COPD is frequently associated with mild to moderate pulmonary hypertension (PH). However, a small subset of patients develops severe PH, which is currently haemodynamically defined as mean pulmonary arterial pressure (mPAP) ⩾35 mmHg, or mPAP ⩾25 mmHg in combination with cardiac index <2.0 L•min −1 •m −2 [1, 2]. These cut-offs are, however, arbitrary and mainly based on expert opinion. In this study we aimed to determine prognostically relevant haemodynamic thresholds for severe PH in COPD by using an unbiased approach.We retrospectively analysed COPD patients with at least 1-year follow-up who underwent right heart catheterisation (RHC) and clinical evaluation at our clinic due to suspected PH between 2003 and 2018. RHC was performed in the supine position, with a mid-thoracic zero reference level, as previously described [3]. All data were included into a prospective local database (GRAPHIC (GRAz Pulmonary Hypertension In COPD) registry). Patients undergoing lung transplantation at any time (n=3) were excluded from this analysis. We performed Cox regression analysis, adjusting for age, sex and forced expiratory volume in 1 s (FEV 1 ) with the primary outcome all-cause mortality. For identification of the best prognostic cut-offs, we searched for the lowest p-values. Continuous baseline characteristics of the groups according to the best cut-off were compared using independent t-tests or Mann-Whitney U-test, as appropriate. Continuous variables are described as mean±SD or median (interquartile range), as appropriate. The study was approved by the institutional ethics board (EK: 32-180 ex 19/20) of the Medical University Graz.We included 139 COPD patients (age 68 (62-73) years; 55.4% male; mPAP 35 (27-43) mmHg; pulmonary vascular resistance (PVR) 4.3 (2.9-7.3) WU; FEV 1 56±20% predicted). 72 patients (52%) died during a follow-up of 8.0 (3.8-11.7) years, with a median time to death of 3.0 (1.3-5.2) years. 61 (44%) patients received any PAH drug at any time-point.Out of the examined haemodynamic parameters, after adjustment for age, sex and FEV 1 , PVR (HR 1.09, 95% CI 1.02-1.16; p=0.007) and mPAP (HR 1.03, 95% CI 1.01-1.05; p=0.001) were associated with survival, while pulmonary arterial wedge pressure (PAWP) and cardiac index were not ( p=0.696 and p=0.171). Among all haemodynamic parameters, PVR >5.0 WU was the best prognostic cut-off (HR 2.59, 95% CI 1.58-4.27; p<0.001) (figure 1a). Patients with PVR >5.0 WU were more frequently males ( p<0.001) and had a lower 6-min walk distance (254±112 versus 333±117 m; p<0.001), lower peak oxygen uptake (41±13 versus 61±23% predicted; p<0.001) and higher N-terminal pro brain natriuretic peptide (2288 (694-3634) versus 442 (160-1126) pg•mL −1 ; p<0.001) as compared to patients with PVR ⩽5.0 WU.For mPAP, the p-values for potential cut-off scores showed two equivalent minimal levels, the first at 33 mmHg (HR 2.26, 95% CI 1.37-3.71; p=0.001) (figure 1b) and the second at 45 mmHg (HR 2.44, 95% CI 1.43-4.16; p=0.001). Out of the patients with mPAP ⩾33 mmHg, n=28 (36%) and n=49 ...

The cardiopulmonary hemodynamic profile observed during exercise may identify patients with early stage pulmonary vascular and primary cardiac diseases, and is used clinically to inform prognosis. However, a standardised approach to interpreting hemodynamics is lacking.We performed a systematic literature search according to PRISMA guidelines to identify parameters that may be diagnostic for an abnormal hemodynamic response to exercise and offer optimal prognostic and differential-diagnostic value. We performed random-effects-meta-analyses of the normal values and reported effect sizes as weighted means and standard deviations (sd). Results of diagnostic and prognostic studies are reported descriptively.We identified n=45 eligible studies with n=5598 subjects. The mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope, pulmonary arterial wedge pressure (PAWP)/CO slope and peak cardiac index (or CO) provided the most consistent prognostic hemodynamic parameters during exercise. The best cut-offs for survival and cardiovascular events were mPAP/CO slope>3 Wood units (WU) and PAWP/CO slope>2 WU. A PAWP/CO slope cut-off>2 WU best differentiated pre- from post-capillary causes of PAP elevation during exercise. Upper limits of normal (defined as mean+2 sd) for the mPAP/CO and PAWP/CO slopes were strongly age-dependent and ranged in 30-to 70-year old healthy subjects from 1.6 to 3.3 WU and 0.6 to 1.8 WU, respectively.Increased mPAP/CO slope during exercise is associated with impaired survival and an independent, prognostically relevant cut-off>3 WU has been validated. A PAWP/CO slope>2 WU may be suitable for the differentiation between pre- and post-capillary causes of PAP increase during exercise.

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Background Pulmonary hypertension (PH) is a frequent complication in COPD and it is associated with decreased exercise capacity and poor prognosis. We hypothesized that even in COPD patients without significant PH at rest, abnormal pulmonary hemodynamics during exercise affect exercise capacity. Methods Consecutive COPD patients with clinically indicated right heart catheterization and resting mean pulmonary arterial pressure (mPAP) < 25 mmHg and age- and sex-matched controls with the same limits of pulmonary hemodynamics but no chronic lung disease who underwent clinical work-up including invasive hemodynamic assessment during exercise, were retrospectively analyzed. Chi-square tests were used to evaluate differences between groups for categorical data and Fisher’s exact test or Mann–Whitney-U-tests for continuous variables. Associations were analyzed with Spearman rank correlation tests. Results We included n = 26 COPD patients (female/male: 16/10, 66 ± 11 yr, FEV1: 56 ± 25%predicted) and n = 26 matched controls (FEV1: 96 ± 22%predicted). At rest, COPD patients presented with slightly increased mPAP (21 (18–23) vs. 17 (14–20) mmHg, p = 0.022), and pulmonary vascular resistance (PVR) [2.5 (1.9–3.0) vs. 1.9 (1.5–2.4) WU, p = 0.020] as compared to controls. During exercise, COPD patients reached significantly higher mPAP [47 (40–52) vs. 38 (32–44) mmHg, p = 0.015] and PVR [3.1 (2.2–3.7) vs. 1.7 (1.1–2.9) WU, p = 0.028] values despite lower peak exercise level [50 (50–75) vs. 100 (75–125) Watt, p = 0.002]. The mPAP/cardiac output slope was increased in COPD vs. controls [6.9 (5.5–10.9) vs. 3.7 (2.4–7.4) mmHg/L/min, p = 0.007] and negatively correlated with both peak oxygen uptake (r = − 0.46, p = 0.007) and 6-min walk distance (r = − 0.46, p = 0.001). Conclusion Even in the absence of significant PH at rest, COPD patients reveal characteristic abnormalities in pulmonary hemodynamics during exercise, which may represent an important exercise-limiting factor.