An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.

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.

Multiple Intramyocardial Masses in an Otherwise Healthy 35-Year-Old Woman.

Sarcoidosis with manifest cardiac involvement typically presents with heart failure, conduction abnormalities, or ventricular arrhythmias. Here, we present a case of a young woman whose presentation raised suspicion for metastatic cardiac disease of unknown primary origin. Further investigation revealed cardiac sarcoidosis with multiple intramyocardial granulomatous masses in the absence of significant enlargement of hilar or mediastinal nodes. This case highlights the following: (i) sarcoidosis can mimic metastatic cardiac tumours; and (ii) hilar and mediastinal lymph nodes can be metabolically active in cardiac sarcoidosis in the absence of significant enlargement.

La sarcoïdose avec atteinte cardiaque patente se manifeste typiquement par une insuffisance cardiaque, des troubles de la conduction ou des arythmies ventriculaires. Nous présentons ici le cas d'une jeune femme dont le tableau clinique évoquait une pathologie cardiaque métastatique d'origine primitive inconnue. Des examens supplémentaires ont révélé une sarcoïdose cardiaque associée à de multiples granulomes intramyocardiques, en l'absence d'hypertrophie importante des ganglions hilaires ou médiastinaux. Ce cas illustre les points suivants : (i) les symptômes de la sarcoïdose peuvent imiter ceux de tumeurs cardiaques métastatiques; et (ii) les ganglions lymphatiques hilaires et médiastinaux associés à une sarcoïdose cardiaque peuvent présenter une activité métabolique en l'absence d'hypertrophie importante.

Brugada Syndrome: Evolving Insights and Emerging Treatment Strategies.

Brugada syndrome (BrS) is a rare inherited arrhythmia disorder associated with sudden cardiac death secondary to malignant ventricular arrhythmias. Since its first mention approximately 25 years ago, major strides have been made towards unraveling the condition's genetic and mechanistic underpinnings. Despite considerable progress, however, gaps in the understanding of BrS continue to persist, and clinical management of affected individuals remains challenging. Identification of an underlying genetic culprit continues to be elusive in the majority of patients, while discord regarding the condition's underlying pathophysiology also persists, with strong lines of evidence present for both the "depolarization" and "repolarization" hypotheses. Exciting new therapeutic options hold significant promise, including substrate-based catheter ablation and the subcutaneous implantable cardioverter-defibrillator, although the decision of when to intervene in the cases of asymptomatic patients remains unclear. Provided that the risk of events in BrS is not truly stochastic, distinct sub-phenotypes of the condition, possessing variable levels of arrhythmic risk, may exist, and their identification may lead to the improved care of BrS patients and their families.