Abstract 14206: The Ryanodine Receptor Calcium Leak Does Not Contribute to the Development of Heart Failure

Abstract

Rationale: Increased sarcoplasmic reticulum (SR) Ca2+ leak via cardiac ryanodine receptor (RyR2) is thought to play a role in heart failure (HF) development. Inhibition of this leak has been suggested to be an emerging therapeutic strategy. However, some studies have raised controversy as to the importance of SR Ca2+ leak in HF development. Previously, we and others have shown that pressure overload (PO) and myocardial infarction (MI) models result in an increased SR Ca2+ leak and maladaptive cardiac remodeling. Objective: We sought to determine whether inhibiting SR Ca2+ leak in PO or MI could avert HF progression. Methods and Results: Wild-type C57BL/6J mice treated with or without RyR2 stabilizer, Rycal S36, were exposed to two model of chronic cardiac stress, transaortic constriction (TAC)-induced PO or permanent coronary artery occlusion-induced MI. Left ventricular structural and functional remodeling were determined after surgeries. SR Ca2+ leak was significantly reduced in S36-treated mice versus placebo controls after surgeries. However, both placebo- and S36-treated mice developed pathological cardiac remodeling and systolic dysfunction nearly to the same extent in both experimental models. Interestingly, there was a trend, but not significant, toward improved survival in S36-treated mice compared to that in placebo (P = 0.12 and 0.13 in TAC-S36 and MI-S36, respectively). Conclusion: These results strongly support the idea that SR Ca2+ leak is irrelevant to the development of cardiac dysfunction after TAC or MI. The minimal reduced mortality after TAC or MI suggests a possible antiarrhythmic effect of the Rycal S36, which needs further investigations.