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Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Supplementary material. Editor's Choice. Succinate dehydrogenase inhibition with malonate during reperfusion reduces infarct size by preventing mitochondrial permeability transition. Laboratory of Experimental Cardiology, Department of Cardiology. Oxford Academic. Ignasi Barba. Marisol Ruiz-Meana. Marina Fuertes-Agudo. Revision received:. Select Format Select format. Permissions Icon Permissions. Abstract Aims.
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Supplementary Data - zip file. View Metrics. Email alerts Article activity alert. Advance article alerts. New issue alert. Receive exclusive offers and updates from Oxford Academic. More on this topic Arginase inhibition mediates cardioprotection during ischaemia—reperfusion. Intermittent activation of bradykinin B 2 receptors and mitochondrial K ATP channels trigger cardiac postconditioning through redox signaling. The coronary circulation in cardioprotection: more than just one confounder.
Indeed, malonate has been shown to exert deleterious effects, including cell death, in neuroblastoma-derived SH-SY5Y cells To avoid potential toxic effects, we selectively applied malonate into the area at risk. Intracoronary drug administration selectively at the area at risk is clinically feasible and it has been previously used for the selective delivery of cardioprotective treatments, as adenosine, in patients with acute myocardial infarction 23 , In the present study we administered malonate selectively in the area at risk using a 2.
The beneficial effect of a cardioprotective treatment on infarct size does not warrant its clinical applicability to patients. Previous studies have demonstrated an increased incidence of VF in pigs treated with an intracoronary acid Krebs infusion pH 6.
Similarly, gap junction uncouplers, which reduce infarct size when given during initial reperfusion 26 , have been shown to have proarrhythmic properties However, this was not the case with the intracoronary administration of malonate at the onset of reperfusion in our pig model. In addition, re-circulation of intracoronary administered malonate could have unwanted effects outside the area at risk.
However, intracoronary infusion of malonate at the dose we found to be effective was associated to undetectable concentrations in distant myocardium and in plasma, and to no measurable effect on distant myocardium. A wide number of therapeutic strategies have been suggested to limit infarct size in experimental models. However, none of them is so far part of standard clinical practice. This failure of translation can be due, at least in part, to the fact that most of these studies were conducted in young and healthy animals lacking comorbidities, comedications or risk factors, and to failures in the design of clinical trials 28 , In addition, considering that ischemia-reperfusion injury might be due to different mechanisms, targeting on individual objectives will unlikely result in reduced infarctions.
In this context, a combination therapy may be an interesting approach to limit myocardial infarct size 30 , as has been described with a combination of remote ischemic conditioning and treatments modulating myocardial metabolism, including exenatide and glucose-insulin-potassium 31 , Malonate, if not individually, in combination with conditioning strategies 30 , 33 , may be a good candidate to reduce myocardial infarct size in patients with STEMI.
Malonate has the advantage, over other tested compounds, that it is a natural metabolite that appears in animal tissues 34 , whose effects are reversible. Its main limitation, its possible toxic effects in other tissues, might be solved by an intracoronary route of administration.
In conclusion, our data demonstrate that selective, intracoronary, administration of malonate at the onset of reperfusion protects against myocardial infarction in in situ pig hearts, and that this effect is not associated with undesirable effects in distant myocardium or with an increased incidence of reperfusion arrhythmias.
The left femoral artery and vein were cannulated for aortic blood pressure and blood sample monitoring, respectively. A midsternotomy was performed, and the pericardium opened, suturing its free margins to the borders of the sternotomy to cradle the heart. The left anterior descending LAD coronary artery was dissected free at its midpoint, below the first diagonal branch, and surrounded by an elastic snare.
This dissection site was used for coronary ligature, whereas a second dissection site, located one centimeter distally, was used for blood flow measurements. Arterial blood gases were monitored during the experimental procedure, and maintained within normal limits. Lead II of electrocardiogram was continuously recorded in a computer to monitor heart rate and ventricular arrhythmias. Regional myocardial function was determined in a control region near the cardiac base distant myocardium supplied by the circumflex coronary artery and in the apical area i.
Ischemia was performed by occluding the LAD coronary artery around the infusion catheter using the elastic snare. In these pigs, the two pairs of polystyrene crystals were placed in the area at risk. In all cases, animals were randomly divided in two groups. Malonate plasma concentrations were analyzed by 1 H-NMR in blood samples obtained from pigs treated under baseline conditions.
Plasma metabolites were extracted using the methanol:chloroform method as described previously Each spectrum consisted in the accumulation of 64 scans using a fully relaxed pulse-and-acquire pulse sequence with presaturation of the residual water signal.
Cardiac metabolites were extracted using the methanol:chloroform method as before. VT was defined as four or more consecutive premature beats of ventricular origin. Area at risk was expressed as percentage of total ventricular weight, whereas infarct size was expressed as percentage of area at risk.
Tissue specimens were obtained both from the area at risk and from a control, distant, myocardial region, and were immediately immersed in paraformaldehyde. Mitochondrial respiration was assessed with a Clark-type oxygen electrode Hansatech, UK at room temperature after addition of respiration substrates. Incidence of VF was analyzed by the Pearson Chi-square test. Non-parametric Mann-Whitney U test was used to assess differences in the number and durations of ventricular arrhythmias.
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