Relationship Between Genotype Status and Clinical Outcome in Hypertrophic Cardiomyopathy

• Published in: Journal of the American Heart Association Vol. 13; no. 10; p. e033565
• Main Authors: Bonaventura, Jiri, Rowin, Ethan J, Chan, Raymond H, Chin, Michael T, Puchnerova, Veronika, Polakova, Eva, Macek, Jr, Milan, Votypka, Pavel, Batorsky, Rebecca, Perera, Gayani, Koethe, Benjamin, Veselka, Josef, Maron, Barry J, Maron, Martin S
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 21-05-2024; Wiley
• Subjects: Adult; Aged; Cardiomyopathy, Hypertrophic - diagnosis; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Hypertrophic - mortality; Death, Sudden, Cardiac - epidemiology; Death, Sudden, Cardiac - etiology; Disease Progression; Female; Genetic Predisposition to Disease; Genetic Testing - methods; Genotype; Heart Failure - genetics; Heart Failure - mortality; Heart Transplantation; Humans; hypertrophic cardiomyopathy; Male; Middle Aged; mortality; Mutation; Original Research; outcomes; Phenotype; Prognosis; Risk Factors; sudden death; Time Factors; mortality; sudden death; hypertrophic cardiomyopathy; outcomes; genotype
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.123.033565

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