Cappelletto, C

Abstract Funding Acknowledgements Type of funding sources: None. Background Etiology identification and risk stratification represent major issues for patients presenting with undefined left ventricular arrhythmogenic cardiomyopathy (ULVACM). Purpose To investigate the role of genetics and histology for ULVACM classification, management, and risk assessment. Methods We retrospectively analyzed a multicenter cohort of patients (screened n=1037) with ULVACM defined by ventricular arrhythmia (VA) onset, nonischemic late gadolinium enhancement (LGE) limited to the LV, and no severe dilated cardiomyopathy (LVEF≥40%). We selected patients undergoing both next generation sequencing (NGS) screening and endomyocardial biopsy (EMB) for etiology definition. When feasible, immunosuppressive therapy (IST) was used to target active myocardial inflammation (AMI). The study endpoint was a composite of cardiac death, heart transplantation and malignant VAs (VT, VF, appropriate ICD treatment). Results The study cohort is composed by 135 ULVACM patients (age 43±14 years, 63% males, LVEF 55±7 %). NGS identified pathogenic or likely-pathogenic variants (PVs/LPVs) consistent with ACM in 21 cases (16%), whereas EMB showed AMI in 78 patients (58%), including 13/21 PVs/LPVs+ (62%). After reclassification of 86 patients (64%), only 49 (36%) remained ULVACM. IST was started in 41/78 AMI patients (53%), including 9/13 PVs/LPVs+ (69%). Twenty patients (15%) met the study endpoint by 12 months, and 36 (27%) by the end of the study (60±27 months). Beyond malignant VT onset, AMI was the only predictor of events by 12 months (HR 5.0, 95%CI 1.4-18.1, p=0.007). No prognostic role was found for PVs/LPVs, except for the subgroup (n=77) with nonsustained VT onset. Among AMI patients, those treated by IST had a significantly lower occurrence of events, both by 12-months (1/41 vs. 16/37, p<0.001) and later (HR 0.05, 95%CI 0.01-0.21, p<0.001). Results were independently confirmed in PVs/LPVs+ and PVs/LPVs- cases. Excluding the IST population, the association of multiple factors among VT onset, PVs/LPVs, and AMI, resulted in an improved discrimination of arrhythmic risk profiles. Conclusion The combined genetic and histological workup allowed reclassification of up to 64% ULVACM patients, and substantially contributed into prognostic assessment. Furthermore, EMB identified suitable candidates for IST, who showed better outcomes irrespectively of their genotype.