Abstract 12893: Early- and Delayed-Afterdepolarizations as Cellular Promoter of Ventricular Fibrillation in Hypertrophic Cardiomyopathy

Abstract

Introduction: Hypertrophic cardiomyopathy (HCM) represents the main cause of sudden cardiac death (SCD) due to ventricular fibrillation in young adults. Recent data suggest that enhanced cellular automaticity as early- and delayed-afterdepolarizations (EADs and DADs) could represent a major trigger of arrhythmogenesis in HCM. Hypothesis: To deeper understand the cellular mechanisms of arrhythmogenesis and to establish an arrhythmic rysk stratification in HCM patients, we performed a translational and retrospective study in 61 HCM patients who underwent surgical interventricular-septum myectomy to relieve refractory obstruction-related symptoms, combining a clinical follow-up study with in vitro assessment of ventricular myocyte arrhythmogenicity. Methods: At the time of surgery, fresh ventricular tissue was collected and used to isolate single ventricular cardiomyocytes, which were then used to perform patch clamp experiments, to assess the occurrence of EADs and DADs. HCM patients were followed up for a median time of 8 years, monitoring the occurrence of non-sustained ventricular tachycardia (NSVT) or life-threatening arrhytmic events (LAE, including sustained VT and VF). Results: Our data show that EADs occurred in 36% of patients (22/61) and were correlated to a prolongation of action potential duration (due to larger I Nal and I CaL density), while DADs occurred in 27% of patients and were associated to an impairment of Ca 2+ handling. During follow up, NSVT events occurred in 19/62 patients, while LAE occurred in 4/62 patients (combined occurrence 37%). Moreover, patients with NSVT/LAE were more likely to show specific "pro-arrhythmic" ECG-patterns. The occurrence of NSVT/ LAE was strongly associated with the presence of DADs in cells but not with the presence of EADs. Interestingly, the occurrence of DADs in cells was also associated with the presence of "proarrhythmic" ECG-patterns. Conclusions: The presence of cellular triggers as DADs, related with changes of ion channels and intracellular calcium homeostasis, appear to be necessary for arrhythmia generation in HCM. Such pro-arrhythmic changes seem to be linked with specific alterations at ECG level, that might be used as clinical arrhythmia predictors in HCM patients.