Xiaowei Zhong, Bo Sun, Alexander Vallmitjana, Tao Mi, Wenting Guo, Mingke Ni, Ruiwu Wang, Ang Guo, Henry J Duff, Anne M Gillis, Long-Sheng Song, Leif Hove-Madsen, Raul Benitez, S R Wayne Chen

Beat-to-beat alternations in the amplitude of the cytosolic Ca(2+) transient (Ca(2+) alternans) are thought to be the primary cause of cardiac alternans that can lead to cardiac arrhythmias and sudden death. Despite its important role in arrhythmogenesis, the mechanism underlying Ca(2+) alternans remains poorly understood. Here we investigated the role of cardiac ryanodine receptor (RyR2), the major Ca(2+) release channel responsible for cytosolic Ca(2+) transients, in cardiac alternans. Using a unique mouse model harboring a suppression-of-function (SOF) RyR2 mutation (E4872Q), we assessed the effect of genetically suppressing RyR2 function on Ca(2+) and action potential duration (APD) alternans in intact hearts, and electrocardiogram (ECG) alternans in vivo. We found that RyR2-SOF hearts displayed prolonged sarcoplasmic reticulum Ca(2+) release refractoriness and enhanced propensity for Ca(2+) alternans. RyR2-SOF hearts/mice also exhibited increased propensity for APD and ECG alternans.  Caffeine, which enhances RyR2 activity and the propensity for catecholaminergic polymorphic ventricular tachycardia (CPVT), suppressed Ca(2+) alternans in RyR2-SOF hearts, whereas carvedilol, a beta-blocker that suppresses RyR2 activity and CPVT, promoted Ca(2+) alternans in these hearts. Thus, RyR2 function is an important determinant of Ca(2+), APD, and ECG alternans. Our data also indicate that the activity of RyR2 influences the propensity for cardiac alternans and CPVT in an opposite manner. Therefore, overly suppressing or enhancing RyR2 function is pro-arrhythmic.