Clinical Outcomes and Natural History of Hypertrophic Cardiomyopathy Due to Thin Filament Mutations: A Retrospective Cohort Analysis.

Abstract

Background and Aims: Hypertrophic cardiomyopathy (HCM) caused by mutations in the thin filament is relatively uncommon, accounting for ~2–10% of all HCM cases, yet it is associated with distinct clinical characteristics. Data on long-term outcomes remain limited in this subgroup. This study aimed to describe the clinical presentation, echocardiographic features, and outcomes of patients with thin filament HCM, and to identify predictors of adverse events, focusing on heart failure (HF), arrhythmic outcomes, and overall mortality. Methods: A retrospective observational study was conducted using an existing dataset from the Bart’s Heart Centre/UCL cardiomyopathy database. Of 2,022 HCM patients, 131 carried pathogenic/likely pathogenic variants in thin filament genes (TNNT2, TNNI3, TPM1, ACTC1, TNNC1). Demographic, ECG, and echocardiographic data were analysed. Endpoints included arrhythmic events, HF hard outcomes, composite HF outcomes, cardiac death, and all-cause mortality. Results: Among 131 patients with thin filament HCM (median age 42.8 years, 57% male), mild to moderate hypertrophy (median left ventricular maximum wall thickness 19 mm), frequent diastolic dysfunction (36.4%), and low rates of obstruction (6.9%) were observed. During follow-up of 11.2 years, arrhythmic events were rare (6.1%), and HF-related mortality (death or transplant) was infrequent (12.2%). In contrast, HF-related morbidity, reflected by the composite HF endpoint, was common, affecting over one-third of patients. Cardiac death occurred in 18.3%, and all-cause mortality in 26.7%. Female sex, atrial fibrillation (AF), and diastolic dysfunction independently predicted composite HF outcomes. Genotype analysis suggested worse HF outcomes in TNNI3 carriers, although statistical significance was not reached; variant-level analysis highlighted p.Arg145Trp and p.Arg141Gln as associated with more severe phenotypes. Conclusions: Thin filament HCM is characterised by modest hypertrophy but a high burden of HF morbidity. Female sex, AF, and diastolic dysfunction independently predict adverse HF outcomes. Trends toward worse outcomes in TNNI3 carriers underscore the importance of integrating genetic and phenotypic data into risk stratification.