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

Abstract

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 10μM) which concentration-dependently decreased the APD₂₀ by 13±8%, 25±5%, 31±6%, and 37±5%, APD₅₀ by 9±8%, 22±6%, 32±7%, and 40±4%, and APD₉₀ by 2±12%, 9±8%, 24±10%, and 34±5% in LA preparations. EGCG (0.1μM) 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, 1μM)-induced burst firing. KT5823 (1μM) or KN93 (1μM) decreased the incidences of ISO-induced LA burst firing, which became lower with EGCG treatment. H89 (10μM) and KN92 (1μM) 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.

Keywords: Atrial fibrillation; Calcium homeostasis; Epigallocatechin-3-gallate; Left atrium.