Prognostic value of symptom-limited cycle ergometer cardiopulmonary exercise testing parameters and their interaction with iron status in patients with heart failure: a prospective cohort study

Background Cardiopulmonary exercise testing (CPET) provides essential prognostic information heart failure (HF) patients. Parameters such as oxygen uptake at the anaerobic threshold (ATVO2), peak oxygen uptake (peakVO2), and the percentage of predicted peakVO2 (peakVO2%pred) are established outcome predictors. Iron deficiency (ID), a common HF comorbidity, adversely impacts exercise capacity and prognosis, yet its interplay with CPET parameters remains unclear. Objective To investigate the prognostic value of ATVO2, peakVO2, and peakVO2%pred in HF patients and explore whether iron status modifies their association with clinical outcomes. Methods This prospective cohort study enrolled 209 patients with NYHA class III–IV HF who underwent symptom-limited cycle ergometer CPET. Echocardiographic assessments were performed at baseline and the 6th month. The primary outcome was a hierarchical composite endpoint comprising 6 ordinal levels: all-cause death or heart transplantation, hospitalization for worsening HF, echocardiographic deterioration, persistent abnormality, improvement without normalization, and maintained or restored normal echocardiographic parameters. Patients were classified by iron status (normal, iron depletion, iron deficiency anemia) based on ferritin, transferrin saturation, and hemoglobin. Multivariable competing risk models were constructed for ATVO2, peakVO2, and peakVO2%pred. Four models were developed with progressive adjustment for demographics, biomarkers, and clinical covariates, with Model 4 based on COX-LASSO variable selection. Correlations between iron status and CPET parameters were visualized using a heatmap. Interaction terms and cumulative incidence function (CIF) curves assessed joint effects. Results Over a median 458-day follow-up, ATVO2, peakVO2, and peakVO2%pred were significant independent outcome predictors (all p<0.001). All three CPET parameters were consistently retained with iron status in COX-LASSO models (Figure 1). A heatmap revealed a progressive decline in CPET parameters with worsening ID. Interaction terms were non-significant, but CIF curves (Figure 2) and hazard ratios showed consistent trends toward worse outcomes in patients with poorer exercise capacity and more severe ID (low-ATVO2*Iron depletion: 2.44[0.516-11.5]; low-peakVO2*Iron depletion: 3.5[0.758-16.2], low-peakVO2%pred*Iron depletion: 1.75[0.453-6.76]). Non-significance likely reflects limited subgroup sample sizes. The observed trend suggests ID amplifies the prognostic impact of impaired exercise capacity. Conclusions ATVO2, peakVO2, and peakVO2%pred significantly predict outcomes in advanced HF. Iron deficiency closely correlates with these parameters and exacerbates risk associated with poor exercise capacity. Integrating iron status with CPET enhances risk stratification. Patients with both impaired exercise capacity and iron deficiency may derive greater benefit from iron supplementation.