P4492Real urban air pollutants induces arrhythmia via oxidative stress and calcium calmodulin kinase II activatioin

Abstract

Background: Particulate air pollution is an environmental health risk factor that is associated with increased cardiovascular morbidity and mortality. Ambient air pollutants (AAP) can increase the incidence of arrhythmia. However, the arrhythmogenic mechanism of AAP is poorly understood. Objective: This study investigated the arrhythmogenic mechanism of AAP. Methods: To analyze and utilize the ambient traffic pollutants under real urban environment (RUE), specially-modifed vehicle, mobile emission laboratory (MEL) equipment was designed. Mice were exposed to control (Control group, n=10) and RUE (RUE group, n=10) for 30 days. According to the analysis of compositions of APP, real urban area environment had 3.5, 2, 3 and 4.5 times higher concentration of particle numbers, BC, PAH and NO, respectively Results: Mice exposed to RUE showed more decreased heart rate, prolonged QRS, QT, QTc intervals (all p<0.001), and had higher incidence of spontaneous ventricular arrhythmia (70% vs. 0%, p<0.01) than control. In dual optical mapping of Vm and Cai, URE group showed longer APD90 and longer Cai duration. Spontaneous early afterdepolarization (EAD) and ventricular tachycardia (VT) were observed in 8 (67%) and 6 (50%) hearts, respectively, versus no spontaneous triggered activity or VT in any control heart. AAP induced APD prolongation was reversed by N-acetylcysteine (5 mmol/L) and active Ca2+/ calmodulin-dependent protein kinase II (CaMKII) blockade, KN 93 (1 μmol/L), but not by inactive CaMKII blockade, KN 92 (1 μmol/L). CaMKII autophosphorylation at Thr287 (221%), and RyR2 phosphorylation at Ser2808 (protein kinase A/CaMKII site, 136%) and Ser2814 (CaMKII site, 20%) were increased in Mice exposed to RUE. Finally, in HL1 cells, AAP (eg, diesel exhaust products) provoked ROS generation in dose dependent manner. DEP (12.5 μg/ml) induced apoptosis, and this effect was prevented by NAC and KN 93. Conclusion: Exposure to real urban environment could induce electrophysiological changes such as APD and QT prolongation, and increase ventricular arrhythmia. These effects might be caused by oxidative stress and CaMKII activation.