Arrhythmia/Electrophysiology Enhanced Sarcoplasmic Reticulum Ca Leak and Increased Na -Ca Exchanger Function Underlie Delayed Afterdepolarizations in Patients With Chronic Atrial Fibrillation
نویسندگان
چکیده
constitutively phosphorylated RyR2 at Ser2814 showed a higher incidence of Ca sparks and increased susceptibility to pacing-induced AF compared with controls. The relationship between [Ca ]i and INCX density revealed INCX upregulation in cAF. Spontaneous Ca release events accompanied by inward INCX currents and delayed afterdepolarizations/triggered activity occurred more often and the sensitivity of resting membrane voltage to elevated [Ca ]i (diastolic [Ca ]i–voltage coupling gain) was higher in cAF compared with control. Conclusions—Enhanced SR Ca leak through CaMKII-hyperphosphorylated RyR2, in combination with larger INCX for a given SR Ca release and increased diastolic [Ca ]i-voltage coupling gain, causes AF-promoting atrial delayed
منابع مشابه
Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation.
BACKGROUND Delayed afterdepolarizations (DADs) carried by Na(+)-Ca(2+)-exchange current (I(NCX)) in response to sarcoplasmic reticulum (SR) Ca(2+) leak can promote atrial fibrillation (AF). The mechanisms leading to delayed afterdepolarizations in AF patients have not been defined. METHODS AND RESULTS Protein levels (Western blot), membrane currents and action potentials (patch clamp), and [C...
متن کاملEnhanced Sarcoplasmic Reticulum Ca-leak and Increased Na-Ca- Exchanger Function Underlie Delayed Afterdepolarizations in Patients with Chronic Atrial Fibrillation
Division of Experimental Cardiology, Dept of Experimental & Clinical Pharmacology, Medical Faculty Mannheim, University of Heidelberg, Mannheim; Dept of Pharmacology & Toxicology, Dresden University of Technology, Dresden, Germany; Dept of Molecular Physiology & Biophysics, Dept of Medicine, Baylor College of Medicine, Houston, TX; Unit of Cardiac Physiology, Manchester Academic Health Sciences...
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BACKGROUND Atrial fibrillation (AF) risk has been associated with leaky ryanodine receptor 2 (RyR2) Ca release channels. Patients with mutations in RyR2 or in the sarcoplasmic reticulum Ca-binding protein calsequestrin 2 (Casq2) display an increased risk for AF. Here, we examine the underlying mechanisms of AF associated with loss of Casq2 and test mechanism-based drug therapy. METHODS AND RE...
متن کاملInhibition of CaMKII phosphorylation of RyR2 prevents induction of atrial fibrillation in FKBP12.6 knockout mice.
RATIONALE Abnormal calcium release from sarcoplasmic reticulum (SR) is considered an important trigger of atrial fibrillation (AF). Whereas increased Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity has been proposed to contribute to SR leak and AF induction, downstream targets of CaMKII remain controversial. OBJECTIVE To test the hypothesis that inhibition of CaMKII-phosphoryl...
متن کاملLoss of microRNA-106b-25 cluster promotes atrial fibrillation by enhancing ryanodine receptor type-2 expression and calcium release.
BACKGROUND Enhanced sarcoplasmic reticulum Ca(2+)-leak via ryanodine receptor type-2 (RyR2) contributes to the pathogenesis of atrial fibrillation (AF). Recent studies have shown that the level of RyR2 protein is elevated in atria of patients with paroxysmal AF, suggesting that microRNA-mediated post-transcriptional regulation of RyR2 might be an underlying mechanism. Bioinformatic analysis sug...
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