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Adiposity of the Heart*, Revisited

Jonathan M. McGavock, PhD; Ronald G. Victor, MD; Roger H. Unger, MD; and Lidia S. Szczepaniak, PhD
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From the University of Texas Southwestern Medical Center, Dallas, Texas.

*The title Adiposity of the Heart, Revisited was borrowed from an article by Smith and Willius that appeared in Archives of Internal Medicine in 1933.

Grant Support: This work was funded by grants from the Donald W. Reynolds Foundation; National Institutes of Health/National Center for Research Resources (USPHS GCRC grant M01-RR00633); National Heart, Lung, and Blood Institute (K-25 award HL-68736); American Diabetes Association (Innovative Methodologies Award #7-04-IN-21); Veterans Affairs Medical Center, Dallas, Texas; National Institute of Diabetes and Digestive and Kidney Diseases; and by a Target Obesity Postdoctoral Fellowship from the Heart and Stroke Foundation of Canada, the Canadian Institutes of Health Research, and the Canadian Diabetes Association.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Lidia Szczepaniak, PhD, Department of Internal Medicine, Division of Hypertension, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8899; e-mail, Lidia.szczepaniak@utsouthwestern.edu.

Current Author Addresses: Drs. McGavock and Szczepaniak: University of Texas Southwestern Medical Center at Dallas, Department of Internal Medicine, Division of Hypertension, 5161 Harry Hines Boulevard, CS8.102, Dallas, TX 75390-8899.

Dr. Victor: University of Texas Southwestern Medical Center at Dallas, Department of Internal Medicine, Division of Hypertension, 5323 Harry Hines Boulevard, J4.134, Dallas, TX 75390-8586.

Dr. Unger: University of Texas Southwestern Medical Center at Dallas, Department of Internal Medicine, Touchstone Center for Diabetes, 5323 Harry Hines Boulevard, Y8.128, Dallas, TX 75390-8854.

Author Contributions: Conception and design: R.G. Victor, R.H. Unger, L.S. Szczepaniak.

Analysis and interpretation of the data: J.M. McGavock, L.S. Szczepaniak.

Drafting of the article: J.M. McGavock, L.S. Szczepaniak.

Critical revision of the article for important intellectual content: J.M. McGavock, R.G. Victor, R.H. Unger, L.S. Szczepaniak.

Final approval of the article: R.G. Victor, R.H. Unger, L.S. Szczepaniak.

Statistical expertise: J.M. McGavock.

Obtaining of funding: J.M. McGavock, R.G. Victor, R.H. Unger, L.S. Szczepaniak.

Collection and assembly of data: L.S. Szczepaniak.

Ann Intern Med. 2006;144(7):517-524. doi:10.7326/0003-4819-144-7-200604040-00011
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Obesity is a major risk factor for heart disease. In the face of obesity's growing prevalence, it is important for physicians to be aware of emerging research of novel mechanisms through which adiposity adversely affects the heart. Conventional wisdom suggests that either hemodynamic (that is, increased cardiac output and hypertension) or metabolic (that is, dyslipidemic) derangements associated with obesity may predispose individuals to coronary artery disease and heart failure. The purpose of this review is to highlight a novel mechanism for heart disease in obesity whereby excessive lipid accumulation within the myocardium is directly cardiotoxic and causes left ventricular remodeling and dilated cardiomyopathy. Studies in animal models of obesity reveal that intracellular accumulation of triglyceride renders organs dysfunctional, which leads to several well-recognized clinical syndromes related to obesity (including type 2 diabetes). In these rodent models, excessive lipid accumulation in the myocardium causes left ventricular hypertrophy and nonischemic, dilated cardiomyopathy. Novel magnetic resonance spectroscopy techniques are now available to quantify intracellular lipid content in the myocardium and various other human tissues, which has made it possible to translate these studies into a clinical setting. By using this technology, we have recently begun to study the role of myocardial steatosis in the development of obesity-specific cardiomyopathy in humans. Recent studies in healthy individuals and patients with heart failure reveal that myocardial lipid content increases with the degree of adiposity and may contribute to the adverse structural and functional cardiac adaptations seen in obese persons. These studies parallel the observations in obese animals and provide evidence that myocardial lipid content may be a biomarker and putative therapeutic target for cardiac disease in obese patients.


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Figure 1.
Concept of lipotoxicity.bottom

Lipotoxicity in humans originates from excessive release of free fatty acids from hypertrophied adipocytes in obese persons. Organ exposure to high levels of free fatty acids causes lipid droplets to accumulate within the cytosol of nonadipose tissues in proximity to mitochondria (white arrows, ). By-products of cytosolic triglyceride accumulation and of lipid metabolism may lead to organ dysfunction and failure.

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Figure 2.
Myocardial lipotoxicity in the Zucker diabetic fatty rat.Top panel.white barslight gray barsdark gray barsBottom panel.

Triglyceride content in the myocardium of Zucker diabetic fatty rats and lean controls at age 7 ( ) and 14 weeks ( ). The myocardial triglyceride accumulation is effectively prevented when thiazolidinedione therapy (troglitazone) is initiated at 7 weeks of age ( ). Functional changes in left ventricular fractional shortening is reduced over time as rats become fat and diabetic, but it is restored by triglyceride-lowering therapy with troglitazone. (Reproduced with permission from Proc Natl Acad Sci U S A. 2000;97:1784-9.)

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Figure 3.
Myocardial-specific lipotoxicity.Top panel.Middle panel.gray barswhite barsBottom panel.

Substantial cardiac hypertrophy in a murine model of myocardial specific triglyceride accumulation, developed by overexpressing a key enzyme involved in triglyceride synthesis, acetyl-CoA synthetase. Transgenic animals displayed substantially higher heart weight ( ) and heart-to-body weight ratio ( ). The hearts of the transgenic mice are characterized by elevated myocardial triglyceride content. Administration of leptin in the transgenic mice attenuates cardiac hypertrophy and normalizes myocardial triglyceride content. (Reproduced with permission from Proc Natl Acad Sci U S A. 2004;101:13624-9.)

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Figure 4.
Magnetic resonance spectroscopy to evaluate skeletal muscle steatosis.leftABboxesmiddleright

High-resolution images ( ) of the calf muscle of a healthy patient ( ) and a patient with lipodystrophy ( ). The image was used to select a testing volume for spectroscopy within skeletal muscle away from adipose fat ( ). In a localized spectroscopy setup, only a signal from the selected volume is collected. Any other signal is destroyed and is not acquired. In these images, fat appears very bright, muscles are gray, and bones are black. Blood flowing into vessels is highlighted, and blood flowing out of vessels is black. The calf of a healthy control has a layer of adipose tissue and white marble fatty spots between muscle fibers. The lipodystrophic patient has no adipose fat present. The magnetic resonance spectrum ( ) from the tested volume contains a strong signal from tissue water and a very intense signal from triglyceride. Enlarged resonance ( ) of triglyceride region in a healthy patient and a patient with lipodystrophy. In the healthy patient, the fat spectrum contains 2 separate resonances: 1 from adipose fat between muscle fibers and 1 from triglyceride droplets within muscle cells. In the patient with lipodystrophy, the fat spectrum resonates exclusively from intramuscular triglyceride.

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Figure 5.
Quantification of triglyceride within the human myocardium with magnetic resonance spectroscopy.leftboxright

In this high-resolution, 4-chamber cardiac magnetic resonance image ( ), heart muscle appears dark gray; blood in myocardial chambers and epicardial and adipose fats are lighter. The volume for testing myocardial tissue ( ) was placed within an intraventricular septum and away from epicardial fat. Magnetic resonance spectrum ( ) with representative myocardial triglyceride resonance at 1.4 ppm. RA = right atria; LA = left atria; RV = right ventricle; LV = left ventricle.

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Figure 6.
Myocardial triglyceride levels correlate positively with body mass index.

In healthy persons without diabetes or hypertension, myocardial triglyceride levels are low and gradually increase as the body mass index increases.

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Submit a Comment/Letter
Posted on April 7, 2006
Gianluca Iacobellis
Cardiovascular Obesity Research and Management at the Michael G deGroote School of Medicine, McMaste
Conflict of Interest: None Declared

Dear Editor, we read with great interest the review "Adiposity of the Heart, revisited" by McGavock and collegueas. The concept of a relationship of myocardial lipid content with generalized adiposity and potentially with cardiac morphology and function in obese subjects is intriguing. We also agree that intramyocardial fat content detected by magnetic resonance spectroscopy could be a target for drugs that interact with the adipose tissue.

Nevertheless, if McGavock et al. reviewed the importance of the adiposity of the heart we would like to point out the the relationship of the adiposity around the heart with visceral adiposity and cardiac structure in humans.

There is now compelling evidence that the epicardial fat tissue, the visceral fat around the heart, is clearly metabolically active and source of various bioactive molecules, as well as adiponectin, inflammatory markers, free fatty acids, that might significantly affect cardiac morphology (2-3). We also previously showed that epicardial fat strongly reflects abdominal visceral adiposity, rather than body mass index, and is associated with metabolic syndrome and impaired insulin sensitivity (4-6). As the epicardial adipose mass reflects intra-abdominal visceral fat, we proposed that echocardiographic assessment of this tissue might serve as a reliable marker of visceral adiposity (4-6). A body of evidences suggests that visceral fat, rather than generalized adiposity, plays an important role in the development of an unfavorable metabolic and cardiovascular risk profile. Echocardiographic assessment of (epicardial) visceral fat would certainly be less expensive than magnetic resonance imaging and an easy diagnostic and therapeutic target.

The presence of excessive epicardial fat adds to the weight of the ventricles and increases the effort involved in pumping blood around the body. Autopsy and echocardiographic findings strongly suggest that an increase in myocardial mass during cardiac hypertrophy is associated with a consensual and proportional increase in epicardial adipose mass (2,7). A number of studies suggest the concept of paracrine interactions between epicardial adipose depots and the myocardium (2). The adipose and muscular component of the heart share the same coronary blood supply and no structures resembling a fascia, as found on skeletal muscle, separate the adipose and myocardial layers in humans (2).Thus, the close anatomical relationship of epicardial adipose tissue to the adjacent myocardium should readily allow local, paracrine, interactions between these tissues. Taken together, these observations suggest that both extra and intra cardiac adiposity could locally modulate the morphology and function of the heart and be easy and reliable biomarkers and therapeutic targets. Future studies in this direction are warranted.


1. McGavock JM, Victor RG, Unger RH, Szczepaniak LS; American College of Physicians and the American Physiological Society. Adiposity of the heart, revisited. Ann Intern Med. 2006;144:517-24 2. Iacobellis G, Corradi D, Sharma AM Epicardial adipose tissue: anatomical, biomolecular and clinical relation to the heart Nat Cardiovasc Clin Pract Med 2005;2:536-43 3. Iacobellis G, Pistilli D , Gucciardo M, Leonetti F, Mirali F, Brancaccio G, Gallo P, di Gioia CR. Adiponectin expression in human epicardial adipose tissue in vivo is lower in patients with coronary artery disease Cytokine. 2005; 29:251-5 4. Iacobellis G, Assael F, Ribaudo MC, Zappaterreno A, Alessi G, Di Mario U, Leonetti F Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction. Obes Res 2003; 11:304"“310 5. Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A, Di Mario U, Leonetti F 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; 88:5163-8. 6. Iacobellis G, Leonetti F. Epicardial adipose tissue and insulin resistance in obese subjects . J Clin Endocrinol Metab. 2005;;90:6300-2 7. Iacobellis G, Ribaudo MC, Zappaterreno A, Iannucci CV, Leonetti F Relation between epicardial adipose tissue and left ventricular mass. Am J Cardiol. 2004; 94:1084-7.

Corresponding author: Gianluca Iacobellis MD PhD Cardiovascular Obesity Research & Management McMaster University Hamilton General Hospital 237 Barton Street East Hamilton, ON, L8L 2X2 Tel> +1-905-527-4322 Ext. 44301 Fax> +1-905-522-4538 Email gianluca@cardio.on.ca

Conflict of Interest:

None declared

Adiposity of the Heart, Revisited
Posted on April 10, 2006
Michael J. Zema
Chief of Cardiology, BMHMC Patchogue NY Clin Prof Medicine, SUNY
Conflict of Interest: None Declared

To the Editor:

The recent review paper by McGavock et.al. (1) probably incorrectly states on p.19, paragraph four, lines one and four that ""¦ overexpression of long chain acyl-CoA synthetase, an enzyme involved in triglyceride synthesis produces an example of cardiac-restricted steatosis." Long chain Acyl-CoA synthetase is an initial enzyme involved with fatty acid beta- oxidation which after subsequent dehydrogenase and hydrolase reactions results in formation of acetyl CoA which upon formation usually enters the Krebs (citric acid) cycle for intracellular energy production. Alternatively of course, these two carbon fragments may be resynthesized back up to fatty acids such as palmitate although the controlling intracellular signaling factors usually do not favor beta-oxidation and fatty acid resynthesis concomitantly.

The correct enzyme to which the authors should probably be referring and which is appropriately referenced in their Figure 3 Legend is the short chain 2 carbon substrate avid enzyme acetyl-CoA synthetase which synthesizes acetyl CoA from acetate and CoA, utilizing high energy phosphate in the form of ATP and requiring magnesium as cofactor. In the presence of citrate and isocitrate formed by the Krebs cycle in the setting of adequate amounts of acetyl CoA, the rate limiting enzyme in fatty acid synthesis, acetyl CoA carboxylase, transforming excess acetyl CoA to malonyl CoA is activated via a process of polymerization of the enzyme subunits. Through a subsequent series of enzymatic reactions including synthetase, reductase , dehydrase and deacylase steps, production of fatty acids, the building blocks of triglycerides is underway leading in this case to their overproduction and cardiac steatosis.

References: 1. McGavock JM, Victor RG, Unger RH, Szczepaniak LS. Adiposity of the Heart, Revisited. Ann Intern Med. 2006;144 (7):517-24.

Conflict of Interest:

None declared

The History of Fatty Heart
Posted on April 12, 2006
Bruce R. Leslie
No Affiliation
Conflict of Interest: None Declared

To The Editor: Readers of the article by McGavock, et al. (1) may be interested to know that the renowned American physician Austin Flint was among the first to describe fatty heart, nearly 150 years ago. In his textbook on diseases of the heart, Flint wrote: "Morbid growth or hypertrophy of the adipose tissue...is often associated with that tendency to superabundance of fat which constitutes obesity. This tendency is directed towards the heart, after middle life, in persons of indolent and luxurious habits...." (2). Flint's observations were made during his tenure as visiting attending physician at New Orleans' Charity Hospital, where he also described the heart murmur that bears his name.

1. McGavock JM, Victor RG, Unger RH, Szczepaniak LS. Adiposity of the heart, revisited. Ann Intern Med. 2006;144 (7):517-24.

2. Flint A. A practical treatise on the diagnosis, pathology, and treatment of diseases of the heart. Philadelphia: Blanchard and Lea; 1859. p. 93.

Conflict of Interest:

None declared

Letter to Editor regarding the article "Adiposity of the heart", Revisited
Posted on April 17, 2006
Balavenkatesh Kanna
Lincoln Hospital, Affiliated to Weill Medical College of Cornell University
Conflict of Interest: None Declared

In reference to the review by McGavock et al (1) on adiposity of the heart, it is of great interest to note that emerging scientific evidence shows myocardial lipid content may be a biomarker of cardiac disease in obese patients. In our study on signal averaged electrocardiogram (SAECG) in obesity (2), we found that abnormal cardiac late potentials occur among obese individuals without clinical cardiac disease symptoms independent of their hypertension or diabetes status. However, hypertension was associated with an increase in abnormalities on SAECG in both obese and non-obese subjects in our study. We believe that our findings of enhanced arrhythmogenecity of the ventricular myocardium as reflected by abnormal cardiac late potentials in obesity without cardiac disease could be corroborated with the findings of increased intra-myocardial lipid content demonstrated on magnetic resonance spectroscopic studies among obese individuals. (3)


1. McGavock J, Victor RU, Roger H, Szczepaniak, LS. Adiposity of the Heart, Revisited. Annals of Int Med. 2006. 144(7):517-524.

2. Lalani AP, Kanna B, John J, Ferrick KJ, Huber MS, Shapiro LE. Abnormal signal-averaged electrocardiogram (SAECG) in obesity. Obes Res. 2000; 8: 20"“28.

3. Szczepaniak LS, Dobbins RL, Metzger GJ, Sartoni-D'Ambrosia G, Arbique D, Vongpatanasin W, et al. Myocardial triglycerides and systolic function in humans: in vivo evaluation by localized proton spectroscopy and cardiac imaging. Magn Reson Med. 2003; 49:417-23.

Conflict of Interest:

None declared

Re: In Response
Posted on August 10, 2006
Lidia S Szczepaniak
University of Texas, Southwestern Medical Center at Dallas, Texas
Conflict of Interest: None Declared

We are gratified by letters regarding our review and we thank for interesting indications for future studies.

Dr. Kanna's suggestion of a relationship between lipid overload of cardiomyocytes and abnormal cardiac late potentials may provide a valuable new dimension in evaluation of the obese heart. It will be of interest to learn if measures that reverse the cardiac steatosis overturn the abnormal late potentials. The role of elevated free fatty acids in the development of cardiac arrhythmias has been explored by others (1,2,3) and may be a primary cause of abnormal late potentials in individuals with type 2 diabetes or metabolic syndrome.

Dr. Leslie points out that Austin Flint described fatty heart disease 150 years ago; however he was not the first. The history of fatty heart dates back to seventeen's century. Sir William Harvey described "cor adiposum" in his 1628 treatise. In 1812 Baron de Corvisart, the physician of Napoleon I, described "fatty degeneration" of the heart, which sounds suspiciously like lipotoxicity. It was also mentioned by Laennec in 1838. The enthusiasm and interest in fatty heart investigations significantly lessened in 1931 when Paul Dudley White, the dean of American College of Cardiology, expressed doubt concerning the existence of fatty heart as a clinical entity. We have not included these references and the one Dr. Leslie cites, as we reviewed the current literature.

Dr. Zema writes that our statement that acyl CoA synthetase produces cardiac steatosis is "incorrect". We respectfully disagree with Dr. Zema, and we suspect that he must be unaware of the elegant studies conducted by Jean Schaffer's group in which overexpression of acyl CoA synthetase (ACS) in cardiomyocytes produced dramatic myocardial steatosis and lipotoxic cardiomyopathy. We recognize that ACS is not the major enzyme responsible for triglyceride synthesis, but rather catalyzes the initial step in fatty acid metabolism within the myocardium, by converting free fatty acids to long chain acyl CoA esters. Under normal conditions, fatty acids uptake and oxidation is tightly coupled, however under certain circumstances (including obesity and transgenic manipulation), excessive flux through this enzyme can lead to intracellular triglyceride accumulation. At first fatty acids are esterified to triacylglycerol, but ultimately they enter the ceramide and other cytotoxic pathways. Fatty acid synthesis inside the cardiomyocytes may also contribute to the fatty acid overload, but in human's obesity most of the surplus is derived directly from ingested fat (chylomicrons) or fat synthesized in the liver and delivered to cardiomyocytes as VLDL.

Dr. Iacobellis makes an extremely important point concerning the relationships between epicardial fat and cardiomyocytes. As he points out, there may indeed be both a metabolic and a paracrine hormonal interplay between these tissues that could account for the consequences of obesity on the heart. It will be of interest to learn if there are vascular connections between the epicardial fat tissue and the myocardium.

1. Manzella D et al. (2002) Elevated post-prandial free fatty acids are associated with cardiac sympathetic overactivity in type II diabetic patients. Diabetologia 45: 1737"“1738

2. Manzella D et al. (2001) Role of free fatty acids on cardiac autonomic nervous system in noninsulin-dependent diabetic patients: effects of metabolic control. J Clin Endocrinol Metab 86: 2769"“2774

3. Paolisso G et al. (1997) Association of fasting plasma free fatty acid concentration and frequency of ventricular premature complexes in nonischemic non-insulin-dependent diabetic patients. Am J Cardiol 80: 932"“937

Conflict of Interest:

None declared

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