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

Patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction demonstrate an increased ventilatory equivalent for carbon dioxide (V̇E /V̇CO2 ) slope. The physiological correlates of the V̇E /V̇CO2 slope remain unclear in the two HF phenotypes. We hypothesized that changes in the physiological dead space to tidal volume ratio (VD /VT ) and arterial CO2 tension (PaCO2 ) differentially contribute to the V̇E /V̇CO2 slope in HFrEF vs. HFpEF. 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/m2 and 33 ± 6 kg/m2 , respectively; P < 0.01] performed cardiopulmonary exercise testing with breath-by-breath ventilation and gas exchange measurements. PaCO2 was measured via radial arterial catheterization. We calculated the V̇E /V̇CO2 slope via linear regression, and VD /VT  = 1 - [(863 × V̇CO2 )/(V̇E  × PaCO2 )]. Resting VD /VT (0.48 ± 0.08 vs. 0.41 ± 0.11; P = 0.04), but not PaCO2 (38 ± 5 mmHg vs. 40 ± 3 mmHg; P = 0.21) differed between HFrEF and HFpEF. Peak exercise VD /VT (0.39 ± 0.08 vs. 0.32 ± 0.12; P = 0.02) and PaCO2 (33 ± 6 mmHg vs. 38 ± 4 mmHg; P < 0.01) differed between HFrEF and HFpEF. The V̇E /V̇CO2 slope was higher in HFrEF compared with HFpEF (44 ± 11 vs. 35 ± 8; P < 0.01). Variance associated with the V̇E /V̇CO2 slope in HFrEF and HFpEF was explained by peak exercise VD /VT (R2  = 0.30 and R2  = 0.50, respectively) and PaCO2 (R2  = 0.64 and R2  = 0.28, respectively), but the relative contributions of each differed (all P < 0.01). Relationships between the V̇E /V̇CO2 slope and both VD /VT and PaCO2 are robust, but differ between HFpEF and HFrEF. Increasing V̇E /V̇CO2 slope appears to be strongly explained by mechanisms influential in regulating PaCO2 in HFrEF, which contrasts with the strong role of increased VD /VT in HFpEF.

Van Iterson EH ，Johnson BD ，Borlaug BA ，Olson TP ... -  《-》

Use of 'ideal' alveolar air equations and corrected end-tidal PCO(2) to estimate arterial PCO(2) and physiological dead space during exercise in patients with heart failure.

Arterial CO2 tension (PaCO2) and physiological dead space (VD) are not routinely measured during clinical cardiopulmonary exercise testing (CPET). Abnormal changes in PaCO2 accompanied by increased VD directly contribute to impaired exercise ventilatory function in heart failure (HF). Because arterial catheterization is not standard practice during CPET, this study tested the construct validity of PaCO2 and VD prediction models using 'ideal' alveolar air equations and basic ventilation and gas-exchangegas exchange measurements during CPET in HF. Forty-seven NYHA class II/III HF (LVEF=21±7%; age=55±9years; male=89%; BMI=28±5kg/m2) performed step-wise cycle ergometry CPET to volitional fatigue. Breath-by-breath ventilation and gas exchange were measured continuously. Steady-state PaCO2 was measured at rest and peak exercise via radial arterial catheterization. Criterion VD was calculated via 'ideal' alveolar equations, whereas PaCO2 or VD models were based on end-tidal CO2 tension (PETCO2), tidal volume (VT), and/or weight. Criterion measurements of PaCO2 (38±5 vs. 33±5mmHg, P<0.01) and VD (0.26±0.07 vs. 0.41±0.15L, P<0.01) differed at rest vs. peak exercise, respectively. The equation, 5.5+0.90×PETCO2-0.0021×VT, was the strongest predictor of PaCO2 at rest and peak exercise (bias±95%LOA=-3.24±6.63 and -0.98±5.76mmHg; R2=0.57 and 0.75, P<0.001, respectively). This equation closely predicted VD at rest and peak exercise (bias±95%LOA=-0.03±0.06 and -0.02±0.13L; R2=0.86 and 0.83, P<0.001, respectively). These data suggest predicted PaCO2 and VD based on breath-by-breath gas exchange and ventilatory responses demonstrate acceptable agreement with criterion measurements at peak exercise in HF patients. Routine assessment of PaCO2 and VD can be used to improve interpretability of exercise ventilatory responses in HF.

Van Iterson EH ，Olson TP 《-》

Exercise ventilatory inefficiency in heart failure and chronic obstructive pulmonary disease.

Dyspnea on exertion is common to both heart failure (HF) and chronic obstructive pulmonary disease (COPD), and it is important to discriminate whether symptoms are caused by HF or COPD in clinical practice. The ventilatory equivalent for carbon dioxide (V̇E/V̇CO2) slope and V̇E intercept (a reflection of pulmonary dead space) are two candidate non-invasive indices that could be used for this purpose. Thus, we compared non-invasive indexes of ventilatory efficiency in patients with HF and preserved or reduced ejection fraction (HFpEF and HFrEF, respectively) or COPD. Patients with HFpEF (n = 21), HFrEF (n = 20), and COPD (n = 22) patients performed cardiopulmonary exercise testing to volitional fatigue. V̇E and gas exchange were measured via breath-by-breath open circuit spirometry. All data from rest to peak exercise were used to calculate V̇E/V̇CO2 slope and V̇E intercept using linear regression. Receiver operating characteristic (ROC) curves were constructed to determine optimized cutoffs for V̇E/V̇CO2 slope and V̇E intercept to discriminate HFpEF and HFrEF from COPD. HFrEF patients had a greater V̇E/V̇CO2 slope than HFpEF and COPD patients (HFrEF: 40 ± 9; HFpEF: 32 ± 7; COPD: 32 ± 7) (p < 0.01). COPD patients had a greater V̇E intercept than HFpEF and HFrEF patients (COPD: 3.32 ± 1.66; HFpEF: 0.77 ± 1.23; HFrEF: 1.28 ± 1.19 L/min) (p < 0.01). A V̇E intercept of 2.64 L/min discriminated COPD from HF patients (AUC: 0.88, p < 0.01), while V̇E/V̇CO2 slope did not (p = 0.11). These findings demonstrate that V̇E intercept, not V̇E/V̇CO2 slope, may discriminate COPD from both HFpEF and HFrEF patients.

Smith JR ，Van Iterson EH ，Johnson BD ，Borlaug BA ，Olson TP ... -  《-》

Exercise Ventilatory Efficiency in Older and Younger Heart Failure Patients With Preserved Ejection Fraction.

Patients with heart failure with preserved ejection fraction (HFpEF) exhibit pulmonary abnormalities, but the studies to date have reported wide variability in the ventilatory equivalent for carbon dioxide (V̇E/V̇CO2) slope. It is possible that aging may contribute to that variability. We sought to compare ventilatory efficiency and its components in older and younger HFpEF patients during exercise. Eighteen older (O; 80 ± 4 y) and 19 younger (Y; 59 ± 7 y) HFpEF patients performed cardiopulmonary exercise testing to volitional fatigue. Measurements of arterial blood gases were used to derive VD/VT, dead space ventilation, and alveolar ventilation. V̇E/V̇CO2 slope was greater in older compared with younger HFpEF patients (O 36 ± 7vs Y 31 ± 7; P = .04). At peak exercise, older HFpEF exhibited greater VD/VT compared with younger HFpEF (O 0.37 ± 0.10vs Y 0.28 ± 0.10; P < .01), whereas PaCO2 was not different between groups (P = .58). V̇E and alveolar ventilation were similar (P > .23), but dead space ventilation was greater in older compared with younger HFpEF at peak exercise (P = .04). Older HFpEF patients exhibit greater ventilatory inefficiency resulting from elevated physiologic dead space during peak exercise compared with younger HFpEF patients. These results suggest that aging can worsen the pathophysiologic mechanisms underlying ventilatory efficiency during exercise in HFpEF.

Smith JR ，Borlaug BA ，Olson TP 《-》

Prognostic Value of Cardiopulmonary Exercise Testing in Heart Failure With Reduced, Midrange, and Preserved Ejection Fraction.

This study aimed to compare the independent and incremental prognostic value of peak oxygen consumption (VO2) and minute ventilation/carbon dioxide production (VE/VCO2) in heart failure (HF) with preserved (HFpEF), midrange (HFmEF), and reduced (HFrEF) ejection fraction (LVEF). In 195 HFpEF (LVEF ≥50%), 144 HFmEF (LVEF 40-49%), and 630 HFrEF (LVEF <40%) patients, we assessed the association of cardiopulmonary exercise testing variables with the composite outcome of death, left ventricular assist device implantation, or heart transplantation (256 events; median follow-up of 4.2 years), and 2-year incident HF hospitalization (244 events). In multivariable Cox regression analysis, greater association with outcomes in HFpEF than HFrEF were noted with peak VO2 (HR [95% confidence interval]: 0.76 [0.67-0.87] versus 0.87 [0.83-0.90] for the composite outcome, Pinteraction=0.052; 0.77 [0.69-0.86] versus 0.92 [0.88-0.95], respectively for HF hospitalization, Pinteraction=0.003) and VE/VCO2 slope (1.11 [1.06-1.17] versus 1.04 [1.03-1.06], respectively for the composite outcome, Pinteraction=0.012; 1.10 [1.05-1.15] versus 1.04 [1.03-1.06], respectively for HF hospitalization, Pinteraction=0.019). In HFmEF, peak VO2 and VE/VCO2 slope were associated with the composite outcome (0.79 [0.70-0.90] and 1.12 [1.05-1.19], respectively), while only peak VO2 was related to HF hospitalization (0.81 [0.72-0.92]). In HFpEF and HFrEF, peak VO2 and VE/VCO2 slope provided incremental prognostic value beyond clinical variables based on the C-statistic, net reclassification improvement, and integrated diagnostic improvement, with models containing both measures demonstrating the greatest incremental value. Both peak VO2 and VE/VCO2 slope provided incremental value beyond clinical characteristics and LVEF for predicting outcomes in HFpEF. Cardiopulmonary exercise testing variables provided greater risk discrimination in HFpEF than HFrEF.

Nadruz W Jr ，West E ，Sengeløv M ，Santos M ，Groarke JD ，Forman DE ，Claggett B ，Skali H ，Shah AM ... -  《Journal of the American Heart Association》