EDITORIAL COMMENT
Virchow's Metamorphosis RevealedTriglycerides in the Heart*
Heinrich Taegtmeyer, MD, DPhil, FACC* and
Romain Harmancey, PhD
Department of Internal Medicine, Division of Cardiology, The University of Texas Medical School at Houston, Houston, Texas
* Reprint requests and correspondence: Dr. Heinrich Taegtmeyer, Department of Internal Medicine, Division of Cardiology, The University of Texas Medical School at Houston, 6431 Fannin, MSB 1.246, Houston, Texas 77030 (Email: Heinrich.Taegtmeyer{at}uth.tmc.edu).
Key Words: cardiac metabolism • triglyceride turnover • insulin resistance
The essence of cardiac metabolism is easy to understand: in the normal human heart, supply and demand of energy-providing substrates is finely balanced to meet the energy needs for contraction by oxidative metabolism of fatty acids and carbohydrates. When it comes to energy, the heart is always on fire, although the relative contribution of different fuels to the fire may differ substantially depending on a number of environmental factors. The concentrations of substrates in the blood, the concentrations of hormones, adipokines and cytokines, oxygen supply, contractile force of the heart, and the metabolic needs of the body are all factors that determine rates of substrate uptake and use by the heart (1). In the end, however, the system takes care of itself by balancing substrate uptake at the level of the sarcolemma and substrate use, mostly at the level of the mitochondria.
It has been known for over one-half of a century that the human heart, with the body at rest and after an overnight fast, oxidizes mostly fatty acids to meet its energy needs for contraction (2). What holds true for the heart in vivo also is evident in the heart ex vivo (3). In a setting of controlled substrate supply, fatty acids suppress glucose oxidation (4) and glucose suppresses fatty acid oxidation (3). In short, there is a highly regulated interplay of substrates, with fatty acids dominating the fuels for respiration.
A further determinant of energy substrate metabolism is the metabolic state of the organism as a whole. A case in point is short-term starvation. Another case in point is insulin-resistant diabetes. Both conditions are characterized by an oversupply of fuels in the bloodstream—starvation mobilizes fatty acids from adipose tissue, whereas insulin-resistant diabetes tissues fail to use fuels efficiently. Heart muscle, like the body as a whole, develops insulin resistance. Although insulin resistance is a marker for poor prognosis in heart diseases, in metabolic terms insulin resistance may actually protect the cardiomyocyte from an oversupply of fuel. Triglyceride accumulation in insulin-resistant muscle must not be confused with fatty atrophy already described in 1858 by Virchow (5) as a "true metamorphosis of the heart muscle cell" and recently redefined in failing human heart muscle of patients undergoing cardiac transplantation (6) and in animal models lacking certain forms of lipases (7,8).
The study by Hammer et al. (9) in this issue of the Journal draws attention to the dynamic nature of triglyceride turnover. The study is the result of exciting new technology using metabolic imaging in the form of proton magnetic resonance spectroscopy (10). The investigators have previously shown that short-term starvation results in myocardial triglyceride accumulation (11). They now show that long-term starvation reverses high triglyceride levels in the hearts of patients with insulin-dependent diabetes. It is not always appreciated that the mammalian heart is capable of taking up triglycerides (12) and also of releasing triglycerides (13). In other words, the heart loves its fatty acids for energy provision, but it also loves to get rid of them when they are present in excess.
A word of caution is in order. Despite evidence for intramyocellular triglyceride accumulation and impaired diastolic function, it is still not proven that this metabolic feature is directly linked to the development of heart failure. If animal studies can be trusted, decreased delivery of fatty acids reverses triglyceride accumulation and contractile dysfunction (14,15). The present study extends these observations to the human heart, where a decreased plasma fatty acid content is associated with a decrease in myocardial triglyceride levels.
However, there is also evidence to support the idea that channeling fatty acids to triacylglycerol synthesis is diverting lipids from toxic metabolic pathways, such as de novo ceramide synthesis, which mediates programmed cell death (16). In skeletal muscle, the intramyocellular triglyceride levels are increased in endurance-trained subjects who show high insulin sensitivity. The "athletes' paradox" has led to the recently reviewed concept proposing that a lower intramyocellular triglyceride turnover, rather than the intramyocellular triglyceride levels per se, is a determinant for impaired insulin sensitivity in muscle from obese people (17).
Despite these limitations, the study is important for 3 reasons. First, it shows the dynamic nature of triglyceride metabolism within the cardiomyocyte. Second, increased triglyceride levels in the heart may be associated with impaired diastolic function, but they are not predicating heart failure (in this point we disagree with the authors' interpretation of their results). Third, there is growing evidence in the biology of aging that caloric restriction improves the life span, even in obese animals placed on caloric restriction (18). So, there is hope for all of us caught up in the "obesity epidemic." We now know one more important aspect of heart metabolism: the dynamic nature of myocardial triglyceride turnover.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Taegtmeyer H. Energy metabolism of the heart: from basic concepts to clinical applications Curr Prob Cardiol 1994;19:57-116.2. Bing RJ, Siegel A, Ungar I, et al. Metabolism of the human heart. II. Studies on fat, ketone and amino acid metabolism. Am J Med 1954;16:504-515.[CrossRef][Web of Science][Medline] 3. Taegtmeyer H, Hems R, Krebs HA. Utilization of energy-providing substrates in the isolated working rat heart Biochem J 1980;186:701-711.[Web of Science][Medline] 4. Randle PJ, Garland PB, Hales CN, et al. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;1:785-789.[Web of Science][Medline] 5. Virchow R. Cellular Pathology as Based Upon Physiological and Pathological HistologyLondon: John Churchill; 1860325. 6. Sharma S, Adrogue JV, Golfman L, et al. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart FASEB J 2004;18:1692-1700.[Abstract/Free Full Text] 7. Augustus AS, Buchanan J, Park TS, et al. Loss of lipoprotein lipase-derived fatty acids leads to increased cardiac glucose metabolism and heart dysfunction J Biol Chem 2006;281:8716-8723.[Abstract/Free Full Text] 8. Haemmerle G, Lass A, Zimmermann R, et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase Science 2006;312:734-737.[Abstract/Free Full Text] 9. Hammer S, Snel M, Lamb HJ, et al. Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases myocardial triglyceride content and improves myocardial function J Am Coll Cardiol 2008;52:1006-1012.[Abstract/Free Full Text] 10. Reingold JS, McGavock JM, Kaka S, et al. Determination of triglyceride in the human myocardium by magnetic resonance spectroscopy: reproducibility and sensitivity of the method Am J Physiol Endocrinol Metab 2005;289:E935-E939.[Abstract/Free Full Text] 11. van der Meer RW, Hammer S, Smit JW, et al. Short-term caloric restriction induces accumulation of myocardial triglycerides and decreases left ventricular diastolic function in healthy subjects Diabetes 2007;56:2849-2853.[CrossRef][Web of Science][Medline] 12. Yagyu H, Chen G, Yokoyama M, et al. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy J Clin Invest 2003;111:419-426.[CrossRef][Web of Science][Medline] 13. Bjorkegren J, Veniant M, Kim SK, et al. Lipoprotein secretion and triglyceride stores in the heart J Biol Chem 2001;276:38511-38517.[Abstract/Free Full Text] 14. Golfman LS, Wilson CR, Sharma S, et al. Activation of PPARgamma enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats Am J Physiol Endocrinol Metab 2005;289:E328-E336.[Abstract/Free Full Text] 15. Yang J, Sambandam N, Han X, et al. CD36 deficiency rescues lipotoxic cardiomyopathy Circ Res 2007;100:1208-1217.[Abstract/Free Full Text] 16. Listenberger LL, Han X, Lewis SE, et al. Triglyceride accumulation protects against fatty acid-induced lipotoxicity Proc Natl Acad Sci U S A 2003;100:3077-3082.[Abstract/Free Full Text] 17. Moro C, Bajpeyi S, Smith SR. Determinants of intramyocellular triglyceride turnover: implications for insulin sensitivity Am J Physiol Endocrinol Metab 2008;294:E203-E213.[Abstract/Free Full Text] 18. Harrison DE, Archer JR, Astle CM. Effects of food restriction on aging: separation of food intake and adiposity Proc Natl Acad Sci U S A 1984;81:1835-1838.[Abstract/Free Full Text]
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