Real-world predictors of adverse outcomes in hcm: who is really at risk?

Introduction

Risk prediction in hypertrophic cardiomyopathy (HCM) remains challenging in routine clinical practice. Although several prognostic markers have been proposed, real-world patients often display substantial phenotypic variability and evolving disease expression, which may limit the performance of conventional risk models. Understanding which clinical features truly reflect long-term vulnerability to adverse events therefore remains essential for optimising management strategies.

Aim

To identify clinical predictors of adverse outcomes in a real-world cohort of patients with HCM.

Methods

We performed a single-centre observational study including consecutive patients diagnosed with HCM according to ESC criteria between 2000 and 2024. All patients had performed genetic testing in a large gene panel by Next- generation sequencing (NGS) method. The ESC HCM-Risk-SCD score was calculated at baseline. The primary endpoint was a composite of appropriate ICD therapies, cardiovascular hospitalisation (CVH), and cardiovascular death (CVD). Survival analyses were performed using Kaplan-Meier curves with log-rank testing, and predictors of the composite outcome were assessed using Cox proportional hazards regression.

Results

A total of 153 HCM patients were included (mean age at diagnosis: 49±2 years; 49% male). Sarcomeric variants were identified in 141 (90%), with Pathogenic/Likely pathogenic mutations mainly in MYH7 (36%) and MYBPC3 (35%). Baseline left ventricular ejection fraction (LVEF) was 62±0.8%, maximal wall thickness 18 ± 0.4 mm; 15% had obstructive physiology, and 13% were classified as high-risk according to the ESC HCM-Risk-SCD score.

Over a mean follow-up of 10±0.9 years, 34 (22%) patients underwent ICD implantation, 14 (9%) had septal reduction therapy, and 48 (31%) developed atrial fibrillation. The composite endpoint occurred in 43 patients (28%), including 9 (5%) appropriate ICD therapies, 32 (21%) CVH and 17 (11%) CVD.

Patients with events had larger left atrial diameter (49 ± 2 vs 42 ± 1 mm; p=0.03), higher ESC HCM-Risk-SCD scores (3.9 ± 0.5 vs 2.8 ± 0.2; p=0.04) and higher follow-up NT-proBNP levels (1582 [438–3916] vs 564 [134–1458] pg/mL; p=0.002). Kaplan–Meier analysis (Fig.1) showed a higher incidence of the composite outcome in patients with moderate–high ESC HCM-Risk-SCD scores, with early and sustained separation of curves. In Cox regression, a moderate–high ESC risk category emerged as an independent predictor of the composite endpoint, conferring an approximately three-fold increased hazard versus low-risk patients (HR=2.7; p=0.01, 95% CI: 1.3–5.2).

Conclusion

In this real-world HCM cohort, larger left atrial size, higher NT-proBNP levels, and a moderate–high ESC HCM-Risk-SCD category were associated with a greater burden of adverse cardiovascular outcomes. The ESC HCM-Risk-SCD score independently predicted the composite endpoint, suggesting that its prognostic value extends beyond SCD alone.For image description, please refer to the figure legend and surrounding text.