Philippe Charron, Julie Proukhnitzky, Rabah Ben Yaou, P. Richard, M Dembélé, Mario Urtis, Thomas Gossios, Saurabh Kumar, Konstantinos Savvatis, Tanya Stojkovic, Frédéric Anselme, Philippe Maury, E Gandjbakhch, Raphaël P. Martins, Frédéric Sacher, Trochu Jn, Stéphanie Rouanet, Julie Lejeune, Ghassan Moubarak, A Fayssoil, E. Marijon, P. Lafôret, Anthony Behin, Sarah Léonard-Louis, G. Sole, F. Labombarda, Corinne Metay, S. Quijano-Roy, Ivana Dabaj, Didier Klug, Gilbert Habib, Marie-Christine Vantyghem, Philippe Chevalier, Emmanuelle Salort-Campana, J M Sellal, Xavier Waintraub, Katja Zeppenfeld, Ahmad S. Amin, Daria Kramarenko, Yigal M Pinto, Andrew P. Landstrom, Alessandra Serio, C. Chikhaoui, Nicolas Combes, Christine Barnérias, Henri-Marc Bécane, Éric Bieth, Franck Boccara, Damien Bonnet, F. Bouhour, Anne‐Claire Bréhin, Pascal Cintas, François Roubille, Nicolas Lamblin, Pascal. De Groote, Pierre-François Winum, Nicolas Piriou, Patricia Réant, Annachiara De Sandre-Giovannoli, Marion Masingue, Isabelle Desguerre, J. Durigneux, Andoni Echaniz-Laguna, Romain Eschalier, A Ferreiro, Mélanie Fradin, Bénédicte Gaborit, Arnaud Gay, A. Hagège, Arnaud Isapof, Isabelle Jéru, Emmanuelle Lagrue, V. Laugel, Arnaud Lazarus, France Leturcq, Armelle Magot, Véronique Manel, Mercier Sandra, Christophe Meune, Maud Michaud, Marie-Christine Minot-Myhié, A. Nadaj-Pakleza, Yann Péréon, Florence Petit, Julien Praline, Anne Rollin, Catherine Sarret, Frederic Taithe, Céline Tard, V. Tiffreau, Laurent Fauchier, C. Vatier, Ulrike Walther-Louvier, Benjamin Schurr, P Bobin, Mohamed El Hachmi, Clarisse Billon, Bertrand Fontaine, Corinne Vigouroux, Neal K Lakdawala
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. Baseline characteristics at genetic testing were assessed and the cumulative incidence of the primary endpoint HF-major adverse cardiac events (HF-MACE) 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 left ventricular ejection fraction (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 endpoint, 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 (interquartile range: 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 and 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 may facilitate early and optimal preventive management. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov Unique identifier: NCT03058185.