Number 27, 2005
Metabolic approach in heart failure

The place of metabolic treatment

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Hanna Szwed
Institute of Cardiology, Warsaw, Poland
Correspondence: Professor Hanna Szwed, Institute of Cardiology, Spartanska 1, 02-637 Warszawa, Poland. E-mail: hszwed@ikard.waw.pl

Introduction
Coronary artery disease is the most common cause of heart failure. The metabolic manipulation of the myocardium is an innovative approach to the treatment of patients with heart failure, a hyperadrenergic state in which the concentrations of circulating free fatty acids (FFAs) are increased [1]. The normal heart derives approximately 60–80% of the energy it consumes from FFAs and the remainder from glucose and lactate (Figure 1). FFA metabolism yields more adenosine triphosphate (ATP) per gram of substrate, but requires greater oxygen consumption. In an ischemic cardiomyocyte, FFA metabolism leads to a decrease in glucose oxidation and an increase in the production of lactate and hydrogen ion, leading in turn to intracellular acidosis; under these conditions, sodium and calcium overload exacerbate myocardial dysfunction. Under conditions of energy demand in the ischemic heart, however, the utilization of glucose can increase markedly [2], although FFA metabolism still predominates.

Inhibitors of free fatty acid ß-oxidation
Trimetazidine and ranolazine (a substituted piperazine compound) act as partial inhibitors of fatty acid oxidation and stimulate glucose oxidation.

Trimetazidine
Trimetazidine (1-[2,3,4-trimethoxybenzyl] piperazine dihydrochloride) is used as an antianginal drug. Recent evidence indicates that its metabolic effect is achieved mainly through the inhibition of long-chain 3-ketoacyl coenzyme A thiolase [6], the last enzyme involved in ß-oxidation, leading to increased glucose oxidation and production of membrane-protective glycolytic ATP, a potential source of energy for the sodium pump. Trimetazidine not only improves energy metabolism, but also exerts a cytoprotective action by decreasing the intracellular accumulation of sodium and calcium ions and protecting cell membranes against the accumulation of hydrogenions.
Several studies have shown the beneficial role of trimetazidine in the treatment of patients with stable angina [7]; it improves exercise test parameters and reduces the number of anginal attacks without any hemodynamic changes. Other studies have demonstrated the usefulness of trimetazidine in heart failure. In an experimental study, long-term treatment with trimetazidine prolonged the life of cardiomyopathic Syrian hamsters by 57% [8]. The drug has also been shown to improve recovery of postischemic left ventricular dysfunction of the isolated arrested rat heart [9]. Clinical studies of patients with chronic congestive heart failure have focused on ischemic cardiomyopathy. In a double-blind, randomized, crossover study by Lu et al [10], patients received trimetazidine 20mg three times daily, or placebo, for 15 days. Trimetazidine improved both resting and dobutamine-induced ischemic dysfunction in patients with impaired left ventricular function. Bellardinelli and Purcaro [11] demonstrated the effects of trimetazidine on the contractile function of chronically dysfunctional myocardium. They studied 38 patients with postinfarction left ventricular dysfunction (mean ejection fraction 33%) who were allocated randomly to groups to receive either trimetazidine 20mg three times daily or placebo, for 2 months. Low-dose dobutamine echocardiography and cardiopulmonary exercise testing were performed at study baseline and after 2 months of treatment. At 2 months, significant improvements in the at-rest and peak systolic wall thickening score index and ejection fraction were observed in the group of patients treated with trimetazidine; peak VO₂ also increased significantly [11]. Due to decrease of insulin sensitivity and elevation of FFA metabolism in the diabetes (Figure 3) pharmacologic agents that inhibit fatty acid oxidation may be especially useful in diabetic patients. In a study by Fragasso et al [12], in 16 patients with diabetes and ischemic cardiomyopathy, both short- (15 days) and long-term periods of treatment with trimetazidine (60mg daily) improved left ventricular ejection fraction, clinical symptoms, glucose metabolism, and endothelial function. Beneficial effects of trimetazidine in diabetic patients with ischemic left ventricular dysfunction were also observed in an earlier study by Rosano et al [13].

Ranolazine
Ranolazine [(+/-)-N-(2,6-dimethyphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine acetamide] is another piperazine derivative. It decreases FFA ß-oxidation, promotes glucose oxidation, and acts indirectly by activation of pyruvate dehydrogenase [16]. The anti-ischemic effect of ranolazine has been demonstrated in experimental and clinical studies. In the Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) study [17], a therapeutic effect of monotherapy with ranolazine (500mg twice daily, 1000mg twice daily, or 1500mg twice daily) was demonstrated in 191 patients. In a double-blind randomized trial (Combination Assessment of Ranolazine in Stable Angina [CARISA]), ranolazine 750mg or 1000mg given twice daily, added to other antianginal drugs, prolonged exercise duration and reduced clinical symptoms. Small dose-related increases in QTc (<10ms compared with placebo, on average) were not associated with persistent prolongation of the QT interval in any patient, or with the occurrence of torsade de pointes; however, five patients taking ranolazine 1000mg twice daily experienced syncope for unknown reasons [18] – a finding that prompted discussion as to the safety of ranolazine. It was postulated that the syncopes may have been caused by postural hypotension in patients treated actively with other drugs such as diltiazem (four of the five patients) and angiotensin-converting enzyme inhibitors (all five patients). It remains an important issue whether high doses of ranolazine would be well tolerated when given to patients treated with maximal doses of other antianginal medications. Since the CARISA trial has been completed, only small studies of ranolazine have been performed, and less is known about its effectiveness in patients with heart failure than is known about trimetazidine.

Carnitine palmitoyl transferase-1 inhibitors
Carnitine palmitoyl transferase-1 (CPT-1) inhibitors inhibit long-chain fatty acid oxidation by inhibiting the entry of long-chain fatty acids into the mitochondria at the level of CPT-1. There is major interest concerning the value of CPT-1 in pharmacological intervention in postischemic, reperfused heart.

Etomoxir
Etomoxir (ethyl-2-tetradecyl glycidate) has been developed for treating non-insulin dependent diabetes mellitus. There has been only one open-label, non-controlled pilot study performed to examine the potential benefits of etomoxir in heart failure. The drug was given to 15 patients with chronic congestive heart failure, in a dose of 80mg daily. After 3 months, improvements in left ventricular function and clinical symptoms were observed [19]. However, the clinical value of this drug is limited by a narrow therapeutic window resulting from its potential to cause phospholipidosis [20].

Perhexiline
Perhexiline, a calcium-channel blocker, was introduced as an effective antianginal agent. It acts by switching myocardial substrate utilization from FFA to carbohydrates through inhibition of CPT-1 and CPT-2, resulting in increased glucose and lactate oxidation [21]. The use of perhexiline is limited because of its side effects, such as hepatotoxicity and peripheral neuropathy.

Drugs with additional metabolic action
Various drugs used in cardiology appear to treat cardiac dysfunction by mechanisms that are not related to their primary pharmacological target. The list of such drugs with additional metabolic activity includes ß-blockers and glucose–insulin–potassium.
ß-Blockers are active antianginal agents. For some, such as bisoprolol, metoprolol and carvedilol, an improvement in left ventricular function in heart failure has been established in major clinical trials. It is postulated that this improved function observed with ß-blockers in heart failure could be, in part, a result of reduced CPT-1 activity and decreased FFA oxidation [22].
The findings of a meta-analysis by Fath-Ordoubadi and Beatt [23] suggested that infusion of glucose–insulin–potassium improves outcome after myocardial infarction. However, the most recent studies have failed to demonstrate a significant improvement in mortality in response to this treatment [24].
Another metabolic agent, carnitine, stimulates the oxidation of pyruvate. In a study of 80 patients with dilated cardiomyopathy and heart failure, administration of L-carnitine 2g daily for 3 years was associated with reduced mortality [25].

Conclusion
Several studies of agents that decrease FFA concentrations or inhibit myocardial oxidation of FFAs have demonstrated that metabolic manipulation is an important new approach to the treatment of heart failure. ?

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REFERENCES

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