Pharmacologic inhibition of the mitochondrial Na+/Ca2+ exchanger protects against ventricular arrhythmias in a porcine model of ischemia-reperfusion

• Published in: Hellenic journal of cardiology 2018-07, Vol.59 (4), p.217-222
• Main Authors: Sventzouri, Stefania, Nanas, Ioannis, Vakrou, Styliani, Kapelios, Chris, Sousonis, Vasilios, Sfakianaki, Titika, Papalois, Apostolos, Manolis, Antonis S., Nanas, John N., Malliaras, Konstantinos
• Format: Article
• Language: English
• Subjects: Arrhythmias; CGP-37157; Ischemia-reperfusion injury; Mitochondrial Na+/Ca2+ exchanger; Myocardial infarction
• ISSN: 1109-9666
• DOI: 10.1016/j.hjc.2017.12.009

The mitochondrial Na+/Ca2+ exchanger (mNCX) has been implicated in the pathogenesis of arrhythmogenicity and myocardial reperfusion injury, rendering its inhibition a potential therapeutic strategy. We examined the effects of CGP-37157, a selective mNCX inhibitor, on arrhythmogenesis, infarct size (IS), and no reflow area (NRA) in a porcine model of ischemia-reperfusion. Forty pigs underwent myocardial ischemia for 60 minutes, followed by 2 hours of reperfusion. Animals were randomized to receive intracoronary infusion of 0.02 mg/kg CGP-37157 or vehicle, either before ischemia (n=17) or before reperfusion (n=17). Animals were monitored for arrhythmias. Myocardial area at risk (AR), IS, and NRA were measured by histopathology. AR, NRA, and IS were comparable between groups. Administration of CGP-37157 before ischemia resulted in the following: (a) suppression of ventricular tachyarrhythmias (events/pig: 1.5±1.1 vs 3.5±1.9, p=0.014), (b) easier cardioversion of ventricular tachyarrhythmias (defibrillations required for cardioversion of each episode: 2.6±2.3 vs 6.2±2.1, p=0.006), and (c) decreased maximal depression of the J point (0.75±0.27 mm vs 1.75±0.82 mm, p=0.007), compared to controls. Administration of CGP-37157 before reperfusion expedited ST-segment resolution; complete ST-segment resolution within 30 minutes of reperfusion was observed in 7/8 CGP-37157-treated animals versus 1/9 controls (p=0.003). In a porcine model of myocardial infarction, intracoronary administration of CGP-37157 did not decrease IS or NRA. However, it suppressed ventricular arrhythmias, decreased depression of the J point during ischemia and expedited ST-segment resolution after reperfusion. These findings motivate further investigation of pharmacologic mNCX inhibition as a potential therapeutic strategy to suppress arrhythmias in the injured heart. [Display omitted]