Heart failure with preserved ejection fraction: The role of intravascular volumes and body composition in exercise-induced progenitor cell mobilization

Background and Aims: Whether exercise training induces plasma volume (PV) expansion and distorts circulating progenitor cell (CPC) assessment in heart failure with preserved ejection fraction (HFpEF) remains unclear, particularly in women, who might have lower CPC concentrations and higher cardiovascular risk due to female-specific risk factors. This study investigated sex-specific differences, skeletal muscle mass (SMM)-normalized baseline values, and exercise-induced changes in intravascular volumes, CPCs, and erythropoietin (EPO). Methods: HFpEF patients completed a 3-months strength-endurance training. Blood volume (BV), PV, red blood cell volume (RBCV), and hemoglobin mass (Hb-mass) were assessed using carbon-monoxide rebreathing, CPCs by flow cytometry, EPO by ELISA. CPC concentrations were adjusted for BV. Training effects, sex interactions, and associations between SMM-normalized CPCs and EPO were examined. Results: At baseline, women had comparable BV, PV, RBCV, Hb-mass, and EPO to men when normalized to SMM (all p > 0.05, uncorrected). After BV adjustment, women showed lower total CPC counts (uncorrected p = 0.031), but this difference disappeared after SMM normalization (uncorrected p = 0.160). Exercise training showed no evidence of affecting SMM-normalized intravascular volumes, Hb-mass, EPO, or BV-(un)adjusted CPC concentrations, with no interaction effects of sex (all p > 0.05, uncorrected). Before SMM normalization, exploratory analysis revealed PV changes being inversely associated with CPC concentration (ρ = -0.57, p = 0.044), but not thereafter. CPC relationships to EPO were non-significant (both p > 0.05). Conclusions: Sex differences in CPCs were evident after adjusting for BV but disappeared after SMM normalization. Exercise training did not increase CPCs, but individual responses depended on CPC expression. Findings require validation in larger HFpEF cohorts.