Different determinants of ventilatory inefficiency at different stages of reduced ejection fraction chronic heart failure natural history

Background- It 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 Results- VE/VCO2slope was fitted up to lowest VE/VCO2ratio, that is, a proxy of the VE/perfusion ratio devoid of nonmetabolic stimuli to ventilatory drive. VE/VCO2slope 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/VCO2slopes in 2 different tertiles were selected. Determinants of VE/VCO2slope changes across tertile pairs 1 versus 2, 2 versus 3, and 1 versus 3 were assessed by exploring changes in VE and VCO2at lowest VE/VCO2and those in VE/work rate (W) and VCO2/W slope. Resting and peak cardiac output (CO) were calculated as VO2/estimated arteriovenous O2difference and the CO/W slope analyzed. Notwithstanding a progressively lower W with increasing tertile, VE at lowest VE/VCO2and VE/W slope were significantly higher in tertiles 2 and 3 versus tertile 1. Conversely, VCO2at lowest VE/VCO2and 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/VCO2slope 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. Conclusions- Ventilatory overactivation is the predominant cause of VE/VCO2slope increase at initial stages of chronic heart failure, whereas hemodynamic impairment plays an additional role at more-advanced pathophysiological stages.