Physiological dead space and arterial carbon dioxide contributions to exercise ventilatory inefficiency in patients with reduced or preserved ejection fraction heart failure

Aims Patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction demonstrate an increased ventilatory equivalent for carbon dioxide (V̇ E /V̇CO 2 ) slope. The physiological correlates of the V̇ E /V̇CO 2 slope remain unclear in the two HF phenotypes. We hypothesized that changes in the physiological dead space to tidal volume ratio (V D /V T ) and arterial CO 2 tension (PaCO 2 ) differentially contribute to the V̇ E /V̇CO 2 slope in HFrEF vs. HFpEF. Methods and results Adults with HFrEF ( n  = 32) and HFpEF ( n  = 27) [mean ± standard deviation (SD) left ventricular ejection fraction: 22 ± 7% and 61 ± 9%, respectively; mean ± SD body mass index: 28 ± 4 kg/m 2 and 33 ± 6 kg/m 2 , respectively; P  < 0.01] performed cardiopulmonary exercise testing with breath‐by‐breath ventilation and gas exchange measurements. PaCO 2 was measured via radial arterial catheterization. We calculated the V̇ E /V̇CO 2 slope via linear regression, and V D /V T  = 1 − [(863 × V̇CO 2 )/(V̇ E  × PaCO 2 )]. Resting V D /V T (0.48 ± 0.08 vs. 0.41 ± 0.11; P  = 0.04), but not PaCO 2 (38 ± 5 mmHg vs. 40 ± 3 mmHg; P  = 0.21) differed between HFrEF and HFpEF. Peak exercise V D /V T (0.39 ± 0.08 vs. 0.32 ± 0.12; P  = 0.02) and PaCO 2 (33 ± 6 mmHg vs. 38 ± 4 mmHg; P  < 0.01) differed between HFrEF and HFpEF. The V̇ E /V̇CO 2 slope was higher in HFrEF compared with HFpEF (44 ± 11 vs. 35 ± 8; P  < 0.01). Variance associated with the V̇ E /V̇CO 2 slope in HFrEF and HFpEF was explained by peak exercise V D /V T ( R 2  = 0.30 and R 2  = 0.50, respectively) and PaCO 2 ( R 2  = 0.64 and R 2  = 0.28, respectively), but the relative contributions of each differed (all P  < 0.01). Conclusions Relationships between the V̇ E /V̇CO 2 slope and both V D /V T and PaCO 2 are robust, but differ between HFpEF and HFrEF. Increasing V̇ E /V̇CO 2 slope appears to be strongly explained by mechanisms influential in regulating PaCO 2 in HFrEF, which contrasts with the strong role of increased V D /V T in HFpEF.