Abstract
Nitro-fatty acids are electrophilic anti-inflammatory mediators which are generated during myocardial ischemic injury. Whether these species exert anti-arrhythmic effects in the acute phase of myocardial ischemia has not been investigated so far. Herein, we demonstrate that pretreatment of mice with 9- and 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO2-OA) significantly reduced the susceptibility to develop acute ventricular tachycardia (VT). Accordingly, epicardial mapping revealed a markedly enhanced homogeneity in ventricular conduction. NO2-OA treatment of isolated cardiomyocytes lowered the number of spontaneous contractions upon adrenergic isoproterenol stimulation and nearly abolished ryanodine receptor type 2 (RyR2)-dependent sarcoplasmic Ca2+ leak. NO2-OA also significantly reduced RyR2-phosphorylation by inhibition of increased CaMKII activity. Thus, NO2-OA might be a novel pharmacological option for the prevention of VT development.
Highlights
Nitro-fatty acids are electrophilic anti-inflammatory mediators which are generated during myocardial ischemic injury
The mechanisms accounting for the development of acute ventricular tachycardia (VT) are diverse: in the acute ischemic phase, 15–30 min after acute myocardial ischemia (AMI), the development of so called 1B arrhythmias has been linked to increased catecholamine release and disturbances in Ca2+ signaling within cardiomyocytes of the ischemic border zone, leading to ventricular conduction blocks and enhanced VT v ulnerability[3,4]
The total time of VT episodes was reduced after N O2-OA-pretreament (Fig. 1D) indicating that VT episodes in N O2-OA pretreated ischemic hearts were rapidly self-terminating
Summary
Nitro-fatty acids are electrophilic anti-inflammatory mediators which are generated during myocardial ischemic injury Whether these species exert anti-arrhythmic effects in the acute phase of myocardial ischemia has not been investigated so far. The mechanisms accounting for the development of acute VT are diverse: in the acute ischemic phase, 15–30 min after AMI, the development of so called 1B arrhythmias has been linked to increased catecholamine release and disturbances in Ca2+ signaling within cardiomyocytes of the ischemic border zone, leading to ventricular conduction blocks and enhanced VT v ulnerability[3,4]. Dietary intervention with endogenously produced antiarrhythmic modulators appears as an attractive therapeutic approach This concept has been recently supported by the randomized double blind trial REDUCE-IT which demonstrates that prophylactic treatment with icosapentaenoic acid-ethyl (VASCEPA) significantly reduces cardiovascular events, the rate of cardiac arrests, and the number of sudden cardiac deaths (SCD)[8]
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