Key result
CASQ2 loss promotes sinoatrial node dysfunction and atrial fibrillation susceptibility via abnormal calcium handling and fibrosis.
Why the study?
Loss-of-function mutations in CASQ2 are associated with CPVT patients exhibiting bradycardia and atrial arrhythmias, but the underlying mechanism is unknown.
Does Calsequestrin 2 deletion cause sinoatrial node dysfunction and atrial arrhythmias in mice?
Does Calsequestrin 2 deletion cause sinoatrial node dysfunction and atrial arrhythmias in mice?
Loss of CASQ2 in mice causes abnormal sarcoplasmic reticulum Ca2+ release and selective interstitial fibrosis, providing a mechanism for SAN dysfunction and atrial fibrillation in CPVT patients.
Answers are grounded in this paper and cite their sources.
CASQ2 deletion disrupts SAN pacemaking and increases AF susceptibility in mice; leaves open relevance to CPVT patients.
AIMS: Loss-of-function mutations in Calsequestrin 2 (CASQ2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT patients also exhibit bradycardia and atrial arrhythmias for which the underlying mechanism remains unknown. We aimed to study the sinoatrial node (SAN) dysfunction due to loss of CASQ2. METHODS AND RESULTS: In vivo electrocardiogram (ECG) monitoring, in vitro high-resolution optical mapping, confocal imaging of intracellular Ca(2+) cycling, and 3D atrial immunohistology were performed in wild-type (WT) and Casq2 null (Casq2(-/-)) mice. Casq2(-/-) mice exhibited bradycardia, SAN conduction abnormalities, and beat-to-beat heart rate variability due to enhanced atrial ectopic activity both at baseline and with autonomic stimulation. Loss of CASQ2 increased fibrosis within the pacemaker complex, depressed primary SAN activity, and conduction, but enhanced atrial ectopic activity and atrial fibrillation (AF) associated with macro- and micro-reentry during autonomic stimulation. In SAN myocytes, CASQ2 deficiency induced perturbations in intracellular Ca(2+) cycling, including abnormal Ca(2+) release, periods of significantly elevated diastolic Ca(2+) levels leading to pauses and unstable pacemaker rate. Importantly, Ca(2+) cycling dysfunction occurred not only at the SAN cellular level but was also globally manifested as an increased delay between action potential (AP) and Ca(2+) transient upstrokes throughout the atrial pacemaker complex. CONCLUSIONS: Loss of CASQ2 causes abnormal sarcoplasmic reticulum Ca(2+) release and selective interstitial fibrosis in the atrial pacemaker complex, which disrupt SAN pacemaking but enhance latent pacemaker activity, create conduction abnormalities and increase susceptibility to AF. These functional and extensive structural alterations could contribute to SAN dysfunction as well as AF in CPVT patients.
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Glukhov et al. (2013) studied Sinoatrial node dysfunction and atrial arrhythmias in CPVT. Casq2 deletion vs. Wild-type (WT) mice was evaluated on Sinoatrial node dysfunction, atrial arrhythmias, and intracellular Ca2+ cycling. Loss of CASQ2 in mice caused abnormal sarcoplasmic reticulum Ca2+ release and selective interstitial fibrosis, disrupting sinoatrial node pacemaking and increasing atrial fibrillation susceptibility.
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