Trimetazidine and the contractile response of dysfunctional myocardium in ischaemic cardiomyopathy

Abstract

The therapeutic effect of anti-ischemic compounds is related to their ability to improve the oxygen supply-demand balance of the ischemic myocardium by increasing myocardial blood flow (calcium-antagonists), by reducing regional myocardial oxygen consumption (verapamil, betablockers) and increasing peripheral pooling of blood (nitrates, nifedipine). All these actions are also accompanied by hemodynamic changes, as evidenced by a lower double product, reduced wall stress, lower pulmonary wedge pressure, and lower systemic arterial pressure. In general, it was found that the combination of a betablocker with nifedipine improved the antianginal effect by further reducing the number and duration of ischemic events. The combination of a nitrate with a beta-blocker is particularly useful because it reduces the risk of heart failure by lowering left ventricular end-diastolic pressure and volume and by attenuating the negative inotropic effect of the betablocker. Although a combination therapy demonstrated benefits in comparison with drug treatment alone, it is associated with a higher incidence of untoward events. Trimetazidine (2, 3, 4 trimethoxybenzyl-piperazine dihydrochloride) is a novel anti-ischemic compound with a peculiar mechanism of action. Its anti-ischemic properties are unrelated to changes in myocardial oxygen supply-to-demand ratio, as shown by no significant effects on heart rate, blood pressure or rate-pressure product both at rest and during dynamic exercise. There are several possible mechanisms of action by which trimetazidine promotes preservation of membrane structures and cellular function: limitation of intracellular acidosis, correction of disturbances of transmembrane ion exchange leading to calcium overload, prevention of an excessive production of free radicals, inhibition of the inflammatory reaction and an antiplatelet effect. These documented actions cooperate to increase the rate of resynthesis of high-energy phosphates within myocardial cells after episodes of ischemia. In several trials, trimetazidine has been tested as an antianginal agent, both as monotherapy and combined with "classical" anti-ischemic compounds. In comparison with nifedipine, trimetazidine had similar efficacy in reducing the number of weekly anginal attacks and in increasing the ischemic threshold in a group of 39 patients with stable angina. However, the incidence of side effects was significantly higher with nifedipine (5 vs 20), and affected 5 patients with trimetazidine and 13 patients with nifedipine (p = 0.03). In a relatively large European study involving 149 patients (Trimetazidine European Multicenter Study, TEMS), trimetazidine (20 mg t.i.d.) was compared with propranolol (40 mg t.i.d.) in patients with stable angina pectoris and documented significant coronary artery stenoses. The number of anginal attacks was reduced equally by both drugs and exercise duration was increased by both treatments. However, in contrast with propranolol trimetazidine did not alter the rate pressure product. In patients already treated with nifedipine or beta-blockers, the addition of trimetazidine (20 mg t.i.d.) was able to reduce the number and the duration of anginal attacks and improved also the exercise capacity. Trimetazidine is generally well tolerated and only minor side effects have been reported (drowsiness, sedation, diarrhea). The improvement in cardiac energy metabolism should theoretically translate into enhancement in mechanical efficiency. This hypothesis has been object of recent investigations in patients with ischemic heart disease with and without left ventricular dysfunction. Brottier, et al. demonstrated that patients with ischemic cardiomyopathy treated with trimetazidine had a higher ejection fraction (measured by radionuclide angiography) than control patients who received a placebo after 6 months of therapy (p < 0.018). The group of Chierchia demonstrated that trimetazidine improved ischemic regional myocardial dysfunction at rest and during stress-induced ischemia in 15 patients with chronic coronary artery disease without affecting the hemodynamic determinants of myocardial oxygen consumption. There is recent demonstration that trimetazidine improves the contractile response of left ventricular hibernating myocardium in patients with ischemic heart disease. Belardinelli et al. showed that trimetazidine improved the contractile response of dysfunctional myocardial to low-dose dobutamine in patients with ischemic heart disease and left ventricular function. Twenty-two patients with prior anterior myocardial infarction and injection fraction < 35% (33 +/- 7%) were randomized into 2 groups. A group (= 11) received trimetazidine (20 mg tid) for 2 months, while another group (= 11) received a placebo. The usual medications were not altered during the study. (ABSTRACT TRUNCATED)