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. 2021 Jul 31;42(29):2842-2850.
doi: 10.1093/eurheartj/ehab294.

Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction

Tom E Verstraelen  1 , Freyja H M van Lint  2   3 , Laurens P Bosman  4 , Remco de Brouwer  5 , Virginnio M Proost  1 , Bob G S Abeln  1 , Karim Taha  4 , Aeilko H Zwinderman  6 , Cathelijne Dickhoff  7 , Toon Oomen  8 , Bas A Schoonderwoerd  9 , Gerardus P Kimman  10 , Arjan C Houweling  2 , Juan R Gimeno-Blanes  11   12 , Folkert W Asselbergs  4   13 , Paul A van der Zwaag  14 , Rudolf A de Boer  5 , Maarten P van den Berg  5 , J Peter van Tintelen  2   3 , Arthur A M Wilde  1   12
Affiliations

Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction

Tom E Verstraelen et al. Eur Heart J. .

Abstract

Aims: This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model.

Methods and results: Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27-55]. During a median follow-up of 4.3 years (IQR 1.7-7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78-0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61-0.75).

Conclusion: This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach.

Keywords: Cardiomyopathy; Implantable cardioverter defibrillator; Phospholamban; Risk stratification; Sudden cardiac death.

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Figures

None
Malignant VA risk prediction in PLN p.Arg14del carriers. With the mutation specific risk factors low and high risk groups can be identified. PLN, Phospholamban; VA, Ventricular arrhythmia.
Figure 1
Figure 1
Flowchart of participant inclusion in the study. Diagram summarizing the inclusion and exclusion of study participants carrying the pathogenic PLN p.Arg14del variant. A baseline test should include at least an electrocardiogram, cardiac ultrasound, or magnetic resonance imaging. VA, ventricular arrhythmia.
Figure 2
Figure 2
Survival analyses. Kaplan–Meier analysis with percentage of carriers with malignant ventricular arrhythmia (y-axis) and follow-up duration in years (x-axis). Upper right side is the Kaplan–Meier curve where the y-axis is zoomed in from 0-30%. VA, ventricular arrhythmia.
Figure 3
Figure 3
Estimates for the cumulative risk of malignant ventricular arrhythmia in the current PLN p.Arg14del cohort (n = 679) stratified by predicted risk quintile compared to the existing phospholamban risk model. Cumulative incidence of malignant ventricular arrhythmia (y-axis) during follow-up (x-axis) stratified by predicted risk quintile with the proposed model (A) or by risk factor (B). LVEF, left ventricular ejection fraction; NSVT, non-sustained ventricular tachycardia.
Figure 4
Figure 4
Risk threshold comparisons for the proposed model and the existing phospholamban risk model in 679 patients. The bars represent the clinical implication of using different 5-year malignant ventricular arrhythmia risk thresholds with the proposed model, where the risk threshold is on the x-axis. The existing phospholamban risk model based on two risk factors is named RF. Each bar represents the complete cohort, where the different colours represent the proportion of carriers experiencing malignant ventricular arrhythmia as well as the placement or non-placement of an implantable cardioverter defibrillator.
Figure 5
Figure 5
Nomogram to predict 5-year malignant ventricular arrhythmia risk.
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