Mortality in hypertrophic cardiomyopathy is unrelated to genotype

Abstract Background Hypertrophic cardiomyopathy (HCM) patients with a pathogenic variant are presumed to have worse prognosis than patients without a pathogenic mutation. However, the genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and relationship between genotype status and outcomes have not been completely resolved. Objective We assessed a large international HCM cohort to define the natural history and clinical consequences of genotype status. Methods Consecutive patients (n=1468) with established clinical HCM diagnosis 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 or a variant of uncertain significance (VUS) were considered genotype negative (G-). Patients were followed for 9.6 ± 8.2 years for clinical outcomes. Results Of 1468 HCM patients, 1156 (79%) were G - and 312 (21%) were G+. Over the follow-up 116 (10%) G- patients died at 70 ± 14 years, including in 26 (2.2%) from HCM-related causes. HCM-related mortality was not significantly different in G- patients (0.3%/year) as compared to G+ patients (0.3%/year) when adjusted for age (HR 0.93, 95% CI 0.38-2.30, p=0.87). All-cause mortality was not different among these groups (0.7%/year G- vs. 0.6%/year G+) when adjusted for age (HR 0.62, 95% CI 0.3-1.2, p=0.14) or comorbidities (HR 0.78, 95% CI 0.46-1.31, p=0.35). Rate of progression to advanced heart failure NYHA class III/IV in nonobstructive patients was not different in G- (4%/ year) vs. G+ (3%/year, HR 1.20, 95% CI 0.63-2.26, p=0.58). Sudden death events (appropriate ICD shocks, aborted cardiac arrest and sudden death) were more frequent in G+ patients (1.7%/year) than in G- patients (0.5%/year), albeit of borderline statistical significance when adjusted for age and SD risk factors (HR 1.58, 95% CI 1.00-2.49, p=0.05). Conclusions In this large consecutive genotyped cohort, all-cause and HCM-related mortality was unrelated to genotype status. Substantial proportion of G- patients experienced progressive HF, at a similar rate when compared to G+ patients. Although G- patients had less frequently SD events, genotype negative status could not be considered benign.FiguresTable