Exercise stress test arrhythmic patterns by genotype in non-desmosomal arrhythmogenic cardiomyopathy

Background Exercise stress testing (EST) is used in arrhythmogenic cardiomyopathy (ACM) to evaluate for ventricular arrhythmias (VA) under adrenergic stress. In non-desmosomal ACM, genotype-specific differences in the magnitude and timing of VA during EST phases remain incompletely characterised. Purpose To characterise phase-specific VA burden by genotype during EST in non-desmosomal ACM. Methods We retrospectively reviewed 1,684 ACM/DCM patients evaluated at a single tertiary medical centre to identify cases with a pathogenic or likely pathogenic variant in non-desmosomal ACM-susceptibility genes (DES, FLNC, LMNA, PLN, RBM20) that completed an EST. Arrhythmias were assessed at baseline, peak exercise, active recovery, and passive recovery EST phases. Arrhythmic burden was recorded as PVCs per minute (PVC/min) and the presence of complex ventricular ectopy (bigeminy, couplets, non-sustained ventricular tachycardia (NSVT) and sustained ventricular tachycardia). Within-genotype comparisons across EST phases were performed using the Friedman test for continuous variables (PVC/min) and Cochran’s Q test for binary variables (complex ventricular ectopy/NSVT). Results Collectively, 158 ESTs from 88 patients with non-desmosomal ACM were analysed (median age 39.6 years [IQR 22.4–49.3]; 57% male), including LMNA (n=36), DES (n=5), FLNC (n=25), PLN (n=6), and RBM20 (n=16) genotypes. Median peak heart rate was 179 bpm [IQR 171–197] and median % predicted VO2max was 71% [IQR 56–95]. At baseline, LMNA- and RBM20-ACM had the greatest PVC burden (median 3.0 PVC/min [IQR 2.0–5.0] and [IQR 2.0–4.0], respectively). At peak, PVC burden was highest in PLN-ACM (median 8.5 PVC/min [IQR 4.8–12.3]). During recovery, DES-ACM demonstrated the highest PVC burden, 8.0 PVC/min [IQR 5.5–8.0] during active recovery and 3.0 PVC/min [IQR 3.0–3.0] during passive recovery. Complex ventricular ectopy/NSVT was uncommon at baseline and peak, but was most frequently observed during recovery, particularly in FLNC-ACM with more couplets during active than passive recovery (n=10 vs 7). In FLNC-ACM, arrhythmogenic propensity varied significantly across EST phases, with phase-dependent differences in both PVC burden (Friedman p = 0.010) and complex ventricular ectopy (Cochran’s Q = 9.84, p = 0.020). DES-ACM, LMNA-ACM, PLN-ACM, and RBM20-ACM did not show statistically significant phase-dependent differences in PVC/min or complex ventricular ectopy (all p > 0.050), despite higher absolute PVC burden observed in LMNA-ACM across EST. Conclusion Phase-resolved EST analysis in non-desmosomal ACM reveals genotype-specific arrhythmic phenotypes. While LMNA-ACMs show higher overall ventricular ectopic burden, FLNC-ACM uniquely demonstrates recovery-phase clustering. These findings underscore the importance of systematic assessment during EST, as genotype-specific patterns may not be evident at peak exercise alone.