Cardiopulmonary exercise test criteria for heart transplantation referral of patients with ambulatory heart failure in the current era

Background: Current guidelines recommend evaluating patients with ambulatory heart failure (HF) for heart transplantation if their peak oxygen consumption (peak VO2) is <12 mL/kg/min. However, these recommendations are based on decades-old data. Methods: We retrospectively analysed 8060 patients with ambulatory HF with cardiopulmonary exercise testing (CPET) data. The primary analysis focused on 1218 patients with left ventricular ejection fraction <40% and peak VO2 <12 mL/kg/min, enrolled between 2010 and 2022. Survival outcomes (composite of death/left ventricular assist device/heart transplantation) were compared with those of heart transplantation recipients from the International Society for Heart and Lung Transplantation registry. Patients were stratified by ventilatory efficiency (ventilation versus CO2 production slope (VE/VCO2) >34 vs ≤34) and presence of exercise oscillatory ventilation. Survival analyses were performed using Kaplan-Meier curves compared with log-rank tests and Cox proportional hazards models, with heart transplantation survival curves reconstructed from aggregate data. Results: Patients with peak VO2 <12 mL/kg/min demonstrated better survival than heart transplantation recipients, with survival curves intersecting at approximately 2.7 years. Among those with VE/VCO2 ≤34, 10-year mortality risk was halved (p<0.01), with survival curves crossing those of heart transplantation recipients around year 4. Absence of exercise oscillatory ventilation was similarly associated with a 50% lower long-term mortality. Combining VE/VCO2 and exercise oscillatory ventilation identified four distinct risk groups with significantly different 10-year outcomes (p<0.01). Patients with peak VO2 <12 mL/kg/min, VE/VCO2 ≤34 and no exercise oscillatory ventilation exhibited survival comparable to heart transplantation recipients at year 5. Conclusions: In contemporary practice, a peak VO2 <12 mL/kg/min alone may not reliably identify patients with HF with sufficiently high short-term mortality to warrant heart transplantation referral. VE/VCO2 and exercise oscillatory ventilation provide important additional risk stratification, supporting re-evaluation of transplant referral criteria to reflect improved HF management and outcomes.