Accelerated Sinus Rhythm Prevents Catecholaminergic Polymorphic Ventricular Tachycardia in Mice and in Patients

1Vanderbilt University Medical School, 1265 MRB4, 2215B Garland Ave, Nashville, Tennessee, 37232-0575, UNITED STATES.
Circulation Research (Impact Factor: 11.02). 01/2013; 112(4). DOI: 10.1161/CIRCRESAHA.111.300076
Source: PubMed

ABSTRACT Rationale:
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) genes. Sinoatrial node dysfunction associated with CPVT may increase the risk for ventricular arrhythmia (VA).

To test the hypothesis that CPVT is suppressed by supraventricular overdrive stimulation.

Methods and results:
Using CPVT mouse models (Casq2(-/-) and RyR2(R4496C/+) mice), the effect of increasing sinus heart rate was tested by pretreatment with atropine and by atrial overdrive pacing. Increasing intrinsic sinus rate with atropine before catecholamine challenge suppressed ventricular tachycardia in 86% of Casq2(-/-) mice (6/7) and significantly reduced the VA score (atropine: 0.6±0.2 versus vehicle: 1.7±0.3; P<0.05). Atrial overdrive pacing completely prevented VA in 16 of 19 (84%) Casq2(-/-) and in 7 of 8 (88%) RyR2(R4496C/+) mice and significantly reduced ventricular premature beats in both CPVT models (P<0.05). Rapid pacing also prevented spontaneous calcium waves and triggered beats in isolated CPVT myocytes. In humans, heart rate dependence of CPVT was evaluated by screening a CPVT patient registry for antiarrhythmic drug-naïve individuals that reached >85% of their maximum-predicted heart rate during exercise testing. All 18 CPVT patients who fulfilled the inclusion criteria exhibited VA before reaching 87% of maximum heart rate. In 6 CPVT patients (33%), VA were paradoxically suppressed as sinus heart rates increased further with continued exercise.

Accelerated supraventricular rates suppress VAs in 2 CPVT mouse models and in a subset of CPVT patients. Hypothetically, atrial overdrive pacing may be a therapy for preventing exercise-induced ventricular tachycardia in treatment-refractory CPVT patients.

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    ABSTRACT: 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. 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. 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.
    European Heart Journal 11/2013; 36(11). DOI:10.1093/eurheartj/eht452 · 15.20 Impact Factor
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    ABSTRACT: Background Calmodulin (CaM) mutations have been identified recently in subjects with congenital long QT syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT), but the mechanisms responsible for these divergent arrhythmia‐susceptibility syndromes in this context are unknown. We tested the hypothesis that LQTS‐associated CaM mutants disrupt Ca2+ homeostasis in developing cardiomyocytes possibly by affecting either late Na current or Ca2+‐dependent inactivation of L‐type Ca2+ current. Methods and Results We coexpressed CaM mutants with the human cardiac Na channel (NaV1.5) in tsA201 cells, and we used mammalian fetal ventricular cardiomyocytes to investigate LQTS‐ and CPVT‐associated CaM mutations (LQTS‐ and CPVT‐CaM). LQTS‐CaM mutants do not consistently affect L‐type Na current in heterologous cells or native cardiomyocytes, suggesting that the Na channel does not contribute to LQTS pathogenesis in the context of CaM mutations. LQTS‐CaM mutants (D96V, D130G, F142L) impaired Ca2+‐dependent inactivation, whereas the CPVT‐CaM mutant N54I had no effect on Ca2+‐dependent inactivation. LQTS‐CaM mutants led to loss of Ca2+‐transient entrainment with the rank order from greatest to least effect: CaM‐D130G~CaM‐D96V>>CaM‐F142L. This rank order follows measured Ca2+‐CaM affinities for wild‐type and mutant CaM. Acute isoproterenol restored entrainment for CaM‐130G and CaM‐D96V but caused irreversible cytosolic Ca2+ overload for cells expressing a CPVT‐CaM mutant. Conclusions CaM mutations associated with LQTS may not affect L‐type Na+ current but may evoke defective Ca2+‐dependent inactivation of L‐type Ca2+ current.
    Journal of the American Heart Association 04/2014; 3(3). DOI:10.1161/JAHA.114.000996 · 4.31 Impact Factor
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    ABSTRACT: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited rhythm disorder characterized by the occurrence of potentially life-threatening polymorphic ventricular tachyarrhythmias in conditions of physical or emotional stress. The underlying cause is a dysregulation in intracellular Ca handling due to mutations in the sarcoplasmic reticulum Ca release channel. Recent experimental work suggests that the sinus bradycardia that is sometimes observed in CPVT patients may be another primary defect caused by CPVT mutations. Here, we review the pathophysiology of CPVT and discuss the role of sinus node dysfunction as a modulator of arrhythmia risk and potential therapeutic target.
    Trends in Cardiovascular Medicine 10/2014; 24(7). DOI:10.1016/j.tcm.2014.07.001 · 2.91 Impact Factor
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