Concordance of calculated arrhythmic risk and guideline-directed ICD indication in PKP2-related ARVC

Background Ventricular arrhythmia (VA) risk stratification in personalised medicine for arrhythmogenic right ventricular cardiomyopathy (ARVC) has gained importance. To aid clinical decision-making regarding ICD implantation for sudden cardiac death (SCD) prevention in ARVC, a risk calculator has been developed and validated for patients with a variant in the plakophilin-2 (PKP2) gene. To date, alignment of the calculated risk with European Society of Cardiology (ESC) guidelines in PKP2-related ARVC remains unclear. Purpose To determine 1) how predicted 5-year sustained ventricular arrhythmia (VA) risk as per ARVC risk calculator corresponds to ESC guideline-directed ICD classification, and 2) its association with observed arrhythmic events in follow-up. Methods We retrospectively included PKP2 (likely) pathogenic (LP/P) variant carriers with available examinations necessary for risk stratification and ICD classification at time of ARVC diagnosis. Patients fulfilling diagnostic criteria for definite ARVC diagnosis were eligible for risk stratification. The ARVC risk calculator was used to predict the 5-year VA risk. ICD indications were classified following the 2022 ESC VA guideline and the 2023 ESC cardiomyopathy (CMP) guideline, comparing both guideline-directed ICD classifications and predicted risk per ARVC risk calculator. In addition, ICD implantation and arrhythmic events during follow-up were assessed. Results Of 104 PKP2 LP/P carriers, 65 fulfilled definite ARVC criteria and were eligible for risk stratification (46% male, age 38±16 years at diagnosis). According to the VA guideline, 4/65 (6%) patients were class I, 20/65 (31%) class IIa and 41/65 (63%) class IIb/III, with a predicted risk as per ARVC risk calculator of 27±17%, 26±15%, and 10±5%, per class indication, respectively. By CMP guideline, 4/65 (6%) patients were class I, 31/65 (48%) class IIa and 30/65 (46%) class IIb/III, with a predicted risk as per ARVC risk calculator of 27±17%, 20±14%, and 9±6%, per class indication, respectively. Mean predicted VA risk increased significantly with stronger ICD indication across both the VA and CMP guidelines (p<0.001). Classification agreement between the two guidelines was moderate (κ= 0.59, p<0.001). Among 65 patients with ARVC diagnosis, 33 (51%) received an ICD: VA vs. CMP guideline class I (9 vs. 9%), class IIa (52 vs. 70%), and class IIb/III (39 vs. 21%), respectively. During 8±6 years of follow-up, 13/33 (39%) experienced appropriate ICD treatment while 3/33 (9%) experienced inappropriate ICD treatment. Conclusions Higher 5-year VA risk as calculated per ARVC risk calculator was in concordance with stronger ESC guideline-directed ICD classification: strong, moderate and weak ICD indications corresponded with a mean predicted 5-year VA risk of 27%, 20-26% and 9-10%, respectively. Observed arrhythmic events during follow-up received appropriate ICD treatment.