Number 26, 2005
Cardiovascular effects of exercise

New therapeutic approach in chronic heart failure: metabolic intervention with trimetazidine

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Hamayak S. Sisakyan
Department of Internal Diseases Diagnostics and Cardiology, University N1 Hospital, Yerevan State Medical University, Yerevan, Armenia
Correspondence: Professor Hamayak S. Sisakyan, Koryun Street 2, Yerevan State Medical University, Yerevan 375025, Armenia.
Tel: +347 1582023, fax: +347 1541350, e-mail: sisakyan@doctor.com

Introduction
The management of heart failure has improved considerably over the past decade. Treatment modalities that influence cardiac remodeling and neuroendocrine activation exert beneficial effects by decreasing symptoms, improving quality of life, and reducing high mortality.
Increased energy metabolism through the free fatty acid pathway may be unfavorable in conditions of decreased delivery of oxygen to the heart [1,2]. One of the pathophysiologic metabolic pathways responsible for the progression of heart failure is the induction of insulin resistance, which initiates sympathetic activity, endothelial dysfunction, and increased activity of proinflammatory cytokines [3]. Influencing the energy metabolism of the failing heart by stimulating pyruvate dehydrogenase activity and facilitating glucose oxidation seems attractive from a pathophysiologic and metabolic point of view, as glucose oxidation needs less oxygen and energy [1–3]; the improvement in cardiac energy metabolism will support the enhancement in mechanical efficiency. This hypothesis has been confirmed by the use of trimetazidine in several studies in patients with left ventricular dysfunction and ischemic cardiomyopathy [4–7]. Trimetazidine, through selective inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase, increases glucose oxidation by a shift of energy substrate preference from fatty acid to glucose oxidation [8].

Effect of trimetazidine on left ventricular function in patients with ischemic cardiomyopathy
We undertook a study to determine whether modified-release trimetazidine (Preductal MR; 35mg twice daily), has a positive effect on left ventricular function in patients with ischemic cardiomyopathy, when taken in conjunction with their standard therapy (angiotensin-converting enzyme [ACE] inhibitors, diuretics, and ß-blockers).
Seventeen patients were recruited to the study, which was performed at Yerevan State Medical University Hospital, Department of Internal Diseases Diagnostics and Cardiology. One patient was excluded after 1 week because of poor compliance with the standard therapy. Inclusion criteria were: stable clinical condition before entry on standard therapy (ACE inhibitors, ß-blockers, diuretics). All patients had an end-diastolic diameter of at least 6.0cm, and ejection fraction less than 45% as determined by echocardiography. A total of 16 patients with ischemic cardiomyopathy designated as New York Heart Association (NYHA) functional Class II or III were allocated randomly to groups to receive additional treatment with modified-release trimetazidine 35mg twice daily (eight patients) or to continue with their standard therapy for heart failure (eight patients). They were followed for 3 months. Echocardiography (ATL Ultramark-9 system, Boston WA, USA) was performed at baseline and after 3 months of treatment. All examinations were recorded on videotape and evaluated by two different specialists. Left ventricular dimensions and diastolic and systolic volumes, ejection fraction, and fractional shortening were determined according to the recommendations of the American Society of Echocardiography [9].
All statistical tests reported are two-tailed t-tests. Values of P =0.05 were considered to be significant.

Results
In the trimetazidine group, three patients improved from NYHA Class III to NYHA class II and two improved from NYHA Class II to Class I; among patients receiving conventional treatment, only two had improved functional class. None of the patients in the trimetazidine group worsened their NYHA functional status. During the first day after initiation of treatment and during the entire period of the study, no hemodynamic effect (change in heart rate or blood pressure) or any cardiovascular complication was observed. No serious clinical adverse events were reported by any of the patients.
The echocardiographic study showed a decrease in the end-systolic diameter of the left ventricle in the trimetazidine group, from 5.6±0.8cm at baseline to 4.92±0.83cm after 3 months of treatment. In the control group, the left ventricular systolic diameters remained unchanged (Table I, Figure 1).

Table I. Echocardiographic data of two groups after 3 months of treatment.

Discussion
The results of our study show that, in patients with moderate chronic ischemic myocardial dysfunction, modified-release trimetazidine is able to relieve symptoms of heart failure and left ventricular function and is well tolerated, without any hemodynamic changes. These findings were not associated with any effects on the patients' heart rates or systolic blood pressures, reflecting the purely metabolic mechanism of action of the drug. To our knowledge, our study is the first to test modified-release trimetazidine with a dose of 70mg/day in patients with ischemic cardiomyopathy. Although the study population was small, we were able to confirm the safety and tolerability of modified-release trimetazidine despite a daily dose that was increased (70mg) in comparison with those previously used in clinical studies (20mg three times a day).
The increase in myocardial contractility during ischemic cardiomyopathy can be explained by the regulation of mitochondrial structure and function, and by the increase in glycolytic adenosine triphosphate (ATP) synthesis [10]. It is possible that hibernated myocardium can be activated by trimetazidine: a favorable effect of trimetazidine on hibernation was demonstrated by Belardinelli and colleagues, who found that trimetazidine improved the contractile response of chronically dysfunctional myocardium to low-dose dobutamine [7,11].
It is well known that the heart has a high rate of energy turnover, with ATP as a basic source of energy. The two coexisting pathways for energy supply are ß-oxidation of free fatty acids and breakdown of carbohydrates. The carbohydrate pathway comprises glycolysis and lactate oxidation, producing pyruvate, which is decarboxylated by pyruvate dehydrogenase to acetyl coenzyme A, which in turn enters the final common pathway of the Krebs cycle. Under aerobic conditions, the myocardium generates energy predominantly by oxidation of free fatty acids (70 to 80%), with a smaller contribution from glycolysis (20 to 30%). The oxidation of glucose ensures the activity of the ion pumps (Na⁺/K⁺ ATPase and Ca²⁺ ATPase), which preserves the myocyte membrane potential and rapid transport of Ca²⁺ between subcellular compartments [12,13]. The glycolytic and pyruvate pathways require less oxygen per mole of ATP produced than does free fatty acid oxidation. The glucose–fatty acid cycle, described by Randle and colleagues in 1964 [14], preserves the balance between available energy substrates. Glucose utilization is controlled by the availability of, and sensitivity to, insulin, and also by competition with the free fatty acid pathway metabolites. Increased metabolism by the free fatty acid mechanism inhibits the glycolytic pathway, which may be unfavorable in a situation of decreased oxygen delivery to the heart or under other conditions (stress, heart failure, diabetes). Trimetazidine selectively inhibits long-chain 3-ketoacyl coenzyme A thiolase – a key enzyme involved in fatty acid ß-oxidation. This compound stimulates glucose uptake, inducing glucose phosphorylation while reducing fatty acid oxidation [15,16].
Brottier and colleagues [4] were the first to demonstrate that patients with ischemic cardiomyopathy treated with trimetazidine for 6 months had ejection fractions (determined by radionuclide angiography) increased by more than 9% compared with a placebo group. The study by Belardinelli and Purcaro [7] in 38 patients with ischemic cardiomyopathy aimed to determine the effect of trimetazidine on cardiac function by echocardiography. The resting ejection fraction in the trimetazidine-treated group increased from 33.1±4.5% to 39.5±5.9% (P=0.001), and the number of dysfunctional segments was reduced from 147 to 137. Low-dose dobutamine improved contractility in 99 of 179 segments, compared with no significant change in patients receiving placebo. This effect in a study of low-dose dobutamine suggests that preserved contractile reserve and viable myocardium may be activated by metabolic intervention with trimetazidine.
The recent study by Vitale and colleagues [5] aimed to assess the effect of trimetazidine on left ventricular function in elderly patients with left ventricular dysfunction, after 6 months. The results have shown that patients receiving trimetazidine had a greater improvement in NYHA class, and a better quality of diastolic function than did those in the placebo group (left ventricular ejection fractions 34.4±2.3% and 27±2.8%, respectively; P <0.0001).
The limitations of our study were the small number of patients and the short (3 months) period of follow-up, which did not allow us to assess mortality with respect to the long-term benefit compared with that associated with other drugs used in chronic heart failure, such as ß-blockers or ACE inhibitors.
Our data have provided support for the therapeutic importance of metabolic treatment with trimetazidine in patients with left ventricular dysfunction and ischemic cardiomyopathy.

Conclusions
Treatment with modified-release trimetazidine 70mg/day in addition to standard therapy, over a 3-month period, improves the functional class and systolic function of patients with ischemic cardiomyopathy. This use of trimetazidine was associated with an excellent tolerance profile. ?

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REFERENCES

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