CineECG detects abnormal electrical activity in the 12-lead ECG of preclinical plakophilin-2 variant carriers

Background: Carriers of (likely) Plakophilin-2 pathogenic variants (PKP2-(L)PV) are at risk of developing arrhythmogenic cardiomyopathy. Early disease detection is crucial because life-threatening arrhythmias may occur early. CineECG is a novel electrocardiogram (ECG) analysis tool that reconstructs the average trajectory of ventricular electrical activity. Objective: The study aimed to describe the electrical depolarization and repolarization CineECG trajectories in PKP2-(L)PV carriers with a normal ECG as per evaluation of 2 cardiologists, who meet no Task Force Criteria other than their PV. Methods: PKP2-(L)PV carriers were 2:1-matched to control subjects, who had atrioventricular nodal reentry tachycardia but no other cardiac abnormalities. Sinus rhythm ECGs of controls were used to create a normal distribution of trajectories. PKP2-(L)PV carriers’ trajectories were compared with the normal distribution. A trajectory was considered abnormal if it fell less than 95% within the normal distribution. Results: Overall, 104 subjects were included (age 24 years [19–36], 43% men): 37 PKP2-(L)PV carriers and 67 controls. Depolarization and repolarization trajectories were abnormal in 51% and 24% of carriers, respectively. In carriers with abnormal depolarization trajectories, significant differences were observed in the direction of the initial depolarization trajectory when compared with controls in the inferior-superior axis (P = .005) and posterior-anterior axis (P = .020). In the left-right axis, the direction significantly differed from carriers with a normal trajectory (P = .020). Conclusion: Abnormal electrical activity was identified in over half of preclinical PKP2-(L)PV carriers with a normal ECG. CineECG could be a sensitive tool to unveil early, subtle abnormalities in ventricular electrical activity that would otherwise not be detected.