Clinical Characteristics and Outcomes of Hypertrophic Cardiomyopathy Associated With Thin Filament Variants: Insights From the SHaRe Registry.

Abstract

Background: Conflicting evidence exists about whether sarcomeric hypertrophic cardiomyopathy (HCM) caused by genes encoding thin filament proteins (TNNT2, TNNI3, ACTC, TPM1, TNNC1; thin filament HCM) has a distinct clinical presentation and natural history from disease caused by the more commonly involved thick filament genes (MYH7, MYBPC3, MYL2, MYL3; thick filament HCM).

Methods: Retrospective analysis of the Sarcomeric Human Cardiomyopathy Registry.

Results: Four hundred eighty-eight patients with thin filament HCM were compared with 3494 patients with thick filament HCM. After controlling for age at diagnosis, sex, and proband status, thin filament HCM was associated with a higher risk of composite ventricular arrhythmias (hazard ratio, 1.48 [95% CI, 1.09-2.01]), cardiac arrest (hazard ratio, 2.02 [95% CI, 1.33-3.06]), and heart transplant or left ventricular assist device implantation (hazard ratio, 2.18 [95% CI, 1.3-3.65]). Younger age at diagnosis was associated with an increased risk for the ventricular arrhythmia composite outcome in thin and thick filament HCM (hazard ratio, 0.93 [95% CI, 0.91-0.94]; hazard ratio, 0.93 [95% CI, 0.93-0.94]; age reported as 5-year increment). Within specific thin filament genes, an increased risk of arrhythmic events or heart transplant/left ventricular assist device implantation was evident for variants in TNNT2 amino acids 92 to 94 (odds ratio versus other TNNT2 variants; odds ratio, 3.02 [95% CI, 1.17-7.49]) and TNNI3 amino acids 191 to 210 (odds ratio versus other TNNI3 variants; odds ratio, 3.5 [95% CI, 1.58-8.02]).

Conclusions: Thin filament HCM seems to carry a higher risk for ventricular arrhythmias and advanced heart failure compared with thick filament HCM. Integrating gene-level and intragene-level information may improve risk stratification in patients with HCM.