Prognostic value of heart rate dynamics during exercise testing in definite ARVC patients

Background: Exercise testing is routinely performed in arrhythmogenic right ventricular cardiomyopathy (ARVC), particularly given the disease’s strong association with exercise and competitive sport (James et al., 2013). However, the prognostic value of test-derived variables remains uncertain. Premature ventricular contractions (PVCs) during exercise and recovery have been linked to adverse events, though replication is limited (Castrichini et al., 2025). Heart rate responses may reflect autonomic imbalance, a contributor to arrhythmic risk, but it remains unclear whether these variables independently predict major adverse cardiac events (MACE) in ARVC (Jouven & Courbon, 2005; Nishime, 2000). Purpose: To determine whether heart rate dynamics and PVC burden during exercise testing are associated with future cardiac events in adults with definite ARVC. Methods: Patients with definite ARVC according to the 2010 Task Force Criteria (Marcus et al., 2010) were retrospectively identified. Heart rate metrics included HRmax, resting heart rate, heart rate reserve (peak minus resting), and heart rate recovery at 30 seconds and minutes 1–5. PVC burden was calculated as total PVCs divided by phase duration. MACE included sustained ventricular tachycardia, ventricular fibrillation and tachycardia, appropriate implantable therapy, arrhythmic syncope, survived sudden cardiac death, heart transplantation, and death. Time-to-event analysis used Kaplan–Meier curves and Cox models, with follow-up censored at five years. Both continuous and ROC-derived categorical variables were evaluated. Results: Forty-five patients were included (mean age 49.1 ± 16.8 years, 37.8% female, 40% PKP2, 66.7% on beta-blockers). Among the 17 patients (37.8%) who experienced MACE, the median time to occurrence was 1.7 years (IQR 0.6–2.7). Baseline clinical and exercise variables did not differ significantly by outcome. HRmax was 146 ± 23 bpm, resting heart rate 67 ± 14 bpm, heart rate reserve 78 ± 19 bpm, and 1-minute heart rate recovery 23 ± 10 bpm. PVC burden increased from exercise to recovery (1.7 vs. 4.4 PVCs/min; p = 0.006), but neither predicted 5-year MACE (exercise: HR 1.05, 95% CI 0.96–1.15, p = 0.30; recovery: HR 1.04, 95% CI 0.99–1.10, p = 0.14). Higher heart rate reserve was associated with increased MACE risk (HR per 1-bpm increase 1.04; 95% CI 1.01–1.07; p = 0.024), remaining significant after adjustment for beta-blocker therapy and PVC burden. Heart rate recovery was most prognostic at minute three (HRR3). ROC analysis identified an HRR3 cutoff of 53 bpm; patients with HRR3 ≥ 53 bpm had greater MACE risk (HR 3.79; 95% CI 1.20–11.98; p = 0.023; AUC = 0.717), independent of beta-blocker therapy. Conclusions: Heart rate reserve and late heart rate recovery, particularly HRR3, are independently associated with 5-year MACE in ARVC, whereas PVC burden during exercise and recovery is not associated with MACE. Exercise test–derived autonomic markers may enhance arrhythmic risk stratification beyond conventional clinical parameters. Larger multicenter studies are needed to validate these findings. References Castrichini, M., Neves, R., Garmany, R., Allison, T., Ackerman, M. J., & Giudicessi, J. R. (2025). Diagnostic and prognostic significance of exercise stress testing in desmosomal arrhythmogenic cardiomyopathy. JACC: Clinical Electrophysiology. Vorab-Onlineveröffentlichung. https://doi.org/10.1016/j.jacep.2025.07.014 James, C. A., Bhonsale, A., Tichnell, C., Murray, B., Russell, S. D., Tandri, H., Mittal, S., Judge, D. P., & Calkins, H. (2013). Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy–associated desmosomal mutation carriers. Journal of the American College of Cardiology, 62(14), 1290–1297. https://doi.org/10.1016/j.jacc.2013.06.033 Jouven, X., & Courbon, D. (2005). Heart rate profile during exercise as a predictor of sudden death. New England Journal of Medicine, 352(19), 1951–1958. https://doi.org/10.1056/NEJMoa043012 Marcus, F. I., McKenna, W. J., Sherrill, D., Basso, C., Bauce, B., Bluemke, D. A., Calkins, H., Corrado, D., Cox, M. G. P. J., Daubert, J. P., Fontaine, G., Gear, K., Hauer, R., Nava, A., Picard, M. H., Protonotarios, N., Saffitz, J. E., Sanborn, D. M., Steinberg, J. S., . . . Zareba, W. (2010). Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: Proposed modification of the Task Force criteria. European Heart Journal, 31(7), 806–814. https://doi.org/10.1093/eurheartj/ehq025 Nishime, E. O., Cole, C. R., Blackstone, E. H., Pashkow, F. J., & Lauer, M. S. (2000). Heart rate recovery and treadmill exercise score as predictors of mortality. JAMA, 284(11), 1392–1398. https://doi.org/10.1001/jama.284.11.1392