Number 41, 2008
Taking genes to heart

Anti-ischemic cardioprotection with trimetazidine

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Pericle Di Napoli
Cardiovascular Section, SMDN-Centre for Cardiovascular Medicine and Cerebrovascular Disease Prevention, Sulmona (AQ), Italy; Villa Pini d’Abruzzo Clinic, Department of Cardiology, Heart Failure Unit, Chieti, Italy
Correspondence: Dr Pericle Di Napoli, Cardiovascular Section, SMDN-Centre for Cardiovascular Medicine and Cerebrovascular Disease Prevention, Via Trento, 41, 67039 Sulmona (AQ), Italy.
Tel/fax: +0039 0864 52716; e-mail: dinapoli@unich.it

The ischemia-reperfusion damage: from bench to bedside
It is commonly accepted that a rapid re-opening of an occluded vessel, by either mechanical means (coronary angioplasty or bypass surgery) or pharmacological means (thrombolytic or antiplatelet drugs), should be performed as soon as possible in patients with acute coronary syndromes. The opening of a coronary artery or the interruption of an ischemic period, such as in effort angina, exposes the entire heart to a complex cascade of events, so-called “reperfusion injury”, that influences the final amount of cellular damage, the endothelial function, the degree of mechanical dysfunction, and the short- and long-term prognosis. Reperfusion injury may affect various aspects of myocardial and endothelial function, with different and complex pathophysiological consequences [1]. The term encompasses several events, including microvascular damage, reperfusion arrhythmias, reversible myocardial mechanical dysfunction (stunning), and cell death (apoptosis or necrosis). Oxidative stress, intracellular calcium overload, neutrophil activation, metabolic alterations, and excessive intracellular osmotic load have all been proposed to explain the pathogenesis and consequences of inflammatory injury in ischemic reperfused myocardium.

Inflammatory and endothelial damage
The inflammatory process characterizes early and late reperfusion and is involved in tissue damage. Neutrophils feature prominently in the inflammatory component of post-ischemic injury. Ischemia-reperfusion prompts a release of oxygen free radicals, cytokines, and other proinflammatory mediators that activate both the neutrophils and the coronary vascular endothelium [2]. Activation of these cells promotes the expression of adhesion molecules on both neutrophils and the endothelium; these recruit neutrophils on the endothelial surface and initiate a specific cascade of cell–cell interactions. This specific series of events is a prerequisite for the full expression of reperfusion injury, including endothelial dysfunction, microvascular collapse, impairment of blood flow (“no-reflow” phenomenon), myocardial infarction and apoptosis [3]. Endothelium-derived factors, such as nitric oxide and adenosine, exhibit a wide range of effects against neutrophil-mediated events and modulate the inflammatory response after reperfusion [3]. Alterations in endothelial function are pivotal in the development of reperfusion damage and the no-reflow phenomenon; here, the enhanced release or increased bioavailability of nitric oxide appears to be central. Besides its well known vasodilatory effects, nitric oxide reduces microvascular dysfunction, platelet adhesion and aggregation, and leukocyte adherence or emigration [3,4].

Apoptotic cell death
Apoptosis is an energy-requiring physiological mechanism of cell death that regulates cell mass in many tissues; it is a genetically directed process that takes place in response to internal or external stimuli. Cardiomyocyte apoptosis has important pathophysiological consequences, contributing to functional abnormalities in the myocardium. It has been reported in a variety of cardiovascular diseases, including myocardial infarction or ischemia [5] and endstage heart failure [6]; a specific association with reperfusion injury has been suggested [7]. The cellular mechanisms underlying both ischemia-reperfusion injury and apoptosis may involve cellular calcium overload, left ventricle wall stresses, overproduction of oxygen-derived free radicals, cellular acidosis, inflammatory reaction, and microcirculatory dysfunction [7–9].

Metabolic changes
A metabolic protection of the ischemic myocardium appears to be a key factor in limiting reperfusion damage [9–11]. Major metabolic changes occurring during the early hours of myocardial infarction include increased secretion of catecholamines and production of circulating free fatty acids (FFAs). Under normal conditions, the myocardium depends on aerobic metabolism, with FFAs as the preferred energy source. During ischemia-reperfusion, FFA concentrations are greatly increased, and exert a toxic effect on the myocardium. This results in increased membrane damage, endothelial dysfunction, tissue inflammation, and decreased cardiac function. Decreasing plasma FFA concentrations and cardiac fatty acid oxidation, together with the stimulation of glucose and lactate uptake, might reduce these detrimental effects. This might be achieved by glucose–insulin–potassium (GIK) solutions at the time of reperfusion [12] and by inhibiting fatty acid oxidation with 3-ketoacyl coenzyme A thiolase inhibitors, such as trimetazidine [9].

Anti-ischemic cardioprotection with trimetazidine
The anti-ischemic cardioprotection achieved with trimetazidine may involve several aspects, summarized in Table I and Figure 1.

Table I. Anti-ischemic cardioprotection with trimetazidine: main effects.

Trimetazidine reduces cell damage: necrosis and apoptosis
Various studies demonstrated that, in experimental conditions, trimetazidine reduces the myocardial damage caused by ischemia-reperfusion [9]. In patients with acute myocardial infarction, pretreatment with trimetazidine (40 mg orally about 15 min before thrombolysis, and then 20 mg every 8 h) can decrease the time to creatine kinase normalization, suggesting that trimetazidine reduces reperfusion damage and infarct size in patients with acute myocardial infarction who undergo thrombolysis, and affects remodeling after myocardial infarction [16]. Ruixing et al [17] reported that, in a rabbit model of ischemia-reperfusion, trimetazidine also reduced cardiomyocyte apoptosis and ischemia-reperfusion injury via antioxidant properties.

Trimetazidine preserves mitochondrial functions
Mitochondria are key factors in energy production in cells. Lipid oxidation is responsible for the production of much ATP resynthesis in the heart, but this process is less oxygen-efficient than glucose oxidation. During ischemia, lipid oxidation is suddenly blocked, but it is markedly increased during reperfusion, causing accumulation of potentially toxic metabolites (acyl carnitines, acyl coenzyme A, lysophospholipids). Trimetazidine inhibits the production of deleterious lipid metabolites and it can also reduce mitochondrial damage, inhibiting mitochondrial permeability transition-pore opening, and protects the heart from prolonged ischemia-reperfusion injury [18].

Trimetazidine protects against toxicity induced by oxygen free radicals
In mitochondria and endothelial or myocardial cells, trimetazidine reduces membrane damage induced by oxygen free radicals. This effect has also been reported in red cells after oral administration [19]. The drug acts as a potent antioxidant, and this mechanism of action could explain its cardioprotective role during ischemia and reperfusion, in which oxygen free radicals are generated and implicated in cardiac cell injury. Trimetazidine, at concentrations greater than 100 μmol/L, competed with cytochrome c in scavenging oxy radicals formed by the reaction catalyzed by the action of the xanthine oxidase enzyme upon xanthine. This scavenger effect was also observed when oxy radicals were generated by active human neutrophils [20].

Trimetazidine protects endothelial function and modulates the myocardial inflammatory reaction
Various studies have demonstrated that trimetazidine reduces inflammation and improves endothelial function in both acute conditions (ischemia-reperfusion damage, coronary angioplasty, thrombolysis) and chronic conditions (ischemic cardiomyopathy, stable angina). Trimetazidine maintains the integrity of cell membranes and of mitochondrial structure, and ensures the protection of myocardial cells that are at risk (Figure 1). Trimetazidine also protects postischemic hearts from neutrophil-mediated injury [21]. Tritto et al [22] reported that trimetazidine inhibited neutrophil activation in vitro and reduced cardiac oxygen radical production at reflow, independently of direct scavenger effects. Trimetazidine is also a useful drug in preventing inflammation after percutaneous transluminal coronary angioplasty (PTCA) [23,24]. Pre-procedural treatment with oral trimetazidine for 3 days significantly suppressed the increase in inflammatory markers before and shortly after PTCA [24]. Recent studies have analyzed the impact of trimetazidine on markers of inflammation in chronic ischemic heart disease. In patients with ischemic cardiomyopathy, we found [25] that plasma concentrations of C-reactive protein remained unchanged in the group of patients receiving trimetazidine, whereas a progressive increase in concentration was seen throughout the follow-up period (18 months) in the control group; this anti-inflammatory effect could be involved in the significant reduction in mortality and admissions to hospital observed in the same patients after 48 months of treatment [26]. In addition, a decrease in the serum concentrations of endothelin-1 has been reported in patients with diabetes receiving treatment with trimetazidine, both after short-term (2 weeks) and after long-term (6 months) treatment [27]. The mechanisms responsible for these favorable effects of trimetazidine on the inflammatory profile and endothelial function are poorly known. We have reported [28] that, in isolated rat heart subjected to ischemia and reperfusion, trimetazidine reduced ischemia-reperfusion damage and increased endothelial nitric oxide synthase mRNA and protein concentrations. In this way, trimetazidine exerts a significant, nitric-oxide-dependent, cardioprotection against ischemia-reperfusion injury and preserves the coronary endothelium. Preservation of the production of endothelial nitric oxide synthase and its bioavailability appears also to be a critical factor in the decrease in release of endothelin-1 and the preservation of endothelial function. Recently, Belardinelli et al [29] reported that trimetazidine improved endothelium-dependent relaxation in patients with ischemic cardiomyopathy. This effect was associated with antioxidant properties as measured by a reduction in plasma malondialdehyde and lipid hydroperoxide concentrations.

Conclusions
In the ischemic myocardium, metabolic antianginal treatment with trimetazidine induces a shift from utilization of FFAs towards utilization predominantly of glucose, increasing ATP generation per unit of oxygen consumption. This represents an innovative approach to the treatment of ischemic heart disease and to the reduction of ischemia-reperfusion damage. Trimetazidine offers unique positive effects and it is useful in improving ischemic cell metabolism and in reducing cell injury and endothelial dysfunction. All these effects could be clinically relevant, improving prognosis and quality of life in patients with coronary artery disease.

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