Heart and Metabolism

Myocardial energy metabolism in heart failure: unanswered questions and therapeutic opportunities

William C. Stanley
Department of Physiology and Biophysics, School of Medicine,
Case Western Reserve University, Cleveland, OH, USA

Correspondence: Dr William C. Stanley, Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106–4970, USA.
Tel: +1 216 368 5585, fax +1 216 368 3952, e-mail: wcs4@po.cwru.edu

Introduction
Chronic heart failure is generally defined as the inability to maintain normal cardiac output, and it classically presents with left ventricular chamber dilation, impaired systolic function, and elevated diastolic filling pressure. Despite optimal medical therapy, heart failure is a progressive disease with a high rate of mortality and morbidity.[1] Multiple neurohormonal systems are overactivated (eg, sympathetic nervous system, renin-angiotensin system, cytokines, endothelin, atrial natriuretic peptide, etc), which contributes to the progression of left ventricular remodeling, cardiac fibrosis, and worsening of clinical symptoms.[2,3] Current pharmacotherapies are aimed at either symptom relief (eg, diuretics for edema or dobutamine for acute cardiac decompensation), or suppression of the over-activation of the renin-angiotensin axis (ACE inhibitors and angiotensin II receptor antagonists) and the sympathetic nervous system (b-adrenergic receptor antagonists).[4] These therapeutic approaches significantly reduce mortality in heart failure patients; however, there is still progression of left ventricular dysfunction and a high rate of mortality and morbidity. In addition, these drugs can acutely compromise hemodynamic function, and they are frequently poorly tolerated. Thus there is a clear need for agents that are free of any negative effects on cardiac function but that will stop or reverse the progression of heart failure and improve cardiac function.

Myocardial energy metabolism in heart failure
Cardiac muscle has an extremely rapid rate of metabolism. Blood flow and oxygen consumption are high and proportional to the rate of formation of ATP in the mitochondria. ATP synthesis is matched by ATP breakdown in the cytosol, which drives the contractile work of the heart and fuels the ion pumps that allow for diastolic relaxation (Figure 1). The content of ATP in the heart is low relative to the rate of ATP breakdown, with complete turnover of the cardiac ATP pool every 10–15 s.[5] ATP is resynthesized via oxidative phosphorylation, a process that is driven by the combustion of carbohydrates and fat in the mitochondrial matrix, and the transfer of electrons from carbon fuels to reduced nicotinamide adenine dinucleotide (NADH) and the electron transport chain (Figure 1).

Figure 1. Pathways of myocardial energy metabolism. ATP is formed by oxidative phosphorylation on the inner mitochondrial membrane, and is broken down in the cytosol to release energy for contractile work, Ca2+ uptake into the sarcoplasmic reticulum, and ion pumps. The metabolism of carbon fuels transfers
hydrogen atoms to reduced nicotinamide adenine dinucleotide (NADH), which fuels the electron transport chain and oxidative phosphorylation. Pi, Inorganic Phosphate; PDH, pyruvate dehydrogenase.

The electron transport chain pumps protons into the mitochondrial intermembrane space, and ATP is formed via oxidative phosphorylation by the mitochondrial ATPase (Figure 1). The heart is an omnivore, and forms ATP with energy released from the combustion of a mixture of lactate (10 to 25% of the total energy), glucose (10 to 25%), and fatty acids (50 to 80%).
There is growing evidence from pharmacology studies that impaired carbohydrate oxidation and high rates of fatty acid oxidation contribute to the mechanical dysfunction of the myocardium and the progression of heart failure.[6–11] Unfortunately, our understanding of the role of changes in myocardial energy metabolism in the natural history of heart failure is poor.[12] Studies in heart failure patients and large animal models of heart failure suggest that the function of cardiac mitochondria is depressed, and there are lower ATP levels.[13–18] Cardiac fuel selection has been measured in NYHA class II–III heart failure patients, showing a significant switch towards fatty acid metabolism, with less carbohydrate oxidation compared with age-matched healthy people.[19] On the other hand, myocardium from patients[20] and dogs[21] in endstage heart failure suggests a switch to glucose oxidation and away from fatty acids as the heart decompensates.

Metabolic therapies for heart failure
There are intriguing data in heart failure patients suggesting that acute treatment with agents that switch substrate oxidation away from fatty acids and towards carbohydrate oxidation improves cardiac function without eliciting any negative hemodynamic effects. Studies in humans and animals found that the contractile performance of the heart at a given rate of oxygen consumption is greater when the heart is oxidizing glucose and lactate rather than fatty acids.[22–24] The rate of fatty oxidation is mainly regulated by the concentration of free fatty acids in the plasma, the activity of carnitine palmitoyl transferase-1 (CPT-1), and the activity of a series of enzymes that catalyze the multiple steps of fatty acid b-oxidation (Figure 2).[25]

Figure 2. Regulation of mitochondrial carbohydrate and fatty acid metabolism. Fatty acids are esterified to fatty acyl-free coenzyme A (CoA) in the cytosol, which cannot pass the inner mitochondrial membrane. The enzyme carnitine palmitoyl transferase-1 (CPT-1) converts fatty acyl-CoA to fatty acyl-carnitine, which is transported into the mitochondrial matrix, reconverted back to fatty acyl-CoA, and undergoes b-oxidation to form acetyl-CoA and generate reduced nicotinamide adenine dinucleotide (NADH). Glucose and lactate are converted to pyruvate, which is oxidized by pyruvate dehydrogenases (PDH) to acetyl-CoA and NADH. The flux of pyruvate to acetyl-CoA through PDH is strongly inhibited by the NADH and acetyl-CoA formed from fatty acid b-oxidation. The antianginal drug trimetazidine inhibits the b-oxidation enzyme 3-ketoacyl thiolase, and increases the oxidation of pyruvate. CoA-SH, free Coenzyme A; NAD+, oxidized NADH.

Fatty acid oxidation strongly inhibits glucose and lactate oxidation at the level of pyruvate dehydrogenase (PDH); this inhibition is mediated by the high ratios of NADH/oxidized NAD and acetyl-CoA/free CoA induced by fatty acid oxidation, which feed back and inhibit flux through PDH (Figure 2). The rate of fatty acid oxidation can be pharmacologically decreased, and the rate of glucose and lactate oxidation increased, by inhibiting the enzymes of fatty acid oxidation or CPT-1 (Figure 2), or by activating PDH through inhibition of PDH kinase, the regulatory enzyme that phosphorylates and inhibits PDH.25 When myocardial carbohydrate oxidation is acutely increased in heart failure patients by inhibiting PDH kinase with intravenous dichloroacetate there is a rapid improvement in left ventricular mechanical function.6 A similar effect is observed when pyruvate oxidation is increased with an intracoronary infusion of pyruvate.[26] We have shown that acute treatment with the partial fatty acid oxidation inhibitor ranolazine results in an increase in cardiac output and external ventricular power without an increase in myocardial oxygen consumption in dogs with microembolism-induced chronic heart failure.[8,9] Thus there is good evidence that acutely reducing the rate of fatty acid oxidation and increasing carbohydrate oxidation improves mechanical function in the failing heart.
Is the progression of heart failure reversed or slowed by chronic treatment with drugs that switch cardiac substrate metabolism away from fat and towards carbohydrate oxidation? The answer to this question is not known. There is strong evidence that this approach works for the treatment of chronic stable angina. In double-blind placebo-controlled trials with partial inhibitors of cardiac fatty acid oxidation, such as the long-chain 3-ketoacyl-CoA-thiolase (3-KAT) inhibitor trimetazidine,[27,28] or with perhexiline[29] or ranolazine,[30] there is a significant improvement in exercise duration and time to 1-mm ST-segment depression in patients with stable angina, despite no effect on heart rate or blood pressure. Trials specifically testing the effects of these agents in heart failure patients have not been reported. A recent open-label study in NYHA class II–III heart failure with etomoxir (a partial inhibitor of fatty acid oxidation acting on CPT-1) showed improvement in exercise performance and left ventricular function (stroke volume and left ventricular ejection fraction at rest increased from 69 ± 4 to 92 ± 9 mL and from 21.5 ± 2% to 27.0
± 2.3%, respectively, after 3 months of treatment).[10,31] As noted by Michael Bristow in his recent editorial in the Lancet,[31] “[these results] are consistent with the hypothesis that etomoxir can favourably alter the expression of dysregulated genes that control contractile function in the failing human heart’. Preclinical results with the 3-KAT inhibitor trimetazidine suggest that direct inhibition of fatty acid oxidation improves survival in heart failure. When cardiomyopathic Syrian hamsters (a rodent model of heart failure with impaired myocardial carbohydrate oxidation)[16] were given trimetazidine in the drinking water to achieve plasma levels similar to those found in clinical trials with stable angina patients, there was a significant 57% increase is survival time from 364 to 560 days.[7] Taken together, these results suggest that inhibition of fatty acid oxidation can slow the progression of heart failure, and that therapies that chronically inhibit fatty acid oxidation and stimulate carbohydrate oxidation in the heart could result in a long-term improvement in clinical outcome.
There is some indication that the efficacy of b-adrenergic receptor antagonists in heart failure patients is associated with a switch in substrate metabolism from fat towards greater carbohydrate oxidation. Chronic treatment of heart failure patients with metoprolol[32] and carvedilol[33] is associated with a significant shift in substrate metabolism away from fatty acids and towards carbohydrate oxidation and improved cardiac function. It remains to be established whether the switch in substrate use is causally related to improvement in left ventricular function.

Conclusion
In summary, the chronically failing heart has been shown to be metabolically abnormal, in both animal models and in patients. At present, there are few data on the effects of heart failure on the rates of myocardial glucose, lactate and fatty acid metabolism and oxidation; thus it is not possible to draw definitive conclusions about cardiac substrate preference in the various stages and manifestations of the disease. There is some indication that compensated NYHA class II–III heart failure patients have impaired carbohydrate oxidation, and that therapies that partially inhibit fatty acid oxidation and increase carbohydrate oxidation result in acute and chronic improvement in left ventricular function, and slow the progression of the disease. This intriguing hypothesis awaits clinical evaluation.

REFERENCES

1: Circulation 1996 Dec 1;94(11):2807-16