The study provides an estimator of risk of LAEs in LQTS that allows a granular estimate of 5-year arrhythmic risk and demonstrate the superiority of nadolol in reducing the risk of LAEs in LQTS.

The high risk of life-threatening arrhythmias in patients with ARVC spans from adolescence to advanced age, reaching its peak between ages 21 and 40 years. Atrial fibrillation, syncope, participation in strenuous exercise after the diagnosis of ARVC, hemodynamically tolerated sustained monomorphic ventricular tachycardia, and male sex predicted lethal arrhythmias at follow-up. The lack of efficacy of antiarrhythmic therapy and the life-saving role of the implantable cardioverter-defibrillator highlight the importance of risk stratification for patient management.

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Variant interpretation for the diagnosis of genetic diseases is a complex process. The American College of Medical Genetics and Genomics, with the Association for Molecular Pathology, have proposed a set of evidence‐based guidelines to support variant pathogenicity assessment and reporting in Mendelian diseases. Cardiovascular disorders are a field of application of these guidelines, but practical implementation is challenging due to the genetic disease heterogeneity and the complexity of information sources that need to be integrated. Decision support systems able to automate variant interpretation in the light of specific disease domains are demanded. We implemented CardioVAI (Cardio Variant Interpreter), an automated system for guidelines based variant classification in cardiovascular‐related genes. Different omics‐resources were integrated to assess pathogenicity of every genomic variant in 72 cardiovascular diseases related genes. We validated our method on benchmark datasets of high‐confident assessed variants, reaching pathogenicity and benignity concordance up to 83 and 97.08%, respectively. We compared CardioVAI to similar methods and analyzed the main differences in terms of guidelines implementation. We finally made available CardioVAI as a web resource (http://cardiovai.engenome.com/) that allows users to further specialize guidelines recommendations.

IMPORTANCEPatients with catecholaminergic polymorphic ventricular tachycardia (CPVT) may experience life-threatening arrhythmic events (LTAEs) despite β-blocker treatment. Further complicating management, the role of implantable cardioverter defibrillator (ICD) in CPVT is debated.OBJECTIVE To investigate the long-term outcomes of patients with RYR2 CPVT treated with β-blockers only and the cost to benefit ratio of ICD.

Abstract. Cardiovascular disease (CVD) and depression are two of the most common human health problems. Patients with depression have an increased risk of developing cardiovascular disease and mortality after experiencing a cardiac event. Both diseases are complex disorders that are influenced by genetic and environmental factors. Brain-derived neurotrophic factor (BDNF) plays a critical role in regulating both vascular development and response to injury, and promotes survival, differentiation, and maintenance of neurons in the peripheral and nervous system. Evidence suggests that BDNF can enhance serotoninergic transmission. Serotonin modulates different brain functions and is known to regulate sleep, appetite, pain and inflammation. The aims of the present casecontrol study were to investigate the possible role of BDNF Val66Met, 5-HTTLPR and -1438 G/A polymorphisms in the development of coronary artery disease (CAD) in patients with and without depression. Regarding BDNF, our data suggest an involvement of the AA genotype in the pathogenesis of CAD in females and in the predisposition to CAD associated with depression. Furthermore, it could be argued that the GG genotype is protective against CAD in the female population and against CAD associated with depression. In our CAD population we also observed a significant increase in the L/L genotype and a decrease in the S/L genotype with respect to the controls. A higher frequency of the L allele, responsible for enhancing the efficiency of transcription, was found in CAD patients. These findings may be responsible for the increased capacity of platelet serotonin uptake previously observed in patients with CAD. Although no differences were found for genotype and allelic frequencies of the -1438 G/A polymorphism between the CAD patients and controls, we cannot exclude the possible role of this receptor in coronary artery disease.

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Background Recently, a novel genetic-based classification for Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) has been proposed to distinguish “typical” (RYR2 and CASQ2 genes) and “atypical” (TRDN, TECRL, CALM1–3, RYR2 loss-of-function [RYR2-LoF]) CPVT variants. Although some genetic forms were reported as malignant forms of CPVT, natural history data comparing typical and atypical CPVT variants are lacking. Purpose We compared the natural history of “typical” and “atypical” forms of CPVT in a large cohort of patients with genetically confirmed CPVT. Methods CPVT was diagnosed according to the criteria defined in the 2015 European Society of Cardiology Guidelines. Based on the genetic background, we classified the patients in two groups: 1) “Typical” CPVT (i.e., carriers of pathogenic or likely pathogenic mutations in RYR2 and CASQ2 genes); 2) “Atypical” CPVT (i.e., carriers of pathogenic or likely pathogenic mutations in TRDN, TECRL, CALM1–3 and RYR2-LoF). Patients with mutations in the CALM1, CALM2 or CALM3 were not identified in our cohort. The outcome was the occurrence of a life-threatening arrhythmic event (LAE), defined as: sudden cardiac death, aborted cardiac arrest or hemodynamically non-tolerated ventricular tachycardia. The Kaplan-Meier life-table method was used to determine the cumulative probability of experiencing a first LAE before the age of 40 years and in the absence of treatment. Outcomes in two groups were compared using the log-rank test. Results The study cohort included 238 patients (56% females, median age at diagnosis 14 years [IQR: 9–28 years]), of whom 226/238 (95%) patients with “typical” CPVT (216 RYR2, 10 CASQ2), and 12/238 (5%) patients with “atypical” CPVT (5 RYR2-LoF, 4 TRDN, 3 TECRL). In the entire population, the cumulative probability of experiencing a first LAE between birth and the diagnosis of CPVT was 2.3%, 21.2 and 40.8% at 5, 20, and 40 years, respectively. At any given age, the probability of a first LAE in the absence of therapy was significantly higher in patients with atypical CPVT (25%, 36%, and 100% at 5, 20, and 40 years, respectively), as compared to patients with typical CPVT (1%, 20%, and 39% at 5, 20, and 40 years, respectively; p=0.003, Figure 1). Patients with atypical CPVT suffered LAEs in early childhood (i.e., by the age of 5 years) significantly more often than patients with typical CPVT (3/5 patients [60%] in atypical CPVT vs. 2/43 patients [5%] in typical CPVT, p<0.001; Figure 2). Conclusions The natural history of CPVT is modulated by the genetic cause. Atypical CPVT variants are rare but are characterized by a worse outcome and a greater likelihood of experiencing an LAE since the early childhood, as compared to typical CPVT. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ricerca Corrente funding scheme of the Italian Ministry of Health