Research ArticleCardiology

Sarcoplasmic reticulum calcium leak contributes to arrhythmia but not to heart failure progression

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Science Translational Medicine  12 Sep 2018:
Vol. 10, Issue 458, eaan0724
DOI: 10.1126/scitranslmed.aan0724

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Cardiac calcium clarified

The subcellular localization of calcium within cardiomyocytes is tightly regulated during the cardiac cycle, and calcium leak from the sarcoplasmic reticulum is linked to alterations in heart rhythm and heart failure. Mohamed et al. investigated whether inhibiting calcium leak by stabilizing the sarcoplasmic calcium channel ryanodine receptor 2 corrected irregular heartbeat and prevented maladaptive myocardial remodeling and heart failure. In a mouse model of pressure overload, reduced calcium leak did not prevent heart failure; increased calcium leak in a volume overload mouse model did not exacerbate heart failure. Rather, inhibiting calcium leak corrected arrhythmias in myocytes derived from patients with heart failure and tachycardia. Although myocardial remodeling was not altered, arrhythmia was mitigated and survival was increased by ryanodine receptor stabilization in mouse models, suggesting a potential therapeutic application for inhibiting sarcoplasmic calcium leak.

Abstract

Increased sarcoplasmic reticulum (SR) Ca2+ leak via the cardiac ryanodine receptor (RyR2) has been suggested to play a mechanistic role in the development of heart failure (HF) and cardiac arrhythmia. Mice treated with a selective RyR2 stabilizer, rycal S36, showed normalization of SR Ca2+ leak and improved survival in pressure overload (PO) and myocardial infarction (MI) models. The development of HF, measured by echocardiography and molecular markers, showed no difference in rycal S36– versus placebo-treated mice. Reduction of SR Ca2+ leak in the PO model by the rycal-unrelated RyR2 stabilizer dantrolene did not mitigate HF progression. Development of HF was not aggravated by increased SR Ca2+ leak due to RyR2 mutation (R2474S) in volume overload, an SR Ca2+ leak–independent HF model. Arrhythmia episodes were reduced by rycal S36 treatment in PO and MI mice in vivo and ex vivo in Langendorff-perfused hearts. Isolated cardiomyocytes from murine failing hearts and human ventricular failing and atrial nonfailing myocardium showed reductions in delayed afterdepolarizations, in spontaneous and induced Ca2+ waves, and in triggered activity in rycal S36 versus placebo cells, whereas the Ca2+ transient, SR Ca2+ load, SR Ca2+ adenosine triphosphatase function, and action potential duration were not affected. Rycal S36 treatment of human induced pluripotent stem cells isolated from a patient with catecholaminergic polymorphic ventricular tachycardia could rescue the leaky RyR2 receptor. These results suggest that SR Ca2+ leak does not primarily influence contractile HF progression, whereas rycal S36 treatment markedly reduces ventricular arrhythmias, thereby improving survival in mice.

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