doi: 10.1161/CIRCULATIONAHA.106.659235
(Circulation. 2006;114:2092-2093.)
© 2006 American Heart Association, Inc.
Editorial |
No Low-Fat Diet for the Failing Heart?
From the University of Texas Houston Medical School, Department of Internal Medicine, Division of Cardiology, Houston, Tex.
Correspondence to Heinrich Taegtmeyer, MD, DPhil, Department of Internal Medicine, Division of Cardiology, University of Texas Houston Medical School, 6431 Fannin, MSB 1.222, Houston, TX 77030. E-mail Heinrich.Taegtmeyer{at}uth.tmc.edu
Key Words: Editorials • diet • heart failure • metabolism • fatty acids
Chances are that everyone knows about the heart’s oxygen requirement, but few would consider the heart’s metabolism of energy-providing substrates a big issue. Since the celebrated work of C. Lovatt Evans and Ernest Starling1,2 at the beginning of the last century, physiologists have recognized the heart as an efficient transducer of energy. Like an engine, the heart turns chemical energy into mechanical energy, efficiently and at a high rate. Metabolism of energy-providing substrates and contractions of the heart are tightly coupled.3 Because the heart’s energy for contraction is derived from oxidative phosphorylation of adenosine diphosphate to adenosine triphosphate, myocardial oxygen consumption is also commonly used to measure cardiac efficiency.4 Another feature of the heart is also worth mentioning. The heart is a metabolic omnivore, and for any given environment it uses the most economic fuel available5 (Figure). In the fasted state, when the fatty acid levels are high, the heart oxidizes predominantly fatty acids.6 Metabolic adaptability comes into play when the heart is stressed and veers toward carbohydrate oxidation. With a short-term increase in workload, the working heart ex vivo covers its increased need for energy through the oxidation of glycogen, lactate, and glucose, in that order.4 For a given amount of oxygen used, the heart in vivo performs up to 40% more efficiently with glucose than with fatty acids as the main energy-providing substrate.7 In a simulated state of exercise, the heart spares glycogen and oxidizes lactate almost exclusively.8 With long-term changes in workload, extensive metabolic remodeling accompanies the structural and functional changes of the heart in the course of hypertrophy, atrophy, and heart failure, and this remodeling includes a reactivation of the fetal metabolic gene program.9,10 A hallmark of energy substrate metabolism of the fetal heart is its reliance on carbohydrates (especially lactate) for energy conversion. In contrast to the fetal heart, however, with its abundant glycogen reserves,11 the failing heart has a depleted metabolic energy reserve. The failing heart relies on exogenous substrate for energy provision because of the lack of endogenous energy reserves.
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We have provided such a detailed introduction because the new findings of an international group of investigators led by Tuunanen et al12 at the Turku PET-Centre in Finland, published in this issue of Circulation, seem to contradict a great deal of what is known about myocardial energy substrate metabolism in the failing heart.13 The investigators used acipimox, a nicotinic acid derivative with profound antilipolytic effects, to manipulate substrate supply to the heart. The drug accomplished the desired goals to lower fatty acid levels in the serum and rates of fatty acid uptake in the heart in a group of patients with idiopathic dilated cardiomyopathy and in a group of normal volunteers. It was anticipated that a shift from fatty acid oxidation to glucose oxidation might improve contractile function in the failing heart. Unexpectedly, in both groups, the stroke volume of the left ventricle decreased, and the rate x pressure product and myocardial perfusion remained unchanged.
How is it possible that changes in metabolic substrate fluxes would lead to impaired contractile function of the heart? There are several explanations for this phenomenon. First, the study by Tuunanen et al12 describes a short-term change in substrate supply. It also lends support to 2 recent reports in lipase-deficient mouse models. Energy metabolism is altered in mice lacking adipose triglyceride lipase,14 and a cardiac-specific loss of hLpL0 lipoprotein lipase–derived fatty acids is associated with cardiac dysfunction in the face of increased cardiac glucose metabolism.15 The data suggest a lipase-derived fatty acid requirement for normal contractile function of the heart. The exact mechanism for these phenomena has not yet been elucidated.
Second, the drug itself may have direct hemodynamic effects independent of its fatty acid–lowering actions. The conclusions of the present study would be stronger if a control group had been included and been given both acipimox and a fatty acid infusion. Furthermore, the hemodynamic data are also consistent with an increase in systemic vascular resistance. Hydraulic resistance (R) is defined by analogy to Ohm’s Law as the ratio of the mean pressure drop (P) to flow (
) between 2 points in a liquid flowing in a tube. This hemodynamic explanation would lead to questions about the causality between decreased rates of fatty acid oxidation and a decreased stroke volume. A third explanation would be that short-term lowering of free acids by acipimox not only enhances peripheral insulin-mediated glucose uptake16 but also lowers insulin secretion by the pancreatic beta cells.17 Because insulin is a vasodilator,18 the fall in insulin levels may have resulted in an increase in systemic vascular resistance. In the present study,12 there is no information on insulin levels after administration of the drug. One likely reason for an abrupt decrease of free fatty acids (FFAs) in the study by Tuunanen et al12 is that the patients developed insulin resistance. The homeostasis model assessment index value for patients, calculated from Table 2 in the Tuunanen et al12 article, is 3.0, which puts patients into the fourth of 5 quintiles, with 5 indicating most serious.19 Therefore, these patients are likely to have defects of their insulin receptors and are less likely able to adapt to the need for a sudden increase of glucose uptake as FFA levels fall. Whatever the mechanism might be, the present study12 is the first to show decreased FFA uptake and inferred reduced oxidation rates with the use of a supposed FFA inhibitor.
After reading the article by Tuunanen et al,12 the practicing cardiologist will ask the obvious question: No low-fat diet for the failing heart? Although it is reasonable to assume that the heart functions best when it oxidizes a variety of substrates, including fats, simultaneously20 (Figure), the complexities of intermediary metabolism continue to challenge the cardiac physiologist. After measuring the homeostasis model assessment index, clinicians need to consider how to treat the probable insulin resistance, for instance, by a low-fat Mediterranean-type diet, by exercise, and, if still needed, by metformin. All of these measures would bring the heart back from the extreme forms of either glucotoxicity or lipotoxicity to a normal or adaptive metabolic state (Figure).
The ancient Greeks knew that the truth has many faces. Remember Diogenes and his lamp? The reason for decreased cardiac efficiency with acipimox may be found both inside and outside the heart. Despite some imperfections in the execution of the study by Tuunanen et al,12 however, one point seems especially important: When it comes to energy substrate metabolism of the heart, extremes are never good.
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Acknowledgments |
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Disclosures
The work in the authors’ laboratory is supported by a grant from the US Public Health Service (RO1-HL 073162).
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
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1. Evans CL. The effect of glucose on the gaseous metabolism of the isolated mammalian heart. J Physiol (Lond). 1914; 47: 407–418.
2. Starling EH, Visscher MB. The regulation of energy output of the heart. J Physiol (Lond). 1928; 62: 243–261.
3. Taegtmeyer H. Cardiac metabolism as a target for the treatment of heart failure. Circulation. 2004; 110: 894–896.
4. Goodwin GW, Taylor CS, Taegtmeyer H. Regulation of energy metabolism of the heart during acute increase in heart work. J Biol Chem. 1998; 273: 29530–29539.
5. Taegtmeyer H, Hems R, Krebs HA. Utilization of energy-providing substrates in the isolated working rat heart. Biochem J. 1980; 186: 701–711.[Medline] [Order article via Infotrieve]
6. Bing RJ, Siegel A, Ungar I, Gilbert M. Metabolism of the human heart: II: studies on fat, ketone and amino acid metabolism. Am J Med. 1954; 16: 504–515.[CrossRef][Medline] [Order article via Infotrieve]
7. Korvald C, Elvenes OP, Myrmel T. Myocardial substrate metabolism influences left ventricular energetics in vivo. Am J Physiol Heart Circ Physiol. 2000; 278: H1345–H1351.
8. Goodwin GW, Taegtmeyer H. Improved energy homeostasis of the heart in the metabolic state of exercise. Am J Physiol Heart Circ Physiol. 2000; 279: H1490–H1501.
9. Depre C, Shipley GL, Chen W, Han Q, Doenst T, Moore ML, Stepkowski S, Davies PJ, Taegtmeyer H. Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy. Nat Med. 1998; 4: 1269–1275.[CrossRef][Medline] [Order article via Infotrieve]
10. Razeghi P, Young ME, Alcorn JL, Moravec CS, Frazier OH, Taegtmeyer H. Metabolic gene expression in fetal and failing human heart. Circulation. 2001; 104: 2923–2931.
11. Taegtmeyer H. Glycogen in the heart: an expanded view. J Mol Cell Cardiol. 2004; 37: 7–10.[CrossRef][Medline] [Order article via Infotrieve]
12. Tuunanen H, Engblom E, Naum A, Nagren K, Hesse B, Airaksinen KEJ, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation. 2006; 114: 2130–2137.
13. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005; 85: 1093–1129.
14. Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, Kratky D, Wagner EF, Klingenspor M, Hoefler G, Zechner R. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 2006; 312: 734–737.
15. Augustus AS, Buchanan J, Park TS, Hirata K, Noh HL, Sun J, Homma S, D’Armiento J, Abel ED, Goldberg IJ. Loss of lipoprotein lipase-derived fatty acids leads to increased cardiac glucose metabolism and heart dysfunction. J Biol Chem. 2006; 281: 8716–8723.
16. Santomauro AT, Boden G, Silva ME, Rocha DM, Santos RF, Ursich MJ, Strassmann PG, Wajchenberg BL. Overnight lowering of free fatty acids with acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes. 1999; 48: 1836–1841.[Abstract]
17. Boden G. Obesity, insulin resistance, type 2 diabetes and free fatty acids. Future Drugs—Expert Rev Endocrinol Metab. 2006; 1: 499–505.[CrossRef]
18. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest. 1994; 94: 1172–1179.[Medline] [Order article via Infotrieve]
19. Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio heart study. Diabetes Care. 2002; 25: 1177–1184.
20. Taegtmeyer H. Energy metabolism of the heart: from basic concepts to clinical applications. Curr Prob Cardiol. 1994; 19: 57–116.
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