Diagnostic and Prognostic Significance of Exercise Stress Testing in Desmosomal Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is characterized by fibrofatty myocardial replacement and increased arrhythmic risk. Although exercise exacerbates desmosomal ACM, the prognostic significance of arrhythmias during exercise stress tests (ESTs) remains unclear.

The goal of this study was to determine the impact of ventricular arrhythmia observed during peak exercise and/or recovery EST phases on the risk of major ventricular arrhythmia (MVA) events in patients with desmosomal ACM.

A retrospective review of 904 patients with ACM was used to identify those with a pathogenic/likely pathogenic variant in DSC2, DSG2, DSP, JUP, and PKP2. After exclusion of patients with no EST data, demographic and electrocardiographic data were extracted from the medical record. The arrhythmic burden (premature ventricular complexes [PVCs], couplet, bigeminy, nonsustained VT, sustained VT, ventricular fibrillation, and PVCs per minute) during each EST phase (baseline, peak, and early and late recovery) were reviewed and correlated with MVA outcomes (sudden cardiac arrest, sustained VT, and appropriate implantable cardioverter-defibrillator therapies).

A total of 326 ESTs from 147 patients (89 PKP2 [60%], 45 DSP [31%], 10 DSG2 [7%], and 3 DSC2 [2%]) were included. PKP2-ACM patients exhibited increased PVCs per minute (P < 0.001), bigeminy (P < 0.001), couplets (P < 0.001), and nonsustained VT (P < 0.001) during recovery. Recovery phase arrhythmias in PKP2-ACM patients were associated with a higher risk of MVA events (HR: 10.580; P = 0.003), a pattern absent in other genotypes (HR: 1.037; P = 0.973). This association remained significant in multivariable analysis (adjusted HR: 3.851; P = 0.040).

PKP2-ACM patients display a distinct recovery phase arrhythmic profile predictive of MVA events, emphasizing the importance of EST in risk stratification and management. Future studies are needed to validate these findings and ascertain the additive value of EST beyond established risk factors.