Abstract 13383: Is Genotype Negative Hypertrophic Cardiomyopathy Really Benign? The Increased Risk of Sudden Death and Advanced Heart Failure in the Absence of Pathogenic Sarcomere Mutations

Abstract

Introduction: The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the genotype-phenotype correlations have not been completely resolved. Patients lacking a pathogenic variant are presumed to have a better prognosis than patients with sarcomeric pathogenic mutations. Aim: We sought to assess the relationship between the genotype status and the adverse clinical events. Methods: Consecutive patients with HCM underwent genetic testing focused on HCM-related genes. Patients with pathogenic or likely pathogenic variants were considered genotype positive (G+), and those without definite disease-causing mutation were considered genotype negative (G-). Patients were followed for 5.2 ±4.9 years for outcomes. Sudden death (SD) events included out-of-hospital cardiac arrests, appropriate ICD interventions, and HCM-related death. Results: Of 988 HCM patients, 212 (21%) were G+, while 776 (79%) were G -. As compared to G-, G+ HCM patients were younger (45 ± 14 vs. 53 ± 13 years), had more extensive LV hypertrophy (maximum wall thickness: 19.6 ± 5 mm vs. 18.4 ± 4 mm, p<0.001), and with no difference in the presence of LVOT obstruction (59% vs. 66%, p=0.06). Despite G- status, 3% of G- patients had extensive scarring on cardiac MRI (≥15% of LV mass; no different from G+, p=0.54). Over follow-up, 66 patients had SD events. While SD events were more common in G+ patients (11.3% vs. 5.4%, p=0.002), the majority of SD events occurred in G- patients (64%). Similarly, end-stage HCM developed 54 patients, more commonly in G+ (9.0% vs. 4.5%, p=0.01), but with majority of events in G- patients (65%). Conclusion: Contrary to certain prevailing views, in this large consecutive genotyped HCM cohort, sarcomere genotype-negative patients (representing a distinctive majority) did not express an entirely benign prognosis. In fact, nearly two-thirds of SD events and end-stage HF progression occurred in G- HCM patients, albeit at somewhat lower rates than in G+ patients. These data do not support that genotype should not be included as a risk marker of adverse arrhythmic and advanced heart failure events.