- Email: [email protected]
Epicardial Steatosis, Insulin Resistance, and Coronary Artery Disease
Epicardial St eat o s is , Ins u lin R e s i s t a n c e , a n d C o ro n a r y Artery Disease Peter P. Toth, MD, PhD, FNLA, FCCPa,b,* KEYWORDS Adipose tissue Coronary artery disease Epicardium Fatty acid Inflammation Insulin resistance Metabolic syndrome
KEY POINTS Insulin resistance is highly correlated with systemic inflammation and alterations in lipid and lipoprotein metabolism that potentiate visceral organ steatosis and failure. Patients with insulin resistance and diabetes mellitus have a dramatic escalation in risk for developing all forms of atherosclerotic disease. Increased ectopic fat deposition is associated with insulin resistance. In the setting of insulin resistance, epicardial fat mass and volume expand significantly. Insulin-resistant epicardial adipose tissue is dysregulated and is an important source of cytokines and interleukins, that appear to augment risk for developing coronary artery disease and increase risk for cardiovascular events. One possible mechanism for this is that insulin-resistant epicardial fat could shower the adventitial aspect of an epicardial coronary artery with toxic lipids, growth factors, and inflammatory cytokines, thereby promoting intravascular inflammation, intimal injury, and atherogenesis. Increased cardiac steatosis also increases risk for reduced coronary flow reserve, endothelial dysfunction, arrhythmogenesis, altered myocardial energy metabolism, and perturbations in contractility.
Insulin resistance (IR) is the accepted primary cause of the metabolic syndrome, a constellation of cardiovascular risk factors that includes abdominal adiposity/obesity, hyperglycemia, elevated blood pressure, and abnormal lipid metabolism (Fig. 1) as manifested by hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C).1 IR is also associated with Heightened systemic inflammation A prooxidative state Hypercoagulability
Endothelial dysfunction Impaired interorgan signaling and functional coordination The metabolic syndrome and IR increase the risk for cardiovascular disease–related morbidity and mortality and incidental type 2 diabetes mellitus (DM) significantly.2 There is a rapidly evolving parallel worldwide epidemic of obesity and DM. In 2011, it was estimated that there were 25.8 million patients with DM in the United States, with an estimated 1.9 million new cases annually (http://www.diabetes.org/diabetes-basics/diabetesstatistics). A staggering 79 million people in the
a
CGH Medical Center, 101 East Miller Road, Sterling, IL 61081, USA; b Department of Family and Community Medicine, University of Illinois School of Medicine, Peoria, IL 61605, USA * CGH Medical Center, 101 East Miller Road, Sterling, IL 61081. E-mail address: [email protected]
Heart Failure Clin 8 (2012) 671–678 http://dx.doi.org/10.1016/j.hfc.2012.06.013 1551-7136/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
heartfailure.theclinics.com
INTRODUCTION
672
Toth
Fig. 1. Metabolic syndrome is a constellation of cardiovascular risk factors that include abdominal adiposity/obesity, hyperglycemia, elevated blood pressure, and abnormal lipid metabolism as manifested by hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C). LDL, low-density lipoprotein.
United States are prediabetic. The World Health Organization estimates a global prevalence of DM of approximately 346 million, with all nations as well as all racial and ethnic groups significantly affected (http://www.who.int/mediacentre/factsheets/ fs312/en). Visceral obesity is inversely correlated with insulin sensitivity.3 Hyperinsulinemia (a surrogate for IR) is highly prevalent in patients with coronary artery disease (CAD).4 Hyperinsulinemia arises in patients with IR as a compensatory response: the pancreas produces more and more insulin in an effort to promote glucose uptake in systemic tissues that are becoming progressively less responsive to insulin. In patients with IR, lipid and lipoprotein metabolism is severely perturbed. Abnormalities in lipid metabolism give rise to steatosis in multiple organs, including the liver, pancreas, skeletal muscle, and heart. Ectopic steatosis is associated with elevated levels of
free fatty acid (FFAs), increased intracellular toxic lipid accumulation and metabolic stress (ie, lipotoxicity), as well as organ dysfunction and failure.5,6 The pathophysiologic impact of steatosis in the liver, pancreas, and skeletal muscle in patients with IR has been recognized for some time. Evidence is rapidly accumulating to show that epicardial steatosis and expansion of coronary fat pad volume are highly deleterious and associated with increased risk for CAD. Epicardial adipocytes can become insulin resistant and appear to potentiate atherosclerotic disease by continually exposing coronary arteries to increased levels of lipids and inflammatory mediators. This article explores these associations from both biochemical and structural standpoints. Although increased epicardial adiposity is often accompanied by increased intramyocellular lipid deposition, this article focuses solely on changes in epicardial adiposity.
Epicardial Steatosis, Insulin Resistance and CAD INSULIN RESISTANCE IR has a complex molecular etiology and is still inadequately understood. In the setting of IR, tissues become progressively less sensitive to the effects of insulin. Under normal circumstances, the binding of insulin to its cell-surface receptor initiates an intracellular signaling cascade that begins with the phosphorylation of tyrosine residues in insulin receptor substrates (IRS)-1 and -2. This in turn activates a series of phosphoinositide3-kinase–dependent reactions, which promote the nuclear expression of glucose transport (GLUT) proteins that are translocated to the cell surface to promote the uptake of glucose from the extracellular milieu.7 In patients with IR, visceral adipose tissue becomes dysregulated. Visceral adipocytes (as found in omentum, perimesenteric fat, and perinephric fat) under normal conditions are highly regulated and hydrolyze triglycerides to FFAs and glycerol in response to systemic energy/substrate demands. Insulin serves to inhibit the activity of hormone-sensitive lipase, the enzyme that hydrolyzes triglycerides stored within adipocytes. In insulin-resistant adipocytes, hormonesensitive lipase remains active and continually allows for the flooding of the portal and systemic circulation with FFAs. As cells take up fatty acid and intracellular FFA levels increase, cells become insulin resistant. The cell undergoes a transition from tyrosine to serine phosphorylation of IRS-1, which alters its ability to initiate the insulin signaling cascade. This process is compounded by the accumulation of toxic intracellular acyl-coenzyme As and diacylglycerol. These changes result in reduced phosphoinositide-3-kinase activity and impaired GLUT expression and translocation.8 Adipose tissue is metabolically highly active, and has both endocrine and paracrine signaling capacity. Under normal circumstances adipocytes produce adiponectin, a molecule that sensitizes tissues to the effects of insulin; serum levels of this hormone are inversely correlated with the degree of adiposity.9 Adipocytes also produce leptin, a hormone that acts on the arcuate nucleus of the hypothalamus to suppress appetite.10 As adipose tissue volume expands, several changes occur: Adiponectin expression decreases Leptin increases because patients become leptin resistant with reduced capacity for appetite suppression The expression of resistin (an adipocytederived hormone that promotes IR) increases 11 Inflammatory mediator expression increases (“adipokines,” including tumor necrosis
factor a [TNF-a], transforming growth factor b, interleukin-1 and interleukin-6, plasminogen activator inhibitor 1, and monocyte chemoattractant protein 1 [MCP-1], among others)12 The expression of inflammatory mediators creates a vicious cycle as these molecules potentiate a worsening of IR. The MCP-1 promotes the influx of monocytes into adipose tissue, the liver, and other organs. Monocytes convert to macrophages, which become activated by FFAs and other chemokines.6 Activated macrophages secrete more inflammatory mediators, and the cycle is propagated and intensified. Adipose tissue that is insulin resistant can thus become an important source of FFAs and a wide variety of inflammatory mediators. Weight loss and increased aerobic activity have been consistently shown to decrease IR,13,14 reduce hyperglycemia and the severity of dyslipidemia, and regress epicardial steatosis.15,16 IR augments cardiovascular risk in numerous other ways. A heralding sign of IR is atherogenic dyslipidemia. In an effort to cope with the massive influx of fatty acid, the liver reassimilates at least some of this fatty acid into triglyceride, which is packaged into very low-density lipoproteins (VLDL) and secreted into the systemic circulation. Because IR is associated with inhibition of lipoprotein lipase, the triglycerides in VLDL particles are not hydrolyzed at a normal rate, and patients become hypertriglyceridemic with impaired clearance of VLDL. As serum triglyceride levels increase, activity of cholesterol ester transfer protein increases and there is increased transfer of triglyceride into HDL and low-density lipoprotein (LDL) particles. This process leads to increased catabolism and clearance of HDL particles and the formation of large numbers of small, dense LDL particles. HDL levels decrease further because of reduced hepatic and adipose tissue biosynthesis of this lipoprotein and decreased release of surface-coat constituents from chylomicrons that can be used to assimilate HDL in serum.17–19 IR potentiates hyperglycemia secondary to reduced peripheral tissue uptake as well as increased hepatic gluconeogenesis and glycogenolysis. IR also promotes the activation of receptors of advanced glycosylated end products (RAGE). The activation of RAGE is proinflammatory and has been shown to accelerate atherogenesis.20 Hypertension is caused by endothelial dysfunction, increased central sympathetic outflow of catecholamines, increased production of angiotensin II and vascular expression of the AT1 receptor, increased sodium reabsorption
673
674
Toth and expansion of intravascular volume, and structural alterations within arterial walls making them less distensible and compliant, among other changes.21
EPICARDIAL ADIPOSE TISSUE Epicardial adipose tissue comprises the fat in between myocardium and the visceral layer of pericardium, and is distinct from pericardial fat, which localizes between the visceral and parietal pericardium.22 Epicardial fat directly overlies myocardium without a fascial boundary, and is a type of visceral fat that can develop IR. Many articles in the literature refer to the terms epicardial and pericardial interchangeably. The epicardium and myocardium are perfused by the same microcirculation.22 The epicardial coronary vessels are cushioned along a layer of epicardial fat. Epicardial fat is derived embryologically from brown fat, and several functions have been attributed to it23,24: 1. Acts as a readily available source of oxidizable substrate 2. Acts as a buffer against high circulating levels of FFAs by sequestering them, storing them as triglyceride, and reducing toxic exposure 3. Protects the coronary vessels against torsional injury during cardiac contraction and during propagation of the arterial pulse wave 4. Allows for positive remodeling (ectatic expansion in the Glagovian25 sense) in areas with atherosclerotic lesions/plaque, because adipose tissue is more compliant than adjacent myocardium 5. Houses and protects the intracardiac nervous system (ganglia and ganglionated plexuses) Several imaging techniques are used to quantitate epicardial fat mass and volume, including echocardiography, computed tomography (CT), and magnetic resonance imaging (MRI).
CORRELATION OF EPICARDIAL FAT WITH IR The use of multidetector CT imaging has provided important new information about the relationship of epicardial fat to IR and CAD. Epicardial fat thickness in the atrioventricular groove correlates directly with elevations in blood pressure, hyperglycemia, dyslipidemia, and serum levels of both resistin and high-sensitivity C-reactive protein (hsCRP).26 Moreover, these investigators showed that as the burden of metabolic syndrome components increased, so did the epicardial fat volume (EFV). Greif and colleagues27 demonstrated that EFV correlated with low serum levels of adiponectin and HDL-C and increased levels of TNF-a and hsCRP.
In addition to correlations with low HDL-C and hyperglycemia, EFV also shows good correlation with visceral adiposity and waist circumference.28 Among postmenopausal women, EFV correlates directly with weight, waist circumference, body mass index (BMI), triglycerides, glucose, systolic blood pressure, and use of antihypertensive drugs, and inversely with HDL-C.29 In the Framingham Heart Study, epicardial fat correlated with low HDL-C, hypertriglyceridemia, hypertension, impaired fasting glucose, DM, and metabolic syndrome after multivariate adjustment.30 The Framingham investigators further demonstrated that increased epicardial fat is negatively correlated with serum adiponectin and positively correlated with resistin in both men and women.31 As shown by echocardiography, epicardial fat thickness correlated with waist circumference, diastolic blood pressure, LDL-C, glucose, adiponectin, HDL-C, and fasting insulin levels.32 Among type I diabetic women with central adiposity, the presence of metabolic syndrome is associated with increased EFV.33 In prepubertal children, increasing thickness of epicardial fat is associated with BMI, insulin levels, and homeostatic model assessment IR.34 There is remarkable consistency in the literature showing that defining components of the metabolic syndrome and heightened systemic inflammatory tone correlate with an increasing burden of epicardial fat deposition.
CORRELATION OF EPICARDIAL FAT WITH CAD It is well established that IR, dyslipidemia, hypertension, hyperglycemia, and inflammation are highly associated with the development of atherosclerotic disease, particularly CAD (Fig. 2). Consistent with this is the observation that EFV correlates strongly with coronary calcium burden and coronary atherosclerotic plaques. The Framingham investigators showed that EFV was associated with coronary artery calcification even after adjusting for Framingham risk factors and visceral adiposity (odds ratio 1.21 per 1 standard deviation increase in EFV).30 In a study by Sarin and colleagues,35 coronary artery calcium scores tripled once EFV exceeded 100 mL, and more patients with elevated EFV had evidence of nonobstructive or obstructive plaques (46% vs 31%, P<.05). EFV correlates with the number of diseased coronary segments, the number of atherosclerotic plaques, and the risk of having noncalcified, calcified, or a mixture of both types of plaque.27 These investigators also demonstrated that an EFV that exceeds 300 mL is the strongest independent risk factor for CAD (odds ratio 4.1, P<.05), with the Framingham risk score, smoking, hypertension, and
Epicardial Steatosis, Insulin Resistance and CAD
Fig. 2. Several factors are highly associated with the development of atherosclerotic disease, particularly coronary artery disease.
diabetes all having lower odds ratios of 2.8, 1.6, 1.8, and 3.0, respectively. Other groups have similarly shown that EFV correlates with coronary calcium burden28 and has a graded relationship with the presence of CAD in women29 as well as patients with BMI of less than 27 kg/m2.36 Among patients with DM, EFV was significantly greater than in nondiabetic patients, and correlated highly and in a graded fashion with coronary calcium score and presence of atherosclerotic plaques that were greater than 50% obstructive.37 A particularly interesting study of 567 patients with CAD assessing epicardial fat burden with echocardiography showed the following: (1) epicardial fat was thicker in patients with CAD compared with those without CAD (4.0 mm vs 1.5 mm, P<.001); (2) patients with unstable angina had thicker epicardial fat than patients with atypical or stable angina; and (3) an epicardial fat thickness that exceeded 3.0 mm was an independent risk factor for CAD, with an odds ratio of 3.36 (P<.001).38 In black patients enrolled in the Jackson Heart Study, increased EFV was significantly associated with coronary artery calcium (odds ratio 1.34, P<.004).39 Carotid intima-media thickness (CIMT) is generally regarded as a validated surrogate for coronary atherosclerosis.40 In patients with metabolic syndrome infected with the human immunodeficiency virus and receiving highly active antiretroviral
therapy, there is a linear relationship between epicardial fat thickness and CIMT.41
METABOLIC ALTERATIONS IN THE EPICARDIAL FAT OF PATIENTS WITH IR IR drives epicardial fat expansion. The metabolism of epicardial fat in patients with metabolic syndrome and IR is active, dysregulated, and abnormal. It is postulated that arterial walls that are showered by lipids and inflammatory mediators undergo recurrent biochemical and histologic injury and are subjected to accelerated atherogenesis.42,43 Evidence is accruing that epicardial fat in insulin-resistant patients is in fact metabolically abnormal. In the setting of IR and CAD, epicardial fat decreases adiponectin production and increases the biosynthesis of TNF-a and leptin.44 Fatty acid–binding proteins bind to, and help to solubilize and traffic, long-chain fatty acids within cells. The epicardial adipose tissue of patients with metabolic syndrome massively increases the expression of fatty acid binding protein 4 compared with subjects without metabolic syndrome, which likely reflects a large increase in the need to store and mobilize fatty acids within the epicardium.45 In patients undergoing cardiac surgery, epicardial adipose tissue has the capacity to increase the production of fibroblast growth factor 2146 as well as resistin, interleukin-6, and MCP-1.47
675
676
Toth These data clearly support the hypothesis that epicardial adipose tissue can serve as a source of growth factors and inflammatory mediators.
OTHER CARDIAC ABNORMALITIES ASSOCIATED WITH INCREASED EPICARDIAL ADIPOSITY Several other manifestations of cardiac disease are associated with increased epicardial adiposity. Among women with chest pain and angiographically normal coronary arteries, increased epicardial fat thickness is associated with reduced coronary flow reserve.48 Traditional Framingham risk factors in this study were not predictive of microvascular dysfunction. An epicardial fat thickness greater than 0.45 cm had 85% sensitivity and 75% specificity in detecting a coronary flow reserve of less than 2 (P<.0001). Consistent with this finding is the observation that there is a negative linear relationship between epicardial fat thickness and flow-mediated dilatation at the brachial artery, suggesting that endothelial dysfunction worsens as epicardial fat thickness increases.49 In patients with metabolic syndrome, hepatic steatosis, and increased epicardial adiposity, the myocardial phosphorylation potential (a measure of how efficiently adenosine triphosphate can be regenerated by mitochondrial oxidative phosphorylation to meet intramyocellular energy demands) is markedly reduced, despite normal left ventricular morphology as well as normal systolic and diastolic function.50 Epicardial fat mass is associated with decreased left ventricular circumferential shortening and reduced regional systolic function51 and, as it expands and increases in mass, increases the workload of cardiac pumping activity.23 Patients with metabolic syndrome and increased epicardial fat thickness have blunted recovery of heart rate after a maximal graded exercise stress test.52 Of interest, epicardial fat thickness of 5.5 mm or more correlates with blunting of heart-rate recovery with 84% sensitivity and 52% specificity. Finally, increased epicardial fat has been proposed to increase predisposition to atrial arrhythmias.53 Increased epicardial fat is associated with increased fatty infiltration of the left atrium and pulmonary vein. Lin and colleagues53 suggest that the combination of these 2 fatty infiltrative phenomena is associated with an increase in ectopic foci, automaticity, triggered activity, and electrical and structural remodeling.
SUMMARY IR increases visceral organ steatosis caused by abnormalities in lipid trafficking and metabolism.
Expansion of epicardial fat thickness, volume, and mass are associated with all components of the metabolic syndrome. Epicardial fat can become insulin resistant and a potent source of lipids, adipokines that regulate insulin sensitivity, inflammatory mediators, and growth factors. Increased epicardial adiposity is associated with coronary atherosclerosis, endothelial dysfunction, reduced coronary flow reserve, impaired intramyocellular energy metabolism, and other cardiac abnormalities. Epicardial adiposity is a clinically significant structural and functional adverse sequela of IR. Epicardial adiposity constitutes an important focus of continued research, and may emerge as a target of therapy in patients with metabolic syndrome and/or DM.
REFERENCES 1. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001;285(19):2486–97. 2. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002; 288(21):2709–16. 3. Fujimoto WY, Abbate SL, Kahn SE, et al. The visceral adiposity syndrome in Japanese-American men. Obes Res 1994;2(4):364–71. 4. Lamarche B, Tchernof A, Mauriege P, et al. Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA 1998;279(24):1955–61. 5. Oresic M. Systems biology strategy to study lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 2010;1801(3):235–9. 6. Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the metabolic syndrome—an allostatic perspective. Biochim Biophys Acta 2010; 1801(3):338–49. 7. Leto D, Saltiel AR. Regulation of glucose transport by insulin: traffic control of GLUT4. Nat Rev Mol Cell Biol 2012;13(6):383–96. 8. Erion DM, Shulman GI. Diacylglycerol-mediated insulin resistance. Nat Med 2010;16(4):400–2. 9. Ukkola O, Santaniemi M. Adiponectin: a link between excess adiposity and associated comorbidities? J Mol Med (Berl) 2002;80(11): 696–702. 10. Myers MG, Cowley MA, Munzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 2008;70:537–56. 11. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature 2001; 409(6818):307–12.
Epicardial Steatosis, Insulin Resistance and CAD 12. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006;444(7121):840–6. 13. Franssila-Kallunki A, Rissanen A, Ekstrand A, et al. Effects of weight loss on substrate oxidation, energy expenditure, and insulin sensitivity in obese individuals. Am J Clin Nutr 1992;55(2):356–61. 14. DeFronzo RA, Sherwin RS, Kraemer N. Effect of physical training on insulin action in obesity. Diabetes 1987;36(12):1379–85. 15. Kim MK, Tomita T, Kim MJ, et al. Aerobic exercise training reduces epicardial fat in obese men. J Appl Physiol 2009;106(1):5–11. 16. Bosy-Westphal A, Kossel E, Goele K, et al. Association of pericardial fat with liver fat and insulin sensitivity after diet-induced weight loss in overweight women. Obesity (Silver Spring) 2010; 18(11):2111–7. 17. Zhang Y, McGillicuddy FC, Hinkle CC, et al. Adipocyte modulation of high-density lipoprotein cholesterol. Circulation 2010;121(11):1347–55. 18. Toth PP. Reverse cholesterol transport: high-density lipoprotein’s magnificent mile. Curr Atheroscler Rep 2003;5(5):386–93. 19. Toth PP. Adiponectin and high-density lipoprotein: a metabolic association through thick and thin. Eur Heart J 2005;26(16):1579–81. 20. Naka Y, Bucciarelli LG, Wendt T, et al. RAGE axis: animal models and novel insights into the vascular complications of diabetes. Arterioscler Thromb Vasc Biol 2004;24(8):1342–9. 21. Toth PP. Pleiotropic effects of angiotensin receptor blockers: addressing comorbidities by optimizing hypertension therapy. J Clin Hypertens (Greenwich) 2011;13(1):42–51. 22. Iacobellis G. Epicardial and pericardial fat: close, but very different. Obesity (Silver Spring) 2009; 17(4):625 [author reply: 626–27]. 23. Iacobellis G, Sharma AM. Epicardial adipose tissue as new cardio-metabolic risk marker and potential therapeutic target in the metabolic syndrome. Curr Pharm Des 2007;13(21):2180–4. 24. Rabkin SW. Epicardial fat: properties, function and relationship to obesity. Obes Rev 2007;8(3): 253–61. 25. Glagov S, Bassiouny HS, Giddens DP, et al. Pathobiology of plaque modeling and complication. Surg Clin North Am 1995;75(4):545–56. 26. Wang TD, Lee WJ, Shih FY, et al. Relations of epicardial adipose tissue measured by multidetector computed tomography to components of the metabolic syndrome are region-specific and independent of anthropometric indexes and intraabdominal visceral fat. J Clin Endocrinol Metab 2009;94(2): 662–9. 27. Greif M, Becker A, von Ziegler F, et al. Pericardial adipose tissue determined by dual source CT is
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
a risk factor for coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2009;29(5):781–6. Dey D, Wong ND, Tamarappoo B, et al. Computeraided non-contrast CT-based quantification of pericardial and thoracic fat and their associations with coronary calcium and metabolic syndrome. Atherosclerosis 2010;209(1):136–41. de Vos AM, Prokop M, Roos CJ, et al. Peri-coronary epicardial adipose tissue is related to cardiovascular risk factors and coronary artery calcification in post-menopausal women. Eur Heart J 2008; 29(6):777–83. Rosito GA, Massaro JM, Hoffmann U, et al. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample: the Framingham Heart Study. Circulation 2008;117(5):605–13. Jain SH, Massaro JM, Hoffmann U, et al. Crosssectional associations between abdominal and thoracic adipose tissue compartments and adiponectin and resistin in the Framingham Heart Study. Diabetes Care 2009;32(5):903–8. Iacobellis G, Ribaudo MC, Assael F, et al. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab 2003;88(11):5163–8. Momesso DP, Bussade I, Epifanio MA, et al. Increased epicardial adipose tissue in type 1 diabetes is associated with central obesity and metabolic syndrome. Diabetes Res Clin Pract 2011;91(1):47–53. Hizli S, Ozdemir O, Abaci A, et al. Relation of subepicardial adipose tissue thickness and clinical and metabolic parameters in obese prepubertal children. Pediatric Diabetes 2010;11(8):556–62. Sarin S, Wenger C, Marwaha A, et al. Clinical significance of epicardial fat measured using cardiac multislice computed tomography. Am J Cardiol 2008;102(6):767–71. Park JS, Ahn SG, Hwang JW, et al. Impact of body mass index on the relationship of epicardial adipose tissue to metabolic syndrome and coronary artery disease in an Asian population. Cardiovasc Diabetol 2010;9:29. Wang CP, Hsu HL, Hung WC, et al. Increased epicardial adipose tissue (EAT) volume in type 2 diabetes mellitus and association with metabolic syndrome and severity of coronary atherosclerosis. Clin Endocrinol 2009;70(6):876–82. Ahn SG, Lim HS, Joe DY, et al. Relationship of epicardial adipose tissue by echocardiography to coronary artery disease. Heart 2008;94(3):e7. Liu J, Fox CS, Hickson D, et al. Pericardial adipose tissue, atherosclerosis, and cardiovascular disease risk factors: the Jackson heart study. Diabetes Care 2010;33(7):1635–9. Crouse JR 3rd, Raichlen JS, Riley WA, et al. Effect of rosuvastatin on progression of carotid intima-media
677
Toth
678
41.
42.
43.
44.
45.
46.
thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 2007; 297(12):1344–53. Iacobellis G, Sharma AM, Pellicelli AM, et al. Epicardial adipose tissue is related to carotid intima-media thickness and visceral adiposity in HIV-infected patients with highly active antiretroviral therapyassociated metabolic syndrome. Curr HIV Res 2007;5(2):275–9. Shimabukuro M. Cardiac adiposity and global cardiometabolic risk: new concept and clinical implication. Circ J 2009;73(1):27–34. Iacobellis G, Willens HJ. Echocardiographic epicardial fat: a review of research and clinical applications. J Am Soc Echocardiogr 2009;22(12):1311–9 [quiz: 1417–8]. Gormez S, Demirkan A, Atalar F, et al. Adipose tissue gene expression of adiponectin, tumor necrosis factor-alpha and leptin in metabolic syndrome patients with coronary artery disease. Intern Med 2011;50(8):805–10. Vural B, Atalar F, Ciftci C, et al. Presence of fattyacid-binding protein 4 expression in human epicardial adipose tissue in metabolic syndrome. Cardiovasc Pathol 2008;17(6):392–8. Kotulak T, Drapalova J, Kopecky P, et al. Increased circulating and epicardial adipose tissue mRNA expression of fibroblast growth factor-21 after cardiac surgery: possible role in postoperative inflammatory response and insulin resistance. Physiol Res 2011; 60(5):757–67.
47. Kremen J, Dolinkova M, Krajickova J, et al. Increased subcutaneous and epicardial adipose tissue production of proinflammatory cytokines in cardiac surgery patients: possible role in postoperative insulin resistance. J Clin Endocrinol Metab 2006; 91(11):4620–7. 48. Sade LE, Eroglu S, Bozbas H, et al. Relation between epicardial fat thickness and coronary flow reserve in women with chest pain and angiographically normal coronary arteries. Atherosclerosis 2009;204(2):580–5. 49. Aydin H, Toprak A, Deyneli O, et al. Epicardial fat tissue thickness correlates with endothelial dysfunction and other cardiovascular risk factors in patients with metabolic syndrome. Metab Syndr Relat Disord 2010;8(3):229–34. 50. Perseghin G, Lattuada G, De Cobelli F, et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology 2008;47(1):51–8. 51. Sironi AM, Pingitore A, Ghione S, et al. Early hypertension is associated with reduced regional cardiac function, insulin resistance, epicardial, and visceral fat. Hypertension 2008;51(2):282–8. 52. Sengul C, Duman D. The association of epicardial fat thickness with blunted heart rate recovery in patients with metabolic syndrome. Tohoku J Exp Med 2011;224(4):257–62. 53. Lin YK, Chen YJ, Chen SA. Potential atrial arrhythmogenicity of adipocytes: implications for the genesis of atrial fibrillation. Med Hypotheses 2010; 74(6):1026–9.
KEY POINTS Insulin resistance is highly correlated with systemic inflammation and alterations in lipid and lipoprotein metabolism that potentiate visceral organ steatosis and failure. Patients with insulin resistance and diabetes mellitus have a dramatic escalation in risk for developing all forms of atherosclerotic disease. Increased ectopic fat deposition is associated with insulin resistance. In the setting of insulin resistance, epicardial fat mass and volume expand significantly. Insulin-resistant epicardial adipose tissue is dysregulated and is an important source of cytokines and interleukins, that appear to augment risk for developing coronary artery disease and increase risk for cardiovascular events. One possible mechanism for this is that insulin-resistant epicardial fat could shower the adventitial aspect of an epicardial coronary artery with toxic lipids, growth factors, and inflammatory cytokines, thereby promoting intravascular inflammation, intimal injury, and atherogenesis. Increased cardiac steatosis also increases risk for reduced coronary flow reserve, endothelial dysfunction, arrhythmogenesis, altered myocardial energy metabolism, and perturbations in contractility.
Insulin resistance (IR) is the accepted primary cause of the metabolic syndrome, a constellation of cardiovascular risk factors that includes abdominal adiposity/obesity, hyperglycemia, elevated blood pressure, and abnormal lipid metabolism (Fig. 1) as manifested by hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C).1 IR is also associated with Heightened systemic inflammation A prooxidative state Hypercoagulability
Endothelial dysfunction Impaired interorgan signaling and functional coordination The metabolic syndrome and IR increase the risk for cardiovascular disease–related morbidity and mortality and incidental type 2 diabetes mellitus (DM) significantly.2 There is a rapidly evolving parallel worldwide epidemic of obesity and DM. In 2011, it was estimated that there were 25.8 million patients with DM in the United States, with an estimated 1.9 million new cases annually (http://www.diabetes.org/diabetes-basics/diabetesstatistics). A staggering 79 million people in the
a
CGH Medical Center, 101 East Miller Road, Sterling, IL 61081, USA; b Department of Family and Community Medicine, University of Illinois School of Medicine, Peoria, IL 61605, USA * CGH Medical Center, 101 East Miller Road, Sterling, IL 61081. E-mail address: [email protected]
Heart Failure Clin 8 (2012) 671–678 http://dx.doi.org/10.1016/j.hfc.2012.06.013 1551-7136/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
heartfailure.theclinics.com
INTRODUCTION
672
Toth
Fig. 1. Metabolic syndrome is a constellation of cardiovascular risk factors that include abdominal adiposity/obesity, hyperglycemia, elevated blood pressure, and abnormal lipid metabolism as manifested by hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C). LDL, low-density lipoprotein.
United States are prediabetic. The World Health Organization estimates a global prevalence of DM of approximately 346 million, with all nations as well as all racial and ethnic groups significantly affected (http://www.who.int/mediacentre/factsheets/ fs312/en). Visceral obesity is inversely correlated with insulin sensitivity.3 Hyperinsulinemia (a surrogate for IR) is highly prevalent in patients with coronary artery disease (CAD).4 Hyperinsulinemia arises in patients with IR as a compensatory response: the pancreas produces more and more insulin in an effort to promote glucose uptake in systemic tissues that are becoming progressively less responsive to insulin. In patients with IR, lipid and lipoprotein metabolism is severely perturbed. Abnormalities in lipid metabolism give rise to steatosis in multiple organs, including the liver, pancreas, skeletal muscle, and heart. Ectopic steatosis is associated with elevated levels of
free fatty acid (FFAs), increased intracellular toxic lipid accumulation and metabolic stress (ie, lipotoxicity), as well as organ dysfunction and failure.5,6 The pathophysiologic impact of steatosis in the liver, pancreas, and skeletal muscle in patients with IR has been recognized for some time. Evidence is rapidly accumulating to show that epicardial steatosis and expansion of coronary fat pad volume are highly deleterious and associated with increased risk for CAD. Epicardial adipocytes can become insulin resistant and appear to potentiate atherosclerotic disease by continually exposing coronary arteries to increased levels of lipids and inflammatory mediators. This article explores these associations from both biochemical and structural standpoints. Although increased epicardial adiposity is often accompanied by increased intramyocellular lipid deposition, this article focuses solely on changes in epicardial adiposity.
Epicardial Steatosis, Insulin Resistance and CAD INSULIN RESISTANCE IR has a complex molecular etiology and is still inadequately understood. In the setting of IR, tissues become progressively less sensitive to the effects of insulin. Under normal circumstances, the binding of insulin to its cell-surface receptor initiates an intracellular signaling cascade that begins with the phosphorylation of tyrosine residues in insulin receptor substrates (IRS)-1 and -2. This in turn activates a series of phosphoinositide3-kinase–dependent reactions, which promote the nuclear expression of glucose transport (GLUT) proteins that are translocated to the cell surface to promote the uptake of glucose from the extracellular milieu.7 In patients with IR, visceral adipose tissue becomes dysregulated. Visceral adipocytes (as found in omentum, perimesenteric fat, and perinephric fat) under normal conditions are highly regulated and hydrolyze triglycerides to FFAs and glycerol in response to systemic energy/substrate demands. Insulin serves to inhibit the activity of hormone-sensitive lipase, the enzyme that hydrolyzes triglycerides stored within adipocytes. In insulin-resistant adipocytes, hormonesensitive lipase remains active and continually allows for the flooding of the portal and systemic circulation with FFAs. As cells take up fatty acid and intracellular FFA levels increase, cells become insulin resistant. The cell undergoes a transition from tyrosine to serine phosphorylation of IRS-1, which alters its ability to initiate the insulin signaling cascade. This process is compounded by the accumulation of toxic intracellular acyl-coenzyme As and diacylglycerol. These changes result in reduced phosphoinositide-3-kinase activity and impaired GLUT expression and translocation.8 Adipose tissue is metabolically highly active, and has both endocrine and paracrine signaling capacity. Under normal circumstances adipocytes produce adiponectin, a molecule that sensitizes tissues to the effects of insulin; serum levels of this hormone are inversely correlated with the degree of adiposity.9 Adipocytes also produce leptin, a hormone that acts on the arcuate nucleus of the hypothalamus to suppress appetite.10 As adipose tissue volume expands, several changes occur: Adiponectin expression decreases Leptin increases because patients become leptin resistant with reduced capacity for appetite suppression The expression of resistin (an adipocytederived hormone that promotes IR) increases 11 Inflammatory mediator expression increases (“adipokines,” including tumor necrosis
factor a [TNF-a], transforming growth factor b, interleukin-1 and interleukin-6, plasminogen activator inhibitor 1, and monocyte chemoattractant protein 1 [MCP-1], among others)12 The expression of inflammatory mediators creates a vicious cycle as these molecules potentiate a worsening of IR. The MCP-1 promotes the influx of monocytes into adipose tissue, the liver, and other organs. Monocytes convert to macrophages, which become activated by FFAs and other chemokines.6 Activated macrophages secrete more inflammatory mediators, and the cycle is propagated and intensified. Adipose tissue that is insulin resistant can thus become an important source of FFAs and a wide variety of inflammatory mediators. Weight loss and increased aerobic activity have been consistently shown to decrease IR,13,14 reduce hyperglycemia and the severity of dyslipidemia, and regress epicardial steatosis.15,16 IR augments cardiovascular risk in numerous other ways. A heralding sign of IR is atherogenic dyslipidemia. In an effort to cope with the massive influx of fatty acid, the liver reassimilates at least some of this fatty acid into triglyceride, which is packaged into very low-density lipoproteins (VLDL) and secreted into the systemic circulation. Because IR is associated with inhibition of lipoprotein lipase, the triglycerides in VLDL particles are not hydrolyzed at a normal rate, and patients become hypertriglyceridemic with impaired clearance of VLDL. As serum triglyceride levels increase, activity of cholesterol ester transfer protein increases and there is increased transfer of triglyceride into HDL and low-density lipoprotein (LDL) particles. This process leads to increased catabolism and clearance of HDL particles and the formation of large numbers of small, dense LDL particles. HDL levels decrease further because of reduced hepatic and adipose tissue biosynthesis of this lipoprotein and decreased release of surface-coat constituents from chylomicrons that can be used to assimilate HDL in serum.17–19 IR potentiates hyperglycemia secondary to reduced peripheral tissue uptake as well as increased hepatic gluconeogenesis and glycogenolysis. IR also promotes the activation of receptors of advanced glycosylated end products (RAGE). The activation of RAGE is proinflammatory and has been shown to accelerate atherogenesis.20 Hypertension is caused by endothelial dysfunction, increased central sympathetic outflow of catecholamines, increased production of angiotensin II and vascular expression of the AT1 receptor, increased sodium reabsorption
673
674
Toth and expansion of intravascular volume, and structural alterations within arterial walls making them less distensible and compliant, among other changes.21
EPICARDIAL ADIPOSE TISSUE Epicardial adipose tissue comprises the fat in between myocardium and the visceral layer of pericardium, and is distinct from pericardial fat, which localizes between the visceral and parietal pericardium.22 Epicardial fat directly overlies myocardium without a fascial boundary, and is a type of visceral fat that can develop IR. Many articles in the literature refer to the terms epicardial and pericardial interchangeably. The epicardium and myocardium are perfused by the same microcirculation.22 The epicardial coronary vessels are cushioned along a layer of epicardial fat. Epicardial fat is derived embryologically from brown fat, and several functions have been attributed to it23,24: 1. Acts as a readily available source of oxidizable substrate 2. Acts as a buffer against high circulating levels of FFAs by sequestering them, storing them as triglyceride, and reducing toxic exposure 3. Protects the coronary vessels against torsional injury during cardiac contraction and during propagation of the arterial pulse wave 4. Allows for positive remodeling (ectatic expansion in the Glagovian25 sense) in areas with atherosclerotic lesions/plaque, because adipose tissue is more compliant than adjacent myocardium 5. Houses and protects the intracardiac nervous system (ganglia and ganglionated plexuses) Several imaging techniques are used to quantitate epicardial fat mass and volume, including echocardiography, computed tomography (CT), and magnetic resonance imaging (MRI).
CORRELATION OF EPICARDIAL FAT WITH IR The use of multidetector CT imaging has provided important new information about the relationship of epicardial fat to IR and CAD. Epicardial fat thickness in the atrioventricular groove correlates directly with elevations in blood pressure, hyperglycemia, dyslipidemia, and serum levels of both resistin and high-sensitivity C-reactive protein (hsCRP).26 Moreover, these investigators showed that as the burden of metabolic syndrome components increased, so did the epicardial fat volume (EFV). Greif and colleagues27 demonstrated that EFV correlated with low serum levels of adiponectin and HDL-C and increased levels of TNF-a and hsCRP.
In addition to correlations with low HDL-C and hyperglycemia, EFV also shows good correlation with visceral adiposity and waist circumference.28 Among postmenopausal women, EFV correlates directly with weight, waist circumference, body mass index (BMI), triglycerides, glucose, systolic blood pressure, and use of antihypertensive drugs, and inversely with HDL-C.29 In the Framingham Heart Study, epicardial fat correlated with low HDL-C, hypertriglyceridemia, hypertension, impaired fasting glucose, DM, and metabolic syndrome after multivariate adjustment.30 The Framingham investigators further demonstrated that increased epicardial fat is negatively correlated with serum adiponectin and positively correlated with resistin in both men and women.31 As shown by echocardiography, epicardial fat thickness correlated with waist circumference, diastolic blood pressure, LDL-C, glucose, adiponectin, HDL-C, and fasting insulin levels.32 Among type I diabetic women with central adiposity, the presence of metabolic syndrome is associated with increased EFV.33 In prepubertal children, increasing thickness of epicardial fat is associated with BMI, insulin levels, and homeostatic model assessment IR.34 There is remarkable consistency in the literature showing that defining components of the metabolic syndrome and heightened systemic inflammatory tone correlate with an increasing burden of epicardial fat deposition.
CORRELATION OF EPICARDIAL FAT WITH CAD It is well established that IR, dyslipidemia, hypertension, hyperglycemia, and inflammation are highly associated with the development of atherosclerotic disease, particularly CAD (Fig. 2). Consistent with this is the observation that EFV correlates strongly with coronary calcium burden and coronary atherosclerotic plaques. The Framingham investigators showed that EFV was associated with coronary artery calcification even after adjusting for Framingham risk factors and visceral adiposity (odds ratio 1.21 per 1 standard deviation increase in EFV).30 In a study by Sarin and colleagues,35 coronary artery calcium scores tripled once EFV exceeded 100 mL, and more patients with elevated EFV had evidence of nonobstructive or obstructive plaques (46% vs 31%, P<.05). EFV correlates with the number of diseased coronary segments, the number of atherosclerotic plaques, and the risk of having noncalcified, calcified, or a mixture of both types of plaque.27 These investigators also demonstrated that an EFV that exceeds 300 mL is the strongest independent risk factor for CAD (odds ratio 4.1, P<.05), with the Framingham risk score, smoking, hypertension, and
Epicardial Steatosis, Insulin Resistance and CAD
Fig. 2. Several factors are highly associated with the development of atherosclerotic disease, particularly coronary artery disease.
diabetes all having lower odds ratios of 2.8, 1.6, 1.8, and 3.0, respectively. Other groups have similarly shown that EFV correlates with coronary calcium burden28 and has a graded relationship with the presence of CAD in women29 as well as patients with BMI of less than 27 kg/m2.36 Among patients with DM, EFV was significantly greater than in nondiabetic patients, and correlated highly and in a graded fashion with coronary calcium score and presence of atherosclerotic plaques that were greater than 50% obstructive.37 A particularly interesting study of 567 patients with CAD assessing epicardial fat burden with echocardiography showed the following: (1) epicardial fat was thicker in patients with CAD compared with those without CAD (4.0 mm vs 1.5 mm, P<.001); (2) patients with unstable angina had thicker epicardial fat than patients with atypical or stable angina; and (3) an epicardial fat thickness that exceeded 3.0 mm was an independent risk factor for CAD, with an odds ratio of 3.36 (P<.001).38 In black patients enrolled in the Jackson Heart Study, increased EFV was significantly associated with coronary artery calcium (odds ratio 1.34, P<.004).39 Carotid intima-media thickness (CIMT) is generally regarded as a validated surrogate for coronary atherosclerosis.40 In patients with metabolic syndrome infected with the human immunodeficiency virus and receiving highly active antiretroviral
therapy, there is a linear relationship between epicardial fat thickness and CIMT.41
METABOLIC ALTERATIONS IN THE EPICARDIAL FAT OF PATIENTS WITH IR IR drives epicardial fat expansion. The metabolism of epicardial fat in patients with metabolic syndrome and IR is active, dysregulated, and abnormal. It is postulated that arterial walls that are showered by lipids and inflammatory mediators undergo recurrent biochemical and histologic injury and are subjected to accelerated atherogenesis.42,43 Evidence is accruing that epicardial fat in insulin-resistant patients is in fact metabolically abnormal. In the setting of IR and CAD, epicardial fat decreases adiponectin production and increases the biosynthesis of TNF-a and leptin.44 Fatty acid–binding proteins bind to, and help to solubilize and traffic, long-chain fatty acids within cells. The epicardial adipose tissue of patients with metabolic syndrome massively increases the expression of fatty acid binding protein 4 compared with subjects without metabolic syndrome, which likely reflects a large increase in the need to store and mobilize fatty acids within the epicardium.45 In patients undergoing cardiac surgery, epicardial adipose tissue has the capacity to increase the production of fibroblast growth factor 2146 as well as resistin, interleukin-6, and MCP-1.47
675
676
Toth These data clearly support the hypothesis that epicardial adipose tissue can serve as a source of growth factors and inflammatory mediators.
OTHER CARDIAC ABNORMALITIES ASSOCIATED WITH INCREASED EPICARDIAL ADIPOSITY Several other manifestations of cardiac disease are associated with increased epicardial adiposity. Among women with chest pain and angiographically normal coronary arteries, increased epicardial fat thickness is associated with reduced coronary flow reserve.48 Traditional Framingham risk factors in this study were not predictive of microvascular dysfunction. An epicardial fat thickness greater than 0.45 cm had 85% sensitivity and 75% specificity in detecting a coronary flow reserve of less than 2 (P<.0001). Consistent with this finding is the observation that there is a negative linear relationship between epicardial fat thickness and flow-mediated dilatation at the brachial artery, suggesting that endothelial dysfunction worsens as epicardial fat thickness increases.49 In patients with metabolic syndrome, hepatic steatosis, and increased epicardial adiposity, the myocardial phosphorylation potential (a measure of how efficiently adenosine triphosphate can be regenerated by mitochondrial oxidative phosphorylation to meet intramyocellular energy demands) is markedly reduced, despite normal left ventricular morphology as well as normal systolic and diastolic function.50 Epicardial fat mass is associated with decreased left ventricular circumferential shortening and reduced regional systolic function51 and, as it expands and increases in mass, increases the workload of cardiac pumping activity.23 Patients with metabolic syndrome and increased epicardial fat thickness have blunted recovery of heart rate after a maximal graded exercise stress test.52 Of interest, epicardial fat thickness of 5.5 mm or more correlates with blunting of heart-rate recovery with 84% sensitivity and 52% specificity. Finally, increased epicardial fat has been proposed to increase predisposition to atrial arrhythmias.53 Increased epicardial fat is associated with increased fatty infiltration of the left atrium and pulmonary vein. Lin and colleagues53 suggest that the combination of these 2 fatty infiltrative phenomena is associated with an increase in ectopic foci, automaticity, triggered activity, and electrical and structural remodeling.
SUMMARY IR increases visceral organ steatosis caused by abnormalities in lipid trafficking and metabolism.
Expansion of epicardial fat thickness, volume, and mass are associated with all components of the metabolic syndrome. Epicardial fat can become insulin resistant and a potent source of lipids, adipokines that regulate insulin sensitivity, inflammatory mediators, and growth factors. Increased epicardial adiposity is associated with coronary atherosclerosis, endothelial dysfunction, reduced coronary flow reserve, impaired intramyocellular energy metabolism, and other cardiac abnormalities. Epicardial adiposity is a clinically significant structural and functional adverse sequela of IR. Epicardial adiposity constitutes an important focus of continued research, and may emerge as a target of therapy in patients with metabolic syndrome and/or DM.
REFERENCES 1. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001;285(19):2486–97. 2. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002; 288(21):2709–16. 3. Fujimoto WY, Abbate SL, Kahn SE, et al. The visceral adiposity syndrome in Japanese-American men. Obes Res 1994;2(4):364–71. 4. Lamarche B, Tchernof A, Mauriege P, et al. Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA 1998;279(24):1955–61. 5. Oresic M. Systems biology strategy to study lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 2010;1801(3):235–9. 6. Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the metabolic syndrome—an allostatic perspective. Biochim Biophys Acta 2010; 1801(3):338–49. 7. Leto D, Saltiel AR. Regulation of glucose transport by insulin: traffic control of GLUT4. Nat Rev Mol Cell Biol 2012;13(6):383–96. 8. Erion DM, Shulman GI. Diacylglycerol-mediated insulin resistance. Nat Med 2010;16(4):400–2. 9. Ukkola O, Santaniemi M. Adiponectin: a link between excess adiposity and associated comorbidities? J Mol Med (Berl) 2002;80(11): 696–702. 10. Myers MG, Cowley MA, Munzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 2008;70:537–56. 11. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature 2001; 409(6818):307–12.
Epicardial Steatosis, Insulin Resistance and CAD 12. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006;444(7121):840–6. 13. Franssila-Kallunki A, Rissanen A, Ekstrand A, et al. Effects of weight loss on substrate oxidation, energy expenditure, and insulin sensitivity in obese individuals. Am J Clin Nutr 1992;55(2):356–61. 14. DeFronzo RA, Sherwin RS, Kraemer N. Effect of physical training on insulin action in obesity. Diabetes 1987;36(12):1379–85. 15. Kim MK, Tomita T, Kim MJ, et al. Aerobic exercise training reduces epicardial fat in obese men. J Appl Physiol 2009;106(1):5–11. 16. Bosy-Westphal A, Kossel E, Goele K, et al. Association of pericardial fat with liver fat and insulin sensitivity after diet-induced weight loss in overweight women. Obesity (Silver Spring) 2010; 18(11):2111–7. 17. Zhang Y, McGillicuddy FC, Hinkle CC, et al. Adipocyte modulation of high-density lipoprotein cholesterol. Circulation 2010;121(11):1347–55. 18. Toth PP. Reverse cholesterol transport: high-density lipoprotein’s magnificent mile. Curr Atheroscler Rep 2003;5(5):386–93. 19. Toth PP. Adiponectin and high-density lipoprotein: a metabolic association through thick and thin. Eur Heart J 2005;26(16):1579–81. 20. Naka Y, Bucciarelli LG, Wendt T, et al. RAGE axis: animal models and novel insights into the vascular complications of diabetes. Arterioscler Thromb Vasc Biol 2004;24(8):1342–9. 21. Toth PP. Pleiotropic effects of angiotensin receptor blockers: addressing comorbidities by optimizing hypertension therapy. J Clin Hypertens (Greenwich) 2011;13(1):42–51. 22. Iacobellis G. Epicardial and pericardial fat: close, but very different. Obesity (Silver Spring) 2009; 17(4):625 [author reply: 626–27]. 23. Iacobellis G, Sharma AM. Epicardial adipose tissue as new cardio-metabolic risk marker and potential therapeutic target in the metabolic syndrome. Curr Pharm Des 2007;13(21):2180–4. 24. Rabkin SW. Epicardial fat: properties, function and relationship to obesity. Obes Rev 2007;8(3): 253–61. 25. Glagov S, Bassiouny HS, Giddens DP, et al. Pathobiology of plaque modeling and complication. Surg Clin North Am 1995;75(4):545–56. 26. Wang TD, Lee WJ, Shih FY, et al. Relations of epicardial adipose tissue measured by multidetector computed tomography to components of the metabolic syndrome are region-specific and independent of anthropometric indexes and intraabdominal visceral fat. J Clin Endocrinol Metab 2009;94(2): 662–9. 27. Greif M, Becker A, von Ziegler F, et al. Pericardial adipose tissue determined by dual source CT is
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
a risk factor for coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2009;29(5):781–6. Dey D, Wong ND, Tamarappoo B, et al. Computeraided non-contrast CT-based quantification of pericardial and thoracic fat and their associations with coronary calcium and metabolic syndrome. Atherosclerosis 2010;209(1):136–41. de Vos AM, Prokop M, Roos CJ, et al. Peri-coronary epicardial adipose tissue is related to cardiovascular risk factors and coronary artery calcification in post-menopausal women. Eur Heart J 2008; 29(6):777–83. Rosito GA, Massaro JM, Hoffmann U, et al. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample: the Framingham Heart Study. Circulation 2008;117(5):605–13. Jain SH, Massaro JM, Hoffmann U, et al. Crosssectional associations between abdominal and thoracic adipose tissue compartments and adiponectin and resistin in the Framingham Heart Study. Diabetes Care 2009;32(5):903–8. Iacobellis G, Ribaudo MC, Assael F, et al. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab 2003;88(11):5163–8. Momesso DP, Bussade I, Epifanio MA, et al. Increased epicardial adipose tissue in type 1 diabetes is associated with central obesity and metabolic syndrome. Diabetes Res Clin Pract 2011;91(1):47–53. Hizli S, Ozdemir O, Abaci A, et al. Relation of subepicardial adipose tissue thickness and clinical and metabolic parameters in obese prepubertal children. Pediatric Diabetes 2010;11(8):556–62. Sarin S, Wenger C, Marwaha A, et al. Clinical significance of epicardial fat measured using cardiac multislice computed tomography. Am J Cardiol 2008;102(6):767–71. Park JS, Ahn SG, Hwang JW, et al. Impact of body mass index on the relationship of epicardial adipose tissue to metabolic syndrome and coronary artery disease in an Asian population. Cardiovasc Diabetol 2010;9:29. Wang CP, Hsu HL, Hung WC, et al. Increased epicardial adipose tissue (EAT) volume in type 2 diabetes mellitus and association with metabolic syndrome and severity of coronary atherosclerosis. Clin Endocrinol 2009;70(6):876–82. Ahn SG, Lim HS, Joe DY, et al. Relationship of epicardial adipose tissue by echocardiography to coronary artery disease. Heart 2008;94(3):e7. Liu J, Fox CS, Hickson D, et al. Pericardial adipose tissue, atherosclerosis, and cardiovascular disease risk factors: the Jackson heart study. Diabetes Care 2010;33(7):1635–9. Crouse JR 3rd, Raichlen JS, Riley WA, et al. Effect of rosuvastatin on progression of carotid intima-media
677
Toth
678
41.
42.
43.
44.
45.
46.
thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 2007; 297(12):1344–53. Iacobellis G, Sharma AM, Pellicelli AM, et al. Epicardial adipose tissue is related to carotid intima-media thickness and visceral adiposity in HIV-infected patients with highly active antiretroviral therapyassociated metabolic syndrome. Curr HIV Res 2007;5(2):275–9. Shimabukuro M. Cardiac adiposity and global cardiometabolic risk: new concept and clinical implication. Circ J 2009;73(1):27–34. Iacobellis G, Willens HJ. Echocardiographic epicardial fat: a review of research and clinical applications. J Am Soc Echocardiogr 2009;22(12):1311–9 [quiz: 1417–8]. Gormez S, Demirkan A, Atalar F, et al. Adipose tissue gene expression of adiponectin, tumor necrosis factor-alpha and leptin in metabolic syndrome patients with coronary artery disease. Intern Med 2011;50(8):805–10. Vural B, Atalar F, Ciftci C, et al. Presence of fattyacid-binding protein 4 expression in human epicardial adipose tissue in metabolic syndrome. Cardiovasc Pathol 2008;17(6):392–8. Kotulak T, Drapalova J, Kopecky P, et al. Increased circulating and epicardial adipose tissue mRNA expression of fibroblast growth factor-21 after cardiac surgery: possible role in postoperative inflammatory response and insulin resistance. Physiol Res 2011; 60(5):757–67.
47. Kremen J, Dolinkova M, Krajickova J, et al. Increased subcutaneous and epicardial adipose tissue production of proinflammatory cytokines in cardiac surgery patients: possible role in postoperative insulin resistance. J Clin Endocrinol Metab 2006; 91(11):4620–7. 48. Sade LE, Eroglu S, Bozbas H, et al. Relation between epicardial fat thickness and coronary flow reserve in women with chest pain and angiographically normal coronary arteries. Atherosclerosis 2009;204(2):580–5. 49. Aydin H, Toprak A, Deyneli O, et al. Epicardial fat tissue thickness correlates with endothelial dysfunction and other cardiovascular risk factors in patients with metabolic syndrome. Metab Syndr Relat Disord 2010;8(3):229–34. 50. Perseghin G, Lattuada G, De Cobelli F, et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology 2008;47(1):51–8. 51. Sironi AM, Pingitore A, Ghione S, et al. Early hypertension is associated with reduced regional cardiac function, insulin resistance, epicardial, and visceral fat. Hypertension 2008;51(2):282–8. 52. Sengul C, Duman D. The association of epicardial fat thickness with blunted heart rate recovery in patients with metabolic syndrome. Tohoku J Exp Med 2011;224(4):257–62. 53. Lin YK, Chen YJ, Chen SA. Potential atrial arrhythmogenicity of adipocytes: implications for the genesis of atrial fibrillation. Med Hypotheses 2010; 74(6):1026–9.