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European Journal of Heart Failure 2002 4(1):3-6; doi:10.1016/S1388-9842(01)00183-0
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© 2002 European Society of Cardiology

Partial fatty acid oxidation inhibitors: a potentially new class of drugs for heart failure

Hani N. Sabbaha and William C. Stanley

Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute Detroit, MI, USA
Department of Physiology and Biophysics, Case Western Reserve University Cleveland, OH, USA

Key Words: Heart failure • Cardiac metabolism • Fatty acid oxidation • Carbohydrates

To meet the high demands of energy by the contracting muscle, the heart must produce a constant and plentiful supply of ATP, energy that is derived from the metabolism of fatty acids and carbohydrates. Fatty acids are the preferred substrate of the myocardium, contributing approximately 60–80% of the energy for ATP synthesis [1]. Fatty acids, however, are not as efficient as glucose as a source of myocardial energy when viewed in terms of oxygen consumption requiring approximately 10% more oxygen to produce the equivalent amount of ATP [1]. Abnormalities of energy metabolism have long been cited as key elements of the failing heart that may be responsible, in part, for the progressive worsening of left ventricular (LV) function that characterizes this disease state. In fact, the failing heart has often been described as ‘energy starved’. Several studies have shown reduced ATP content and dysfunctional mitochondria in the failing heart while others have shown increased fatty acid oxidation and decreased carbohydrate oxidation in patients with heart failure compared with normal age-matched healthy volunteers [2–7]. These maladaptations of cardiac energy metabolism in heart failure, when viewed in concert, serve as impetus for the development of novel, target specific, therapies aimed at reversing these metabolic abnormalities and by doing so, effect an improvement in the contractile performance of the failing heart.

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. Breakdown of ATP in the cytosol drives the contractile power of the LV and fuels the ion pumps that allow for diastolic relaxation (Fig. 1) [8,9]. 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 [8]. 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 NADH and FADH2 and the electron transport chain (Fig. 1). The electron transport chain pumps protons into the mitochondrial intermembrane space and ATP is formed via oxidative phosphorylation by the mitochondrial F1-F0 ATPase (Fig. 1).


Figure 1
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  		Fig. 1 Schematic depiction of myocardial energy metabolism. ATP is formed by oxidative phosphorylation by the F1–F0 ATPase on the inner mitochondrial membrane. ATP is transported out to the cytosol where it is broken down to release energy for contractile work, Ca2+ uptake into the sarcoplasmic reticulum and other ion pumps. The metabolism of carbon fuels releases hydrogen atoms in the form on NADH that fuels the electron transport chain and oxidative phosphorylation. ATP, adenosine triphosphate; ADP, adenosine diphosphate; NADH, reduced nicotinomide dinucleotide; PDH, pyruvate dehydrogenase.

 
At present there are no therapies aimed at increasing the mechanical efficiency of the failing myocardium through optimization of myocardial energy metabolism. Current medical therapies are directed at the relief of symptoms, as is the case with diuretics and the acute administration of beta-adrenergic agonists and phosphodiesterase inhibitors and at attenuation of progressive LV remodeling with a goal toward improved survival, as is the case with chronic therapy with angiotensin converting enzyme inhibitors, beta-adrenergic receptor blockers and possibly aldosterone antagonists. Of the many drugs currently used in the treatment of heart failure, only beta-blockers have been suggested to act, in part, by modulation of myocardial energy metabolism [10,11]. Clearly, drugs designed specifically to improve myocardial efficiency by optimizing myocardial energy metabolism, such that greater cardiac work can be achieved for a given amount of oxygen consumed, would be a welcome addition to the existing arsenal of therapies aimed at the treatment of chronic heart failure.

There is growing evidence that impaired carbohydrate oxidation and high rates of fatty acid oxidation contribute to the progression of myocardial dysfunction in heart failure. Studies in humans and animals have 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 [12–14]. The rate of fatty oxidation is mainly regulated by the concentration of free fatty acids in the plasma, the activity of carnitine palmitoyl transferase-I (CPT-I), and the activity of a series of enzymes that catalyze the multiple steps of fatty acid β-oxidation (Fig. 2) [8,9]. Fatty acid oxidation strongly inhibits glucose and lactate oxidation at the level of pyruvate dehydrogenase. This inhibition is mediated by the high ratios of NADH/NAD+ and acetyl-CoA/free CoA induced by fatty acid oxidation, which feed back and inhibit flux through PDH (Fig. 2) [9].


Figure 2
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  		Fig. 2 Regulation of mitochondrial carbohydrate and fatty acid metabolism. Fatty acids are esterified to fatty acyl-CoA in the cytosol, which cannot pass the inner mitochondrial membrane. The enzyme CPT-I converts fatty acyl-CoA to fatty acyl-carnitine, which is transported into the mitochondrial matrix by CAT, reconverted back to fatty acyl-CoA by CPT-II, and undergoes -oxidation to form acetyl-CoA and generate NADH. Glucose and lactate are converted to pyruvate, which is oxidized by PDH to acetyl-CoA and NADH. The flux of pyruvate to acetyl-CoA throughout PDH is strongly inhibited by the NADH and acetyl-CoA formed from fatty acid -oxidation. CoA, free coenzyme A; CAT, carnitine acyl tranlocase; CPT-I, carnitine palmitoyl transferase; CPT-II, carnitine palmitoyl transferase II; DAC, dicholoracetate; NAD+ and NADH, reduced and oxidized nicotinomide dinucleotide; PDH, pyruvate dehydrogenase.

 
Since high fatty acid oxidation rates markedly decrease glucose oxidation, one approach to increasing glucose oxidation is to inhibit fatty acid oxidation. The rate of fatty acid oxidation can be pharmacologically decreased and the rate of glucose and lactate oxidation increased by: (a) inhibiting the enzymes of fatty acid β-oxidation; (b) inhibiting CPT-I and the entry of fatty acids into the mitochondrion; or (c) activating PDH by inhibiting PDH kinase, the regulatory enzyme that phosphorylates and inhibits PDH [8]. With respect to the latter, when myocardial carbohydrate oxidation is acutely increased in heart failure patients by activating PDH with intravenous dichloroacetate, there is a rapid improvement in LV performance [15]. This strongly suggests that impaired carbohydrate oxidation at the level of PDH contributes to the contractile dysfunction in heart failure patients and more importantly, that increasing flux through PDH will improve contractile function, presumably without increasing myocardial oxygen consumption.

Pharmacological suppression of cardiac fatty acid oxidation with reciprocal activation of carbohydrate oxidation, has been successfully applied to the treatment of angina pectoris [6]. The partial fatty acid oxidation (pFOX) inhibitor ranolazine directly inhibits fatty acid β-oxidation and thus reduces inhibition of PDH by fatty acid oxidation, presumably by decreasing the ratios of NADH/NAD+ and acetyl-CoA/free CoA in the mitochondrial matrix (Fig. 2). Another compound that is used in the treatment of angina pectoris and directly inhibits fatty acid β-oxidation is the 3-ketoacyl-coenzyme A thiolase (3-KAT) inhibitor trimetazidine [1]. These orally active agents have been shown to significantly improve exercise-induced anginal symptoms in patients with coronary artery disease without eliciting any of the classic anti-ischemic effects of traditional therapies such as a decrease in heart rate, coronary vasodilation, or a decrease in arterial blood pressure [16,17]. Similar metabolic and anti-anginal effects are found with inhibition of CPT-I using oxfenicine or perhexiline [18–21].

There is now evidence to suggest that partial fatty acid oxidation inhibitors may also have application for the treatment of chronic heart failure. We recently showed that, in dogs with experimentally-induced heart failure, acute intravenous administration of the pFOX inhibitor ranolazine, improves LV ejection fraction as well as other indexes of LV performance [22]. In contrast ranolazine had no effect on LV function in normal dogs, suggesting that this agent was devoid of any classical cAMP-mediated positive inotropic effects [22]. In contrast to dobutamine, a classic beta-agonist, ranolazine improved LV systolic function without increasing coronary blood flow or myocardial oxygen consumption [23]. Instead, ranolazine significantly improved myocardial efficiency calculated as the ratio of LV power to LV energy expenditure [23]. These studies suggest that pharmacologically switching the oxidative fuel of the heart away from fatty acids towards carbohydrate can improve mechanical efficiency of the failing heart.

Is there any evidence to suggest that chronic partial inhibition of fatty acid oxidation would be beneficial in the treatment of heart failure? The answer is yes, but the available data are sparse. A mortality study in Syrian cardiomyopathic hamsters, an animal model of congenital heart failure that also manifests impaired cardiac PDH activity [24], showed that chronic treatment with the 3-KAT inhibitor trimetazidine increased median survival time by 196 days compared to placebo [25]. Chronic treatment with the CPT-I inhibitor etomoxir in rats with LV hypertrophy produced by aortic banding prevented the deterioration in LV function and sarcoplasmic reticulum Ca2+ handling compared to placebo [26]. A pilot study in patients with heart failure (NYHA Class II-III) showed that 3-months therapy with etomoxir significantly improved maximal cardiac output and stroke volume during exercise [27]. This study, however, was not blinded and did not include a placebo-controlled group [27]. At present there are two ongoing Phase II trials with ranolazine and etomoxir in heart failure patients.

We now recognize that mitochondria of the failing heart have an impaired ability to generate ATP. This impairment is further complicated by the knowledge that the failing heart relies more heavily on fatty acid oxidation for the production of energy, a condition requiring greater oxygen utilization. Therapies that partially inhibit fatty acid oxidation and increase carbohydrate oxidation in the failing heart appear to improve ATP production with subsequent improvement in cardiac mechanical efficiency leading to improved LV systolic performance. These metabolism modulating drugs are particularly attractive in that they elicit robust benefits in heart failure while preserving hemodynamic stability. As we anxiously await the completion of current phase-II clinical trials and look forward to upcoming phase-III mortality trials with drugs such as pFOX inhibitors and 3-KAT inhibitors in patients with heart failure, we are optimistic that we stand at the dawn of a new class of drugs for the treatment of heart failure, new drugs that improve myocardial efficiency through optimization of myocardial energy metabolism.


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