Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies
Authors: Wahbi Karim , Ben Yaou Rabah , Gandjbakhch Estelle , Anselme Frédéric , Gossios Thomas , Lakdawala Neal K. , Stalens Caroline , Sacher Frédéric , Babuty Dominique , Trochu Jean-Noel , Moubarak Ghassan , Savvatis Kostantinos , Porcher Raphaël , Laforêt Pascal , Fayssoil Abdallah , Marijon Eloi , Stojkovic Tanya , Béhin Anthony , Leonard-Louis Sarah , Sole Guilhem , Labombarda Fabien , Richard Pascale , Metay Corinne , Quijano-Roy Susana , Dabaj Ivana , Klug Didier , Vantyghem Marie-Christine , Chevalier Philippe , Ambrosi Pierre , Salort Emmanuelle , Sadoul Nicolas , Waintraub Xavier , Chikhaoui Khadija , Mabo Philippe , Combes Nicolas , Maury Philippe , Sellal Jean-Marc , Tedrow Usha B. , Kalman Jonathan M. , Vohra Jitendra , Androulakis Alexander F.A. , Zeppenfeld Katja , Thompson Tina , Barnerias Christine , Bécane Henri-Marc , Bieth Eric , Boccara Franck , Bonnet Damien , Bouhour Françoise , Boulé Stéphane , Brehin Anne-Claire , Chapon Françoise , Cintas Pascal , Cuisset Jean-Marie , Davy Jean-Marc , De Sandre-Giovannoli Annachiara , Demurger Florence , Desguerre Isabelle , Dieterich Klaus , Durigneux Julien , Echaniz-Laguna Andoni , Eschalier Romain , Ferreiro Ana , Ferrer Xavier , Francannet Christine , Fradin Mélanie , Gaborit Bénédicte , Gay Arnaud , Hagège Albert , Isapof Arnaud , Jeru Isabelle , Juntas Morales Raul , Lagrue Emmanuelle , Lamblin Nicolas , Lascols Olivier , Laugel Vincent , Lazarus Arnaud , Leturcq France , Levy Nicolas , Magot Armelle , Manel Véronique , Martins Raphaël , Mayer Michèle , Mercier Sandra , Meune Christophe , Michaud Maud , Minot-Myhié Marie-Christine , Muchir Antoine , Nadaj-Pakleza Aleksandra , Péréon Yann , Petiot Philippe , Petit Florence , Praline Julien , Rollin Anne , Sabouraud Pascal , Sarret Catherine , Schaeffer Stéphane , Taithe Frederic , Tard Céline , Tiffreau Vincent , Toutain Annick , Vatier Camille , Walther-Louvier Ulrike , Eymard Bruno , Charron Philippe , Vigouroux Corinne , Bonne Gisèle , Kumar Saurabh , Elliott Perry , Duboc Denis 
Published: June 2019

Background:

An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with
LMNA
mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation.

Methods:
We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator–treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range].

Results:
We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0–7.2] and 5.1 [2.0–9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642–0.959), and the calibration slope was 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach.

Conclusions:
In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT03058185.