Arrhythmia/Electrophysiology Paradoxical Effect of Increased Diastolic Ca Release and Decreased Sinoatrial Node Activity in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia
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چکیده
spark frequency was increased by 2-fold in RyR2 SAN. Whole-cell patch-clamp experiments performed on isolated RyR2 SAN cells showed that L-type Ca current (ICa,L) density was reduced by 50%, an effect blunted by internal Ca buffering. Isoproterenol dramatically increased the frequency of Ca sparks and waves by 5 and 10-fold, respectively. Interestingly, the sarcoplasmic reticulum Ca content was significantly reduced in RyR2 SAN cells in the presence of isoproterenol, which may contribute to stopping the “Ca clock” rhythm generation, originating SAN pauses. Conclusion—The increased activity of RyR2 in SAN leads to an unanticipated decrease in SAN automaticity by a Ca -dependent decrease of ICa,L and sarcoplasmic reticulum Ca 2 depletion during diastole, identifying subcellular pathophysiological alterations contributing to the SAN dysfunction in catecholaminergic polymorphic ventricular
منابع مشابه
Paradoxical Effect of Increased Diastolic Ca Release and Decreased Sinoatrial Node Activity in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia
Catecholaminergic polymorphic ventricular tachycardia is a congenital arrhythmogenic disease linked to -adrenergic–induced ventricular arrhythmias that has a high mortality in children and young adults when untreated. As common features of the catecholaminergic polymorphic ventricular tachycardia phenotype, supraventricular arrhythmias have also been described in catecholaminergic polymorphic v...
متن کاملParadoxical effect of increased diastolic Ca(2+) release and decreased sinoatrial node activity in a mouse model of catecholaminergic polymorphic ventricular tachycardia.
BACKGROUND Catecholaminergic polymorphic ventricular tachycardia is characterized by stress-triggered syncope and sudden death. Patients with catecholaminergic polymorphic ventricular tachycardia manifest sinoatrial node (SAN) dysfunction, the mechanisms of which remain unexplored. METHODS AND RESULTS We investigated SAN [Ca(2+)](i) handling in mice carrying the catecholaminergic polymorphic ...
متن کاملAbnormal Ca2+ homeostasis, atrial arrhythmogenesis, and sinus node dysfunction in murine hearts modeling RyR2 modification
Ryanodine receptor type 2 (RyR2) mutations are implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT) thought to result from altered myocyte Ca(2+) homeostasis reflecting inappropriate "leakiness" of RyR2-Ca(2+) release channels arising from increases in their basal activity, alterations in their phosphorylation, or defective interactions with other molecules or ions. The la...
متن کاملDantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia
Coordinated release of calcium (Ca(2+) ) from the sarcoplasmic reticulum (SR) through cardiac ryanodine receptor (RYR2) channels is essential for cardiomyocyte function. In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease characterized by stress-induced ventricular arrhythmias in young patients with structurally normal hearts, autosomal dominant mutations in RY...
متن کاملCalcium Leak Through Ryanodine Receptors Leads To Atrial Fibrillation In Three Mouse Models of Catecholaminergic Polymorphic Ventricular Tachycardia
Rationale: Atrial fibrillation (AF) is the most common cardiac arrhythmia, however the mechanism(s) causing AF remain poorly understood and therapy is suboptimal. The ryanodine receptor (RyR2) is the major calcium (Ca) release channel on the sarcoplasmic reticulum (SR) required for excitationcontraction coupling in cardiac muscle. Objective: In the present study we sought to determine whether i...
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تاریخ انتشار 2012