Ser194Leu DSG2 mutation, associated with arrhythmogenic left ventricular cardiomyopathy and ventricular tachycardia.

INTRODUCTION: Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibro-fatty replacement of cardiomyocytes, leading to life-threatening ventricular arrhythmia and heart failure. Pathogenic variants of desmoglein2 gene (DSG2) have been reported as genetic etiologies of AC. In contrast, many reported DSG2 variants are benign or variants of uncertain significance. Correct genetic variant classification is crucial for determining the best medical therapy for the patient and family members. METHODS: Pathogenicity of the DSG2 Ser194Leu variant that was identified by whole exome sequencing in a patient, who presented with ventricular tachycardia and was diagnosed with AC, was investigated by electron microscopy and immunohistochemical staining of endomyocardial biopsy sample. RESULTS: Electron microscopy demonstrated a widened gap in the adhering junction and a less well-organized intercalated disk region in the mutated cardiomyocytes compared to the control. Immunohistochemical staining in the proband diagnosed with AC showed reduced expression of desmoglein 2 and connexin 43 and intercalated disc distortion. Reduced expression of DSG2 and Connexin 43 were observed in cellular cytoplasm and gap junctions. Additionally, we detected perinuclear accumulation of DSG2 and Connexin 43 in the proband sample. CONCLUSION: Ser194Leu is a missense pathogenic mutation of DSG2 gene associated with arrhythmogenic left ventricular cardiomyopathy.

Evaluation of MADIT-II Risk Stratification Score Among Nationwide Registry of Heart Failure Patients With Primary Prevention Implantable Cardiac Defibrillators or Resynchronization Therapy Devices.

The current guidelines advocate prophylactic implantable cardioverter-defibrillator (ICD) for all patients with symptomatic heart failure (HF) with low left ventricular ejection fraction. Because many patients will never use their device, a score delineating subgroups with differential ICD benefit is crucial. We aimed to evaluate the MADIT-II-based Risk Stratification Score (MRSS) feasibility to delineate the ICD survival benefit in a nationwide registry of patients with HF with prophylactic ICDs. Accordingly, all Israeli patients with HF with prophylactic ICD/cardiac resynchronization therapy defibrillators were categorized into MRSS-based risk subgroups. The study end points included overall mortality, sustained ventricular arrhythmia (VA), and a competing risk of VA (potential preventable arrhythmic death, where ICD could benefit survival) versus nonarrhythmic death. Potential ICD survival benefit was estimated by the area between these cumulative incidence curves. In 2,177 patients with HF implanted prophylactic device, 189 patients (8.7%) had VA and 316 (14.5%) died during a median follow-up of 2.9 years. The MRSS risk subgroups were significantly associated with overall mortality (p <0.001) and weakly with VA (p = 0.3). The competing risk analysis of VA versus nonarrhythmic death revealed a significantly shorter duration (p <0.001) and smaller magnitude of ICD survival benefit with increased risk subgroups, yielding an estimated 76, 60, 38, and 0 life days gained from prophylactic ICD implant during a 5-year follow-up for the MRSS low-, intermediate-, high-, and very high-risk subgroups, respectively (p for trend <0.05). In conclusion, MRSS use in a nationwide registry of patients with ischemic and nonischemic cardiomyopathy, revealed subgroups with differing ICD survival benefit, suggesting it could help evaluate prophylactic ICD survival benefit.