Longitudinal validation of the phospholamban (PLN) p.Arg14del risk model

Abstract Background/Introduction Recently, a variant-specific prediction model for PLN p.Arg14del variant carriers was developed to predict individual malignant ventricular arrhythmia (VA) risk to inform decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts malignant VA risk from data at diagnosis, but iterative evaluation of malignant VA risk may be warranted considering that the risk factors for malignant VA are progressive. Purpose To evaluate the diagnostic performance of the PLN p.Arg14del risk model. Methods/Results Date were collected of 278 PLN p.Arg14del variant carriers at 3 year follow-up. This was considered the new baseline for the survival analysis. Patients with history of malignant VA at both baseline and during the first 3 years after baseline were excluded. At 3 year patients were aged 40.1±18.0 year and 40.7% was male. Median left ventricular ejection fraction (LVEF) was 53% and percentage with microvoltages was 10.3. During a median follow-up of 4 years (Interquartile range 1.8–6.5) 31 (11%) carriers experienced malignant VA, defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. Reevaluation of the predictors with the 3 year follow-up data revealed hazard rates that were similar to those in the original PLN p.Arg14del risk model; LVEF per 1% decrease (hazard ratio (HR) 1.10 [95% confidence interval (CI), 1.06–1.12]; p<0.001), premature ventricular contraction count/24h (HR 1.51 [95% CI, 1.15–1.98]; p=0.003) and the presence of low-voltage electrocardiogram (HR 12.24 [95% CI, 5.21–28.8); p<0.001). Negative T waves did not remain significant as a predictor. The 5-year malignant VA risk was calculated for each variant carrier, after multiple imputation for dealing with incomplete cases, by applying the PLN p.Arg14del risk model to the 3 year follow-up data. Afterwards the cohort was divided into tertiles of predicted risk. This clearly demonstrated the lowest risk tertile having a low malignant VA rate and the highest risk tertile having a high malignant VA rate, which resulted in an optimism-corrected C-statistic of 0.85 (95% CI 0.78–0.92). Conclusion The PLN p.Arg14del risk model is valid at 3 year follow-up in PLN p.Arg14del variant carriers with no history of malignant VA and can therefore be used to inform decision-making for primary prevention ICD implantation not merely at diagnosis, but also during follow-up and can be seen as a type of validation in a cohort where no other large cohort is present to perform external validation. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): 1. PSIDER: From pluripotent stem cells to prime editing gene therapy for inheritedcardiomyopathies. ZOn-MW.2. PREDICT2: Predicting sudden cardiac arrest. The Dutch Heart Foundation.