Cellular determinants of arrhythmic rysk in hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is the commonest inherited cardiac disease, with a prevalence of 1/500 in general population. The most devastating consequence HCM sudden death (SCD) due to ventricular fibrillation, particularly common children and young adults (age <30 years). positive correlation between extent late gadolinium enhancement (LGE, reflecting myocardial fibrosis) arrhythmic risk suggests that arrhythmias are held originate from fibrotic regions, by mechanism electrical re-entry. However, recent data suggest enhanced cellular automaticity (i.e. early- or delayed-afterdepolarizations, EADs DADs-), rather than macro-reentry, may be clinically relevant promoting patients. Purpose Aiming better understand molecular mechanisms arrhythmogenesis establish reliable stratification patients, we performed translational study patients who underwent surgical myectomy, combining clinical follow-up vitro assessments arrhythmogenicity cardiomyocytes. Methods We retrospectively studied 61 interventricular-septum myectomy relieve refractory obstruction-related symptoms. At time surgery, fresh tissue was collected used isolate single cardiomyocytes (CMs), which were for patch-clamp measurements assess occurrence DADs. Patients followed up median 8 years non-sustained tachycardia (NSVT) life-threatening events (LAE) monitored. Moreover, ECG contract magnetic-resonance studies collected. Results occurred CMs 36% associated prolonged action potential duration. DADs 24% abnormalities CM intracellular Ca2+ handling. NSVT/ LAE strongly presence but not EADs. NSVT/LAE more likely show specific “pro-arrhythmic” pathological ECG-patterns. Among LGE, cells behaved as necessary pre-requisite NSVT/LAE, none evidence fibrosis negative had events. Conclusions pro-arrhythmic changes appears arrhythmia generation seems related alterations at level, might predictors Fibrosis per se major predictor contribute generate sustained substantial triggers (DADs). FUNDunding Acknowledgement Type funding sources: Public grant(s) – EU funding. Main source(s): Horizon 2020. Grant number 777204 (silico FCM).