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.

Here, we present a small Russian family, where the index patient received a diagnosis of left-ventricular non-compaction cardiomyopathy (LVNC) in combination with a skeletal myopathy. Clinical follow-up analysis revealed a LVNC phenotype also in her son. Therefore, we applied a broad next-generation sequencing gene panel approach for the identification of the underlying mutation. Interestingly, DES-p.A337P was identified in the genomes of both patients, whereas only the index patient carried DSP-p.L1348X. DES encodes the muscle-specific intermediate filament protein desmin and DSP encodes desmoplakin, which is a cytolinker protein connecting desmosomes with the intermediate filaments. Because the majority of DES mutations cause severe filament assembly defects and because this mutation was found in both affected patients, we analyzed this DES mutation in vitro by cell transfection experiments in combination with confocal microscopy. Of note, desmin-p.A337P forms cytoplasmic aggregates in transfected SW-13 cells and in cardiomyocytes derived from induced pluripotent stem cells underlining its pathogenicity. In conclusion, we suggest including the DES gene in the genetic analysis for LVNC patients in the future, especially if clinical involvement of the skeletal muscle is present.

Left ventricular non-compaction cardiomyopathy (LVNC) is a rare heart disease, with or without left ventricular dysfunction, which is characterized by a two-layer structure of the myocardium and an increased number of trabeculae. The study of familial forms of LVNC is helpful for risk prediction and genetic counseling of relatives. Here, we present a family consisting of three members with LVNC. Using a next-generation sequencing approach a combination of two (likely) pathogenic nonsense mutations DSG2-p.S363X and TBX20-p.D278X was identified in all three patients. TBX20 encodes the cardiac T-box transcription factor 20. DSG2 encodes desmoglein–2, which is part of the cardiac desmosomes and belongs to the cadherin family. Since the identified nonsense variant (DSG2-p.S363X) is localized in the extracellular domain of DSG2, we performed in vitro cell transfection experiments. These experiments revealed the absence of truncated DSG2 at the plasma membrane, supporting the pathogenic relevance of DSG2-p.S363X. In conclusion, we suggest that in the future, these findings might be helpful for genetic screening and counseling of patients with LVNC.

Background— Genetic mutations are the most common cause of hypertrophic cardiomyopathy (HCM) and an increasingly recognized cause of dilated cardiomyopathy. Autosomal dominant HCM is caused by mutations in sarcomere proteins; such mutations are not universally present, however, and fail to account for &40% of cases of phenotypic HCM. To add further complexity, other genetic origins can mimic the gross clinical phenotype of HCM, and mutations in sarcomere genes have been demonstrated to cause dilated cardiomyopathy. Methods and Results— To explore novel genetic causes of inherited cardiomyopathies, genome-wide linkage analysis was used to study one kindred (4 generations, 32 individuals) with predominant clinical features of left ventricular hypertrophy in addition to cardiac dilation, end-stage heart failure, and sudden death. Of note, histopathology from 2 family members did not demonstrate myocyte disarray and fibrosis, indicating that this phenotype is not typical sarcomere mutation HCM. Direct DNA sequencing was performed on sarcomere genes known to cause HCM and dilated cardiomyopathy, and no mutations were identified. Linkage was then established to a novel locus on chromosome 7 (7p12.1-7q21). A maximum 2-point logarithm of odds score of 4.11 was obtained. Recombination events refine the disease interval between D7S506 and D7S3314 , corresponding to a distance of 27.2 megabases. Conclusions— The discovery of a novel genetic locus in this family provides more evidence that molecular pathways leading to inherited cardiac hypertrophy extend beyond the sarcomere. Identification of the causal gene mutation and additional genotype-phenotype correlation studies will provide fundamental insight into mechanisms of cardiac remodeling.