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BackgroundIt is not known whether determinants of ventilation (VE)/volume of exhaled carbon dioxide (VCO2) slope during incremental exercise may differ at different stages of reduced ejection fraction chronic heart failure natural history. Methods and ResultsVE/VCO2 slope was fitted up to lowest VE/VCO2 ratio, that is, a proxy of the VE/perfusion ratio devoid of nonmetabolic stimuli to ventilatory drive. VE/VCO2 slope tertiles were generated from our database (<27.5 [tertile 1], ≥27.5 to <32.0 [tertile 2], and ≥32.0 [tertile 3]), and 147 chronic heart failure patients with repeated tests yielding VE/VCO2 slopes in 2 different tertiles were selected. Determinants of VE/VCO2 slope changes across tertile pairs 1 versus 2, 2 versus 3, and 1 versus 3 were assessed by exploring changes in VE and VCO2 at lowest VE/VCO2 and those in VE/work rate (W) and VCO2/W slope. Resting and peak cardiac output (CO) were calculated as VO2/estimated arteriovenous O2 difference and the CO/W slope analyzed. Notwithstanding a progressively lower W with increasing tertile, VE at lowest VE/VCO2 and VE/W slope were significantly higher in tertiles 2 and 3 versus tertile 1. Conversely, VCO2 at lowest VE/VCO2 and CO/W slope significantly decreased across tertiles, whereas VCO2/W slope did not. Difference (Δ) in VE/W slope between tertiles accounted for 71% of ΔVE/VCO2 slope variance, with ΔVCO2/W slope explaining an additional 26% (model r=0.99; r2=0.97; P<0.0001). Similar results were obtained substituting ΔVCO2/W slope with ΔCO/W slope. ConclusionsVentilatory overactivation is the predominant cause of VE/VCO2 slope increase at initial stages of chronic heart failure, whereas hemodynamic impairment plays an additional role at more‐advanced pathophysiological stages.