Epigallocatechin-3-gallate modulates arrhythmogenic activity and calcium homeostasis of left atrium

Background: Atrial fibrillation (AF) is the commonest sustained arrhythmia, and increases the risk of stroke, heart failure, and mortality. Calcium (Ca2+) overload and oxidative stress are thought to participate in the pathogenesis of AF. Epigallocatechin-3-gallate (EGCG) has an antioxidative effect and been shown to be beneficial in promoting cardiovascular health. However, it is not clear if EGCG directly modulates the electrophysiological characteristics and Ca2+ homeostasis of the left atrium (LA). Methods and results: Conventional microelectrodes, whole-cell patch-clamp, and Fluo-3 fluorometric ratio technique were performed using the isolated rabbit LA preparations or isolated single LA cardiomyocytes before and after EGCG treatment. EGCG (0.01, 0.1, 1, and 10 mu M) which concentration-dependently decreased the APD(20) by 13 +/- 8%, 25 5%, 31 6%, and 37 5%, APD(50) by 9 8%, 22 6%, 32 7%, and 40 4%, and APD(90) by 2 12%, 9 8%, 24 10%, and 34 5% in LA preparations. EGCG (0.1 mu M) decreased the late sodium (Na+) current, L-type Ca2+ current, nickel-sensitive Na+-Ca2+ exchanger current, and transient outward current, but did not change the Na+ current and ultra-rapid delayed rectifier potassium current in LA cardiomyocytes. EGCG decreased intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content in LA cardiomyocytes. Furthermore, EGCG decreased isoproterenol (ISO, 1 mu M)-induced burst firing. KT5823 (1 mu M) or KN93 (1 mu M) decreased the incidences of ISO-induced LA burst firing, which became lower with EGCG treatment. H89 (10 mu M) and KN92 (1 mu M) did not suppress the incidence of ISO-induced LA burst firing. However, EGCG decreased the incidences of ISO-induced LA burst firing in the presence of H89 or KN92. Conclusion: EGCG directly regulates LA electrophysiological characteristics and Ca2+ homeostasis, and suppresses ISO-induced atrial arrhythmogenesis through inhibiting Ca2+/calmodulin or cGMP-dependent protein kinases. (C) 2016 Published by Elsevier Ireland Ltd.