Background: 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.
Methods: 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.
Results: 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).
Conclusions: 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. (C) 2017 Hellenic Society of Cardiology.
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