Family Screening in Relatives at Risk for Plakophilin-2-Associated Arrhythmogenic Right Ventricular Cardiomyopathy

Area of Science:

• Cardiology
• Genetics
• Clinical Medicine

Background:

• Arrhythmogenic right ventricular cardiomyopathy (ARVC) risk and ventricular arrhythmias (VAs) are genotype-dependent.
• Current ARVC screening lacks personalization, necessitating genotype-informed protocols.
• Plakophilin-2 (PKP2) gene variants are a common cause of ARVC, making PKP2-specific screening crucial.

Purpose of the Study:

• To develop a safe and evidence-based screening algorithm specific to PKP2 variants in ARVC.
• To enable personalized recommendations for family screening based on genetic and clinical data.
• To improve the efficiency of clinical resource allocation in ARVC management.

Main Methods:

• Included 295 relatives with pathogenic/likely pathogenic PKP2 variants from 145 families.
• Phenotype assessment using ECG, Holter monitoring, and cardiac imaging based on 2010 Task Force Criteria.
• Cox regression and multistate modeling to determine ARVC development predictors and VA occurrence.

Main Results:

• 12% of relatives experienced VAs, exclusively in those with a definite ARVC diagnosis.
• Relatives with borderline ARVC progressed 5x faster to definite ARVC compared to genotype-positive/phenotype-negative relatives.
• Younger relatives (20-40 years) had a 2.23-fold increased risk of developing ARVC.

Conclusions:

• Developed a 3-tiered, evidence-based longitudinal screening algorithm for PKP2-related ARVC.
• Algorithm integrates age, symptoms, and baseline phenotype for tailored screening.
• Personalized screening can enhance patient care and optimize clinical resource use.