The phospholamban (PLN) p.Arg14del risk model; Longitudinal validation and reevaluation of predictors regarding sudden cardiac death (SCD)

FUNDING ACKNOWLEDGEMENTS: Type of funding sources: Public Institution(s). Main funding source(s): PSIDER (ZOn-MW) PREDICT2 (Hartstichting) BACKGROUND: The PLN p.Arg14del risk model is a mutation-specific risk model developed to predict individual malignant ventricular arrhythmia (VA) risk to inform decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. While the risk model has proven to be valid, two main points of criticisms remain to be discussed: first, the risk model is only validated at baseline and second, appropriate ICD therapy and sustained ventricular tachycardia (VT) <250 bpm is an imperfect surrogate outcome for SCD. PURPOSE: To evaluate the diagnostic performance of the PLN p.Arg14del risk model longitudinal at 3 year follow-up and to reevaluate the predictors regarding SCD. METHODS: Clinical data of 278 PLN p.Arg14del mutation carriers with no history of malignant VA at both baseline and 3 year follow-up were collected. During a median follow-up of 4 years (Interquartile range (IQR) 1.8-6.5), 31 (11%) carriers experienced malignant VA, defined as sustained VA, appropriate ICD intervention, or (aborted) SCD. The reevaluation of the predictors with the 3 year follow up data revealed hazard ratio’s (HR) that were similar to the baseline PLN p.Arg14del risk model for left ventricular ejection fraction (HR 1.10 [95% CI, 1.06-1.12], p<0.001), low-voltage ECG (HR 12.24 [95% CI, 5.21-28.8], p<0.001) and the PVC count per 24h (HR 1.51 [1.15-1.98], p=0.003). The 5-year malignant VA risk was divided into tertiles of predicted risk. The tertiles clearly demonstrated good discrimination between risk group as shown in figure 1 and this resulted in an C-statistic of 0.85 (95% CI 0.78-0.92). To reevaluate the predictive performance of the PLN p.Arg14del risk model for a more strict surrogate of SCD we redefined the outcome as VT >250 beats per minute sustained (lasting ≥30 seconds) or terminated by ICD, ventricular fibrillation, aborted SCD and SCD. We included 669 PLN p.Arg14del carriers with no presentation or history of sustained VA or (aborted) SCD. During a median follow-up of 4.75 years (IQR 1.9-7.9), 33 (5%) carriers experienced the outcome. Results of the univariable analysis are shown in table 1. The PLN p.Arg14del risk model yielded a C-statistic of 0.75 (95% CI 0.70-0.80). Adding risk factors sex, age and sustained VT <250 bpm did not change its performance. CONCLUSION: The PLN p.Arg14del risk model was validated longitudinal at 3 year follow-up and it held its performance with a more strict definition of SCD. [Figure: see text] [Figure: see text]