Future CardiologyVol. 5, No. 5 EditorialFree AccessTrimetazidine: the future of cardiac function?Pericle Di Napoli & Alfonso A TaccardiPericle Di Napoli† Author for correspondenceVilla Pini d’Abruzzo Clinic, Department of Cardiology, Heart Failure Unit, Via dei Frentani 228, 66100, Chieti, Italy. Search for more papers by this authorEmail the corresponding author at dinapoli@unich.it & Alfonso A TaccardiVilla Pini d’Abruzzo Clinic, Department of Cardiology, Heart Failure Unit, Via dei Frentani 228, 66100, Chieti, Italy. Search for more papers by this authorEmail the corresponding author at elentcit@yahoo.itPublished Online:28 Aug 2009https://doi.org/10.2217/fca.09.26AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail The continuous knowledge of the pathophysiological background of heart failure is fundamental in the management of this complex disease. Although there are considerable modern therapeutic advances, heart failure remains a leading cause of morbidity and mortality in developed [1] and increasingly in developing countries [2] with a 5-year mortality rate of approximately 50%, which exceeds that of many cancers [3]. The prognosis worsens with the advancement of heart failure and the mortality rate in patients in New York Heart Association (NYHA) class IV is as high as 50% per year. The mode of death depends mainly on the NYHA class. Patients with less advanced heart failure; more frequently die suddenly (arrhythmic death), while those in NYHA class IV are more likely to die of irreversible heart failure (pump failure) [4,5]. Early neurohumoral activation with sympathetic overdrive interplaying with progressive hemodynamic changes constitutes the main characteristic of heart failure independent of its etiology [6]. This unacceptably high residual mortality and morbidity has mandated a re-evaluation of cardiac biology with the aim to identify novel therapeutic approaches for heart failure.Over the past 20 years, there has been considerable progress in the treatment of chronic heart failure with angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists, β-receptor blockers and resynchronization therapy [7,8]. Current medical treatment of heart failure is mainly directed at fluid overload and neurohormonal activation. Diuretics, digoxin and inotropes treat fluid overload and improve hemodynamic; while ACE-inhibitors, angiotensin II receptor antagonists, β-blockers and aldosterone antagonists restrain neurohormonal activation [8]. Despite these treatments, there is usually an ineluctable progression of contractile dysfunction and continuing left ventricular remodeling.Currently, new treatments for heart failure that act independently of mechanisms already targeted, are under investigation and emerging evidence suggests that myocardium dysfunction in heart failure is also the consequence of alterations in substrate metabolism [7]. In particular, there is evidence that in the failing heart, shifting metabolism away from a preference for fatty acid towards more carbohydrate oxidation can improve contractile function, slowing the ineluctable progression of pump failure and improving prognosis in patients with heart failure [9].Trimetazidine, an anti-ischemic or ‘cytoprotective’ agent acting via metabolic pathways, has proved to be effective in the treatment of chronic stable angina and, more recently, left ventricle dysfunction. This drug has an inhibitory effect on the enzyme 3-ketoacyl coenzyme A thiolase, which plays a critical role in the β-oxidation pathway in the myocardium [10]. As a result, there is a switch of cardiac metabolism from free fatty acid to glucose oxidation, which represents a more efficient metabolic pathway in terms of oxygen consumption and energy (adenosine triphosphate) production. Recent studies have outlined the potential benefits that trimetazidine may offer in myocardial dysfunction owing to its ability to increase utilization of glucose and lactate, improving oxygen consumption of the myocardium by 16–26% [11].Many studies have been carried out to establish which factors increase mortality and morbidity in patients with ischemic heart disease and heart failure. Factors that have been demonstrated to be predictors of mortality are increasing age, history of diabetes mellitus or renal dysfunction, measures of higher functional disability such as NYHA class, lower left ventricular ejection fraction (LVEF), lower sodium concentrations and lower quality-of-life scores [12–14]. Recently, intense interest has emerged in the predictive value of plasma biochemical markers such as C-reactive protein, B-type natriuretic peptide (BNP) and cardiac troponin T [15,16]. A variety of clinical studies provided evidence that trimetazidine treatment could also positively influence these prognostic factors.For all these reasons, a therapeutic approach using trimetazidine could positively influence left ventricle dysfunction and remodeling with potential prognostic relevance in heart failure patients.On the basis of the hypothesis that free fatty acid inhibitors could act as metabolic modulators in the protection of ischemic myocardium, the effects of trimetazidine have been previously assessed in patients with ischemic cardiomyopathy. In these patients, mortality rate and quality-of-life are unsatisfactory and left ventricular dysfunction is the result of the progressive process of myocardial fibrosis, or hibernating or stunned myocardium. An early therapeutic management of hibernating and stunned myocardium is fundamental in ischemic cardiomyopathy, because they are potentially reversible conditions. Belardinelli et al. reported that trimetazidine exerted beneficial effects on chronically dysfunctional myocardium [17]. In patients with ischemic cardiomyopathy, a previous acute myocardial infarction, multivessel coronary artery disease and ventricular dysfunction (ejection fraction 33%), trimetazidine therapy (2 months) improved contractile response to low-dose dobutamine in chronically dysfunctional myocardium. Fragasso et al. demonstrated that trimetazidine restored the energetic status of myocardium in patients with heart failure [18]. In these patients, the phosphocreatine and adenosine triphosphate (PCr:ATP) ratio, an important index of energetic status, was similar to that in healthy individuals and significantly improved compared with that in a placebo group. These results appear particularly interesting, especially in view of previous evidence suggesting the PCr:ATP ratio to be a significant predictor of mortality [19]. The beneficial effects of trimetazidine in patients with ischemic cardiomyopathy are confirmed in longer follow-up. Brottier et al.assessed the value of trimetazidine treatment with in patients with severe ischemic cardiomyopathy [20]. After 6 months of treatment, the patients reported a considerable improvement in symptoms and demonstrated a greater LVEF compared with the placebo group. These effects are also evident in long-term follow-up [21], in elderly and diabetic patients. Vitale et al. reported 47 patients (aged 78 ± 3 years) with ischemic cardiomyopathy who were treated with trimetazidine and achieved significant improvement in ejection fraction and quality of life [22]. Fragasso et al. reported an improvement in ejection fraction in diabetic patients with ischemic cardiomyopathy [23].The cardioprotective effects of trimetazidine were also detected in patients with systolic dysfunction heart failure of different etiologies, not only that secondary to coronary artery disease [24]. Recently, Tuunanen et al.reported in 19 nondiabetic patients with idiopathic dilated cardiomyopathy that trimetazidine increase LVEF from 31 to 35% (p = 0.027); this increase was associated with a significant decrease of insulin resistance. In this way, the effects of trimetazidine could be related to an improvement of whole-body insulin sensitivity and glucose control, thus hypothetically countering the myocardial damage of insulin resistance [25].Trimetazidine exerts positive effects on the inflammatory status that characterizes ischemic cardiomyopathy and have been related to higher rates of readmission to hospital and mortality [26]. It has been also observed that trimetazidine was able to reduce the release of endothelin-1 in patients with heart failure [24]. Despite the recognized adaptive advantage of endothelin-1 in supporting the contractility of the failing heart, persistent increases in its expression in the failing heart have a pathophysiologically maladaptive aspect, and are associated with the severity of myocardial dysfunction [9]. In patients with left ventricular dysfunction, the plasma concentration of BNP is also significantly reduced during treatment with trimetazidine [27]. If we consider BNP as a marker of myocardial load, trimetazidine treatment could positively redirect the neurohormonal pathway in patients with ischemic cardiomyopathy and reduce the progressive cellular damage and lost that characterizes the chronic evolution of left ventricle remodeling.Trimetazidine is also able to increase the myocardial cell resistance to cardiac overload that usually occurs in patients with ventricular dilation or dysfunction. In patients with chronic heart failure, during acute decompensation myocardial cell damage, expressed as troponin T release, is significant reduced and the direct correlation between BNP (index of cardiac load) and troponin T plasma concentrations– usually observed in heart failure patients– is lost [28]. This means increased cell resistance to injury.All these results could contribute to explaining the reduction of ventricular remodeling and the preservation of left ventricle function during trimetazidine treatment. Although these findings are highly suggestive, it remains to be ascertained whether the benefits discussed above would translate in no doubt improved survival rates. The question of whether there are prognostic benefits during trimetazidine treatment in patients with heart failure is still under investigation and needs more clarifications. We know the prognostic value of an improvement in ejection fraction, NYHA class and biochemical markers in these patient but, at the moment, the prognostic relevance of trimetazidine is no more than speculative or fruit of an incomplete clinical experience. In patients with ischemic left ventricular dysfunction and multivessel coronary artery disease, El-Kady et al.reported positive effects of trimetazidine on prognosis:survival at 2 years was 92% among patients treated with trimetazidine and 62% among those treated with placebo [29]. In a post hoc analysis obtained from the 48-month extension of the Villa Pini d’Abruzzo trimetazidine trial, trimetazidine treatment reduced all-cause mortality (17 versus 39% in controls) and admission to hospital owing to heart failure (decreased by 47%) [30].In summary, the correction of the metabolic alterations that characterize dilated cardiomyopathy and heart failure could represent a promising novel therapeutic approach useful in improving prognosis. The metabolic modulator trimetazidine represents the most studied and valued drug with positive effects in patients with chronic coronary artery disease and heart failure. Although its true relevance to prognosis needs to be ascertained by large multicenter, randomized, placebo-controlled trials, the selective inhibition of 3-KAT with trimetazidine could represent a new therapeutic opportunity in the management of left ventricle dysfunction and remodeling in heart failure patients.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Kannel WB: Incidence and epidemiology of heart failure. Heart Fail. 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Pharmacol.50(5),585–589 (2007).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByEffectiveness of Trimetazidine in Patients with Chronic Heart Failure Stratified by the Expression of Soluble Suppression of Tumorigenicity-2 (sST2): A Prospective Cohort Study12 October 2022 | Advances in Therapy, Vol. 39, No. 12Trimetazidine Attenuates Exhaustive Exercise-Induced Myocardial Injury in Rats via Regulation of the Nrf2/NF-κB Signaling Pathway5 March 2019 | Frontiers in Pharmacology, Vol. 10Overcoming interference of plasma phospholipids using HybridSPE for the determination of trimetazidine by UPLC-MS/MS2 October 2017 | Biomedical Chromatography, Vol. 32, No. 2Effects of sustained-release trimetazidine on chronically dysfunctional myocardium of ischemic dilated cardiomyopathy – Six months follow-up resultIndian Heart Journal, Vol. 68, No. 6Doping control analysis of trimetazidine and characterization of major metabolites using mass spectrometric approaches9 June 2014 | Drug Testing and Analysis, Vol. 6, No. 11-12The prevalence of trimetazidine use in athletes in Poland: excretion study after oral drug administration24 November 2014 | Drug Testing and Analysis, Vol. 6, No. 11-12Food Effect on Bioavailability of Modified-Release Trimetazidine Tablets7 March 2013 | The Journal of Clinical Pharmacology, Vol. 52, No. 10New potential of Trimetazidine MB for coronary heart disease treatment in the real-world clinical practice: results of the Russian multi-centre randomised study PERSPECTIVE (Part II)20 December 2011 | Cardiovascular Therapy and Prevention, Vol. 10, No. 6 Vol. 5, No. 5 Follow us on social media for the latest updates Metrics History Published online 28 August 2009 Published in print September 2009 Information© Future Medicine LtdFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

The goal of this study was to determine the effects of trimetazidine on all-cause mortality and heart failure hospitalizations in patients with ischemic cardiomyopathy. We performed an extension to 48 months and a post-hoc analysis of the Villa Pini d'Abruzzo trimetazidine trial; in this single-center, open-label, randomized trial with the metabolic inhibitor trimetazidine in chronic heart failure, 61 patients were randomized to either receive trimetazidine (20 mg tid) in addition to their conventional treatment or to continue their usual drug therapy for 4 years. Patients were evaluated at baseline and at 6, 12, 18, 24, 32, 36, 42, and 48 months with clinical examination, echocardiography, and 6-minute walking test. Trimetazidine added to usual treatment significantly reduces all-cause mortality (-56%; hazard ratio, 0.258; 95% CI, 0.097 to 0.687; log-rank test, P = 0.0047), heart failure hospitalization (-47%; log-rank test, P = 0.002), and improves patient functional status (NYHA class and 6-min walking test). In trimetazidine-treated patients, a significant increase of the left ventricle ejection fraction was also detected (LVEF P < 0.001 at 48 months). It is therefore concluded that long-term trimetazidine significantly reduces all-cause mortality and heart failure hospitalization in patients with ischemic cardiomyopathy. If confirmed in large-scale randomized trials, this treatment could be useful in the management of left ventricle dysfunction and remodeling in patients with ischemic heart disease.

Objective: Due to reported modulatory effects of statins on nitric oxide synthase (NOS) expression, we tested the hypothesis of protective effects of in vivo chronic treatment with rosuvastatin, a novel 3-hydroxy-3-methyl-glutaryl coenzyme A-reductase inhibitor, on ischemia-reperfusion injury, and investigated mechanisms involved.Methods: After 3 weeks of in vivo treatment with rosuvastatin (0.2-20 mg/kg/day) or placebo, excised hearts from Wistar rats were subjected to 15 min global ischemia and 22-180 min reperfusion. We evaluated creatine-phosphokinase and nitrite levels in the coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and the expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) (by reverse-transcription polymerase chain reaction and Western blotting).Results: Rosuvastatin 0.2 and 2 mg/kg/day significantly reduced myocardial damage and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions. At 2 mg/kg/day, rosuvastatin significantly increased eNOS mRNA and protein compared with untreated hearts, and conversely decreased iNOS mRNA and protein, as well as nitrite production after ischemia reperfusion. The addition of the NOS inhibitor N-infinity-nitro-L-arginine methylester (L-NAME, 30 mu mol/L) significantly reduced cardioprotection against ischemia-reperfusion.Conclusions: Chronic treatment with rosuvastatin before ischemia reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte damage by NO-dependent mechanisms. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

The purpose of our study was to evaluate the effect of chronic exposure to low cellular oxygen tension (90% N2 and 10% O2 for 14 days) in inducing apoptosis and activation of transcription and translation of inducible nitric oxide (NO) synthase (iNOS) in rat hearts tissue. Rats were divided into four groups: normoxic, hypoxic, rats maintained in normoxic condition for 7 days and subjected to hypoxic conditions for another 7 days, and rats maintained in hypoxic condition for 7 days and subjected to normoxic conditions for another 7 days. At the 7th and 14th days, five rats from each group were sacrificed. Immunohistochemical and Western blot analysis were performed on myocardial tissue to reveal the presence of iNOS. Expression of iNOS was determined by RT-PCR. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and by detection of internucleosomal DNA fragmentation by electrophoresis. Electrophoretic analysis of DNA showed oligonucleosomal fragmentation in the hypoxic groups, but no ladder was observed in the other groups. This data was confirmed through end labeling with streptavidin-biotin (biotin d-UTP). iNOS expression was evaluated through immunohistochemical techniques (Ab anti-iNOS) and Western blotting, and the results were quantified with a computerized imaging analysis. The expression of iNOS protein was greater in the hypoxic groups; in the normoxic groups, only a nonspecific background was detected. This data was supported with results obtained through RT-PCR, which showed the specific transcription of mRNA for iNOS in the same experimental conditions. In addition, the iNOS activity was also evaluated and was found to be more active in the hypoxic groups (0.1 +/- 0.01 vs 0.02 +/- 0.003). The present study shows that exposure to low oxygen tension is capable of inducing programmed cell death and activating iNOS.

Background Apoptosis has been implicated as a possible mechanism in the development of heart failure (HF), but the mechanisms involved remain unclear. In patients with severe dilated cardiomyopathy, we evaluated cardiomyocyte apoptosis in relation to the transmural distribution of Box and Bcl-2 proteins (2 molecules inhibiting or promoting apoptosis, respectively) and left ventricular wall stresses.Methods We studied the presence and distribution of cardiomyocyte apoptosis in 90 tissue samples obtained from 8 patients who were undergoing left ventricular reduction with the Batista (ventricular remodeling) operation. Apoptosis was assessed in tissue samples taken from the entire left ventricular thickness (subdivided in subepicardial, midmyocardial, and subendocardial sections) with the terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling (TUNEL) technique and DNA agarose gel electrophoresis. The expression of Bcl-2 and Box proteins were determined with both Western analysis and immunohistochemistry.Results TUNEL-positive cells (apoptotic index) were 2.3% +/- 1.4%. Apoptotic cells were predominantly distributed in the subendocardium, where higher levels of Box protein were detected. The ratio of Box to Bcl-2 proteins (Bax/Bcl-2) was similar in the midmyocardium or subepicardium, but increased in the subendocardium, where it was directly related to systolic wall stress (y = 0.009x - 0.629; r(2) = 0.85, P <.001). The apoptotic index was also directly related to systolic and end-diastolic stresses calculated from hemodynamic and echocardiographic data (r(2) = 0.77, P <.001 and r(2) = 0.40, P <.01, respectively).Conclusions In patients with dilated cardiomyopathy, in whom cardiomyocyte apoptosis is an important cause of cell loss, apoptosis is more extensively localized in the subendocardium and strictly related to ventricular wall stresses and the Box/Bcl-2 ratio.

Hypoxia is a potent regulator of various biological process. Mammalian cells respond to hypoxia by increased expression of several genes. The aim of this study was to evaluate the effects of chronic exposure to low oxygen tension on the induction of inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) in rat heart. Male Wistar rats were assigned randomly to 4 groups: (A) control rats maintained in normoxic conditions for 7 and 14 days; (B) rats maintained in hypoxic conditions for 7 and 14 days; (C) rats maintained in normoxic conditions for 7 days and then transferred to hypoxic conditions for 7 days; and (D) rats maintained in hypoxic conditions for 7 days and then transferred to normoxic conditions for 7 days. In Group A, iNOS and HO-1 immunoreactivities were not evident; in Group B these immunoreactivities increased from day 7 to 14; in Group C the immunoreactivities decreased on day 7, compared to day 14; and in Group D, the immunoreactivities increased on day 7, compared to day 14. These findings were confirmed by Western blot analyses of the respective proteins and by rt-PCR assays of the corresponding mRNAs. The results indicate that the adaptive response to hypoxia involves up-regulation of HO-1 through iNOS activation in cardiac cells. HO-1 helps to regulate vascular tone via CO and thereby participates in an important cardiac defense mechanism.

We tested the hypothesis of beneficial effects of the calcium-blocker verapamil in a model of ischemia-reperfusion, and investigated its effects against coronary microcirculation and cardiomyocyte apoptosis. Isolated working rat hearts were subjected to 15 min global ischemia and 22-180 min reperfusion in the presence or absence of verapamil (0.25 &mgr;M). We evaluated creatinephosphokinase (CK) in coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and cardiomyocyte apoptosis (by 1.5% agarose gel electrophoresis and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling technique). In this model, 0.25 &mgr;M verapamil significantly reduced myocardial damage, CK release and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions; on the contrary, 0.25 &mgr;M verapamil was unable to reduce cardiomyocyte apoptosis. In conclusion, in the absence of perfusing granulocytes, the acute administration of a pharmacologically relevant verapamil concentration reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte necrotic cell death but it is unable to reduce apoptotic cell death in isolated working rat hearts.

Background: the cardiac Renin-Angiotensin system (RAS) plays an important role in the regulation of coronary flow and cardiac function and structure in normal and pathological conditions such as ischemia-reperfusion (I/R) injury. The aim of this study was to investigate the effects of the Angiotensin II type 1 (AT-1) receptor antagonist MK-954 (losartan potassium) on postischemic endothelial dysfunction and NOS mRNA expression (inducible nitric oxide synthase, iNOS; endothelial nitric oxide synthase, eNOS) in isolated working rat hearts. Methods: isolated working rat hearts were subjected to 15 min global ischemia and 180 min reperfusion. MK-954 was added to perfusion buffer (a modified Krebs-Henseleit solution) at 1 muM concentration. We assessed functional parameters, creatin kinase (CK) release, heart weight changes, microvascular postischemic hyperpermeability (FITC-albumin extravasation) and morphological ultrastructural alterations. eNOS and iNOS mRNA levels were also detected by the means of multiplex RT-PCR technique using glyceraldehyde-3-phosphate dehydrogenase (G3PDH) gene as internal control; results were expressed as densitometric ratio. Results: in Losartan-treated hearts we observed a significant reduction of postischemic contractile dysfunction, CK release and myocardial ultrastructural damage; postischemic FITC-albumin extravasation was significantly reduced respect to controls. Moreover, 1 muM Losartan produced a significant reduction of eNOS/G3PDH respect to untreated hearts submitted to I/R. Regarding iNOS/G3PDH ratio, no significant changes were detected in Losartan-treated hearts compared with controls. Conclusions: our study revealed that Losartan treatment before ischemia, and during reperfusion, is able to reduce the reperfusion injury of the rat heart by reducing mechanical and microcirculatory dysfunction and necrotic cell death, ameliorating cardiac ultrastructure and endothelial protection, probably inducing eNOS over-expression and reducing post-ischemic hyperpermeability of coronary microcirculation. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

Several studies suggest that nitric oxide (NO) production is reduced in diabetes and that the decrease of NO may be related to the pathogenesis of diabetic endothelial damage. NO synthase (NOS) catalyses the conversion of L-arginine to L-citrulline in the presence of oxygen and NADPH-diaphorase (NADPH-d). In this study, we evaluated the expression of endothelial NOS (eNOS) enzyme and its co-enzyme in diabetic rat hearts. Male Wistar rats (n = 20, 4 mo old) and 20 male Bio Breeding Wistar (BB/W) rats of the same age were used; the Wistar rats represent the control non-diabetic rats while the BB/W rats represent the diabetic group. After the hearts were excised, the NADPH-d co-enzyme was visualized by a histochemical method and the endothelial isoform of NOS was localized by immunohistochemistry. In addition, eNOS gene expression was estimated by rt-PCR, and eNOS protein level was detected by Western blot analysis. The eNOS visualization, which involved immunoprecipitation, and the NADPH-d visualization, which involved histochemical staining, were both diminished in endothelial cells of the vascular wall of diabetic hearts, compared to non-diabetic hearts. The eNOS protein level, evaluated by Western blotting, was evident as an intense band in cardiac homogenates of non-diabetic and diabetic rats. The expression of mRNA for eNOS did not differ significantly between the two groups. These findings indicate that, in this rat heart model, diabetes does not influence the overall eNOS protein level or its mRNA level. However, there a diminution in the deposition of eNOS in cardiac endothelial cells of diabetic rats, versus non-diabetic controls, suggesting a relation between eNOS and the loss of vasodilatory response that is observed in diabetes.

Objective: We tested the hypothesis of beneficial effects of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitor simvastatin in a model of ischemia-reperfusion, and investigated potential mechanisms. Methods: Isolated working rat hearts were subjected to 15 min global ischemia and 22-180 min reperfusion in the presence or absence of simvastatin (10-100 muM). We evaluated creatinephosphokinase and nitrite levels in coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and the expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) (by reverse-transcribed polymerase chain reaction and Western blotting) in the presence or absence of the transcriptional inhibitor actinomycin-D. Results: Simvastatin (25 muM) significantly reduced myocardial damage and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions. Protection became less evident at 50 muM and reverted to increased damage at 100 muM. At 25 muM, simvastatin significantly increased eNOS mRNA and protein compared with untreated hearts, probably due to a post-transcriptional regulation since unaltered by animal pretreatment with actinomycin D. Simvastatin also significantly decreased iNOS mRNA and protein, as well as nitrite production after ischemia-reperfusion. The addition of the NOS inhibitor N-w-nitro-L-arginine methylester (L-NAME, 30 muM) to 25 muM simvastatin-treated hearts significantly reduced cardioprotection against ischemia-reperfusion. Conclusions: In this model, in the absence of perfusing granulocytes, the acute administration of a pharmacologically relevant simvastatin concentration reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte damage by cholesterol-independent, NO-dependent mechanisms. (C) 2001 Elsevier Science BY. All rights reserved.

Myocardial infarction is the major cause of death in the world. Over the last two decades, coronary reperfusion therapy has become established for the management of acute myocardial infarction (AMI). However, restoration of blood flow to previously ischemic myocardium results in the so-called ischemia/reperfusion (IR)-injury. The different clinical manifestations of this injury include myocardial necrosis, arrhythmia, myocardial stunning and endothelial- and microvascular dysfunction including the no-reflow phenomenon. The pathogenesis of ischemia/reperfusion injury consists of many mechanisms. Recently, there's increasing evidence for an important role in IR-injury on hypercontracture induced by high levels of cytosolic calcium or by low concentrations of ATP.In the last years, many studies on experimental models were investigated, but the clinical trials confirming these effects remain spare. Recently, the beneficial effect of Na+/H+-exchange inhibitor cariporide and of the oxygen-derived free radical (ODFR) scavenger vitamin E on coronary bypass surgery-induced IR-injury were demonstrated. Also recently, the beneficial effect of allopurinol on the recovery of left ventricular function after rescue balloon-dilatation was demonstrated. The beneficial effect of magnesium and trimetazidine on IR-injury remains controversial. The beneficial effect of adenosine remains to be further confirmed. There's also increasing interest in agentia combining the property of upregulating NO-synthase (e.g. l-arginine) and restoring the balance between NO and free radicals (e.g. tetrahydrobiopterin). One of such agents could be folic acid.In this review article the authors give an overview of the recent insights concerning pathogenesis and therapeutic possibilities to prevent IR-induced injury.