Browsing by Author "Duff, Henry Joseph"

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    The Role of Suppressed RyR2 Function in Cardiac Alternans and Ventricular Fibrillation
    (2017) Zhong, Xiaowei; Chen, Suirong Wayne; Duff, Henry Joseph; Schnetkamp, Paul; French, Robert John; Accili, Eric
    Cardiac ryanodine receptors (RyR2) are intracellular Ca2+ release channel localized in the sarco/endoplasmic reticulum (SR/ER). Mutations of RyR2 are linked to arrhythmias and diseases. Interestingly, most of the RyR2 mutations are gain-of-function (GOF) mutations that increase the sensitivity of the channel to activation by luminal and/or cytosolic Ca2+. A4860G, located in the transmembrane domain, is the first loss-of-function (LOF) RyR2 mutation that diminishes luminal Ca2+ activation of RyR2 and abolishes spontaneous Ca2+ release. This finding raises an interesting question of whether there is more LOF RyR2 mutations that present and represent a distinct entity of arrhythmia that has yet to be appreciated. Cardiac alternans is described as a periodic, beat-to-beat alternation in every heartbeat. It is a well-recognized risk factor of ventricular fibrillation (VF) and sudden cardiac death (SCD). Ca2+ alternans is believed to be the primary cause of cardiac alternans but the mechanism underlying Ca2+ alternans remains unclear. The goal of this study is to understand the role of suppressed RyR2 function in cardiac alternans and VF. Clinical evaluations on idiopathic VF patients carrying RyR2-A4860G or RyR2-D4646A mutations have shown no arrhythmias during exercise stress test. Our studies have found three additional LOF RyR2 mutations- E4146K, D4646A, and G4936R. E4146K and D4646A suppress caffeine-induced Ca2+ release and abolish spontaneous Ca2+ release in HEK293 cells, and suppress or diminish both cytosolic or luminal Ca2+ activation of RyR2 channel in lipid bilayers. RyR2-G4936R, non-functional itself, exerts a dominant negative impact on WT function. RyR2-E4872Q+/- mice, with suppressed RyR2 function, prolong SR Ca2+ release refractoriness and enhance the propensity of cardiac alternans in intact heart. RyR2KO mice with reduced RyR2 level are also susceptible to cardiac alternans. Both mouse models are resistant to stress-triggered CPVT. Caffeine, which enhances RyR2 activity and the propensity for CPVT, suppresses Ca2+ alternans; whereas carvedilol, a beta-blocker that suppresses RyR2 activity and CPVT, promotes Ca2+ alternans in RyR2-E4872Q+/- hearts. On the other hand, the GOF mutation RyR2-R4496C increases resistance to alternans. Overall, VF that associated with loss of RyR2 function represents a distinct ventricular arrhythmia from CPVT. The activity of RyR2 influences the propensity for cardiac alternans and CPVT in an opposite manner.