Anti-arrhythmic and anti-fibrotic effects of nitrated fatty acids in myocardial remodeling.

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Nitrated fatty acids (NO2-FA) are endogenously generated signalling mediators that have been shown to exert potent anti-inflammatory effects in a variety of disease models. Thus, our group was able to demonstrate that nitro-9-cis-octadecenoic acid (OA-NO2) is abundantly generated, reduces infarct size and preserves left ventricular function during myocardial reperfusion and exhibits potent anti-fibrotic effects on the atrial and ventricular level. Ongoing research in the field revealed that dietary modifications can increase these compounds to therapeutic levels, while clinical phase 1 and 2a studies with 10-nitro-9(E)-octadec-9-enoic acid (CXA-10), the 10-isomer of OA-NO2 show a favourable side effect profile and encouraging preliminary results. In an effort to further our understanding of their therapeutic potential the current proposal aims to define the therapeutic effects of endogenous generation of NO2-FA by dietary supplementation with conjugated linoleic acid (racemic mixture of (9Z,11E)-cLA and (10E,12Z)-cLA) and nitrite and the effects of exogenously applied synthetic nitrated oleic acids (OA-NO2) throughout different, clinically meaningful, stages of acute myocardial infarction. In preliminary studies OA-NO2 potently suppressed inducibility of ventricular fibrillation after two minutes of myocardial ischemia, raising the question whether OA-NO2 could emerge as preventive strategy for infarct-related sudden cardiac death, particularly given the possibility for dietary modification of plasma levels. The observations will be extended to investigate the effects of both the dietary and synthetic approach on phase 1a and phase 1b ventricular tachycardias. Finally, long-term effects of NO2-FA on ventricular fibrotic remodeling will be evaluated in a 3-week model of permanent LAD ligation.