Trimetazidine inhibits mitochondrial permeability transition pore opening and prevents lethal ischemia–reperfusion injury

Argaud, Laurent; Gomez, Ludovic; Gateau-Roesch, Odile; Couture-Lepetit, Elisabeth; Loufouat, Joseph; Robert, Dominique; Ovize, Michel

doi:10.1016/j.yjmcc.2005.09.012

Cited by 95 publications

(71 citation statements)

References 32 publications

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“…Outros estudos e ensaios clínicos experimentais nessa área têm demonstrado que a Tmz exerce efeito antiisquêmico direto, limitando o acúmulo de cálcio e da acidose, a inflamação e a produção de radicais hiperóxidos após reperfusão 4,18,37 , e mais recentemente, na proteção mitocondrial contra o dano pelo estresse oxidativo 38 . Maridonneau-Parini e Harley 39 relatam que a Tmz protege a membrana celular da agressão e do dano que seguem a liberação de radicais livres hiperóxidos.…”

Section: Gráfico 2 -Creatinofosfoquinase-mb Ao Longo Do Tempo Segundounclassified

Trimetazidina na injúria de isquemia e reperfusão em cirurgia de revascularização do miocárdio

Martins¹,

Filho²,

Santos³

et al. 2011

Arq. Bras. Cardiol.

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ResumoFundamento: A injúria de isquemia e reperfusão constitui um mecanismo fisiopatológico frequente e de difícil controle durante a Cirurgia de Revascularização do Miocárdio (CRVM) com circulação extracorpórea, sendo o momento crítico o término da cirurgia, quando ocorre o desclampeamento da aorta e a liberação dos radicais hiperóxidos causadores da injúria.Objetivo: Avaliar, em estudo prospectivo, duplo-cego randomizado, controlado com placebo, os efeitos da Trimetazidina (Tmz) sobre a injúria de isquemia e reperfusão miocárdica, identificando a variação dos marcadores plasmáticos de agressão miocárdica (troponina T e CPK-Mb), e as alterações ecocardiográficas da função ventricular.Métodos: Foram estudados 60 pacientes, divididos em dois grupos (Placebo e Tmz) com, no máximo, disfunção ventricular leve, estratificados por ecocardiografia e recebendo medicação/placebo na dose -no pré-operatório sem medicação, 12 a 15 dias de medicação/placebo colhida cinco minutos após o desclampeamento aórtico, e nas 12, 24 e 48 horas seguintes. Resultados: Tanto a troponina T como a CPK-Mb atingiram valores altamente significativos (p = 0,0001) no grupo tratado em relação ao grupo controle nos quatro momentos analisados − 5 min, 12 h, 24 h e 48 h. As variáveis ecocardiográficas não evidenciaram mudanças evolutivas em cada grupo isoladamente e quando comparados em conjunto. Conclusão AbstractBackground: The ischemia and reperfusion ischemia is a common physiopathological mechanisms, which has difficult control during Coronary Artery Bypass Grafting (CABG) with cardiopulmonary bypass, the critical moment of which happening by the end of surgery, when there is declamping of aorta and release of hyperoxic radicals causing the injury.

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Section: Gráfico 2 -Creatinofosfoquinase-mb Ao Longo Do Tempo Segundounclassified

Trimetazidina na injúria de isquemia e reperfusão em cirurgia de revascularização do miocárdio

Martins¹,

Filho²,

Santos³

et al. 2011

Arq. Bras. Cardiol.

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“…They also showed that both mechanical and chemical postconditioning increase the Ca 2+ load that is required to open the mPTP (Argaud et al, 2005a;Argaud et al, 2005b). Thus, specific inhibition of mPTP opening at reperfusion provided powerful antinecrotic and anti-apoptotic protection to the ischemic myocardium (Fig.…”

Section: Exploring the Mechanisms Of Postconditioningmentioning

confidence: 92%

Postconditioning: from experimental proof to clinical concept

Mewton

Ivanès

Cour

et al. 2010

Disease Models &Amp; Mechanisms

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)The therapeutic strategies for acute myocardial infarction in the last decade have, among other therapeutic targets, focused on myocardial reperfusion injury, which accounts for a significant part of the final infarct size. Although several experiments in the last 20 years have reported that pharmacological interventions at reperfusion might reduce myocardial reperfusion injury, this could not be consistently confirmed in animal models or human studies. An alternative to chemical modifiers, postconditioning (brief repeated periods of ischemia applied at the onset of reperfusion) is the first method proven to be efficient in different animal models and to be confirmed in a recent human study. This simple method, applied in the first minute of reperfusion, reduces the final infarct size by 30-50%. This review will focus on the postconditioning technique and show how the data from different animal models and experimental settings have advanced our understanding of both the mechanisms and the definition of an accurate protocol that is easily applicable in human patients in the setting of acute myocardial infarction. Disease Models & Mechanisms DMMlonger ischemic insult on experimental models (Murry et al., 1986), the idea of mechanical postconditioning emerged as a potential therapeutic strategy applicable to AMI patients. The initial, experimental proof-of-concept study was developed by Zhao et al. on an ischemia-reperfusion model of open-chest dogs (Zhao et al., 2003). In this first experiment, after 60 minutes of left anterior descending coronary artery (LAD) occlusion, reperfusion was initiated for 30 seconds followed by 30 seconds of reocclusion, which was repeated for three cycles (i.e. the total intervention lasted for 3 minutes). Reperfusion was continued for a total of 3 hours in all experiments. The results of this study showed that the infarct size in the postconditioning group was 44% smaller than that in the control group and that there was no statistical difference in infarct size between the preconditioning and postconditioning groups (Fig. 1).In this same experimental study, the authors found that postconditioning was associated with a significant reduction of myocardial edema at the myocardial area at risk. Postconditioning reduced the accumulation of polymorphonuclear neutrophils (PMNs) in the same area and attenuated PMN adherence to the endothelium by reducing P-selectin expression on coronary vascular endothelium. Postconditioning also significantly reduced the lipid peroxidation in the myocardial area at risk compared with the control group. All those results showed that postconditioning significantly reduced the reperfusion injury phenomenon.This observation has since been confirmed in several experimental preparations and with different animal species (rats, rabbits and mice), showing that, when applied at the time of reperfusion, postconditioning significantly reduced infarct size with results comparable to preconditioning (Bopassa et al., 2006;Bopassa et al., 2005; Kin et al., 2005; Kin et...

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“…Clinical studies have shown that TMZ has cardioprotective effects in the setting of myocardial ischemia including acute myocardial infarction. [9][10]. The effect of TMZ on myocardial necrosis could be explained by its metabolic and biological effects on mechanism while TMZ has [11].…”

Section: Trimetazidine (Tmz; 1-[234-trimethoxybenzyl] Piperazine)mentioning

confidence: 99%

“…TMZ is also beneficial in preventing ischemiareperfusion injury. In fact, an animal experiment demonstrated that TMZ could limit lethal ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening, which represents a crucial event in cardiomyocyte death following myocardial ischemia-reperfusion [9]. Our result is consistent with a previous report by Demirelli et al who observed that Trimetazidine treatment commencing prior to PCI and continued after PCI in patients with NSTEMI provides improvements in the myocardial performance index and left ventricular end diastolic volume and a decrease in brain natriuretic peptide levels [6].…”

Section: Trimetazidine (Tmz; 1-[234-trimethoxybenzyl] Piperazine)mentioning

confidence: 99%

The Clinical Short-term Outcome of Atorvastatin and Trimetazidine Combination Treatment in Patients with Non-ST Segment Elevation Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention

Wang

Han²,

Song³

et al. 2016

ICFJ

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Background and Objectives: To investigate the effects of atorvastatin (ATV) and trimetazidine (TMZ) combination treatment in patients with non-ST segment elevation acute coronary syndromes (NSTE-ACS) undergoing percutaneous coronary intervention. Subjects and Methods: A total of 92 patients with NSTE-ACS were randomly divided into the pretreatment with ATV group (80mg 12h before PCI, with a further 20mg every day to 30th days after PCI, n=44) or the pretreatment with ATV (as the ATV group) and TMZ (60mg 30min before PCI, with a further 20mg tid to 30th days after PCI, n=48). Echocardiography was executed and plasma N-terminal pro brain natriuretic peptide (NT-pro-BNP) levels were measured just prior to the PCI and 30th days after PCI. The main end point was a 30-day incidence of major adverse cardiac events.Result: Major adverse cardiac events occurred in 9.1% of patients in the ATV group and 4.2% of those in the ATV+TMZ group (P=0.189). NT-pro-BNP of the two groups were decreased 30th days after PCI, however, NT-pro-BNP in the ATV+TMZ group were significantly lower than those in the ATV group (P<0.05). Cardiac function in NSTE-ACS patients, as reflected by the increased LVEF, FS as well as decreased LVEDd (P<0.05) in all groups at 30 days after intervention, but cardiac function parameters were more obviously improved in the group administered with ATV+TMZ (p<0.05).Conclusion: Short-term pretreatment with the combination of ATV and TMZ administration prior to PCI can prominently decrease NT-pro-BNP and improve cardiac function compared to a single administration of the ATV.

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Trimetazidine inhibits mitochondrial permeability transition pore opening and prevents lethal ischemia–reperfusion injury

Cited by 95 publications

References 32 publications

Trimetazidina na injúria de isquemia e reperfusão em cirurgia de revascularização do miocárdio

Trimetazidina na injúria de isquemia e reperfusão em cirurgia de revascularização do miocárdio

Postconditioning: from experimental proof to clinical concept

The Clinical Short-term Outcome of Atorvastatin and Trimetazidine Combination Treatment in Patients with Non-ST Segment Elevation Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention

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