Number 34, 2007
Picture my heart!

Efficacy of the metabolic approach in ischemic heart diseases

Non invasive assessment of myocardial perfusion, metabolism, and left ventricular function

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Romualdo Belardinelli
Cardiologia Riabilitativa e Preventiva, Lancisi Heart Institute, Ancona, Italy
Correspondence: Dr Romualdo Belardinelli, Via Conca 71, 60020 Ancona, Italy. Tel: +39071 5965344; fax: +39 071 5965042; e-mail: r.belardinelli@ao-umbertoprimo.marine.it

Introduction
Coronary artery disease is the leading cause of death in the United States and Europe [1] and, despite the trend toward a decrease in incidence over the past 20 years, it still represents an heavy economic burden for all developed countries. Moreover, there is epidemiological and clinical evidence that, since 1990, coronary artery disease has become the most frequent cause of chronic heart failure. In the 21 multicenter congestive heart failure treatment trials involving 35 000 patients that have been reported by the New England Journal of Medicine over the past 15 years, the underlying cause of congestive heart failure was coronary artery disease in about 65% of patients [2].
The differentiation between viable and non viable myocardium is an important diagnostic issue in patients referred for revascularization. In fact, it has been estimated that between 25 and 40% of patients with chronic coronary artery disease and left ventricular dysfunction have the potential for significant improvement in systolic performance after undergoing revascularization [3]. Left ventricular ejection fraction may increase by up to 50% at 6 months after coronary artery bypass surgery [4], and this improvement is predicted by presurgical detection of viable myocardium [5]. Rahimtoola [6] coined the term ‘hibernating myocardium’ to describe a state of persistently impaired myocardial and left ventricular function at rest as a result of reduced coronary blood flow that can be partially or completely restored to normal by reducing demand or improving blood flow, or both.
In conditions of multiple coronary artery disease and left ventricular dysfunction, imaging techniques have clearly shown that cardiac impairment is caused, not only by the consequences of necrosis, but also by a different amount of viable dysfunctional myocardium that may surround the necrotic area or may be evident in distal territories served by other stenotic vessels (Table I).

Table I. Comparison of technical and clinical aspects of non invasive imaging methods to detect myocardial viability.

Cellular fatty acid inhibition and left ventricular function: clinical evidence
In conditions of chronic reduction in blood flow, free fatty acid concentrations are increased as a result of the lipolytic action of sympathetic activation, causing depressed myocardial contractility, increased concentrations of cAMP, and increased oxygen consumption without concomitant increase in myocardial work [9]. A shift toward glucose oxidation is likely to benefit hypoperfused myocardium, because ATP production per mole of oxygen required is greater when glucose is the preferential substrate. In fact, the number of moles of ATP produced per mole of oxygen consumed is approximately 12% greater for glucose than for fatty acids. As fatty acid metabolism increases, glucose oxidation decreases, leading to uncoupling of glycolysis from glucose oxidation and an increase in proton and lactate production. This uncoupling increases the rate of pyruvate production without a concomitant increased rate of glucose oxidation in the mitochondria, generating cellular damage and contractile dysfunction. In this setting, the inhibition of fatty acid oxidation and the increased glucose oxidation may induce beneficial effects and may theoretically improve left ventricular function [10].
The most studied metabolic agent is trimetazidine, which inhibits the mitochondrial long-chain 3-ketoacyl coenzyme A thiolase [11]. Thus glucose oxidation is increased by shift of energy substrate preference from fatty acid to glucose oxidation [12]. As a result of this action, trimetazidine ensures antianginal and anti-ischemic efficacy and improves left ventricular function.
The effects of trimetazidine were studied in 38 patients with postnecrotic left ventricular dysfunction and multivessel coronary artery disease [13]. Patients were allocated randomly to two matched groups: one received trimetazidine 20 mg for 2 months, and the other received placebo. Treated patients exhibited significant improvements in systolic wall thickening score index (13% and 21%, at rest and in a stress test at peak dobutamine infusion, respectively; P < 0.001), in left ventricular ejection fraction (19.7% and 14.1%, at rest and in a stress test at peak dobutamine infusion, P < 0.001 [Figure 1]), and in peak oxygen consumption (15%). These benefits were obtained without concomitant changes in heart rate and blood pressure, suggesting that cytoprotection unrelated to hemodynamic effects is likely to occur. No side effects were observed among the treated patients. These findings are in agreement with those described by Brottier et al [14] in patients with ischemic cardiomyopathy, of a 9.3% improvement in radionuclide ejection fraction after a 6 month treatment with trimetazidine at the same dose. Left ventricular ejection fraction remained unchanged with trimetazidine at 3 months, and showed a mean improvement of 9.3% at 6 months. In contrast, patients receiving placebo experienced a 4.5% decrease in left ventricular ejection fraction at 3 months, and a further 15.6% deterioration at 6 months, as compared with baseline values (P = 0.018). Cardiac volume on chest X-ray remained stable in the two groups during the first 3 months, whereas at 6 months it had decreased significantly in the trimetazidine group compared with those who received placebo (P = 0.034). Treated patients also had enhanced functional capacity, as shown by improvement in New York Heart Association (NYHA) functional class (P < 0.001).

Summary
Ischemic heart disease is a metabolic disease in which dysfunctional myocardium may recover contractility as a consequence of inhibition of fatty acid oxidation in favor of glucose oxidation. Thus the metabolic approach with trimetazidine, beyond its well demonstrated antianginal efficacy, leads also to a significant improvement in left ventricular function.
Imaging techniques have different characteristics that may be utilized in clinical practice to quantify changes in contractility and myocardial perfusion after metabolic modulation. Both low-dose dobutamine echocardiography and thallium/tetrofosmin SPECT imaging have been utilized in studies in which left ventricular dysfunction improved after the administration of trimetazidine, showing a good diagnostic accuracy in detecting changes compared with baseline during follow-up studies. Positron emission tomography images have greater spatial resolution and specificity than SPECT, but the high costs and limited availability of the technique have hampered its clinical application in studies on metabolic modulation.

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