Cardiac ischemia/reperfusion injury is associated with the formation and action of lipid mediators derived from polyunsaturated fatty acids. Among them, linoleic acid (LA) is metabolized to epoxyoctadecanoic acids (EpOMEs) by cytochrome P450 (CYP) epoxygenases and further to dihydroxyoctadecanoic acids (DiHOMEs) by soluble epoxide hydrolase (sEH). We hypothesized that EpOMEs and/or DiHOMEs may affect cardiac post-ischemic recovery and addressed this question using isolated murine hearts in a Langendorff system. Hearts from C57Bl6 mice were exposed to 12,13-EpOME, 12,13-DiHOME, or vehicle (phosphate buffered sodium; PBS). Effects on basal cardiac function and functional recovery during reperfusion following 20 min of ischemia were investigated. Electrocardiogram (ECG), left ventricular (LV) pressure and coronary flow (CF) were continuously measured. Ischemia reperfusion experiments were repeated after administration of the sEH-inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA). At a concentration of 100 nM, both EpOME and DiHOME decreased post-ischemic functional recovery in murine hearts. There was no effect on basal cardiac parameters. The detrimental effects seen with EpOME, but not DiHOME, were averted by sEH inhibition (AUDA). Our results indicate that LA-derived mediators EpOME/DiHOME may play an important role in cardiac ischemic events. Inhibition of sEH could provide a novel treatment option to prevent detrimental DiHOME effects in acute cardiac ischemia.
BACKGROUND: Single nucleotide polymorphisms (SNPs) of EPHX2 alter sEH activity and are associated with increased [rs41507953 (K55R)] or reduced [rs751141 (R287Q)] cardiovascular risk via modulation of fibrosis, inflammation or cardiac ion channels. This indicates an effect on development and therapy response of AF. This study tested the hypothesis that variations in the EPHX2 gene encoding human soluble epoxide hydrolase (sEH) are associated with atrial fibrillation (AF) and recurrence of atrial fibrillation after catheter ablation. METHODS AND RESULTS: A total of 218 consecutive patients who underwent catheter ablation for drug refractory AF and 268 controls were included. Two SNPs, rs41507953 and rs751141, were genotyped by direct sequencing. In the ablation group, holter recordings 3, 12 and 24months after ablation were used to detect AF recurrence. No significant association of the SNPs and AF at baseline was detected. In the ablation group, recurrence of AF occurred in 20% of the patients 12months after ablation and in 35% 24months after ablation. The presence of the rs751141 polymorphism significantly increased the risk of AF recurrence 12months (odds ratio [OR]: 3.2, 95% confidence interval [CI]: 1.237 to 8.276, p=0.016) and 24months (OR: 6.076, 95% CI: 2.244 to 16.451, p<0.0001) after catheter ablation. CONCLUSIONS: The presence of rs751141 polymorphism is associated with a significantly increased risk of AF recurrence after catheter ablation. These results point to stratification of catheter ablation by genotype and differential use of sEH-inhibitory drugs in the future.
