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Trimetazidine: Potential Mechanisms of Action in Hypertrophic Cardiomyopathy

D'hahan, Nathalie

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Journal of Cardiovascular Pharmacology: March 1999 - Volume 33 - Issue 3 - p 500-506
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Abstract

Many authors have described hypertrophic cardiomyopathy through its multiple cellular alterations, including ischemic disorders associated with abnormal cellular homeostasis, abnormalities in cell-to-cell arrangement, disorganization of the myofibrillar architecture within a given cardiomyocyte, and compensatory hypertrophy (1,2). [Hypertrophy is defined as an adaptive process to cell loss, which occurs after myocardial necrosis (3)].

Conventional pharmacologic management of this disease includes the use of β-blockers (4), antiarrhythmics, calcium channel antagonists, and long-acting nitrates (5). These classes of drugs are now established as therapeutically useful antiischemic compounds, acting mainly through a hemodynamic mechanism. However, they have cardiodepressant activity (6) and induce side effects. Therefore, there have been numerous experimental investigations to identify drugs with similar antianginal properties, but without such drawbacks.

Trimetazidine [1-(2,3,4 trimethoxybenzyl) piperazine di-hydrochloride] is currently used in clinical treatment of anginal disease, a discomfort in the chest caused by myocardial ischemia and associated with a disturbance of myocardial function (7,8). Trimetazidine has led to improvement of the clinical status of patients with severe ischemic cardiomyopathy (9). Trimetazidine improves performance capacity in angina pectoris, as demonstrated by a significant increase in the duration of exercise, the total work performance, and the improvement in electrocardiogram signs of ischemia (10). In sharp contrast to other commonly used antianginal drugs, trimetazidine neither reduces oxygen consumption nor increases blood supply. Moreover, under trimetazidine treatment, no significant changes in heart rate, blood pressure, or rate-pressure product have been observed at rest or during exercise (8,10). This absence of central hemodynamic effects suggests that the drug acts by a novel antiischemic mechanism involving direct myocardial cytoprotection (11). Although the mechanisms underlying the positive effects of trimetazidine are still unknown, experimental studies suggest a metabolic effect (12), possibly due to protection of myocardial cell function during ischemia by (a) preventing the decrease in adenosine 5′-triphosphate (ATP; 13); (b) limiting the content of free radicals (14,15); and (c) preventing the accumulation of protons, sodium, and calcium in the myocyte (16,17).

This review summarizes the cellular disorders associated with cardiomyopathy, discusses recent available information on the cardio- and cytoprotective properties of trimetazidine and its mechanisms of action, and presents the evidence for the positive effects of a long-term monotherapy with trimetazidine in BIO 14:6 Syrian hamsters, a useful model of human cardiomyopathy. We conclude by considering the novel aspects of trimetazidine therapy and its advantages over the classic drugs currently used for this disease.

HYPERTROPHIC CARDIOMYOPATHY: A CELLULAR DISORDER

Spontaneous cardiomyopathies have been evaluated in hamsters, turkeys, and dogs (18). Two Syrian myopathic hamster strains have been extensively investigated as potential models of human heart failure disease (19): the BIO 14.6 strain for hypertrophic cardiomyopathy and BIO 53.58 for dilated cardiomyopathy (20). Syrian hamster cardiomyopathy can be described by four distinct phases: a latent phase, a necrotic phase, a phase of hypertrophy and dilatation, and a terminal phase (18). This model offers a number of advantages: (a) it is predictive of mortality and symptoms, (b) it is easy to use (noninvasive), (c) it makes it possible sufficient numbers of experiments to allow statistical analyses, and (d) it is economical and requires less drugs than required for large animal models. Finally, it is amenable to pharmacologic investigations. Animal models of myocardial ischemia involve lesions induced by coronary ligation, coronary embolism, and chronic hypoxia (21,22). Unlike the Syrian hamster model, the drawbacks of these models include (a) a variability in the discrete myocardial lesions, (b) the requirement for thoracotomy (an invasive technique), and (c) a high initial mortality rate. Although the etiologic factors of hypertrophic cardiomyopathy remain unknown, several studies indicated that the myocardium of the cardiomyopathic hamster (CMH) is chronically ischemic on the basis of microvascular spasms of the circulation and is characterized by alterations of cellular homeostasis (3,4). Therefore the BIO 14:6 Syrian hamster is an interesting animal model for ischemic cardiomyopathy.

Recent available information about the markers of disease in the BIO 14:6 Syrian hamster are summarized in Table 1. The disease is thus characterized by the outcome of several mechanisms of ischemia, including energetic and cellular dysfunction: alterations in membrane structure and permeability leading to disturbances in ion transport and tissue calcium accumulation associated with cell necrosis. Ischemia is characterized by dysfunction of energy production, acidosis, and overproduction of free fatty acids and oxygen-derived free radicals, responsible for disturbed cellular homeostasis (33 for review). A consequence is an increase in the cellular calcium concentrations (34), and this tends to block many vital enzymatic functions and leads to necrosis.

TABLE 1
TABLE 1:
Parallel between phenomena associated with ischemia and cardiomyopathic features of the Syrian hamster BIO 14:6

α-Tocopherol (an antioxidant) therapy has a protective effect in BIO 14:6 hamsters treated during the early stage of cardiomyopathy (≤90 days; 25). Vitamin E administration in the myocardium of 60-day-old CMH restores the creatine kinase activity and decreases the lipid peroxide content, thus returning them to normal control levels. Therefore, as trimetazidine activities have been suggested to involve each of the intracellular events that characterize cellular ischemia (26), a protective effect of trimetazidine is expected (See Table 1).

POSITIVE EFFECTS OF A LONG-TERM MONOTHERAPY WITH TRIMETAZIDINE IN THE BIO 14:6 CARDIOMYOPATHIC HAMSTER

Promising results were obtained in our laboratory with trimetazidine in cardiomyopathy (27,28). We investigated the effects of a long-term oral therapy, from 30 to 350 days, with trimetazidine on BIO 14:6 cardiomyopathic Syrian hamsters. Trimetazidine was compared with verapamil, a well-known calcium channel antagonist, which also is used as an antianginal agent (29,30). The concentration of trimetazidine obtained in the plasma was within the range observed in human patients treated for cardiovascular disorders (1.5 × 10−7M).

The effects of ischemia are numerous and closely interconnected, but alterations of cellular homeostasis seem to be the primary event responsible for the cascade of alterations (31). Therefore cytosolic and total calcium levels were investigated by spectrofluorimetry and histochemistry. At the late stage of the disease, CMHs display a total calcium overload amounting to a factor of 2 and a cytosolic calcium overconcentration amounting to a factor of 4 (27). Long-term oral treatment with trimetazidine has been successful: the total calcium level in CMH reverted to that of F1Bs (healthy golden hamsters), and the cytosolic calcium overload was limited to a factor of 2 (27). These results were comparable to those obtained with verapamil. Trimetazidine possesses indirect antagonist activity inhibiting, at least partly, intracellular acidosis in the heart (16,17) and consequently may be indirectly involved in reducing the accumulation of calcium (17,32). This could in turn reduce ischemic contracture (33,34). One possibility is that trimetazidine, limiting acidosis (16), increases intrinsic cardiac H+ buffering power (βi; 17). As a result, trimetazidine would slow the activity of Na+/Ca2+ exchange (35). Because an increase in cellular sodium content may be the driving force for cell swelling during ischemia (36), trimetazidine, by limiting Na+ influx, may prevent the volume modification that causes hypertrophy. By preventing the Na+-linked Ca2+ overload, trimetazidine may postpone the onset of irreversible damage to cardiac cells, thereby limiting the compensatory ventricular hypertrophy. Indeed, ventricular hypertrophy was +22% (n = 17; p < 0.05 vs. controls) in untreated CMH but only +7% (n = 5; not significant vs. controls) in trimetazidine-treated CMH (27). The degree of ventricular hypertrophy also correlates with the magnitude of the heavy-chain myosin isoenzyme V1 to V3 transition (37). The relative content of the V3 form, which exhibits the lowest adenosine triphosphatase (ATPase) activity, increases with time at the expense of that of V1, in cardiomyopathy (38). Thus we attempted to prevent the redistribution from V1 to V3 by treating the animals with trimetazidine. Trimetazidine did not reverse the decline in V1 content but increased the V3 content at the beginning of the treatment (65 days) and maintained it at a constant level (∼20%) throughout the treatments from 65 to 220 and 350 days (28).

The reduction of high calcium levels and normalization of ventricular hypertrophy with trimetazidine could explain the improved survival of CMHs (27). The increase in survival was indeed noticeable: ∼150-200 days, which is larger than that obtained with a structural analog of verapamil, gallopamil (D-600; 39). Our study was the first to evaluate survival with trimetazidine therapy in an animal model of cardiac disease. Because these beneficial effects of trimetazidine do not appear to correlate with a normalization of the cardiac myosin isoenzyme composition, this finding suggests that myosin heavy-chain (MHC) transitions toward the V3 form are not necessarily an aggravating factor of the disease. They may be adaptive compensatory events, as has often been suggested in overloaded hearts (37,38,40). Favoring the β-MHC, which has lower ATPase activity and may use less energy for contraction, trimetazidine would help conserve energy by limiting the decrease in the intracellular ATP concentration caused by ischemia (13). This would be coherent with the hypothesis that trimetazidine induces a reduced activity state or a "normoxic" metabolic switch (41). In short, trimetazidine may cause slower but more economic functioning of the myocardial cell and thus enhance myocardial energy efficiency (42), which could explain the prolonged survival.

PROPERTIES AND ADVANTAGES OF TRIMETAZIDINE, AS COMPARED WITH CLASSIC ANTIISCHEMIC AGENTS

Properties and potential targets of trimetazidine

The cardio- and cytoprotective effects of trimetazidine are summarized in Tables 2 and 3. Although the exact mechanism of action is not fully understood, trimetazidine probably acts on a cellular level, in each step of the ischemia sequence of events (26). Trimetazidine acts on ischemia-induced (a) deterioration of energy production (Table 4A), (b) distortion of cellular homeostasis (Table 4B), and (c) overproduction of free radicals in the cell (Table 4C).

TABLE 2
TABLE 2:
Cardioprotective effect of trimetazidine
TABLE 3
TABLE 3:
Cytoprotective effect of trimetazidine
TABLE 4A
TABLE 4A:
Effect of trimetazidine on energetic metabolism
TABLE 4B
TABLE 4B:
Effect of trimetazidine on cellular homeostasis
TABLE 4C
TABLE 4C:
Antioxidant effect of trimetazidine

Trimetazidine is devoid of hemodynamic effects

Trimetazidine exerts its antiischemic effects without any associated central hemodynamic change, either at rest or during exercise (43). Trimetazidine belongs to a new class of antiischemic agents (44) and is unusual in that it causes no measurable changes in the variables known to affect the supply-demand ratio. Used clinically, trimetazidine improves exercise capacity without altering heart rate or blood pressure (8,10). Drugs such as trimetazidine or ranolazine, a piperazine derivative modulating myocardial metabolism (45), have this property.

Drugs such as β-blockers, calcium channel antagonists, and long-acting nitrates (5) increase exercise tolerance and reduce symptoms. Although there are many pharmacologic differences between them, these three classes of compounds act mainly through a hemodynamic mechanism (coronary dilatation, reduced peripheral resistance) that induces a reduction of myocardial oxygen consumption during effort (44). Not only do these drugs act outside the ischemic area (on peripheral veins or arteries, sinus node, endoepicardial blood-flow ratio, etc.; 46), they also exhibit cardiodepressant activity or may increase coronary artery spasms or both, or cause the reduction of blood pressure, headache, tachycardia, and peripheral edema in some patients (6).

CONCLUSION

Currently available experimental data show that trimetazidine possesses particularly valuable properties for the treatment of various forms of myocardial ischemia (49). Positive results obtained with long-term trimetazidine-treated CMHs, in agreement with clinical studies, favor the use of trimetazidine for the metabolic management of hypertrophic cardiomyopathy. The mechanisms underlying the positive effects of trimetazidine are still unknown. Investigations using this in vivo animal model will be continued to determine the mechanism of action of this novel drug. These studies also demonstrate the usefulness of the CMH model for evaluating compounds with antiischemic properties. Finally, the safety of trimetazidine, assessed by clinical trials, and its widespread use, especially in Japan and France, are important considerations favoring its use for preventing human congestive heart failure of similar etiology.

Acknowledgment: Trimetazidine was a gift from IRIS (Institut de Recherches Internationales Servier, France). Part of this work was supported by grants from IRIS and by predoctoral fellowships of Institut de Formation Supérieure Bio Médicale (IFSBM, Villejuif, France) to Nathalie D'hahan. I thank Dr. Arnaud Lucien from IRIS for the helpful discussions.

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        Keywords:

        Trimetazidine; Ischemia; Hypertrophic cardiomyopathy; Syrian hamster

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