Number 22, 2004
Endothelial Dysfunction

Evidence-based efficacy of Vastarel in patients with ischemic cardiomyopathy

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Huay Cheem Tan
National University Hospital, The Heart Institute, Singapore
Correspondence: National University Hospital, The Heart Institute, Singapore. e-mail: cheem001@pacific.net.sg

Introduction
The use of metabolic agents in patients with overt myocardial ischemia in the form of stable angina pectoris is well recognized. Through selective inhibition of 3-ketoacyl coenzyme A thiolase, an enzyme of fatty acid -oxidation, Vastarel MR increases the oxidation of pyruvate formed from glucose, glycogen, and lactate, and decreases the use of free fatty acids as a myocardial fuel source. The resulting enhanced cardiac efficiency and energy production increase the myocardial cellular ischemic threshold and provide cytoprotection. These beneficial effects occur in the absence of significant changes in hemodynamic parameters, including heart rate and systolic blood pressure. Clinical studies have established the efficacy of Vastarel MR in improving exercise duration time, time to angina, and exercise capacity in patients with stable angina pectoris. By the same cytoprotective effect, Vastarel MR can also improve the left ventricular dysfunction of patients with coronary artery disease. This paper reviews the literature on the benefits of Vastarel in patients with ischemic cardiomyopathy. Table I summarizes the findings of some relevant studies.

Table I. Effects of trimetazidine in ischemic cardiomyopathy.

Effect of Vastarel in chronic ischemic left ventricular dysfunction
Brottier et al [1] were the first to report the effect of Vastarel on severe ischemic cardiomyopathy. Their group of patients with ischemic congestive cardiomyopathy and severely depressed ventricular ejection fraction were given oral Vastarel for 6 months. By 6 months, radionucleide ejection fraction had increased by more than 9%, in relative terms, and functional capacity had improved. These improvements occurred in the absence of obvious hemodynamic changes and the effect was probably attributable to improved myocardial metabolism.
Further support for the role of Vastarel in patients with moderate chronic ischemic dysfunction was provided by Lu et al [2], who showed that this agent not only prevents and delays the progression of ischemic cardiomyopathy, but also improves the resting left ventricular function of patients. In a double-blind, placebo-controlled, crossover design study in 15 patients with documented chronic coronary artery disease, the patients were randomly assigned to receive Vastarel or placebo in addition to their usual antianginal medications. Crossover took place after 15 days and the duration of the trial was 30 days. All patients underwent dobutamine echocardiography at day 0, day 15, and day 30. The mean period of dobutamine infusion required to bring about the onset of new dysfunction, or worsening of pre-existing dysfunction, was 15.24.1min with placebo and increased to 17.54.9min with Vastarel (P=0.04). The mean dose of dobutamine required to bring about the changes was 22.15.8g/kg per min with placebo and increased to 27.98.0g/kg per min with Vastarel (P=0.006). Both in the resting condition and at peak dobutamine infusion, wall motion score index was significantly lower with Vastarel than with placebo (at rest: 1.340.37 compared with 1.400.42, P=0.013; at peak: 1.610.40 compared with 1.710.45, P=0.018). These results were achieved with no effect on the patients' heart rate, systolic blood pressure, and ratepressure product. They indicate that Vastarel not only may protect the heart from dobutamine-induced ischemic dysfunction, but also can improve resting regional left ventricular function as demonstrated by improved peak and resting wall motion score index.
Similar improvement in patients with severe ischemic cardiomyopathy was observed by Belardinelli and Purcaro [3]. They studied 38 patients with severe ischemic cardiomyopathy who were randomly assigned to receive either Vastarel (20mg tid, n=19) or placebo. At the end of the 2-month treatment period, all patients underwent echocardiography, both at rest and during infusion of low-dose dobutamine, and a cardiopulmonary exercise test. The resting ejection fraction in Vastarel treated patients increased from 33.14.5% to 39.55.9% (P=0.001); left ventricular systolic volume decreased from 121.89.2mL to 110.213mL (P=0.003); and the number of dysfunctional segments was reduced from 147 to 137. Low-dose dobutamine (520g/kg per min) improved contractility in 99 of 179 segments (a 30% increase relative to the initial study), compared with no significant changes in patients receiving placebo. In addition, the peak oxygen consumption increased significantly, from 16.41.4mL/kg per min to 18.91.7mL/kg per min in patients receiving active treatment. It was concluded that Vastarel improves resting contractile function, in addition to the contractile response to inotropic stimulation by low-dose dobutamine, in patients with severe ischemic dysfunction. These improvements suggest that the metabolic mode of action of Vastarel has a direct cytoprotective effect on myocardial cells, which carries potential prognostic implications in patients with heart failure.

Effect of Vastarel on microcirculation and in diabetic patients
Diabetic patients are known to have structural abnormalities of the small vessels (microcirculation) affecting vasodilatory reserve, in addition to having epicardial coronary obstruction. Microcirculatory resistance is neither constant in time nor uniform in different perfusion areas. Di Girolamo et al [4] assessed the effect of Vastarel on myocardial microcirculation in patients with stable coronary artery disease and showed a significant reduction in defects in exercise stress thallium-201 scintigraphy, and an improvement in the ischemic threshold. The beneficial effects were postulated to be from the reversal of cellular edema and extravascular compression of the coronary microvascular network brought about by Vastarel.
Diabetic patients are also more likely to have metabolic abnormalities such as impaired glycolysis, pyruvate oxidation, and lactate uptake, and greater dependency on fatty acids as a source of acetyl coenzyme A. Vastarel, with its specific metabolic action, is a suitable treatment for these patients. Fragasso et al [5] studied the short- and long-term specific beneficial effects of Vastarel in a small cohort of diabetic patients with severe ischemic dilated cardiomyopathy in whom it produced an improvement in left ventricular ejection fraction and fractional shortening after 2 weeks of treatment. This positive effect was maintained in the long term, after 6 months of treatment (Figure 1). Szwed et al [6] showed that diabetic patients with stable angina pectoris enjoyed the same level of benefits as nondiabetic individuals in having improvement in total exercise duration and time to 1mm ST-segment depression, and significant decreases in weekly frequency of anginal episodes and weekly consumption of nitrate medication.

Effect of Vastarel on patients after myocardial infarction
Acute myocardial infarction results in profound myocardial ischemia and potential permanent loss of myocytes and function. Reperfusion treatment remains the cornerstone of the treatment of these patients, but metabolic intervention seems a promising approach to lessen myocardial injury and limit infarct size. Infusion of glucose, insulin, and potassium  a form of metabolic intervention  has been studied and found to be associated with a reduction in infarct size and enhancement of functional recovery [7,8].
The Limitation of Infarct Size by Trimetazidine (LIST) study was a double-blind, randomized trial that included 94 patients who presented with a first episode of myocardial infarction with ST-segment elevation [9]. The patients were admitted within 6hours of the onset of symptoms and had a totally occluded (TIMI grade 0 or 1) culprit artery that was adjudged to be amenable to percutaneous transluminal coronary angioplasty. The treatment regimen was an intravenous bolus dose of 40mg Vastarel, followed by an infusion of 60mg/day for 48hours. In the Vastarel group, the return to baseline of the ST segment was achieved significantly earlier than in the placebo group (P=0.014). In addition, there was a trend toward a less frequent exacerbation of ST-segment elevation immediately after reperfusion, which is a marker of reperfusion injury (23% compared with 42%; P=0.11). Papadopoulos et al [10] showed that, in comparison with placebo, Vastarel significantly decreased the onset of reperfusion arrhythmias in patients who had undergone angioplasty [10].
For metabolic intervention treatment to work, it is imperative that myocardial viability remains preserved after myocardial injury. Vastarel has been shown to improve myocardial function after revascularization treatment in patients with ischemic cardiomyopathy who had demonstrable myocardial viability before operation. Ciavolella et al [11] studied 12 patients treated with Vastarel and reported a significant increase in tracer uptake, mainly in viable segments (proven on technetium-99m sestamibi single photon emission computed tomography and echocardiography) that showed improved myocardial function postoperatively.
Finally, a recent review by Marzilli has summarized all the available clinical evidence showing how a metabolic intervention with Vastarel can protect the heart from the deleterious consequences of ischemia (12).

Conclusions
Optimizing energy metabolism in the ischemic heart is a novel approach for the management of both ischemic heart disease and heart failure. The stimulation of myocardial glucose oxidation directly through the use of metabolically active agents, or indirectly through secondary inhibition of fatty acid oxidation, improves the production and utilization of energy at cellular level. These changes in cardiac metabolism are critical steps in affording benefit to a wide spectrum of patients, from those with stable angina to those with ischemic cardiomyopathy. Clinical findings with Vastarel MR, the first 3-ketoacyl coenzyme A thiolase inhibitor, have shown promise in such a metabolic interventional approach.

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REFERENCES

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