Key result
Novel 4-factor score predicts severe HF risk in laminopathies with a C-index of ~0.76.
Why the study?
Patients with LMNA gene variants are at high risk for dilated cardiomyopathy and heart failure, yet no prediction model for severe HF events previously existed.
Cohort (n=715)
Yes
This study developed and externally validated the first clinical risk prediction model for severe heart failure events in adult-onset laminopathies, enabling risk stratification to guide monitoring and early referral for advanced heart failure therapies.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Heart failure in Laminopathies: A major unmet need. Congratulations to Karim Wahbi for leading this initiative.”
May support risk stratification in LMNA laminopathies; leaves open prospective validation before guiding therapy.
Background and aims Patients with LMNA gene variants are at high risk for dilated cardiomyopathy and heart failure (HF), but no prediction model for severe HF events exists. This study aimed to describe the incidence of severe HF events and develop a prediction model in a large cohort of patients with adult-onset laminopathies. Methods From a population of 660 patients enrolled in the French LMNA nationwide registry, 470 adults were included in the derivation cohort. An independent international validation cohort included 245 additional patients (from Australia, Italy, Netherlands, UK, USA). Baseline characteristics at genetic testing were assessed and the cumulative incidence of the primary endpoint HF-MACE (major adverse cardiovascular event) was calculated, defined as HF hospitalization, HF-related death, mechanical circulatory support or heart transplantation.Predictors of HF-MACE were studied after excluding patients with LVEF <30% at baseline using a Fine-Gray competing risk model, adjusted hazard ratio (aHR) with 95% confidence interval (CI), and Harrell’s concordance (C-) index. A secondary composite end-point, without hospitalization, was also studied. Results Among 470 patients of the derivation cohort, HF-MACE occurred in 65 over a median follow-up of 7.1 years (IQR 3.4; 12.1). Four independent predictors of HF-MACE were identified: male sex (aHR, 1.86; 95% CI, 1.060-3.290), LVEF <50% (aHR, 2.18; 95% CI, 1.080-4.400), missense variants in head & rod domains (aHR, 2.91; 95% CI, 1.110-7.630), and complete left bundle branch block (aHR, 2.99; 95% CI, 1.400-6.400). The C-index of the model was 0.750 (95% CI, 0.720–0.780) in the derivation cohort and 0.758 (95% CI, 0.720–0.800) in the validation cohort. The 5-year cumulative incidence of HF-MACE was 1.5% (95% CI, 0.6–3.6), 5.0% (95% CI, 1.8–8.2), and 22.0% (95% CI, 15.6–28.4) among patients with 0, 1, and ≥2 risk factors, respectively. In patients with LVEF <30% at baseline, the 1-year incidence of HF-MACE was 50%, and those patients were excluded from the risk score. Conclusions The first prediction model for severe HF events in adult laminopathies was developed, which has the potential to guide the selection of patients who may benefit from enhanced monitoring protocols, early medical treatment, and timely referral for heart transplantation management.
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Charron et al. (2026) conducted a cohort in Adult-onset laminopathies (LMNA gene variants) (n=715). LMNA risk prediction model (male sex, LVEF <50%, missense variants in head & rod domains, complete LBBB) vs. 0 risk factors (vs 1 or ≥2 risk factors) was evaluated on HF-MACE (composite of heart failure hospitalization, HF-related death, mechanical circulatory support, or heart transplantation) (C-index 0.750 (derivation); C-index 0.758 (validation), 95% CI 0.720-0.780). A 4-factor risk model predicted severe HF events in adult laminopathies with C-indices of 0.750 (derivation) and 0.758 (validation), stratifying 5-year risk from 1.5% to 22.0%.
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