Relationship Between Genotype Status and Clinical Outcome in Hypertrophic Cardiomyopathy.

Background: The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the relationship between genotype status and clinical outcome is incompletely resolved.

Methods And Results: We assessed a large international HCM cohort to define in contemporary terms natural history and clinical consequences of genotype. Consecutive patients (n=1468) with established HCM diagnosis underwent genetic testing. Patients with pathogenic (or likely pathogenic) variants were considered genotype positive (G+; n=312; 21%); those without definite disease-causing mutations (n=651; 44%) or variants of uncertain significance (n=505; 35%) were considered genotype negative (G-). Patients were followed up for a median of 7.8 years (interquartile range, 3.5-13.4 years); HCM end points were examined by cumulative event incidence. Over follow-up, 135 (9%) patients died, 33 from a variety of HCM-related causes. After adjusting for age, all-cause and HCM-related mortality did not differ between G- versus G+ patients (hazard ratio [HR], 0.78 [95% CI, 0.46-1.31]; =0.37; HR, 0.93 [95% CI, 0.38-2.30]; =0.87, respectively). Adverse event rates, including heart failure progression to class III/IV, heart transplant, or heart failure death, did not differ (G- versus G+) when adjusted for age (HR, 1.20 [95% CI, 0.63-2.26]; =0.58), nor was genotype independently associated with sudden death event risk (HR, 1.39 [95% CI, 0.88-2.21]; =0.16). In multivariable analysis, age was the only independent predictor of all-cause and HCM-related mortality, heart failure progression, and sudden death events.

Conclusions: In this large consecutive cohort of patients with HCM, genotype (G+ or G-) was not a predictor of clinical course, including all-cause and HCM-related mortality and risk for heart failure progression or sudden death. G+ status should not be used to dictate clinical management or predict outcome in HCM.