Background-Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder causing life-threatening arrhythmias whenever sympathetic activity increases. β-Βlockers are the mainstay of therapy; when they fail, implantable cardioverter-defibrillators (ICDs) are used but often cause multiple shocks. Preliminary results with flecainide appear encouraging.We proposed left cardiac sympathetic denervation (LCSD) as useful additional therapy, but evidence remains anecdotal. Methods and Results-We report 63 patients with CPVT who underwent LCSD as secondary (n=54) or primary (n=9) prevention. The median post-LCSD follow-up was 37 months. The 9 asymptomatic patients remained free of major cardiac events. Of the 54 patients with prior major cardiac events either on (n=38) or off (n=16) optimal medical therapy, 13 (24%) had at least 1 recurrence: 0 patients had an aborted cardiac arrest, 2 patients had syncope only, 10 patients had ≥1 appropriate ICD discharges, and 1 patient died suddenly. The 1-and 2-year cumulative event-free survival rates were 87% and 81%. The percentage of patients with major cardiac events despite optimal medical therapy (n=38) was reduced from 100% to 32% (P<0.001) after LCSD, and among 29 patients with a presurgical ICD, the rate of shocks dropped by 93% from 3.6 to 0.6 shocks per person per year (P<0.001). Patients with an incomplete LCSD (n=7) were more likely to experience major cardiac events after LCSD (71% versus 17%; P<0.01) than those with a complete LCSD. Conclusions-LCSD is an effective antifibrillatory intervention for patients with CPVT. Whenever syncope occurs despite optimal medical therapy, LCSD could be considered the next step rather than an ICD and could complement ICDs in patients with recurrent shocks.

Background: Genetic variants in calsequestrin-2 ( CASQ2 ) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2 -CPVT was sought through an international multicenter collaboration. Methods: Genotype-phenotype segregation in CASQ2 -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6–11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3–8.0; P =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6–269.1; P <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. Conclusions: This international multicenter study of CASQ2 -CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.

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We are glad to have the opportunity to respond to the points kindly raised by Drs Patanè and Gow in reference to our recent article on catecholaminergic polymorphic ventricular tachycardia (CPVT). 1 We are obviously aware of the article by Faggioni et al, 2 which includes 1 of the coauthors of our article, Dr Wilde. We also have direct experience with a few CPVT patients who had a reduction or disappearance of the ventricular arrhythmias induced by exercise when heart rate increased further (usually to >140 bpm). We have not discussed atrial overdrive pacing simply because we do not believe that these data and observations have direct relevance to the ongoing clinical management of CPVT patients in everyday life. The concept of atrial high-rate pacing (>120 bpm) may be of potential value in the in-hospital management of emergencies, but we find it difficult to recommend that heart rate should be increased permanently, or during exercise, to >140 bpm. In addition, how would it be possible to exclude that such an intervention, activated in the out-of-hospital setting, would not precipitate ventricular tachycardia or ventricular fibrillation? Our article was focused on how to reduce the incidence of life-threatening arrhythmias in the safest way. Rate support of CPVT patients who have symptomatic bradycardia in response to therapeutic β-blockade is always a consideration in CPVT.We acknowledge the comments concerning the possibility of anatomic variations in the cervicothoracic ganglion. Dr Gow has downplayed the statements by a recognized expert in the field (Andrew Armour), 3 who wrote that "all major cardiopulmonary nerves were found to arise from the stellate ganglia" and focused on the conclusions by Marcer et al 4 and Pather et al, 5 largely based on embalmed cadavers and on fetuses, that in ≈20% of cases the inferior cervical ganglion and the first thoracic ganglion were separate. In our personal experience of >40 years in hundreds of patients in whom we performed left (and sometimes right) cardiac sympathetic denervation, we have always found the stellate ganglion to be the fusion of the last cervical and first thoracic ganglia. The current video-assisted thoracoscopic approach allows a clear and comprehensive visualization of the anatomy and excludes the possibility of missing a significant anatomic variant.Another part of Dr Gow's letter is clinically relevant. He suggests a correlation between the possibility of anatomic variations of the stellate ganglion and the recurrence of syncope, and very seldom of cardiac arrest, in CPVT patients (and in patients with long QT syndrome) treated with left cardiac sympathetic denervation. Although we consider the issue of anatomic variability of minor importance in favoring the occurrence of arrhythmia recurrences, the deliberate lack of removal of either T4 or of the lower part of the stellate ganglion (T1), to exclude any risk of Horner syndrome, is a true concern. Patients with intentionally incomplete denervation did show a much higher risk of recurrences than p...