Laminopathies : natural history and risk prediction of heart failure
P Charron, J Proukhnitzky, R Ben Yaou, P Richard, S Kumar, K Savvatis, T Stojkovic, F Anselme, P Maury, C Vigouroux, N K Lakdawala, E Arbustini, P Elliott, G Bonne, K WahbiAbstract
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.Figure LMNA & HF ESC Congress