Abstract Body (Do not enter title and authors here): Background : Heart failure (HF) in hypertrophic cardiomyopathy (HCM) is poorly characterized, especially in patients with preserved left ventricular ejection fraction (LVEF). Clarifying HF characteristics in HCM is essential to guide patient selection for emerging therapies.

Research Questions : What is the prevalence of HF in HCM patients? What are the risk markers of HF?

Methods : The study is a cross-sectional analysis of HiRO-HCM, an ongoing multicenter registry. This study included HCM patients aged ≥ 16 years with available data to allow for central ascertainment of HF, defined as i) history of hospitalization for HF requiring diuretics, heart transplantation or mechanical circulatory support; and/or ii) New York Heart Association (NYHA) class ≥ II with increased filling pressure (E/e′ ratio ≥ 14 and/or a NT-proBNP ≥ 400 ng/L [≥800 ng/L in atrial fibrillation]). The association of risk markers with HF was assessed with logistic regression. Analyses were performed in the overall cohort, and in 3 subgroups: obstructive HCM (oHCM), non-obstructive HCM (nHCM) with LVEF≥50%, and nHCM with LVEF<50%. The presence of obstruction and LVEF were assessed from echocardiography performed within 4 years (median 0.6 year) of HF ascertainment, using corelab interpretation when images are available (59% of the study cohort). NT-proBNP was systematically measured in patients with available plasma (81% of the cohort).

Results : We included 1,632 patients (33% females; age 58±14 years). The maximal left ventricular wall thickness was 18±4 mm, and 613 (45%) patients carried a causal genetic variant. The median NT-proBNP was 490 [189-1140] ng/L and mean E/e’ was 11±4. In the overall cohort, 510 (31%) patients met the definition of HF, including 93 hospitalized for HF and 26 transplanted. The prevalence of HF was 41% in the oHCM subgroup, 26% in nHCM with LVEF≥50%, and 65% in nHCM with LVEF<50% (P<0.001). Several variables were associated with increased odds for HF (Figure). In multivariable analysis, female sex emerged as a strong risk factor for HF in all 3 subgroups, with a 3-fold increased risk for HF (P<0.001).

Conclusion : HF affects one-third of patients with HCM. Female sex is a robust and consistent predictor of HF across all phenotypes. The findings underscore the importance of sex-specific evaluation and earlier recognition of HF symptoms in HCM management. These findings may inform risk stratification and selection for novel therapies targeting HCM-related HF.