Timing of cardioverter-defibrillator implantation in patients with cardiac laminopathies—External validation of the LMNA-risk ventricular tachyarrhythmia calculator

Abstract

LMNA genotype-positive patients have high risk of experiencing life-threatening ventricular tachyarrhythmias (VTAs). The LMNA-risk VTA calculator published in 2019 has not been externally validated. The purpose of this study was to validate the LMNA-risk VTA calculator. We included LMNA genotype-positive patients without previous VTAs from 2 large Scandinavian centers. Patients underwent electrocardiography, 24-hour Holter monitoring, and echocardiographic examinations at baseline and repeatedly during follow-up. Validation of the LMNA-risk VTA calculator was performed using Harrell's C-statistic derived from multivariable Cox regression analysis. We included 118 patients (age 37 years [IQR 27-49 years]; 39 [33%] probands; 65 [55%] women; 100 [85%] with non-missense LMNA variants). Twenty-three patients (19%) experienced VTA during 6.1 years (interquartile range 3.0-9.1 years) follow-up, resulting in 3.0% (95% confidence interval 2.0%-4.5%) yearly incidence rate. Atrioventricular block and reduced left ventricular ejection fraction were independent predictors of VTAs, while nonsustained ventricular tachycardia, male sex, and non-missense LMNA variants were not. The LMNA-risk VTA calculator showed 83% sensitivity and 26% specificity for identifying patients with VTAs during the coming 5 years, and a Harrell's C-statistic of 0.85, when applying ≥7% predicted 5-year VTA risk as threshold. The sensitivity increased to 100% when reevaluating risk at the time of last consultation before VTA. The calculator overestimated arrhythmic risk in patients with mild and moderate phenotype, particularly in men. Validation of the LMNA-risk VTA calculator showed high sensitivity for subsequent VTAs, but overestimated arrhythmic risk when using ≥7% predicted 5-year risk as threshold. Frequent reevaluation of risk was necessary to maintain the sensitivity of the model.