Myocardial fat content refers to the storage of triglyceride droplets within cardiomyocytes. Inaddition, the heart and arteries are surrounded by layers of adipose tissue, exerting vasocrine andparacrine control of the subtending tissues. The rapid development of the field of noninvasiveimaging has made it possible to quantify ectopic fat masses and contents with an increasingdegree of accuracy. Myocardial triglyceride stores are increased in obesity, impaired glucosetolerance, and type 2 diabetes. The role of intramyocardial triglyceride accumulation in thepathogenesis of left ventricular (LV) dysfunction remains unclear. Increased triglyceride contentis associated with states of fatty acid overload to the heart, saturating the oxidative capacity. Itmay initially serve as a fatty acid sink to circumscribe the formation of toxic lipid species andsubsequently foster cardiac damage. Epicardial and perivascular fat depots may exert a protectivemodulation of vascular function and energy partition in a healthy situation, but their expansionturns them into an adverse lipotoxic, prothrombotic, and proinflammatory organ. They areaugmented in patients with metabolic disorders and coronary artery disease (CAD). However,the progressive association between the quantity of fat and disease severity in terms of extent ofplaque calcification or noncalcified areas, markers of plaque vulnerability, and number of vesselsinvolved is less confirmed. Functional or hybrid imaging may contribute to a better definition ofdisease severity and unveil the direct myocardial and vascular targets of adipose tissue action.
Diabetes Care 34(Suppl. 2):S371–S379, 2011
The last decade has witnessed a re-newed interest in heart adiposity,especially as the result of the rapid
development in the field of noninvasiveimaging, which has made it possible toquantify ectopic fat masses and contentswith increasing levels of accuracy. Thisreview addresses recent knowledge pro-vided by imaging studies of the fatty heartin metabolic and heart disease in humans.
DEFINITIONS—Myocardial fat con-tent refers to the storage of triglyceridedroplets within cardiomyocytes, whichcan be measured in humans by use ofproton magnetic resonance spectroscopy(1H-MRS) (1). In addition, the heart andvessels are surrounded by layers of adi-pose tissue, which is a complex organcomposed of adypocytes, stromal cells,macrophages, and a neuronal network,all nourished by a rich microcirculation.The layers surrounding the heart include
intra- and extrapericardial fat. Theirthicknesses and volumes can be quanti-fied by echocardiography and computedtomography or magnetic resonance imag-ing, respectively (2–4). Intrapericardialfat is in direct contact with the surface ofthe myocardium and coronary vessels,with no separation by a physical fascia.Thus, the diffusion of secreted moleculesand the migration of cells between theseadjacent structures may occur. Thisadherent fat layer has been defined as epi-cardial (between myocardium and vis-ceral pericardium), whereas the termpericardial fat has been variably used toidentify fat between myocardium andpericardium, which may include adiposetissue in the space between visceral andparietal pericardium, or just external butattached to the parietal pericardium. Peri-vascular fat surrounds arteries and arte-rioles. The epicardial fat layer originatesembryologically from mesothelial cells
migrating from the septum transversumand hence obtains its vascular supplyfrom the coronary arteries. The term ex-trapericardial (or intrathoracic or paracar-dial) defines thoracic adipose tissueexternal to the parietal pericardium. Itoriginates from primitive thoracic mesen-chymal cells and thus derives its bloodsupply from noncoronary sources (5).
FAT INSIDE THE HEART—Studieswith 1H-MRS show that the heart pos-sesses an endogenous triglyceride depotof #1.0% organ mass in healthy lean in-dividuals (1), which increases with age. Inhealthy subjects, short-term caloric re-striction and starvation provoked adose-dependent increase in myocardialtriglyceride content and decrease in dia-stolic function (6). Instead, high-fat dietsof short duration, resulting in greatly in-creased plasma lipid concentrations and adecline in diastolic function, had no in-fluence on myocardial triglyceride con-tent (6). These studies suggest thatcirculating free fatty acids (which are ele-vated in starvation) participate in the reg-ulation of intramyocardial fat depots, andthat the latter have rapid adaptive (i.e.,buffering) capacities. In the physiologi-cally aging male heart, myocardial triglyc-eride content increased in associationwith the age-related decline in diastolicfunction (7). Nonobese women with nor-mal glucose tolerance have significantlyless myocardial fat content, in inverse re-lationship with circulating adiponectinlevels, compared with healthy men ofsimilar age (8).
Obesity, diabetes, and metabolicsyndromeWe and others have recently documentedthat cardiac steatosis is a hallmark ofobesity and type 2 diabetes (1,8,9),representing a potentially remarkable en-dogenous source of cytosolic fatty acids.Myocardial triglyceride stores in thesediseases are increased on average bytwo- to fourfold compared with those incontrol individuals (8). Cardiac adiposityis associated with greater LV mass andwork, suppressed septal wall thickening,and impaired diastolic function. Weobserved a relationship with sex, which
c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
From the Institute of Clinical Physiology, National Research Council, Pisa, Italy.Corresponding author: Patricia Iozzo, [email protected] publication is based on the presentations at the 3rd World Congress on Controversies to Consensus in
Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement weremade possible in part by unrestricted educational grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Ethicon Endo-Surgery, Generex Biotechnology, F. Hoffmann-LaRoche, Janssen-Cilag, Johnson & Johnson, Novo Nordisk, Medtronic, and Pfizer.
cited, the use is educational and not for profit, and thework is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
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may play a part in lowering the risk ofcardiovascular disease in nondiabeticwomen. Notably, chronic hyperglycemiacancelled the sex-related difference,which may to some extent explain theloss of a cardioprotective status in womendeveloping diabetes (8).
Metabolic interventionIn patients with type 2 diabetes, theresponse to short-term caloric restriction,leading to an elevation in fatty acid levels,
promoted an accumulation of myocardialtriglycerides that was associated with adecline in LV diastolic function, as inhealthy individuals. These effects werenot observed when the rise in fatty acidlevels was pharmacologically prevented,thus underscoring the causal role of anextramyocardial supply of fatty acids inmodulating the cardiac lipid pool (10).Conversely, the prolongation of a very-low-calorie diet for 6–16 weeks reducedmyocardial fat content in nondiabetic
obese and in type 2 diabetic patients(11,12). This finding was accompaniedby a decline in LV mass and work (12)and by an improvement in diastolic func-tion (11). In one study, glitazones havebeen shown to slightly reverse cardiacsteatosis in insulin-treated type 2 diabeticpatients (13). In a subsequent study (14)conducted in 78 diabetic men assigned topioglitazone or metformin or placebo for24 weeks, neither drug changed cardiactriglyceride content, despite a decrease in
Figure 1—A: Fatty acids entering cardiomyocytes are conjugated with acyl-CoA and transported to the mitochondria to undergo b-oxidation forcellular energy needs. Myocardial fatty acid oxidation is, in fact, increased in human obesity and diabetes and in animal models overexpressing acyl-CoA synthase (top left). Mitochondrial respiration by the electron transport chain and NADPH oxidase are the likely predominant myocardialgenerators of ROS, resulting in modification of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) as well as cardiac fibrosis and hypertrophy.As oxidation becomes saturated, triglyceride accumulation provides a buffer against the formation of fatty acid intermediate species, but progressiveexhaustion of storage capacity provokes the build-up of acyl-CoA and ceramide in the cytoplasm (top right), contributing to lipotoxicity. Ampli-fication of storage capacity by enzymatic overexpression of diacylglycerol acyltransferase 1 (DGAT1) slows the progression of cardiac damage(bottom right), suggesting a defensive role of triglyceride accumulation in fatty acid overload states. B: Adipose tissue surrounding vessels andmyocardium may protectively serve as energy source and buffer and promote vascular relaxation (left panel). Its expansion is typical in metabolicand cardiovascular diseases, and leads to a cascade of events (right panel), likely triggered by adipocyte enlargement, hypoxia, consequentmacrophage and T-cell recruitment, and inflammation. Changing patterns in the release of adipokines, cytokines, substrates, smooth muscle cellgrowth factors, and angiogenesis promoters from stromal and fat cells propagate to the subtending tissues, via simple diffusion and through newlyformed adventitial vasa vasorum, and may thereby contribute to the progression of cardiac and vascular lipotoxicity, inflammation, and athero-sclerosis. FFA, free fatty acid; SMC, smooth muscle cells; VEGF, vascular endothelial growth factor.
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cardiac work by metformin and an im-provement in LV diastolic function bypioglitazone.
Does cardiac steatosis play a rolein heart disease in humans?Though diastolic dysfunction and a fattyheart are usually concomitant findings inmetabolic disorders, they may (11,13) ormay not (6,14) be simultaneously in-duced or reversed by metabolic interven-tion, and their changes are not alwayscorrelated (6,14). In cross-sectional eval-uations (9), multivariable analysis modelsdocumented that the individual contribu-tion of myocardial fat content in explain-ing the observed diastolic dysfunction intype 2 diabetic patients was modest, andits correlations with the ratio of early (E)and late (atrial, A) ventricular filling ve-locity (E/A) and E peak deceleration wasnot consistently observed (15), suggest-ing that other unmeasured pathologicprocesses, coexisting in the hearts of pa-tients with diabetes or obesity may bemore directly responsible for the dysfunc-tion.
It is important to underline that thelevel of circulating fatty acids has beenone main correlate of human myocardialtriglyceride content. The sequence ofevents following fatty acid overload tothe heart is summarized in Fig. 1A, showingprimary hyperactivation of b-oxidation,as seen in human obesity and diabetes,leading to excess formation of reactiveoxygen species (ROS) (16), and resultingin modulation of sarco(endo)plasmic re-ticulum Ca2+-ATPase, which is an earlycontributor of diastolic dysfunction in theinsulin-resistant myocardium (16) and ofmyocardial fibrosis and hypertrophy. Inmouse lines overexpressing long-chainacyl-CoA synthetase in the heart (17), LVdysfunction occurs in parallel with an over-stimulation of oxidation and ROS andceramide formation, although cardiac stea-tosis and hypertrophy are concomitantlypresent.
The independent role of triglycerideaccumulation in the pathogenesis ofdisease remains elusive because the trans-genic overexpression of the triglyceride-synthesizing enzyme diacylglycerol
acyltransferase 1 (DGAT1) in the heartresults in a physiologic hypertrophy, serv-ing a cytoprotective function, especiallyin lipid overload states (18). Accordingly,in cultured cells (19) exposed to an excessof palmitic acid, this fatty acid is poorlyincorporated into triglycerides and causesapoptosis, and unsaturated fatty acidsrescue palmitate-induced apoptosis bychanneling palmitate into triglyceridepools. In the nonischemic failing com-pared with normal human heart, cardiactriglyceride content was either reduced(20) or unchanged in subjects without obe-sity or diabetes (21), and myocardial fattyacid oxidation was activated in obese anddiabetic patients with cardiac steatosis.
Taken together, these studies make itreasonable to speculate that increasedtriglyceride content is a consequence offatty acid overload to the heart, progress-ing more rapidly after saturation of theoxidative capacity. Under these circum-stances, triglyceride accumulation may beseen as a maladaptive defense response,initially serving as a fatty acid sink tocircumscribe the formation of toxic lipid
↓↓
↑↑
Figure 1—Continued.
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Table 1—Studies on epicardial and perivascular fat versus CAD prediction or staging
Ref. Sampling technique(s)Number of patients(specific features) Evaluation of CAD
Relationship vs.epi- or pericardialor perivascular fat
Adjusted forrisk factors
and/or adiposity
(2) Computerized tomography +invasive angiography
251 presence of CAD YES yes/yesseverity YES
(40) Echocardiography +invasive angiography
139 presence of CAD NO n.a.degree + no. stenoses NO
(42) Echocardiography +invasive angiography
203 presence of CAD YES yes/yesseverity (Gensini score) YES
(30) Echocardiography 527 presence of CAD YES yes/yesdegree of stenosis YESunstable angina YES
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species, and eventually undergoing per-oxidation and saturation, thereby fosteringthe build-up of fatty acid intermediatesin the cytoplasm and functional damageto the heart. The available studies do notimply causality but suggest that accumu-lation of myocardial triglyceride may beat least an indirect marker of early cardiacdysfunction in selected stages of diseaseprogression.
FAT AROUND THE HEARTAND VESSELS—The heart, coronar-ies, and virtually all arteries are surroundedby a significant amount of adipose tissue.The thickness of epicardial fat at the levelof the right ventricle free wall is normally,7 mm in healthy lean individuals(3,22). The distribution of fat thick-nesses among different locations of the
myocardium demonstrates a spread of val-ues between 15 and 1 mm. Fat volumesaround the heart correlate with advancingage (8,23), and they are larger in men thanin women (8,23). Ethnicity is anotherpotential confounder in epicardial fatstudies, since this adipose depot is largerin Caucasians, followed by Asians, blacks,and Hispanics (23).
Fat around vessels and the heart mayserve a supportive, mechanical purpose,attenuating vascular tension and torsion,participating in vessel remodeling, andbeing a vasocrine and paracrine source ofcytokines, substrates, and adipokines(Fig. 1B). The rates of fatty acid incorpo-ration and release are higher in the cardiacthan in other adipose depots, and lipo-genesis is stimulated by insulin only inthis fat depot. Cardiac and perivascular
adipose tissuemay act as local energy sup-plier and/or as a buffer against toxic levelsof free fatty acids in the myocardium andin the arterial circulation (24). The vaso-crine action on nutritive tissue flow hasbeen involved in modulating substratefluxes to organs. Adiponectin and adipo-cyte-derived relaxing factors are releasedby perivascular fat to decrease contractileresponses to vasoconstrictive agents, thusexerting a protective antihypertensivefunction via the control of endothelium-dependent (modulation of the nitric oxide-to-endothelin-1 ratio) and independentmechanisms (cell hyperpolarization, andproduction of ROS, hydrogen peroxide)(25,26). Moreover, resident macrophagescan increase the release of the anti-inflammatory cytokine interleukin (IL)-10(27).
Table 1—Continued
Ref. Sampling technique(s)Number of patients(specific features) Evaluation of CAD
Relationship vs.epi- or pericardialor perivascular fat
996 IMT common carotid artery YES nointernal carotid artery YES yes in men
(53) Computerized tomography 311 (coronary segmentsfor plaques and fat volume)
presence of CAD YES yes/yesplaque burden YES
(46) Computerized tomography 171 (suspected CAD) presence of CAD YES yes/yesstenotic plaque (+/2) NOcalcif. vs. mix vs. noncalcif.plaque
NO
(23) Computerized tomography 214 (mixed ethnicity) a) calcif. vs. no plaque NOb) mixed vs. noncalcif. NOa) vs. b) YES yes/yescalcium score YES yes/yesseverity of stenoses YES yes/yes
Studies include patients referred to imaging for known or suspected CAD, with few exceptions given in parentheses. The last column shows whether the relationshipsaremaintained after adjustment for cardiovascular risk factors or (/) alternative indices of adiposity, namely BMI (in amajority of studies) or waist or amount of visceralfat. ACS, acute coronary syndrome; CHD, coronary heart disease; CVD, cardiovascular disease; calcif., calcification; EAT, epicardial adipose tissue; FDG,18F-fluorodeoxyglucose; IMT, intima-media thickness; LAD, left anterior descending coronary artery; n.a., not applicable; n.d., indicates that the confoundingvariables have not beenmeasured, or that they have beenmeasured but not included in amultivariate regressionmodel investigating the target relationship; noncalcif.,noncalcified.
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Obesity, diabetes, and metabolicsyndromeA positive relationship has been establishedbetween the amount of fat surroundingthe heart and vessels and several com-ponents of the metabolic syndrome.Iacobellis and Willens (3) showed asso-ciations with insulin resistance, centraladiposity, and clinical parameters ofcardiovascular risk, including LDL cho-lesterol and blood pressure, togetherwith inverse relationships with adiponec-tin levels. Epicardial and pericoronaryfat volumes gradually increased withthe number of metabolic syndromecomponents (4,28), and pericardial fatshowed a progressive increment fromlean to obese individuals with normalglucose tolerance, to those with impairedglucose tolerance, and those with type 2diabetes (8). Conversely, in overweightchildren, epicardial fat was a good indicatorof visceral fat, but not an independent pre-dictor of themetabolic syndrome (29). Epi-cardial fat thickness was associated withC-reactive protein (30) and with proa-therogenic and proinflammatory adipo-kines (3). However, the FraminghamOffspring study, screening for 15 bio-markers of inflammation and oxidativestress, demonstrated that intrathoracicbut not pericardial fat was independentlyassociated with C-reactive protein andurinary isoprostanes, after adjustmentfor other adiposity indexes (31), andthat visceral adipose tissue was a strongercorrelate of most metabolic risk factors(32). Instead, other authors (33) reportedthat the thickness rather than the volumeof epicardial fat was an independentpredictor of metabolic syndrome andC-reactive protein levels, also whenaccounting for intrathoracic and visceralfat depots.
In brief, most studies show relation-ships between epicardial/perivascularadiposity and metabolic and inflam-matory markers, though some suggestthat these correlations may be at leastpartly mediated by the confounding as-sociation existing between extra- andintrapericardial and visceral abdominalfat volumes.
Metabolic interventionA 6-month very-low-calorie diet program(3) decreased epicardial fat thickness rel-atively more than other fat depots, andthe observed changes in LV mass and di-astolic function were more strongly cor-related with epicardial fat changes thanwith those of other adiposity indices. A
12-week exercise training program inobese men (34) resulted in a greater per-cent reduction in epicardial fat thicknessthan in waist and BMI, and the changewas independently related with those insystolic blood pressure and insulin sensi-tivity. Conversely, a 24-week study com-paring the effects of pioglitazone andmetformin treatment in type 2 diabeticpatients (35) showed an increase in peri-cardial fat volume in pioglitazone-treatedpatients, in spite of an improvement indiastolic function, leading the authors toquestion the notion of a causal relation-ship between pericardial fat volume andLV dysfunction.
The lack of a contextual measurementof intracardiac triglycerides, which arestrongly correlated with epicardial fatvolume, diastolic dysfunction, and car-diac mass in patients with diabetes orobesity, may limit the mechanistic inter-pretation of these findings.
Does adjacent adipose tissue havea role in cardiac mechanicaldysfunction?We documented that the entire mass(intra- and extrapericardial) of fat sur-rounding the heart ranges on averagefrom 100 g (in healthy lean individuals)to 400 g (in type 2 diabetic patients),extending to values of 800–900 g in somepatients (8). This magnitude may pose anoticeable mechanical burden on cardiacexpansion. It was associated (though notindependently) with cardiac remodellingand mass, peripheral vascular resistance,and lower ejection fraction and cardiacoutput. Pathology and in vivo imagingstudies suggest that during the hypertro-phic process, pericardial fat and cardiacmass increase in parallel. Results of theFramingham study (36) showed that theassociation was not independent of, orstronger than, that of other proxy mea-sures of visceral adiposity. An importantexception was left atrial dimension inmen, extending the previous evidence ofan association between epicardial fatthickness and atria enlargement or im-pairment in diastolic filling in morbidlyobese subjects (3).
Overall, the above studies indicatethat the systemic effects of obesity oncardiac structure and function may out-weigh the local pathogenic effects ofpericardial fat. Conversely, the lattermay directly affect LV diastolic fillingand consequently induce atrial enlarge-ment.
Does adjacent adipose tissue have arole in cardiovascular disease?Table 1 summarizes studies conducted toexplore relationships between cardiacand perivascular fat and CAD. Vascularaging and subclinical atherosclerosis, asrevealed by carotid stiffness and intima-media thickness, were related to epicardialfat thickness better than waist circumfer-ence in hypertensive patients (22). In theMulti-Ethnic Study of Atherosclerosis theassociation with carotid stiffness, but notintima-media thickness persisted after ad-justing for cardiovascular risk factors(37,38). In the Second Manifestations ofARTerial Disease (SMART) study (39),intra-abdominal fat accumulation wasassociated with larger infrarenal aorticdiameters in patients with clinically evidentarterial disease.
Atherosclerotic lesions are absent insegments of coronary arteries lackingpericardial fat, such as intramyocardialbridges, as compared with intraepicardialportions of the main coronary artery inboth humans and animals (5). A host ofnoninvasive imaging studies—with oneexception (40)—have shown that pa-tients with CAD have greater depots ofadipose tissue within the pericardiumand around arteries compared withhealthy individuals. However, the exis-tence of a progressive association relatingthe amount of pericardial fat with the se-verity of atherosclerosis, evaluated asnumber of stenotic vessels and/or degreeof obstruction (23,41–43), total coronaryocclusion (28), stable versus unstable an-gina (30), or prevalent myocardial infarc-tion (44) was reported in some but not inother studies (40,45–47) or was foundonly in selected subgroups (47). A recentreport (48) suggested that pericardial fatis a better predictor of incident CAD thanare more general measures of adiposity,but cardiac adiposity was determined atfollow-up and not at baseline.
The extent of vessel wall or plaquecalcification has been used as an addi-tional index of severity of disease. In sub-jects free from clinical CAD, pericardial fatwas independently associatedwith vascularcalcification (32,49,50), and the relation-ship was consistent between sexes andgroups of different ethnicity (49). Thoracicaortic fat was associated with abdominalaortic and coronary artery calcification(51). In healthy postmenopausal women(52), pericoronary fat thickness was relatedto calcification in respective coronaries.Instead, in patients with CAD the relation-shipwas not progressive (45), orwas found
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only in subjects with normal BMI (47). Assuggested, the presence of mere calcifica-tion could represent an advanced but stablephase of atherosclerosis, and pericardial fatmay be more strongly associated with anactive process as proven by the presenceof noncalcified plaques. This associationwas observed in one retrospective (23),but not in three subsequent studies(43,46,53).
It is important to keep in mind thatthe number of coronary stenoses andsize of plaque/obstruction may not beoptimal predictors of cardiovascularevents or the best guidance for manage-ment, and that the paracrine and vaso-crine nature of the interaction betweenfat and myocardium or arteries is mostlikely mediated by functional ratherthan anatomical outcomes, includingactive inflammation, vascular overtone,and tissue ischemia. The uptake of 18F-fluorodeoxyglucose in the left anteriordescending coronary artery, measuredwith positron emission tomographyas a marker of plaque inflammationand vulnerability, was correlated withCAD, calcified plaque burden, and peri-cardial fat volume (54). The assessmentof coronary flow to identify ischemic re-gions in women complaining of chestpain (55) demonstrated that epicardialfat thickness was the only independentinverse predictor of coronary flowreserve, as opposed to traditional riskfactors for atherosclerosis. Our findingsextend this observation to patients ofboth sexes with and without CAD show-ing that only those with a severe impair-ment in coronary vasodilatation have asignificant increase in intrapericardialfat.
MechanismsEpicardial and perivascular fat depots areimportant mechanical guides of contractingorgans and vessels, and critical regulators ofsubstrate fluxes to subtending organs be-cause they store or release fatty acids withgreat flexibility to fulfill the energy needs ofarterial walls and heart muscle and to avoidlipotoxicity. Their protective vasocrinefunction is likely mediated by adiponectinand unidentified relaxing factors. In meta-bolic and cardiovascular disease states,these fat tissues expand, becoming hypoxicand dysfunctional (25,56) and recruitingphagocytic cells (57). The changes in adi-pocyte size and increase in the infiltrationof macrophages and T cells (57) reducethe production of protective in favor ofdetrimental adipocytokines such as leptin,
resistin, IL-6, tumor necrosis factor-a, orIL-17. These molecules can reach the myo-cardial tissue and vessel walls by directdiffusion or by traveling in adventitial neo-vascularization, and it has been recentlyshown that epicardial adipose tissue canpartially contribute to adiponectin levelsin the coronary circulation (3). Thus, in-flammation may propagate to the underly-ing arterial walls, and alter the balancebetween vascular nitric oxide, endothelin-1,and superoxide production, promotingvasoconstriction (26). Samples of pericardialfat from CAD patients showed increasedmRNA and protein levels of chemokineand inflammatory cytokines relative to sub-cutaneous fat (58), and lower expression ofadiponectin relative to that in patients with-out CAD. Perivascular adipose tissue canstimulate smooth muscle cell proliferationvia release of hydrosoluble protein growthfactor(s) and contribute to the progressionof atherosclerosis (59). Large and inflamedadipocytes display insulin resistance andgreater release of fatty acids, likely over-flowing toward the myocardium, therebyincreasing cardiac work and oxygen con-sumption and alimenting cardiac steato-sis. In fact, pericardial and myocardialadiposities are strongly correlated (8). Inresponse to the reduced vascular densityand hypoxia in obesity, macrophages mayexpress platelet-derived growth factorin adipose tissue to facilitate capillaryformation (56). This process and media-tors may extend to the vessel wall ofarteries adjacent to the adipose depot.Plaque neoangiogenesis is associatedclosely with plaque progression and intra-plaque hemorrhage, and is predominantlythought to arise from the adventitia vasavasorum (60). This complex series ofevents is summarized in Fig. 1B.
CONCLUSIONS—Cardiac adipositywas characterized in the 19th century,including the distinction between surfaceand intracellular fat, its association withobesity and coronary obstruction, and itsdual protective or hazardous roles. Sub-sequently, cardiac damage was thought tobe caused by inflammation; more recentlythis was supplanted by the idea thatcoronary obstruction is the central path-ogenetic mechanism of cardiovasculardisease. Current advancements in technol-ogy and knowledge indicate that adiposity,inflammation, and arterial obstruction aresimultaneously operative in modulatingtissue ischemia and plaque vulnerability.In this interaction, adipose tissue and in-tracellular triglycerides may shift from
being protective to being detrimental, de-pending on their residual substrate buffer-ing capacity and inflammatory status. Themagnitude of adiposity appears as a relativeindex in these complex dynamics, but itsdetermination alone may be insufficientto predict its functional impact on thevulnerability of adjacent tissues. The com-plementary use of molecular/functionalimaging to depict substrate oxidation, ac-tive inflammation, and organ perfusion canaid in this assessment.
Acknowledgments—No potential conflicts ofinterest relevant to this article were reported.
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