Phenotype-genotype evaluation of sudden cardiac arrest/ death cohort study

Background Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) represent major public health concerns. They may also occur in young individuals without any previously known health condition, with an incidence of approximately 1:47,000 among people aged 12–35 years. Prior knowledge of a genetic predisposition to SCA/SCD may enable the implementation of preventive or therapeutic strategies, with the potential to reduce future major adverse cardiovascular events (MACE). Purpose To evaluate the phenotypic characteristics of genotype-positive and genotype-elusive SCA/SCD patients and to assess the incidence of major cardiovascular events (MACE) during follow-up in SCA survivors. Methods a cohort of patients who experienced SCA/ SCD without significant coronary artery disease were included in our high-volume center. SCA patients underwent comprehensive cardiological assessment and genetic counselling, followed by cardiogenetic testing. Next generation sequencing was performed using Illumina TruSight Cardio panel sequencing of 174 genes on a MiSeq instrument, followed by multidisciplinary group assessment. Contrast-enhanced cardiac magnetic resonance (CMR) was performed in patients with suspicion of structural heart disease. SCA patients were followed up prospectively. MACE was defined as cardiac death, heart transplantation, hospitalization due to heart disease, stroke or appropriate ICD shock. Results Altogether 99 patients were enrolled, the mean age was 35±16.5 years with a male:female ratio of 51:48. In 20% of cases, SCA was triggered by sports activity; 2% occurred during emotional stress, 2% during sleep, and 76% during daytime activity. In 59.6% of cases, SCA was the first manifestation without any previously known cardiac disease. SCA resulted in SCD in 8.1% of cases. Pathogenic or likely pathogenic variants were identified in 21.2% of patients, while variants of uncertain significance were detected in 26.3%. The most frequently affected gene was MYBPC3, associated with hypertrophic cardiomyopathy (HCM), detected in 9.1% of patients. Variants in desmosomal genes (DSP, DSC2, DSG2, DES, and PKP2) associated with arrhythmogenic cardiomyopathy were collectively observed in another 9.1% of patients. CMR was performed in 67 patients and revealed myocardial fibrosis in 66% of genotype-positive and 48.8% of genotype-elusive patients. The mean follow-up period for SCA survivors was 4.8 years, during which the MACE rate was 16.5%. Malignant ventricular arrhythmias occurred more often in genotype positive patients (19% vs. 12.2%). Conclusion(s) SCA/SCD occurred in almost 60% of patients as the first cardiac symptom. Relevant gene variants were detected in 45.4% of SCA/SCD patients. Depiction of genotypes following SCA can contribute to improvement of clinical diagnosis and greater prognostic value.