Distinguishing exercise intolerance in early-stage pulmonary hypertension with invasive exercise hemodynamics: Rest VE /VCO2 and ETCO2 identify pulmonary vascular disease

Abstract

Background: Among subjects with exercise intolerance and suspected early-stage pulmonary hypertension (PH), early identification of pulmonary vascular disease (PVD) with noninvasive methods is essential for prompt PH management.

Hypothesis: Rest gas exchange parameters (minute ventilation to carbon dioxide production ratio: V_E /VCO₂ and end-tidal carbon dioxide: ETCO₂ ) can identify PVD in early-stage PH.

Methods: We conducted a retrospective review of 55 subjects with early-stage PH (per echocardiogram), undergoing invasive exercise hemodynamics with cardiopulmonary exercise test to distinguish exercise intolerance mechanisms. Based on the rest and exercise hemodynamics, three distinct phenotypes were defined: (1) PVD, (2) pulmonary venous hypertension, and (3) noncardiac dyspnea (no rest or exercise PH). For all tests, *p < .05 was considered statistically significant.

Results: The mean age was 63.3 ± 13.4 years (53% female). In the overall cohort, higher rest V_E /VCO₂ and lower rest ETCO₂ (mm Hg) correlated with high rest and exercise pulmonary vascular resistance (PVR) (r ~ 0.5-0.6*). On receiver-operating characteristic analysis to predict PVD (vs. non-PVD) subjects with noninvasive metrics, area under the curve for pulmonary artery systolic pressure (echocardiogram) = 0.53, rest V_E /VCO₂ = 0.70* and ETCO₂ = 0.73*. Based on this, optimal thresholds of rest V_E /VCO₂ > 40 mm Hg and rest ETCO₂ < 30 mm Hg were applied to the overall cohort. Subjects with both abnormal gas exchange parameters (n = 12, vs. both normal parameters, n = 19) had an exercise PVR 5.2 ± 2.6* (vs. 1.9 ± 1.2), mPAP/CO slope with exercise 10.2 ± 6.0* (vs. 2.9 ± 2.0), and none included subjects from the noncardiac dyspnea group.

Conclusions: In a broad cohort of subjects with suspected early-stage PH, referred for invasive exercise testing to distinguish mechanisms of exercise intolerance, rest gas exchange parameters (V_E /VCO₂ > 40 mm Hg and ETCO₂ < 30 mm Hg) identify PVD.

Keywords: ETCO2; VE/VCO2; cardiopulmonary exercise test; invasive exercise hemodynamics; pulmonary hypertension; pulmonary vascular disease.

Figure 1

Representative figure of invasive exercise hemodynamics with cardiopulmonary exercise testing. CPET, cardiopulmonary exercise test.

Figure 2

Correlation of rest ETCO₂ (A&B) and V _E/VCO₂ (C&D) with rest and exercise PVR. ETCO₂, end‐tidal carbon dioxide pressure; PVR, pulmonary vascular resistance; V _E/VCO₂, minute ventilation to carbon dioxide production ratio.

Figure 3

Distribution of rest gas exchange parameters among the overall cohort and hemodynamic profile. Abnormal thresholds for rest ETCO₂ (<30 mm Hg) and V _E/VCO₂ (>40 mm Hg) Both normal: green (n = 26), one abnormal: blue (n = 17), both abnormal: red (n = 12). ANOVA p < .001 for all three analyses. For pairwise comparisons, both normal (green) = a, one abnormal (blue) = b, and both abnormal (red) = c. ANOVA, analysis of variance; CO, cardiac output; ETCO₂, end‐tidal carbon dioxide pressure; mPAP, mean pulmonary artery pressure; PET, cardiopulmonary exercise test; PVR, pulmonary vascular resistance; V _E/VCO₂, minute ventilation to carbon dioxide production ratio.