Stretch-induced sarcoplasmic reticulum calcium leak is causatively associated with atrial fibrillation in pressure-overloaded hearts

Yi Zhang, Ying Qi, Jing-Jing Li, Wen-Jin He, Xiao-Hang Gao, Yu Zhang, Xia Sun, Jie Tong, Jianbao Zhang, Xiu-Ling Deng, Xiao-Jun Du, Wenjun Xie
Cardiovascular Research 2020 June 12

AIMS: Despite numerous reports documenting an important role of hypertension in the development of atrial fibrillation (AF), the detailed mechanism underlying the pathological process remains incompletely understood. Here, we aim to test the hypothesis that diastolic sarcoplasmic reticulum (SR) Ca2+ leak in atrial myocytes, induced by mechanical stretch due to elevated pressure in the left atrium (LA), plays an essential role in the AF development in pressure-overloaded hearts.

METHODS AND RESULTS: Isolated mouse atrial myocytes subjected to acute axial stretch displayed an immediate elevation of SR Ca2+ leak. Using a mouse model of transverse aortic constriction (TAC), the relation between stretch, SR Ca2+ leak and AF susceptibility was further tested. At 36 hours post TAC, SR Ca2+ leak in cardiomyocytes from the LA (with hemodynamic stress), but not right atrium (without hemodynamic stress), significantly increased, which was further elevated at 4 weeks post TAC. Accordingly, AF susceptibility to atrial burst pacing in the 4-week TAC mice were also significantly increased, which was unaffected by inhibition of atrial fibrosis or inflammation via deletion of galectin-3. Western blotting revealed that type 2 ryanodine receptor (RyR2) in LA myocytes of TAC mice was oxidized due to activation and upregulation of Nox2 and Nox4. Direct rescue of dysfunctional RyR2 with dantrolene or rycal S107 reduced diastolic SR Ca2+ leak in LA myocytes and prevented atrial burst pacing stimulated AF.

CONCLUSION: Our study demonstrated for the first time the increased SR Ca2+ leak mediated by enhanced oxidative stress in LA myocytes that is causatively associated with higher AF susceptibility in pressure-overloaded hearts.

TRANSLATIONAL PERSPECTIVE: RyR2 is the major Ca2+ channel in cardiac myocytes, strongly affecting cellular activities. Several types of heart diseases, including heart failure and ventricular arrhythmias, are related to RyR2 dysfunction in ventricular myocytes. The present study expands RyR2 dysfunction as a critical contributor in pressure-overload associated AF. As AF is usually accompanied with cardiac remodeling and dysfunction in the setting of hypertension, which is a common risk factor for different cardiovascular diseases, the convergence of several pathological processes on the dysfunctional RyR2 makes it a common therapeutic target in these diseased settings.

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