the pathogenesis of insulin
for a great proportion of mechanisms under the resistance is widely accepted. Simultaneously, lipids
obesity endemic era. Thus, global cardiometabolic in ectopic (non-adipose) tissues such as liver and
risk (the global risk of cardiovascular disease re- skeletal muscle are of increasing interest. Liver fat
sulting from traditional risk factors combined with is elevated in insulin-resistant subjects (12, 13) and,
the additional contribution of the metabolic syn- furthermore, is strongly correlated with the amount
drome and/or insulin resistance) should be consid- of visceral fat in a prediabetic population (14). In
ered individually (6-8). Despite the fact that abdomi- addition, high intramyocellular fat is a marker of
nal obesity is a highly prevalent feature of MetS, insulin resistance (15, 16). Thus, determination of
ectopic fat deposition, especially in liver and skele- fat in the visceral depot and in the ectopic tissues
tal muscle, has been implicated in the pathophysi- liver and muscle is thought to be a predictor for
ology of diabetes, insulin resistance and obesity- subjects who are insulin resistant and have a high
related disorders (Fig. 1) (6-8). Also, ectopic fat risk of type 2 diabetes and cardiovascular dieases
deposition in the cardiovascular components is now (Fig 2). Recenlty, we evaluated the relationship be-
recognized as a new cardiometabolic risk marker, tween hepatic and muscular lipid deposition and vis-
as it is associated with increased insulin resistance, ceral fat accumulation in middle-aged Japanese men
visceral fat and, in general, with the metabolic syn- with MetS and found that visceral fat accumulation is
drome (6, 9-11). In this review, the contribution of accompanied by excess lipid deposition in skele-
ectopic fat deposition to global cardiometabolic risk tal muscle (iliopsoas muscle, back muscle, rectus

High fat diet +

Physical inactivity Visceral fat obesity
Hypertension
Visceral fat obesity Dyslipidemia
Glucose intolerance

Enhanced FFA eflux

Metabolic syndrome

Tissue fat deposition Pancreatic

fat deposition

Whole body Abnormal Cardiac

Insulin resistance insulin secretion fat deposition

Glucose intolerance/Type 2 diabetes Cardiovascular

diseases

Fig. 1. Ectopic fat deposition rather the whole-body fat distribution causes insulin resistance and vascular failure.
 The Journal of Medical Investigation Vol. 60 February 2013 3

Whole-body Blood Ectopic fat Insulin Vascular

adiposity circulation deposition resistance failure

fat Lipids
Normal lean fat
leptin, adiponectin

Subcutaneous Lipids
fat fat
fat obesity
leptin, adiponectin

Visceral fat Lipids

obesity fat fat
leptin, adiponectin

Generalized Lipids fat

no fat
lipodystrophy
no leptin, no adiponectin

Fig 2. Ectopic fat deposition causes metabolic derrangements and cardiovascular diseases
Visceral fat obesity rather than subcutaneous fat obesity leads to lipid (free fatty acid) spreading to end-organs, causing ectopic fat
deposition and resultant insulin resistance via lipotoxicity mechanism(s)). Vascular failure is a consequence of insulin resistance/
glucose intolerance. Generalized lipodystrophy, genetic or acquired disorders without capacity to store fat in adipose tissue, shows
lipotoxic damage such as severe insulin resistance and vascular failure.

abdominis muscle) and the liver (17). Interstingly, liver enzymes, and use of medications, the presence
changes in lipid contents by atnti-diabetic medica- of NAFLD was significantly associated with an in-
tions were different in the tissues (visceral fat " creased CVD risk (odds ratio 1.84, P!0.001). Ad-
liver fat "muscle fat), suggesting that ectopic fat ditional adjustment for the metabolic syndrome ap-
desposion is regulated differently in these tissues. preciably attenuated, but did not abolish, this asso-
Contribution of ectopic fat desposion to cardiovas- ciation (1.53, P=0.02).
cular disease are discussed below. One form of ectopic fat deposition, epicardial adi-
pose tissue (EAT), is correlated with various car-
1.1. Coronary heart diseases diovascular risk factors, independent of abdominal
In the INTERHEART study (18), Yusuf et al. re- visceral adiposity, body mass index (BMI), hyper-
ported the effect of various measures of adiposity tension, and diabetes mellitus (9-11). Two popu-
on rates of acute myocardial infarction (AMI) by lation-based studies, the Multi-Ethnic Study of
comparing 12,461 AMI cases and 14,637 standard- Atherosclerosis and the Framingham Heart Study,
ized-controls of variable ethnicity from 52 countries. showed that EATV is an independent risk predictor
BMI showed a modest association with AMI (un- for cardiovascular disease (20, 21). EAT is shown
adjusted odds ratio [OR] 1.44 for the top quintile to be metabolically active and the source of pro-
vs. the bottom quintile), but this association was atherogenic mediators and adipocytokines. We (22)
lost after adjustment for other risk factors. Mean- and others (23) showed that proinflammatory cytoki-
while, adjusted OR for quintile of waist-to-hip ratio nes and adipocytokines are expressed and secreted
was consecutively higher than that of the previous at a higher level in the adipose tissue of individuals
one (OR 1.15 ; 1.39 ; 1.90 ; and 2.52, respectively). with coronary artery disease (CAD) than in indi-
Targher et al. assessed prospectively whether viduals without CAD. Abdominal fat distribution is
Nonalcoholic fatty liver disease NAFLD, a typical dissimilar between men and women : Visceral fat
phenotype of ectopic fat deposition, predicts future obesity is the dominant form in men, while subcu-
CVD events including nonfatal coronary heart dis- taneous fat obesity is the dominant form in women
ease (myocardial infarction and coronary revascu- (24, 25). We evaluated gender disparities in EATV
larization procedures), ischemic stroke, or cardio- and its impact on coronary atherosclerosis by us-
vascular death, among type 2 diabetic individuals ing multi-detector computed tomography (MDCT)
(19). After adjustment for age, sex, smoking his- (Fig. 3). EATV/body surface area (BSA) was higher
tory, diabetes duration, HbA1c, LDL cholesterol, among men in the CAD group than in the non-CAD
 4 M. Shimabukuro, et al. Ectopic fat and cardiometabolic risk

EATV/body surface area Men Women

cm3/m2

non-CAD CAD

Cardiovasc Diabetol, 2012

Fig 3. Men with coronary atherosclerotic disease (CAD) showed an increase in epicardial adipose tissue (EAT) volume

group (62 !13 vs. 33 !10 cm3/m2, p!0.0001), but predictor of CHF, independent of established CHF
did not differ significantly among women in the 2 risk factors (hypertension, T2DM, LV hypertrophy
groups (49 !18 vs. 42 !9 cm3/m2, not significant) and smoking) (29). There is strong evidence for
(26). Multivariate logistic analysis showed that lipotoxic mechanisms in rodents showing that lipid
EATV/BSA was the single predictor for "50% coro- accumulation in the heart leads to heart failure. 1H-
nary luminal narrowing in men (p!0.0001). Thus, MRS has been adapted to quantify lipid content in
increased EATV might be strongly associated with cardiac muscle of human subjects (30), showing that
coronary atherosclerosis only in men (26). triglyceride (TG) was detectable in the myocardium
of healthy human subjects even in those who are
1.2. Cardiac dysfunction and heart failure very lean. In overweight subjects myocardial TG
Echocardiographical measures of left ventricu- content was elevated and was accompanied by in-
lar (LV) structure and LV function were altered in creased left ventricular mass and a subtle reduc-
metabolic syndrome (27). Patients with metabolic tion of septal wall thickening, which represents
syndrome appeared more likely to show LV diastolic mild systolic dysfunction (30). Myocardial fat was
dysfunction, independently of LV mass (27). Thus, found to be higher in obese than in lean subjects
Veglobal, an index of global LV relaxation function, and myocardial fat correlated with FFA levels,
decreased progressively from absent group (0 of epicardial fat, and waist-to-hip ratio (31). Epicardial
metabolic syndrome component), pre-metabolic fat was positively associated with peripheral vascu-
syndrome group (1-2 component), to metabolic syn- lar resistance and negatively with the cardiac in-
drome group ("=3 component), even after adjust- dex. Combined, the cardiac accumulation of TG is
ment for LV mass (27). In patients hospitalized for related to FFA exposure, generalized ectopic fat
CHF, 30%-40% present only with LV diastolic dys- excess, and peripheral vascular resistance and that
function but not with LV systolic dysfunction (28). these changes precede left ventricular overload and
The presence of metabolic syndrome provides im- hypertrophy (32).
portant risk information beyond that of established
risk factors also for congestive heart failure (CHF). 1.3. Cerebrovascular diseases
In a community-based sample of middle-aged men, In the Atherosclerosis Risk in Communities
BMI and/or metabolic syndrome was a significant (ARIC) study, which included 14,448 men and
 The Journal of Medical Investigation Vol. 60 February 2013 5

women, Ohira et al. determined contribution of risk susceptibility to atrial fibrillation (39). Among the
factors on ischemic stroke subtype (33). In addi- metabolic syndrome components, obesity (BMI "=
tion to traditional risk factors such as hypertension, 25) (age- and sex-adjusted HR, 1.64), as well as ele-
current smoking and T2DM, waist-to-hip ratio was vated blood pressure (systolic pressure "=130
associated with increased risk for nonlacunar and mmHg and/or diastolic pressure "= 85 mmHg)
cardioembolic stroke, but not with lacunar stroke. (HR 1.69), low HDL-cholesterol (HR 1.52), and high
The population-attributable fraction for hyperten- fasting plasma glucose ("=110 mg/dL) (HR 1.44),
sion was approximately 35% for all ischemic stroke showed an increased risk for atrial fibrillation (39).
subtypes. The each population-attributable fraction The association between the metabolic syndrome
for T2DM, current smoking, and waist-to-hip ratio and atrial fibrillation remained significant in subjects
were 26.3%, 22.0% and -5.6% for lacunar ; 11.3%, without treated hypertension or T2DM (HR 1.78).
11.4%, and 9.7% for nonlacunar stroke ; 16.4%, 20.7% Obesity and metabolic syndrome were also shown
and 2.9% for cardioembolic stroke. In Japanese popu- to be independent risk factors for atrial fibrillation
lation of the Hisayama Study, the multivariate-ad- after coronary artery bypass graft surgery (40).
justed incidence of non-ischemic and ischemic Whether the increased atrial fibrillation risk in meta-
stroke appeared higher in subjects with metabolic bolic syndrome is due to the syndrome as a whole
syndrome in men (hazard ration [HR] 1.68, p=0.06 or simply the sum of the risks of its individual
and 2.54, p=0.02) and women (1.78, p=0.01 and components is currently equivocal. A recent report
0.99, p=0.91), as compared with those without meta- showed that EAT volume measured by MDCT was
bolic syndrome (34). highly associated with AF, independent of traditional
risk factors including left atrial (LA) enlargement
1.4. Atrial fibrilation, arrhythmic events and sudden (41). A large sample from the Framingham Heart
death Study (n=3,217) has shown that pericardial fat vol-
In the Paris Prospective Study I, which investi- ume was associated with AF even after adjustment
gated mortality of 6,678 middle-aged men, sagittal for risk factors, including body mass index (42).
abdominal diameter, substituted for waist circum- Nakanishi et al. also demonstrated that the peri-
ference, and the presence of metabolic syndrome atrial EAT volume predicted future AF events more
were associated with an increase in !1 hour sud- accurately than total EAT volume during follow-up
den death (multivariate adjusted HR, 2.26 and 2.02), of 3.3!1.0 years (43). These results suggest the
so as with non-sudden death from AMI (HR 1.69 potential role of peri-atrial EAT in the development
and 1.60) (35). Sudden death could be coming from of AF such as local and direct effects on LA struc-
arrhythmic events including lethal ventricular fib- tures, generation of inflammatory cytokines, and
rillation, since patients with metabolic syndrome had modulation of the intrinsic autonomic nervous sys-
significantly higher values of corrected QT interval tem.
(QTc) and QT dispersion (QTd) on electrocardio-
gram, which reflects myocardial refractoriness and 1.5. Peripheral arterial disease
electrical instability (36). In the Multicenter Auto- There are few studies examining the relationship
matic Defibrillator Implantation Trial II (MADIT- between obesity and peripheral arterial disease
II) study (37), obesity (BMI "=30 kg/m2) was a (PAD). Whether obesity is a risk factor for devel-
risk factor for sustained ventricular tachyarrhythmia opment of PAD remains controversial (44, 45). The
in patients after myocardial infarction with severe discrepancy may be due to the higher prevalence
left ventricular dysfunction (LV ejection fraction! of PAD in elderly males and in smokers ; elderly
30%). males show a weaker relationship between obesity
In analysis of Japanese 592 hospitalized patients and CVD, and smokers tend to have lower BMI
without obvious structural heart diseases (38), the than non-smokers (46). A recent prospective cohort
metabolic syndrome was a significant risk factor for study revealed a positive relationship between waist-
paroxysmal atrial fibrillation/flutter, independently to-hip ratio, not BMI, and PAD prevalence (47).
of left atrial diameter ("44 mm) or age ("70 years) Mechanisms by which obesity causes PAD (if any),
(OR 2.8, p!0.01). In a community - based cohort could be different to CHD, two do have different
in Japan ("28,000 subjects), Watanabe et al. dem- risk profiles ; e.g. cigarette smoking is more strongly
onstrated an apparent correlation between the associated with development of PAD than CHD
presence of metabolic syndrome and increased (48). Studies should be done to clarify effects of
 6 M. Shimabukuro, et al. Ectopic fat and cardiometabolic risk

obesity on onset of PAD, complications such as endocrine manner (3-8). It is believed that anti-
rupture of aortic aneurysm and severity of limb atherosclerotic adipocytokine such as leptin and
ischemia. adiponectin and pro-atherosclerotic cytokines such
as interleukin-6 (IL-6) and tumor necrosis factor α
1.6. Venous thromboembolism (TNFα) cooperatively regulate metabolic and car-
Numerous studies have shown a clear relation- diovascular homeostasis at local and remote site
ship between obesity and the risk of idiopathic ve- (Table) (3-8, 51). Obesity and atherosclerotic proc-
nous thromboembolism (deep vein thrombosis and ess at least partly share an inflammatory etiology
pulmonary embolism), independent of other tradi- (52, 53), which hypothetically causes imbalance in
tional risk factors (48, 49). In a study from Sweden, the interaction between nitric oxide (NO) and re-
men with a waist circumference "=100 cm had a 4- active oxygen species (ROS) and result in a pro-
fold higher risk of venous thromboembolism than atherogenic vascular bed (54).
with !100 cm (49). Obese patients have chronically Comorbidity of hypertension, glucose intolerance
raised intra-abdominal pressure and decreased and dyslipidemia individually may cause cardiac
blood velocity in the common femoral vein. Inac- dysfunction directly via impaired relaxation of LV
tivity, poor gait, as well as other co-morbidity may and/or via vascular failure (endothelial dysfunction)
collectively impair venous return from the lower (55). The excess production of ROS may elicit tis-
limbs. Alternatively, obesity, in particular visceral sue damage in the heart, as shown in experimen-
obesity, may have prothrombotic propensity via tally induced-heart failure model (56). ROS could
mechanisms including : actions of adipocytokines, be involved in the pathophysiology of human CHF
increased activity of the coagulation cascade and (57). Systemic oxidative stress is enhanced in
decreased activity of the fibrinolytic cascade, inflam- obese animals and in humans with visceral obesity
mation, oxidative stress, endothelial dysfunction, and (58) or the metabolic syndrome (59). ROS derived
disturbances in lipids and glucose homeostasis (50). from visceral fat could affect LV geometry and LV
function.

2.2. Lipotoxicity
2. MECHANISTIC LINK BETWEEN ECTOPIC
Obesity is associated with lipid accumulation
FAT DESPOSION AND CARDIOVASCULAR
not only in adipose tissue, but also in non-adipose
DISEASE tissues (60). The latter is known as ectopic fat depo-
2.1. Adipocytokine and insulin resistance sition and lipotoxicity, which is theorized to produce
There is solid evidence supporting the notion that obesity comorbidities such as insulin resistance,
excess abdominal fat is predictive of insulin resis- T2DM and cardiovascular disease (Fig. 3). We first
tance and of the presence of related metabolic ab- described this concept in pancreatic β cells (β cell-
normalities currently referred to as the metabolic lipotoxicity) (61-63) and expand this to other tissues
syndrome (3-8). Despite the fact that abdominal including the heart (64, 65). As obesity develops,
obesity is a highly prevalent feature of the metabolic insulin secretion increases parallel to insulin resis-
syndrome, the mechanisms by which abdominal tance in order to maintain normal glucose homeo-
obesity is causally related to the metabolic syndrome stasis. Patients predisposed to diabetes, however,
are not fully elucidated. When categorized by whole- fail to compensate for greater insulin requirements,
body distribution of adiposity, insulin sensitivity is and develop T2DM (60).
well explained by ectopic fat deposition in insulin- The remarkable hyperlipolytic activity of the vis-
sensitive non-adipose tissue (Fig. 1, 3). Obese sub- ceral adipose tissue, over the subcutaneous adipose
jects constantly deliver more lipids and dysregulated tissue, contributes to exposure the liver, skeletal
adipocytokine than normal lean subjects ; visceral muscle and even the cardiovascular system to ex-
fat obese can produce more pro-atherogenic adi- cess FFA. This impairs insulin-dependent metabolic
pocytokine including free fatty acid (FFA) than process, and leads to hyperinsulinemia, glucose in-
subcutaneous fat obese. Adipose tissue is not only tolerance (an increase in hepatic glucose production
an energy storage tissue, but also a metabolically and decreases in skeletal and hepatic glucose up-
active organ secreting hormones, cytokines and take), hypertriglyceridemia (an increase in VLDL-
growth factors, collectively called as adipocytokine apolipoprotein B secretion), low plasma HDL-cho-
(adipokine), that act in an autocrine, paracrine or lesterol level, and cardiovascular disturbance (60).
 The Journal of Medical Investigation Vol. 60 February 2013 7

developed LV concentric hypertrophy. This obser-

2.3. Cardiac adiposity and epicardial fat : cardiac vation suggests that high myocardial TG levels her-
lipotoxicity ald contractile dysfunction in humans.
Mechanisms by which abdominal adiposity im-
duces cardiac dysfunction remain unknown (27- 2.3.3. Perivascular fat
32). From evidence described here, one of authors Perivascular fat is another candidate of mediator
(MS) previously proposed an idea that ectopic fat for obesity-associated cardiovascular risk. It is de-
deposition in the heart is causally related to car- fined as the accumulation of fat around vascular
diac performance and structural remodeling at multi- structures, mostly in the proximity of all blood ves-
ple component by (A) circulatory and locally-re- sels and around the coronaries and the aorta. Con-
cruited fat (66), (B) intra- and extra-myocellular fat ventionally, perivascular fat was considered to act
(64, 65), (C) perivascular fat (67-69), and (D) peri- largely as a structural support for vasculature. Re-
cardial fat (6-11), collectively to be called ”cardiac cent experimental data from ex-vivo epicardial adi-
lipotoxicity”. pose tissue and arteries suggest that periadventitial
fat can modulate vascular responsiveness to vasoac-
2.3.1. Circulatory and locally-recruited fat (Vascu- tive agents (55, 56) (68-70). Perivascular fat can
lar lipotoxicity) secrete a variety of cytokines and chemokines and
An oversupply of FFA to the bloodstream from could contribute to the pathogenesis and/or pro-
visceral adipose tissues may disturb vascular homeo- gression of obesity-induced atherosclerosis.
stasis. We found a ”vascular lipotoxicity” phenome-
non that FFA does directly activate vascular ROS 2.3.4. Pericardial fat
production and leads endothelial dysfunction in Accumulation of excess pericardial fat, which
obese model (66). Circulating FFA can acutely in- shares the capacity to secrete cytokines with vis-
crease vascular ROS signals and chronically enhance ceral fat might be related to cardiac remodeling (6-
vascular expression of NADPH oxidase multisubunit 11). Its quantity is well correlated with the mass of
complex, which is the major source of superoxide visceral adipose tissue. Human pericardial adipose
anion in the vasculature (70, 71). Two general tissue has a considerable secretory activity ; epicar-
mechanisms underlying activation of NADPH oxi- dial adipose tissue from patients undergoing elec-
dase are either an acute increase in oxidase com- tive coronary aortic bypass grafting contained more
plex formation secondary to post-translational modi- mRNA and protein for IL-1β, IL-6, monocyte
fication of regulatory subunits or mitochondrial un- chemoattractant protein 1 (MCP-1) and TNFα com-
coupling (72, 73), or a chronic increase in the ex- pared to subcutaneous adipose tissue (22, 23). In
pression and abundance of component subunits (70, pericardial tissue, the cytokine concentrations were
71). The locally produced ROS (66) and fat-de- correlated well with an accumulation of inflamma-
rived ROS (58) simultaneously react with NO, gen- tory cells, such as T-lymphocytes, macrophages
erate peroxynitrite, and finally impair cGMP-de- and mast cells. Adiponectin might also play a role
pendent vasodilatation. in pericardial adipose tissue, as patients with ad-
vanced coronary heart disease have lower level of
2.3.2. Intra- and extra-myocellular fat epicardial adiponectin. A recent clinical study
Contents of intra- and extra-myocellular fat are showed that pericardial adipose tissue represents
shown to be closely related to visceral fat adiopos- a novel indicator of cardiovascular risk (20, 21).
ity in animal model (64, 65) and in human (69). Fat
accumulation of the myocardium is associated with
LV hypertrophy and dysfunction that ultimately pro- 3. MANAGEMENT STRATEGY FOR GLOBAL
gresses to lipotoxic heart disease (64). Myocardial
CARDIO-METABOLIC RISK
fat accumulation and lipotoxic cardiomyopathy in
this model can be prevented by an insulin sensitizer 3.1. Individual risk factors and global cardio-meta-
treatment initiated at an early age (60). In human, bolic risk
Szczepaniak et al. showed that the contractile func- Although remarkable progress has been made
tion of myocardium measured by MRS was nega- in the management of traditional CVD risk fac-
tively correlated with myocardial TG levels (69), tors such as hypertension, elevated LDL-choles-
and also found that elevated myocardial TG levels terol, smoking, and diabetes mellitus, approach to
 8 M. Shimabukuro, et al. Ectopic fat and cardiometabolic risk

abdominal obesity/metabolic syndrome have not cardiovasuclar disease (Fig. 4).

been reached to a worldwide consunsus (7, 8, 74). It is also claimed that the Framingham risk score
The American Diabetes Association (ADA) and the does not properly assess lifetime risk particularly
European Association for the Study of Diabetes among young adults or adolescents with abdomi-
(EASD) as well as the International Chair on Car- nal obesity (77), which are not considered at a risk
diometabolic Risk have emphasized the critical im- of CVD by current algorithms because of young
portance of first using global risk calculators such age. Surrogate markers to detect abnormalities in
as the Framingham risk score, the PROCAM algo- ROS and renin-angiotensin-aldosterone system
rithm or the European SCORE (74, 75). However, (RAAS), vascular failure (endothelial dysfunction),
there is evidence to suggest that the risk assess- neurohumoral stress and arrhythmogenicity could
ment algorithms may not accurately estimate the have additional powers in long-term assessment of
global CVD risk in patients with visceral obesity/ global CVD risk.
metabolic syndrome. Thus, it is essential to de-
velop a risk assessment model of global CVD in 3.2. Visceral fat management
the presence of traditional risk factors and emerg- Obesity management goals should encompass re-
ing markers found in individuals with visceral obe- duction in total cardiovascular morbidity and mor-
sity. Després et al. defined this model as global tality. Losing 5% to 10% of body weight reduces the
cardio-metabolic risk (76). Under this model, car- traditional CV risks (78). Increasing physical activ-
diometabolic risk is the global risk of CVD result- ity, in combination with a diet that emphasizes fresh
ing from the presence of traditional risk factors fruits and vegetables, whole grains, and low-fat dairy
combined with the possible additional contribution products, can help patients reduce weight and obe-
of the metabolic syndrome. Namely, the metabolic sity comorbidity.
syndrome cannot be used to assess global CVD Less is known about the long-term effect of weight
risk but is at best one more modifiable CVD risk loss on the development of T2DM and CVD out-
factor. To modify this model for clinical setting, comes in the form of death, myocardial infarction,
we propose cardiometabolic risk cascade causing and stroke. A trial to answer the most important

5%/10 yrs

Visceral
Obesity 8-10%/10
MetS•IGT•PPHG
MetS•I
+
dyslipidemia
yslipidemia Insulin
resistance Non-obese
+ diabetes
hyper (No insulin
tension resistance)

+
Macroangiopathy
athy Hyper Micro
CVD glycemia
g
glycemi angiopathy

Type 2 diabetes
AMI CVD 17%/10 yrs

Fig 4. Cardiometabolic risk cascade causing cardiovascular disease

CVD, cardiovascular disease ; MetS, metabolic syndrome ; IGT, impaired glucose tolerance ; PPHG, postprandial hyperglycaemia
 The Journal of Medical Investigation Vol. 60 February 2013 9

question whether the improvements in cardiovas- and 4 years, both diabetes control (glucose, HbA1c)
cular risk factors by managed weight loss will be and most cardiovascular disease risk factors (blood
associated with reduction in long-term cardiovas- pressure, HDL cholesterol, triglycerides) were more
cular events was investigated (The Look AHEAD favorable in the lifestyle intervention than in the con-
(Action for Health in Diabetes) trial) (79). The study trol group with the exception of LDL cholesterol,
enrolled 5,145 people with type 2 diabetes and a which was not different between groups at year 1.
BMI greater than 25, randomizing half to a life- At year 4, those in the intensive lifestyle interven-
style intervention and half to a general program of tion group continued to have more favorable dia-
diabetes support and education (80). Although those betes control and CVD risk factor reduction, with
in the intervention group kept off 5% of their initial the exception of LDL-C in which there were slightly
body weight at 4 years, there was no difference be- greater reductions in the standard care group. Par-
tween them and the standard care group in the rate ticipants in the lifestyle intervention group main-
of myocardial infarction, stroke, hospitalizations for tained greater improvements in fitness at both years
angina, and cardiovascular death -- the primary out- 1 and 4.
come. Despite no reduction in cardiovascular events According to AHA/ACCF Secondary Prevention
in those in the intense intervention arm, they did and Risk Reduction Therapy for Patients With Coro-
experience other health benefits. Patients in this nary and Other Atherosclerotic Vascular Disease :
group saw improvements in sleep apnea and mobil- 2011 Update : Intervention Recommendations With
ity, as well as quality of life. In addition, their dia- Class of Recommendation and Level of Evidence
betes medications were reduced. In addition, at 1 (Fig. 5) (81), weight management is recognized as

Fig 5. Body weight management : AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients With Coronary
and Other Atherosclerotic Vascular Disease : 2011 Update : Intervention Recommendations With Class of Recommendation and
Level of Evidence
 10 M. Shimabukuro, et al. Ectopic fat and cardiometabolic risk

Class I (Procedures/Treatment should be per- REFERENCE

formed/administered), but estimated of certainty of
treatment effect is named as Level B or Levels C. 1. Olshansky SJ, Passaro DJ, Hershow RC, Layden
When indicated, exercise, caloric intake, and formal J, Carnes BA : A potential decline in life expec-
behavioral programs are recommended to main- tancy in the United States in the 21st century.
tain/achieve a body mass index between 18.5 and N Engl J Med 352 : 1138-1145, 2005
24.9 kg/m2 (Level of Evidence : B), or to achieve 2. Hossain P, Kawar B, E1 Nahas M : Obesity and
waist circumference (!89 cm) in women and (!102 diabetes in the developing world-a growing
cm) in men or to reduce body weight by approxi- challenge. N Engl J Med 356 : 213-215, 2007
mately 5% to 10% from baseline. 3. Matsuzawa Y, Funahashi T, Nakamura T : Mo-
lecular mechanism of metabolic syndrome X :
Contribution of adipocytokines adipocyte-de-
CONCLUSION rived bioactive substances. Ann NY Acad Sci
18 : 146-154, 1999
The concept of the metabolic syndrome takes 4. Montague CT, O’Rahilly S : The perils of port-
into account the central role that visceral fat plays liness : Causes and consequences of visceral
essential role in the development of metabolic and adiposity. Diabetes 49 : 883-888, 2000
cardiovascular diseases, and indicates how waist 5. Eckel RH, Grundy SM, Zimmet PZ : The meta-
circumference measurement is useful in aiding pa- bolic syndrome. Lancet 365 : 1415-1428, 2005
tient identification in a clinical setting. The meta- 6. Shimabukuro M : Cardiac adiposity and global
bolic syndrome cannot be used to assess global cardiometabolic risk : new concept and clini-
CVD risk but is at best one more modifiable CVD cal implication. Circ J 73 : 27-34, 2009
risk factor. Thus, global cardiometabolic risk should 7. Després JP : Body fat distribution and risk of
be considered individually. Increased visceral fat cardiovascular disease : an update. Circulation
is associated with a shift in the normal balance of 126 : 1301-1313, 2012
the adipocytokines resulting in pro-inflammatory 8. Cardiometabolic Risk Working Group : Execu-
and pro-atherosclerotic state. Although evidence for tive Committee, Leiter LA, Fitchett DH, Gilbert
therapeutic efficacy in the treatment of abdominal RE, Gupta M, Mancini GB, McFarlane PA,
adiposity and clustering of cardiometabolic risks Ross R, Teoh H, Verma S, Anand S, Camelon
are limited, this should be a promising challenge K, Chow CM, Cox JL, Després JP, Genest J,
to reduce the highly contagious state around the Harris SB, Lau DC, Lewanczuk R, Liu PP,
world. Lonn EM, McPherson R, Poirier P, Qaadri S,
Rabasa-Lhoret R, Rabkin SW, Sharma AM,
Steele AW, Stone JA, Tardif JC, Tobe S, Ur E :
ACKNOWLEDGEMENTS Cardiometabolic risk in Canada : a detailed
analysis and position paper by the cardiome-
This work was supported by Grants-in-Aid for tabolic risk working group. Can J Cardiol 27 :
Scientific Research from the Japanese Society for e1-e33, 2011
the Promotion of Science, the Ministry of Education, 9. Cherian S, Lopaschuk GD, Carvalho E : Cellu-
Culture, Sports, Science and the Technology and lar cross-talk between epicardial adipose tissue
Ministry of Health, Labour and Welfare. Authors and myocardium in relation to the pathogenesis
sincerely thanks to every collaborators especially of cardiovascular disease. Am J Physiol Endo-
to Dr Roger H. Unger, Chris B. Newgard, and J crinol Metab 303 : E937-949, 2012
Dennis McGarry for superb mentorship ; Drs 10. Iacobellis G, Bianco AC : Epicardial adipose tis-
Yoichiro Hirata, Minoru Tabata, Hirotsugu Kurobe, sue : emerging physiological, pathophysiologi-
Hirofumi Izaki, Hiroomi Kanayama, and Shuichiro cal and clinical features. Trends Endocrinol
Takanashi for crucial collaborations ; Mss Hiromi Metab 22 : 450-457, 2011
Sato, Etsuko Uematsu, Junko Yata, Horoko Goda 11. Sacks HS, Fain JN : Human epicardial fat : what
for secretary dedication. is new and what is missing? Clin Exp Pharma-
col Physiol 38 : 879-887, 2011
12. Utzschneider KM, Kahn SE : Review : The role
of insulin resistance in nonalcoholic fatty liver
 The Journal of Medical Investigation Vol. 60 February 2013 11

disease. J Clin Endocrinol Metab 91 : 4753- DA, Carr JJ : The association of pericardial fat
4761, 2006 with incident coronary heart disease. The Multi-
13. Thamer C, Machann J, Stefan N, Haap M, Ethnic Study of Atherosclerosis (MESA). Am
Schafer S, Brenner S, Kantartzis K, Claussen J Clin Nutr 90 : 499-504, 2009
C, Schick F, Haring H, Fritsche A : High vis- 22. Hirata Y, Tabata M, Kurobe H, Motoki T,
ceral fat mass and high liver fat are associated Akaike M, Nishio C, Higashida M, Mikasa H,
with resistance to lifestyle intervention. Obe- Nakaya Y, Takanashi S, Igarashi T, Kitagawa
sity (Silver Spring) 15 : 531-538, 2007 T, Sata M : Coronary atherosclerosis is associ-
14. Thamer C, Machann J, Haap M, Stefan N, ated with macrophage polarization in epicar-
Heller E, Schnödt B, Stumvoll M, Claussen C, dial adipose tissue. J Am Coll Cardiol 58 : 248-
Fritsche A, Schick F, Haring H : Intrahepatic 255, 2011
lipids are predicted by visceral adipose tissue 23. Kremen J, Dolinkova M, Krajickova J, Blaha
mass in healthy subjects. Diabetes Care 27 : J, Anderlova K, Lacinova Z, et al. : Increased
2726-2729, 2004 subcutaneous and epicardial adipose tissue pro-
15. Krssak M, Falk Petersen K, Dresner A, duction of proinflammatory cytokines in cardiac
DiPietro L, Vogel SM, Rothman DL, Roden M, surgery patients : possible role in postoperative
Shulman GI : Intramyocellular lipid concentra- insulin resistance. J Clin Endocrinol Metab
tions are correlated with insulin sensitivity in 91 : 4620-4627, 2006
humans : a 1H NMR spectroscopy study. Dia- 24. Kotani K, Tokunaga K, Fujioka S, et al. : Sexual
betologia 42 : 113-116, 1999 dimorphism of age-related changes in whole-
16. Kelley DE, Goodpaster BH, Storlien L : Muscle body fat distribution in the obese. Int J Obes
triglyceride and insulin resistance. Annu Rev Relat Metab Disord 18 : 202-207, 1994
Nutr 22 : 325-346, 2002 25. Camhi SM, Bray GA, Bouchard C, et al. : The
17. Taira S, Shimabukuro M, Higa M, Yabiku K, relationship of waist circumference and BMI to
Kozuka C, Ueda R, Sunagawa S, Kawamoto E, visceral, subcutaneous, and total body fat : sex
Nakayama Y, Nakamura H, Iha T, Tomoyose and race differences. Obesity (Silver Spring)
T, Ikema T, Yamakawa K, Masuzaki M : Lipid 19 : 402-408, 2011
deposition in various sites of skeletal muscle 26. Dagvasumberel M, Shimabukuro M, Nishiuchi
and liver shows correlation with visceral fat T, Ueno J, Takao S, Hirata Y, Kurobe H, Soeki
accumulation in male patients with metabolic T, Iwase T, Kusunose K, Niki T, Tamaguchi
syndrome. Intern Med. in press K, Taketani Y, Yagi S, Tomita N, Yamada H,
18. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum Wakatsuki T, Harada M, Kitagawa T, Sata M :
A, Lanas F, et al. : Effect of potentially modifi- Gender disparities in the association between
able risk factors associated with myocardial epicardial adipose tissue volume and coronary
infarction in 52 countries (the INTERHEART atherosclerosis : A 3-dimensional cardiac com-
study) : case-control study. Lancet 364 : 937- puted tomography imaging study in Japanese
952, 2004 subjects. Cardiovasc Diabetol 11 : 106, 2012
19. Targher G, Bertolini L, Poli F, Rodella S, Scala 27. de las Fuentes L, Brown AL, Mathews SJ,
L, Tessari R, Zenari L, Falezza G : Nonalcoholic Waggoner AD, Soto PF, Gropler RJ, et al. :
fatty liver disease and risk of future cardiovas- Metabolic syndrome is associated with abnor-
cular events among type 2 diabetic patients. mal left ventricular diastolic function independ-
Diabetes 54 : 3541-3546, 2005 ent of left ventricular mass. Eur Heart J 28 :
20. Rosito GA, Massaro JM, Hoffmann U, Ruberg 553-559, 2007
FL, Mahabadi AA, Vasan RS, O’Donnell CJ, 28. Redfield MM, Jacobsen SJ, Burnett JC Jr,
Fox CS : Pericardial fat, visceral abdominal fat, Mahoney DW, Bailey KR, Rodeheffer RJ : Bur-
cardiovascular disease risk factors, and vascular den of systolic and diastolic ventricular dysfunc-
calcification in a community-based sample : the tion in the community : appreciating the scope
Framingham Heart Study. Circulation 117 : of the heart failure epidemic. JAMA 289 : 194-
605-613, 2008 202, 2003
21. Ding J, Hsu FC, Harris TB, Liu Y, Kritchevsky 29. Ingelsson E, Arnlov J, Lind L, Sundstrom J :
SB, Szklo M, Ouyang P, Espeland MA, Metabolic syndrome and risk for heart failure
Lohman KK, Criqui MH, Allison M, Bluemke in middle-aged men. Heart 92 : 1409-1413, 2006
 12 M. Shimabukuro, et al. Ectopic fat and cardiometabolic risk

30. Szczepaniak LS, Dobbins RL, Metzger GJ, fibrillation : the Niigata preventive medicine
Sartoni-D’Ambrosia G, Arbique D, Vongpatanasin study. Circulation 117 : 1255-1260, 2008
W, et al. : Myocardial triglycerides and systolic 40. Echahidi N, Mohty D, Pibarot P, Després JP,
function in humans : in vivo evaluation by lo- O’Hara G, Champagne J, et al. : Obesity and
calized proton spectroscopy and cardiac imag- metabolic syndrome are independent risk fac-
ing. Magn Reson Med 49 : 417-423, 2003 tors for atrial fibrillation after coronary artery
31. Reingold JS, McGavock JM, Kaka S, Tillery T, bypass graft surgery. Circulation 116(Suppl) :
Victor RG, Szczepaniak LS, et al. : Determina- I213-I219, 2007
tion of triglyceride in the human myocardium 41. Al Chekakie MO, Welles CC, Metoyer R,
by magnetic resonance spectroscopy : repro- Ibrahim A, Shapira AR, Cytron J, et al. : Peri-
ducibility and sensitivity of the method. Am J cardial fat is independently associated with
Physiol Endocrinol Metab 289 : E935-939, 2005 human atrial fibrillation. J Am Coll Cardiol
32. Kankaanpaa M, Lehto HR, Parkka JP, Komu 56 : 784-788, 2010
M, Viljanen A, Ferrannini E, et al. : Myocardial 42. Thanassoulis G, Massaro JM, O’Donnell CJ,
triglyceride content and epicardial fat mass in Hoffmann U, Levy D, Ellinor PT, et al. : Peri-
human obesity : relationship to left ventricu- cardial fat is associated with prevalent atrial
lar function and serum free fatty acid levels. J fibrillation : The Framingham Heart Study. Circ
Clin Endocrinol Metab 91 : 4689-4695, 2006 Arrhythm Electrophysiol 3 : 345-350, 2010
33. Ohira T, Shahar E, Chambless LE, Rosamond 43. Nakanishi K, Fukuda S, Tanaka A, Otsuka K,
WD, Mosley TH Jr, Folsom AR : Risk factors Sakamoto M, Taguchi H, et al. : Peri-atrial
for ischemic stroke subtypes : the Atheroscle- epicardial adipose tissue is associated with
rosis Risk in Communities study. Stroke 37 : newonset nonvalvular atrial fibrillation. Circ J
2493-2498, 2006 76 : 2748-2754, 2012
34. Ninomiya T, Kubo M, Doi Y, Yonemoto K, 44. Bainton D, Sweetnam P, Baker I, Elwood P :
Tanizaki Y, Rahman M, et al. : Impact of meta- Peripheral vascular disease : consequence for
bolic syndrome on the development of cardio- survival and association with risk factors in the
vascular disease in a general Japanese popula- Speedwell prospective heart study. Br Heart J
tion : the Hisayama study. Stroke 38 : 2063- 72 : 128-132, 1994
2069, 2007 45. Smith GD, Shipley MJ, Rose G : Intermittent
35. Empana JP, Duciemetiere P, Balkau B, Jouven claudication, heart disease risk factors and mor-
X : Contribution of the metabolic syndrome to tality : the Whitehall Study. Circulation 82 :
sudden death risk in asymptomatic men : the 1925-1931, 1990
Paris Prospective Study I. Eur Heart J 28 : 46. Planas A, Clara A, Pou JM, Vidal-Barraquer
1149-1154, 2007 F, Gasol A, De Moner A, et al. : Relationship of
36. Pietrasik G, Goldenberg I, McNitt S, Moss AJ, obesity distribution and peripheral arterial oc-
Zareba W : Obesity as a risk factor for sustained clusive disease in elderly men. Int J Obes Relat
ventricular tachyarrhythmias in MADIT II pa- Metab Disord 25 : 1068-1070, 2001
tients. J Cardiovasc Electrophysiol 18 : 181-184, 47. Hansson PO, Eriksson H, Welin L, Svardsudd
2007 K, Wilhielmsen L : Smoking and abdominal obe-
37. Soydinc S, Davutoglu V, Akcay M : Uncompli- sity : risk factors for venous thromboembolism
cated metabolic syndrome is associated with among middle-aged men : “the study of men
prolonged electrocardiographic QTc interval born in 1913.” Arch Intern Med 159 : 1886-
and QTc dispersion. Ann Noninvasive Electro- 1890, 1999
cardiol 11 : 313-317, 2006 48. Leng GC, Lee AJ, Fowkes FG, Lowe GD,
38. Umetani K, Kodama Y, Nakamura T, Mende Housley E : The relationship between cigarette
A, Kitta Y, Kawabata K, et al. : High prevalence smoking and cardiovascular risk factors in pe-
of paroxysmal atrial fibrillation and/or atrial flut- ripheral arterial disease compared with ischae-
ter in metabolic syndrome. Circ J 71 : 252-255, mic heart disease. The Edinburgh Artery Study.
2007 Eur Heart J 16 : 1542-1548, 1995
39. Watanabe H, Tanabe N, Watanabe T, Darbar 49. Samama MM : An epidemiologic study of risk
D, Roden DM, Sasaki S, et al. : Metabolic factors for deep vein thrombosis in medical
syndrome and risk of development of atrial outpatients : the Sirius study. Arch Intern Med
 The Journal of Medical Investigation Vol. 60 February 2013 13

160 : 3415-3420, 2000 PA, Asad K : Increased extracelluar matrix re-

50. Darvall KA, Sam RC, Silverman SH, Bradbury modeling during the development of a specific
AW, Adam DJ : Obesity and thrombosis. Eur J diabetic cardiomyopathy in the Zucker Fatty
Vasc Endovasc Surg 33 : 223-233, 2007 Rats. Circulation 98(Supple) : 180, 1998
51. Kadowaki T, Yamauchi T, Kubota N, Hara K, 65. Zhou YT, Grayburn P, Karim A, Shimabukuro
Ueki K, Tobe K : Adiponectin and adiponectin M, Higa M, Baetens D, et al. : Lipotoxic heart
receptors in insulin resistance, diabetes, and disease in obese rats : implications for human
the metabolic syndrome. J Clin Invest 116 : obesity. Proc Natl Acad Sci USA 97 : 1784-
1784-1792, 2006 1789, 2000
52. Ross R : Atherosclerosisdan inflammatory dis- 66. Chinen I, Shimabukuro M, Yamakawa K, Higa
ease. N Engl J Med 340 : 115-126, 1999 N, Matsuzaki T, Noguchi K, et al. : Vascular
53. Hansson GK : Inflammation, atherosclerosis, lipotoxicity : endothelial dysfunction via fatty
and coronary artery disease. N Engl J Med acid-induced reactive oxygen species over-
352 : 1685-1695, 2005 production in obese Zucker diabetic fatty rats.
54. Harrison DG : Cellular and molecular mecha- Endocrinology 148 : 160-165, 2007
nisms of endothelial cell dysfunction. J Clin 67. Yudkin JS, Eringa E, Stehouwer CD :
Invest 100 : 2153-2157, 1997 “Vasocrine” signalling from perivascular fat :
55. Inoue T, Node K : Vascular failure : A new clini- a mechanism linking insulin resistance to vas-
cal entity for vascular disease. J Hypertens cular disease. Lancet 365 : 1817-1820, 2005
24 : 2121-2130, 2006 68. Henrichot E, Juge-Aubry CE, Pernin A, Pache
56. Seddon M, Looi YH, Shah AM : Oxidative stress JC, Velebit V, Dayer JM, et al. : Production of
and redox signalling in cardiac hypertrophy chemokines by perivascular adipose tissue : a
and heart failure. Heart 93 : 903-907, 2007 role in the pathogenesis of atherosclerosis?
57. Ingelsson E, Arnlov J, Sundstrom J, Zethelius Arterioscler Thromb Vasc Biol 25 : 2594-2599,
B, Vessby B, Lind L : Novel metabolic risk fac- 2005
tors for heart failure. J Am Coll Cardiol 46 : 69. Szczepaniak LS, Victor RG, Orci L, Unger RH :
2054-2060, 2005 Forgotten but not gone : the rediscovery of fatty
58. Furukawa S, Fujita T, Shimabukuro M, Iwaki heart, the most common unrecognized disease
M, Yamada Y, Nakajima Y, et al. : Increased in America. Circ Res 101 : 759-767, 2007
oxidative stress in obesity and its impact on 70. Takaoka M, Suzuki H, Shioda S, Sekikawa K,
metabolic syndrome. J Clin Invest 114 : 1752- Saito Y, Nagai R, Sata M : Endovascular injury
1761, 2004 induces rapid phenotypic changes in perivas-
59. Fujita K, Nishizawa H, Funahashi T, Shimomura cular adipose tissue. Arterioscler Thromb Vasc
I, Shimabukuro M : Systemic oxidative stress. Biol 30 : 1576-82, 2010
A potential biomaker for visceral fat obesity 71. Brandes RP, Kreuzer J : Vascular NADPH oxi-
and metabolic syndrome. Circ J 70 : 1437-1442, dases : molecular mechanisms of activation.
2006 Cardiovasc Res 65 : 16-27, 2005
60. Unger RH : Lipotoxic diseases. Annu Rev Med 72. Mueller CF, Laude K, McNally JS, Harrison
53 : 319-336, 2002 DG : Redox mechanisms in blood vessels. Ar-
61. Shimabukuro M, Ohneda M, Lee Y, Unger RH : terioscler Thromb Vasc Biol 25 : 274-278, 2005
Role of nitric oxide in obesity-induced β-cell 73. Du X, Edelstein D, Obici S, Higham N, Zou
disease. J Clin Invest 100 : 290-295, 1997 MH, Brownlee M : Insulin resistance reduces
62. Shimabukuro M, Koyama K, Chen G, Wang arterial prostacyclin synthase and eNOS activi-
MY, Trieu F, Lee Y, et al. : Direct antidiabetic ties by increasing endothelial fatty acid oxida-
effect of leptin through triglyceride depletion tion. J Clin Invest 116 : 1071-1080, 2006
of tissues. Proc Natl Acad Sci USA 94 : 4637- 74. Kahn R, Buse J, Ferrannini E, Stern M : The
4641, 1997 metabolic syndrome : time for a critical ap-
63. Shimabukuro M, Zhou Y-T, Levi M, Unger praisal : joint statement from the American Dia-
RH : Fatty acid-induced β-cell apoptosis : A link betes Association and the European Associa-
between obesity and diabetes. Proc Natl Acad tion for the Study of Diabetes. Diabetes Care
Sci USA 95 : 2498-2502, 1998 28 : 2289-2304, 2005
64. Shimabukuro M, Meng F, Zhou YT, Grayburn 75. Conroy RM, Pyorala K, Fitzgerald AP, Sans S,
 14 M. Shimabukuro, et al. Ectopic fat and cardiometabolic risk

Menotti A, De Backer G, et al. : Estimation of 80. Wing RR, Lang W, Wadden TA, Safford M,
ten-year risk of fatal cardiovascular disease in Knowler WC, Bertoni AG, Hill JO, Brancati
Europe : the SCORE project. Eur Heart J 24 : FL, Peters A, Wagenknecht L ; Look AHEAD
987-1003, 2003 Research Group : Benefits of modest weight
76. Després JP, Lemieux I, Bergeron J, Pibarot P, loss in improving cardiovascular risk factors
Mathieu P, Larose E, et al. : Abdominal obe- in overweight and obese individuals with type
sity and the metabolic syndrome : contribution 2 diabetes. Diabetes Care 34 : 1481-1486, 2011
to global cardiometabolic risk. Arterioscler 81. Smith SC Jr, Benjamin EJ, Bonow RO, Braun
Thromb Vasc Biol 28 : 1039-1049, 2008 LT, Creager MA, Franklin BA, Gibbons RJ,
77. Grundy SM : Metabolic syndrome : a multiplex Grundy SM, Hiratzka LF, Jones DW, Lloyd-
cardiovascular risk factor. J Clin Endocrinol Jones DM, Minissian M, Mosca L, Peterson
Metab 92 : 399-404, 2007 ED, Sacco RL, Spertus J, Stein JH, Taubert
78. Selwyn AP, Weight reduction and cardiovascu- KA ; World Heart Federation and the Preven-
lar and metabolic disease prevention : Clinical tive Cardiovascular Nurses Association. AHA/
trial update. Am J Cardiol 100(suppl) : 33-37, ACCF Secondary Prevention and Risk Reduc-
2007 tion Therapy for Patients with Coronary and
79. Look AHEAD Research Group : Reduction in other Atherosclerotic Vascular Disease : 2011
weight and cardiovascular disease risk factors update : a guideline from the American Heart
in individuals with type 2 diabetes : one-year Association and American College of Cardi-
results of the Look AHEAD trial. Diabetes Care ology Foundation. Circulation 124 : 2458-2473,
30 : 1374-1383, 2007 2011