Abstract 10163: Ca 2+ Within the Mitochondria Can Affect the Occurrence of Triggered Arrhythmias in Rats with Right Ventricular Hypertrophy

Abstract

Background: Ca 2+ within the sarcoplasmic reticulum affects the propagation of intracellular Ca 2+ (Ca i ) waves, and the velocity of Ca i waves play important roles in the occurrence of triggered arrhythmias. It is still unknown, however, whether Ca 2+ within the mitochondria (Ca m ) affects the velocity of Ca i wave and the occurrence of arrhythmias in right ventricular (RV) hypertrophy. Objective: To know the roles of Ca m in the velocity of Ca i waves and the occurrence of triggered arrhythmias in rats with RV hypertrophy. Methods: Rats were subcutaneously injected with 60 mg/kg monocrotaline (MCT-rats) or solvent (Ctr-rats). Four weeks after the injection, trabeculae were dissected from the RVs. The force was measured using a silicon strain gauge, Ca m using rhod-2, Ca i using microinjected fura-2 and a CCD camera, and production of reactive oxygen species (ROS) from the slope DCF fluorescence during electrical stimulation. Ca 2+ waves and arrhythmias were induced by electrical stimulation (24°C). Results: MCT-rats showed a higher RV pressure, a larger weight ratio of RV free wall to left ventricle (RV/LV), and faster and larger Ca i waves than Ctr-rats (p<0.01). Among MCT-rats, Ru360 (10 μM), a mitochondrial calcium uniporter (MCU) inhibitor, decreased the occurrence of arrhythmias in trabeculae from rats with a higher RV pressure and a larger RV/LV (n=19). Ru360 decreased rhod-2 signal within trabeculae depending on the RV/LV (r=-0.85, p<0.01, n=10) without changes in Ca i transients, suggesting that inhibition of MCU decreases Ca m in MCT-rats with more severe RV hypertrophy. In addition, Ru360 decreased the velocity of Ca i waves depending on systolic RV pressure (r=-0.60, n=6) and the RV/LV (r=-0.64, n= 7), suggesting that inhibition of MCU decreased the velocity of Ca i waves in MCT-rats with higher RV pressure and more severe RV hypertrophy. Ru360 decreased the slope of DCF fluorescence (p<0.01, n=13). Conclusions: In the hearts with severe RV hypertrophy, inhibition of MCU can cause larger reduction of Ca m , decrease ROS production, and decrease the velocity of Ca i waves and arrhythmias. Thus, in the hearts with severe RV hypertrophy, more Ca 2+ may enter the mitochondria through the MCU, and higher Ca m may be involved in the occurrence of arrhythmias.