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Original Research: Pulmonary Vascular Disease |

Hemodynamic Thresholds for Precapillary Pulmonary Hypertension OPEN ACCESS

Christian Gerges, MD; Mario Gerges, MD; Nika Skoro-Sajer, MD; Yi Zhou, PhD; Lixia Zhang, PhD; Roela Sadushi-Kolici, MD; Johannes Jakowitsch, PhD; Marie B. Lang, MD; Irene M. Lang, MD
Author and Funding Information

FUNDING/SUPPORT: This research was funded by educational grants from Bayer [Grant 15662] and United Therapeutics Corporation [Grant REG-NC-002].

CORRESPONDENCE TO: Irene M. Lang, MD, Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria


Copyright 2016, The Authors. All Rights Reserved.


Chest. 2016;149(4):1061-1073. doi:10.1378/chest.15-0928
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Background  Hemodynamic differentiation between pulmonary arterial hypertension (PAH) and postcapillary pulmonary hypertension (PH) is important because treatment options are strikingly different for the two disease subsets. Whereas patients with PAH can be treated effectively with targeted therapies, their use in postcapillary PH is currently not recommended. Our aim was to establish an algorithm to identify patients who are likely to experience a significant hemodynamic treatment response.

Methods  We determined hemodynamic cutoffs to discriminate between idiopathic PAH and postcapillary PH in a large database of 4,363 stable patients undergoing first diagnostic right and left heart catheterizations. In a second step, we performed a patient-level pooled analysis of four randomized, placebo-controlled trials including 541 patients with PAH who received treprostinil or placebo, to validate hemodynamic cutoffs with regard to treatment response.

Results  Receiver operating characteristic analysis identified mean pulmonary arterial wedge pressure (mPAWP) < 12 mm Hg and diastolic pulmonary vascular pressure gradient (DPG) ≥ 7 mm Hg as the best hemodynamic discriminators between idiopathic PAH and postcapillary PH. In our treatment study, only patients with mPAWP < 12 mm Hg, DPG > 20 mm Hg or a combination of both had a significant placebo-corrected improvement in hemodynamics.

Conclusions  mPAWP < 12 mm Hg and DPG > 20 mm Hg identify patients with PAH who are likely to have significant hemodynamic improvement with prostacyclin treatment.

Figures in this Article

Pulmonary arterial hypertension (PAH) affects the precapillary arteriolar compartment. By contrast, postcapillary pulmonary hypertension (PH) results from the passive hydrostatic transmission of pulmonary vascular pressure in left heart disease (LHD). Whereas targeted therapies may improve hemodynamics and functional capacity in PAH, randomized controlled trials failed to demonstrate their beneficial effect in heart failure,, and postcapillary PH., Therefore, the use of PAH-targeted therapies in patients with postcapillary PH currently is not recommended. Because of the difficult diagnostic differentiation between precapillary and postcapillary PH, particularly in the presence of left ventricular diastolic dysfunction, patients with postcapillary PH were enrolled in past and current trials of PAH. Currently, mean pulmonary arterial wedge pressure (mPAWP) ≤ 15 mm Hg serves to distinguish between precapillary and postcapillary disease. However, the upper limit of normal mPAWP in healthy subjects has been reported to be 11 mm Hg. Based on this observation, an mPAWP < 12 mm Hg was an entry criterion in the National Institutes of Health registry of primary PH and this threshold is still recommended for the diagnosis of heart failure with preserved ejection fraction. In addition, elevated diastolic pulmonary vascular pressure gradient (DPG) is associated with pulmonary vascular disease, right ventricular (RV) dysfunction, and decreased survival.,,,,

Despite treatment with targeted therapies, pulmonary vascular resistance (PVR) remains elevated and pulmonary arterial compliance (CPA) remains low in the vast majority of patients, with a high annual mortality rate of PAH of 8% to 15%., Previous studies identified baseline PVR, RV ejection fraction, and CPA as predictors of survival in PAH. Changes in RV afterload parameters in patients who are treated with targeted therapies and their impact on survival have been less well studied, and it remains unclear which patients respond best to targeted therapies. We hypothesized that a precapillary hemodynamic profile is characterized by an mPAWP that is lower than currently accepted, an elevated DPG, and a beneficial response to PAH-targeted therapies.

The purposes of this study were (1) to define hemodynamic thresholds between precapillary and postcapillary PH with the goal of excluding patients with left heart disease as the cause or comorbidity of PH; (2) to identify hemodynamic predictors of treatment response in PAH (treatment response study), and (3) to study changes in correlates of RV afterload in patients who are treated with targeted therapies, and their impact on outcomes (outcome study).

Retrospective Cohort

Between May 1996 and June 2006, 4,363 stable patients underwent a first diagnostic right heart catheterization (RHC) at the Medical University of Vienna, a national PH referral center (Fig 1A). In 3,524 patients (81%), the procedure was combined with a left heart catheterization. Catheterizations were performed for various indications, mostly for suspected PH, but also before major surgical procedures. Patients were stable, able to remain in a supine position for the duration of the catheterization, receiving optimized diuretic treatment, and not receiving oral anticoagulation and oxygen.

Figure 1
Figure Jump LinkFigure 1 Patient disposition. A, Retrospective cohort. A total of 1,410 patients were classified as having postcapillary PH, 257 as having precapillary PH, and 43 as having Multiple PH. Of these, 38 patients had iPAH. B, Treatment cohort. The cohort consisted of patients who were enrolled in four randomized placebo-controlled trials (gray shading; P01:03 [n = 26], P01:04 [n = 224], P01:05 [n = 246], and TRUST [n = 45]) and one open-label trial (P01:06 [n = 437]) of parenteral treprostinil in PAH. aOf those 283 patients, 238 received SC treprostinil; the remaining 45 patients (who were enrolled in TRUST) were treated with IV treprostinil. Cpc-PH = combined precapillary and postcapillary PH; CTEPH = chronic thromboembolic pulmonary hypertension; iPAH = idiopathic PAH; Ipc-PH = isolated postcapillary PH; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; RHC = right heart catherization; SC = subcutaneous; TRUST = Treprostinil IV for Untreated Symptomatic PAH Trial.Grahic Jump Location

For hemodynamic assessment, a 7F Swan-Ganz catheter (Edwards Lifesciences, Irvine, CA) was inserted using a femoral or jugular approach. Mean pulmonary artery pressure (mPAP), mean right atrial pressure (mRAP), RV pressure, mPAWP, and respective oxygen saturations, including inferior and superior vena cava, were measured. Left atrial pressure was measured transseptally when indicated. Left ventricular end-diastolic pressure (LVEDP) was measured with a 5F pigtail catheter (Cordis, Bridgewater, NJ). All pressures were recorded as averages of eight time-pressure integral derivations during several respiratory cycles., Cardiac output (CO) was assessed by thermodilution. In the presence of systemic-to-pulmonary shunts, the Fick method was applied. Zero reference was at midthoracic level.

PH was defined by an mPAP ≥ 25 mm Hg and was classified based on a combination of clinical, hemodynamic, and imaging data (echocardiography, ventilation-perfusion lung scintigraphy, multidetector CT, and pulmonary angiography). In case of disagreement, clinical phenotyping was allowed to overrule hemodynamics. For example, a 70-year-old obese diabetic patient with arterial hypertension, atrial fibrillation, stable ischemic heart disease, a normal ventilation-perfusion scan, and diastolic dysfunction on echocardiography but with an mPAWP of 11 mm Hg would have been classified as having postcapillary PH. A 35-year-old patient classified as New York Heart Association functional class IV with no cardiovascular or pulmonary comorbidities, a normal ventilation-perfusion scan and an mPAWP of 16 mm Hg would have been classified as having advanced idiopathic PAH (iPAH) with mPAWP elevation as a consequence of right heart failure. As a rule, at least three clinical risk factors for LHD were required to overrule a single hemodynamic criterion. Patients with PAH associated with connective tissue disease, congenital heart disease, portal hypertension, or HIV as well as PH resulting from interstitial lung disease (moderate to severe) and/or COPD (GOLD 3/4) and/or OSA, and chronic thromboembolic PH, diagnosed in association with LHD, were classified as having a combination of diagnoses (“Multiple PH”) (Fig 1A). The Ethics Committee of the Medical University of Vienna approved data analyses (Nos. 617/2011 and 1177/2011).

Treatment Cohort

We used deidentified individual patient data from four randomized placebo-controlled trials (P01:03 [n = 26], P01:04 [n = 224], P01:05 [n = 246], and Treprostinil IV for Untreated Symptomatic PAH Trial (TRUST) [n = 45]) and one open-label trial (P01:06 [n = 437]) of treprostinil in PAH, with similar inclusion criteria and data collection processes, as well as written informed consent.,, Short-term and long-term data from 978 patients were available for survival analyses (outcome study) (Fig 1B). RHC was performed in all patients at baseline. Patients in the placebo-controlled trials underwent follow-up RHC after 8 (P01:03) or 12 weeks (P01:04, P01:05, and TRUST) of treatment (n = 541; treatment response study) (Fig 1B). Hemodynamic data were incomplete in 26 patients. Treprostinil was administered as a continuous subcutaneous infusion, or IV in TRUST. Patients randomized to treprostinil continued receiving treprostinil at the same dose they were receiving at the end of the prior study, with subsequent dose adjustments. Patients receiving placebo in previous controlled studies and de novo patients started treprostinil at a dosage of 1.25 ng/kg/min with increases in dosage based on PAH signs and symptoms, and side effects. Patients were observed for a median of 15.8 months (25th and 75th percentiles at 4.1 and 28.6 months, respectively).

Hemodynamic Definitions

Transpulmonary gradient (TPG) was calculated by subtracting mPAWP from mPAP; PVR was calculated by dividing TPG by CO and expressed in Wood units (WU) (mm Hg × min × L-1). DPG was calculated as the difference between diastolic pulmonary artery pressure and mPAWP., CPA was defined as stroke volume divided by pulmonary arterial pulse pressure (the difference between systolic and diastolic pulmonary artery pressure).

Deltas (Δ) were calculated to assess changes between baseline and follow-up (Δ = value at follow-up – value at baseline) in the treatment response study (n = 541).

Statistical Analysis

Quantitative variables are described as mean and SD. Two-sample Student t test was used to compare continuous variables between groups. Qualitative variables are described as counts and percentages. The potential of various hemodynamic parameters to distinguish iPAH from postcapillary PH was assessed with receiver operating characteristic (ROC) curves. ROC analyses were also performed to assess interactions between changes in afterload. Cutoff values were determined by maximizing the Youden index, which is the sum of sensitivity and specificity – 1. The method of DeLong et al was used to compare areas under two ROC curves. Univariate and multivariate Cox proportional hazards regression models were used to examine the effects of several variables on survival. Multivariate models were adjusted for age, World Health Organization (WHO) functional class, 6-min walk distance (6-MWD), and heart rate at baseline. Proportionality and linearity assumptions were evaluated for continuous variables. We added interaction terms of covariates and log of survival time to the model to improve the model performance when proportionality assumptions were not satisfied. The flexible Cox proportional hazard model using smoothing methods such as restricted cubic spline function was implemented when the linear functional relationship between the covariate of interest and survival (linearity assumption) was violated. Colinearity, numerical stability, and influence measures were also evaluated. Cox proportional hazard models were assessed using a global goodness-of-fit test and Cox-Snell residuals. Data were analyzed with SPSS Statistics (version 21 for Mac) and SAS (version 9.2 for Windows). All P values result from two-sided tests, with significance at .05.

Hemodynamic Discrimination Between Precapillary and Postcapillary PH

A total of 2,957 complete datasets of the retrospective cohort were available (Fig 1A, Table 1), 1,247 were classified as normal (“Non-PH”, mPAP < 25 mm Hg) and a total of 1,710 patients had PH (mPAP ≥ 25 mm Hg; Fig 1A). 1,410 were classified as having postcapillary PH (82.5%), 257 as having precapillary PH (15.0%), and 43 as having “Multiple PH” (2.5%). Of 257 patients with precapillary PH, 38 had iPAH. There were 1,209 patients with postcapillary PH who were classified as having isolated postcapillary PH (DPG < 7 mm Hg) and 201 who were classified as having combined precapillary and postcapillary PH (DPG ≥ 7 mm Hg).,

Table Graphic Jump Location
Table 1 Retrospective Cohort: Clinical and Hemodynamic Characteristics of Patients With Precapillary and Postcapillary PH

iPAH = idiopathic pulmonary arterial hypertension; PH = pulmonary hypertension; WHO = World Health Organization; WU = Wood units.

The best hemodynamic parameters for discriminating between iPAH and isolated postcapillary PH were mPAWP (area under the curve [AUC], 0.999) (Fig 2A) and DPG (AUC, 0.998) (Fig 2B). For example, a DPG ≥ 7 mm Hg was 100% specific for an iPAH diagnosis against an isolated postcapillary PH diagnosis. AUCs for mPAWP and DPG were significantly larger than AUCs derived from TPG, PVR, CPA, and mRAP (all P < .01). The highest Youden index for mPAWP was at a threshold of 12 mm Hg (0.962), and for DPG at 7 mm Hg (0.968). AUCs, sensitivities, specificities, and Youden indexes of the different hemodynamic parameters are provided in e-Table 1. Similar thresholds were obtained when all patients with PAH (n = 125) and postcapillary PH (n = 1,410) were considered.

Figure 2
Figure Jump LinkFigure 2 Hemodynamic thresholds discriminating iPAH from isolated postcapillary PH. A, B, Receiver operating characteristic curves of mPAWP, CPA, mRAP, DPG, TPG, and PVR. A, Hemodynamic parameters that are higher in Ipc-PH. B, Hemodynamic parameters that are elevated in iPAH. Cutoffs were determined by maximizing the Youden index: mPAWP of 12 mm Hg, DPG of 7 mm Hg, TPG of 22 mm Hg, PVR of 4.5 WU, CPA of 1.3 mL/mm Hg, and mRAP of 7 mm Hg. AUC = area under the curve; CPA = pulmonary arterial compliance; DPG = diastolic pulmonary vascular pressure gradient; mPAWP = mean pulmonary arterial wedge pressure; mRAP = mean right atrial pressure; PVR = pulmonary vascular resistance; ROC = receiver operating characteristic; TPG = transpulmonary gradient; WU = Wood units. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Treatment Response Study: Hemodynamic Correlates of Afterload

Table 2 lists baseline hemodynamics and patient characteristics of the treatment cohort (n = 978). Patients with a DPG ≤ 20 mm Hg were older, heavier, and more likely to have comorbidities associated with LHD than were those who had a higher DPG. Patients with an mPAWP > 12 mm Hg were heavier and more likely to be diabetic than were those with a lower mPAWP (e-Tables 2, 3). In 541 patients who underwent follow-up RHC, CPA did not change from baseline, whereas PVR (Mean [95% CI], –2.4 WU [–3.3 to –1.4]) was significantly reduced from baseline with treprostinil compared with placebo. Based on the hyperbolic relationship between resistance and compliance, we assessed the PVR threshold for a significant change in Cpa. ROC analysis revealed that PVR had to be reduced by at least 1 WU to achieve an increase in CPA (AUC, 0.85). Patients with an increase in CPA showed a significant reduction in afterload (ΔmPAP: –3.2 ± 8.6 mm Hg; ΔPVR: –3.0 ± 4.8 WU), unlike patients with a decrease in CPA (ΔmPAP: 1.6 ± 7.5 mm Hg; ΔPVR: 1.8 ± 3.9 WU).

Table Graphic Jump Location
Table 2 Treatment Cohort: Baseline Clinical and Hemodynamic Characteristics of Patients Receiving Treprostinil or Placebo
a BMI missing for four patients receiving treprostinil.
b 6-MWD available for 283 patients in the treprostinil group.
c Cause missing for two patients in the placebo group.

6-MWD = 6-min walk distance; WU = Wood units. See Table 1 for expansion of other abbreviation.

Baseline Hemodynamic Predictors of Treatment Response

To identify patients with a significant improvement in RV afterload, those undergoing follow-up RHC were stratified using an mPAWP of 12 mm Hg and a DPG of 20 mm Hg. A DPG threshold with a higher sensitivity at 20 mm Hg (Youden index of 0.823) was used to minimize the chances of misclassifying patients with postcapillary PH as having precapillary PH (87% of iPAH patients had a DPG > 20 mm Hg). Only eight patients (1.5%) in the treatment cohort had a DPG < 7 mm Hg.

mPAWP < 12 mm Hg (n = 362) vs mPAWP ≥ 12 mm Hg (n = 153)

Patients who were treated with treprostinil and who had an mPAWP < 12 mm Hg showed a significant placebo-corrected improvement in CO (0.4 L/min; 95% CI, 0.2-0.6), mRAP (–2.6 mm Hg; 95% CI, 3.6 to –1.5), mPAP (–3.5 mm Hg; 95% CI, –5.2 to –1.7), DPG (–3.1 mm Hg; 95% CI, –4.8 to –1.3), TPG (–2.65 mm Hg; 95% CI, –4.5 to –0.8), PVR (–2.8 WU; 95% CI, –3.9 to –1.7), and CPA (0.1 mL/mm Hg; 95% CI, 0-0.2) (Fig 3). By contrast, patients with an mPAWP ≥ 12 mm Hg improved only in CO (0.5 L/min; 95% CI, 0.2-0.8) compared with placebo. Patients who were treated with treprostinil and had an mPAWP < 12 mm Hg (22.9 m; 95% CI, 7.0-38.7) and those with an mPAWP ≥ 12 mm Hg (34.8 m; 95% CI, 11.9-57.8) showed significant placebo-corrected improvement in 6-MWD. There was no difference in the proportion of patients under treprostinil who had ≥ 15% deterioration in 6-MWD with an mPAWP < 12 mm Hg (12.8%) vs an mPAWP > 12 mm Hg (16.3%; P = .346).

Figure 3
Figure Jump LinkFigure 3 Hemodynamic changes from baseline. Placebo-corrected changes from baseline in mRAP (A), PVR (B) and CPA (C). All values were normally distributed. P values are results of independent-sample t tests between placebo and treprostinil. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
DPG ≤ 20 mm Hg (n = 84) vs DPG > 20 mm Hg (n = 431)

Patients who were treated with treprostinil and had a DPG > 20 mm Hg showed a significant placebo-corrected improvement in CO (0.5 L/min; 95% CI, 0.3-0.7), mRAP (–2.1 mm Hg; 95% CI, –3.2 to –1.1), mPAP (–2.4 mm Hg; 95% CI, –4.2 to –0.7), DPG (–2.7 mm Hg; 95% CI, –4.5 to –0.9), TPG (–2.0 mm Hg; 95% CI, –3.8 to –0.3), PVR (–2.8 WU; 95% CI, –3.9 to –1.7), and CPA (0.1 mL/mm Hg; 95% CI, 0-0.2) (Fig 3). By contrast, hemodynamics in patients who were treated with treprostinil and had a DPG ≤ 20 mm Hg did not change (Fig 3) compared with hemodynamics in those who were given a placebo. Only patients who were treated with treprostinil and had a DPG > 20 mm Hg showed significant placebo-corrected improvements in 6-MWD (26.8 m; 95% CI, 12.7-41.0). Patients who were treated with treprostinil and had a DPG ≤ 20 mm Hg were more likely to experience ≥ 15% deterioration in 6-MWD (21.6%) compared with those who had a DPG > 20 mm Hg (12.3%; P = .034).

mPAWP < 12 mm Hg and DPG > 20 mm Hg (n = 309) vs mPAWP ≥ 12 mm Hg and/or DPG ≤ 20 mm Hg (n = 206)

Patients who were treated with treprostinil and who had a combination of mPAWP < 12 mm Hg and DPG > 20 mm Hg showed a significant placebo-corrected improvement in CO (0.5 L/min; 95% CI, 0.3-0.8), mRAP (–2.9 mm Hg; 95% CI, –4.0 to –1.7), mPAP (–3.4 mm Hg; 95% CI, –5.3 to –1.5), DPG (–3.3 mm Hg; 95 CI, –5.3 to –1.3), TPG (–2.7 mm Hg; 95% CI, –4.7 to –0.7), PVR (–3.2 WU; 95% CI, 4.5 to –2.0), and CPA (0.1 mL/mm Hg; 95% CI, 0-0.2) (Fig 3). By contrast, in patients who were treated with treprostinil and had an mPAWP ≥ 12 mm Hg and/or a DPG ≤ 20 mm Hg, only CO (0.3 L/min; 95% CI, 0-0.6) showed a significant placebo-corrected increase. Patients who were treated with treprostinil and had a combination of mPAWP < 12 mm Hg and DPG > 20 mm Hg (23.7 m; 95% CI, 6.2-41.1) and those who had an mPAWP ≥ 12 mm Hg and/or a DPG ≤ 20 mm Hg (30.3 m; 95% CI, 10.5-50.1) showed significant placebo-corrected improvements in 6-MWD. There was no difference in the proportion of patients who were treated with treprostinil who had ≥ 15% deterioration in 6-MWD (mPAWP < 12 mm Hg and DPG > 20 mm Hg: 12.4% vs mPAWP ≥ 12 mm Hg and/or DPG ≤ 20 mm Hg: 15.9%; P = .310).

Outcome Study: Predictors of Survival/Freedom of Lung Transplantation
Baseline Predictors

Univariate flexible hazard ratio analysis of various hemodynamic parameters at baseline identified mRAP and PVR as predictors of survival/freedom of lung transplantation (both P < .001). After adjustment for baseline age, WHO functional class, 6-MWD, and heart rate in a multivariate flexible hazard model, mRAP (P = .01) and PVR (P < .001) remained significant predictors of survival/freedom of lung transplantation (Fig 4A, 4B).

Figure 4
Figure Jump LinkFigure 4 Hemodynamic predictors of survival/freedom of lung transplantation. A-D, Multivariate flexible hazard ratio functions for mRAP and PVR at baseline (A, B) and follow-up (C, D). Analyses were adjusted for age, World Health Organization functional class, 6-min walk distance, and heart rate. Dashed blue lines mark CIs of the hazard functions. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
On-Treatment Predictors

Univariate analysis of changes in hemodynamics from baseline to follow-up revealed that only ΔmRAP (P = .003) was an on-treatment predictor of survival/freedom of lung transplantation whereas ΔPVR showed only a statistical trend (P = .063). In the multivariate model, ΔmRAP (P = .017) and ΔPVR (P = .045) predicted survival/freedom of lung transplantation.

At follow-up, mRAP and PVR (both P < .001) were significant univariate predictors of outcome. After adjusting for age, WHO functional class, 6-MWD, and heart rate at baseline, mRAP and PVR (both P < .001) remained significant predictors of survival/freedom of lung transplantation (Fig 4C, 4D).

Our data show that: (1) an mPAWP < 12 mm Hg and a DPG ≥ 7 mm Hg best discriminate between iPAH and postcapillary PH; (2) patients with an mPAWP < 12 mm Hg combined with a DPG > 20 mm Hg are likely to have a significant response to PAH-targeted therapy; (3) to increase CPA, a minimal reduction in PVR by 1 WU is required; and (4) mRAP and PVR are baseline and on-treatment independent predictors of long-term survival/freedom of lung transplantation. Although a deterioration in 6-MWD was associated with poor prognosis in a recent REVEAL (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management registry) subanalysis, neither an absolute nor a relative change in 6-MWD was correlated with survival in other studies.,,, Therefore, we used survival as the best measure of clinical benefit in our study.

We determined hemodynamic cutoffs to differentiate between iPAH and postcapillary PH (Fig 2) in a large contemporary database of a national referral and tertiary care center dedicated to the science and management of pulmonary vascular disease since 1980. In principle, we confirmed the proposal of Naeije et al. mPAWP < 12 mm Hg had a sensitivity of 99.4% and specificity of 96.8% to diagnose iPAH. We relied on mPAWP as a mean across the respiratory cycle rather than on end-expiratory values. Although some data suggest that patients with precapillary PH may be mislabeled as having PH-LHD if measurements are limited to end-expiratory pressures, the practice of averaging mPAWP over the respiratory cycle to estimate LVEDP has also been challenged. End-expiratory mPAWP was almost equal to end-expiratory LVEDP, whereas the averaged mPAWP underestimated end-expiratory LVEDP. However, those authors failed to compare averaged mPAWPs with averaged LVEDPs and did not consider that there is a physiological gradient of 3 mm Hg between mPAWP and LVEDP. As proposed in our algorithm (Fig 5), exercise testing and fluid challenge might be additional tools to unmask LHD. In the 3,128-patient multicenter, US-based, observational REVEAL registry of patients who have received a diagnosis of PAH, patients with an mPAWP of 16-18 mm Hg had outcomes similar to those of patients with an mPAWP ≤ 15 mm Hg; yet, when mPAWP was > 19 mm Hg in subsequent assessments, prognosis was significantly worse. These data document the high rate of contamination of a contemporary PAH cohort with postcapillary PH, and although thresholds were different, a signal of “higher mPAWP begets worse prognosis with PAH treatments” is reproduced.

Figure 5
Figure Jump LinkFigure 5 Hypothetical hemodynamic algorithm for the identification of PAH patients who are likely to experience a significant hemodynamic treatment response. Because of the retrospective nature of our study, prospective validation is needed. HFpEF = heart failure with preserved ejection fraction. See Figure 1 and 2 legends for expansion of other abbreviations.Grahic Jump Location

We also identified DPG ≥ 7 mm Hg as a predictor of iPAH with a sensitivity of 97.1% and specificity of 92.1%. The recent assertion that DPG is limited in clinical usefulness is based on two retrospective database analyses that were significantly limited by the characteristics of patients., Whereas the first study was based on a population of patients with cardiac transplants, the latter analyzed patients with (sub)acute heart failure,, all of which significantly differ from the original prognostic study of DPG.,

Patients in the treatment cohort with an mPAWP < 12 mm Hg or DPG > 20 mm Hg, or a combination of both experienced significant placebo-corrected improvement in RV afterload (Fig 3) with treprostinil. The reduction in PVR was similar to that in the recent SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) trial, in which macitentan significantly delayed a combined morbidity and mortality end point. By contrast, in treprostinil-treated patients who had an mPAWP ≥ 12 mm Hg and/or a DPG ≤ 20 mm Hg, only CO improved relative to placebo, as in randomized controlled trials of PAH-targeted therapies in heart failure,, and PH-LHD, which failed to meet their primary end points., A single-center study in patients with PH-LHD and a mean DPG of 7.1 mm Hg in the placebo group and 9.6 mm Hg in the sildenafil-treated group resulted in a favorable effect on hemodynamics.

CPA reflects the pulsatile load of the RV and has been shown to be of greater prognostic importance than PVR in patients with iPAH. However, CPA did not predict survival/freedom of lung transplantation in our study neither at baseline nor under treatment, and CPA was lower (treprostinil: 1.1 ± 0.7 mm Hg/mL; placebo: 1 ± 0.5 mm Hg/mL) than in the patients with iPAH in the study by Mahapatra et al (1.43 ± 0.73 mL/mm Hg). Mahapatra et al performed a 4-year follow-up of 104 patients with iPAH. In the univariate Cox proportional hazard model, CPA was the strongest predictor of survival, and in the successive bivariate analysis CPA was the sole independent predictor of mortality. In contrast to our study, those authors were not able to perform a multivariate analysis because there were only 21 deaths, probably because the sample size was too small. Based on a much larger population (n = 978), we performed a survival analysis using univariate and multivariate flexible hazard ratio functions. The use of cubic spline functions in these models allows investigation of nonlinear effects of continuous covariates and flexible assessment of time-by-covariate interactions. We found that mRAP and PVR at baseline and follow-up, as well as their change from baseline (Δ) are predictors of outcome. However, follow-up was shorter in our study compared with that of Mahapatra et al (15.8 vs 48 months, respectively) and our cohort was a population with mixed PAH (53% iPAH vs 100% iPAH, respectively).

Treprostinil was the only PAH-targeted therapy in our study. Data for 49 patients with inoperable chronic thromboembolic PH were considered only for survival analyses (Table 2).

We propose a hemodynamic algorithm (Fig 5), using mPAWP and DPG in sequence, to identify patients who are likely to improve with prostacyclin treatment, presumably those with classical pulmonary arteriopathy. In a next step, the algorithm needs to be validated to ensure applicability for other PAH-targeted therapies. Our data substantiate the value of baseline and on-treatment hemodynamics for the clinical follow-up of patients with PAH.

Author contributions: I. M. L. had full access to all the data in the study and had final responsibility for the decision to submit for publication. C. G., M. G., and I. M. L. contributed to the study concept and design; C. G., M. G., N. S. S., Y. Z., L. Z., R. S. K., J. J., M. B. L., and I. M. L. acquired the data; C. G., M. G., N. S. S., Y. Z., L. Z., J. J., M. B. L., and I. M. L. statistically analyzed and interpreted the data; C. G., M. G., and I. M. L. drafted the manuscript; C. G., M. G., N. S. S., Y. Z., L. Z., M. B. L., and I. M. L. contributed to critical revision of the manuscript: and C. G., M. G., N. S. S., Y. Z., L. Z., R. S. K., J. J., M. B. L., and I. M. L. gave final approval to the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: C. G. and M. G. have received compensation for scientific symposia from AOPOrphan Pharmaceuticals AG and GlaxoSmithKline. M. G. is holding an educational grant from United Therapeutics Corporation (Grant No. REG-NC-002) and CG is holding an educational grant from Bayer (Grant No. 15662). N. S. S. has relationships with drug companies including AOPOrphan Pharmaceuticals, Actelion, Bayer, Astra-Zeneca, Servier, Cordis, Medtronic, GlaxoSmithKline, Novartis, Pfizer, and United Therapeutics. Y. Z. and L. Z. served as paid statisticians for United Therapeutics. R. S. K. has served as a paid consultant for AOPOrphan Pharmaceuticals AG and has received compensation for scientific symposia from Actelion, GlaxoSmithKline, Pfizer, United Therapeutics, and AOPOrphan Pharmaceuticals AG. I. M. L. has relationships with drug companies including AOPOrphan Pharmaceuticals, Actelion, Bayer-Schering, Astra-Zeneca, Servier, Cordis, Medtronic, GlaxoSmithKline, Novartis, Pfizer and United Therapeutics. In addition to being an investigator in trials involving these companies, relationships include consultancy service, research grants, and membership of scientific advisory boards. None declared (J. J. and M. B. L.).

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.

Califf R.M. .Adams K.F. .McKenna W.J. .et al A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1997;134:44-54 [PubMed]journal. [PubMed]
 
Luscher T.F. .Enseleit F. .Pacher R. .et al Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT). Circulation. 2002;106:2666-2672 [PubMed]journal. [CrossRef] [PubMed]
 
Redfield M.M. .Chen H.H. .Borlaug B.A. .et al Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309:1268-1277 [PubMed]journal. [CrossRef] [PubMed]
 
Bonderman D. .Ghio S. .Felix S.B. .et al Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation. 2013;128:502-511 [PubMed]journal. [CrossRef] [PubMed]
 
Bonderman D. .Pretsch I. .Steringer-Mascherbauer R. .et al Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study. Chest. 2014;146:1274-1285 [PubMed]journal. [CrossRef] [PubMed]
 
Vachiery J.L. .Adir Y. .Barbera J.A. .et al Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol. 2013;62:D100-D108 [PubMed]journal. [CrossRef] [PubMed]
 
Hellems H.K. .Haynes F.W. .Dexter L. . Pulmonary capillary pressure in man. J Appl Physiol. 1949;2:24-29 [PubMed]journal. [PubMed]
 
D’Alonzo G.E. .Barst R.J. .Ayres S.M. .et al Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343-349 [PubMed]journal. [CrossRef] [PubMed]
 
Paulus W.J. .Tschope C. .Sanderson J.E. .et al How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007;28:2539-2550 [PubMed]journal. [CrossRef] [PubMed]
 
Gerges C. .Gerges M. .Lang M.B. .et al Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in “out-of-proportion” pulmonary hypertension. Chest. 2013;143:758-766 [PubMed]journal. [CrossRef] [PubMed]
 
Gerges M. .Gerges C. .Pistritto A.M. .et al Pulmonary hypertension in heart failure: epidemiology, right ventricular function and survival. Am J Respir Crit Care Med. 2015;192:1234-1246 [PubMed]journal. [CrossRef] [PubMed]
 
Naeije R. .Vachiery J.L. .Yerly P. .et al The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease. Eur Respir J. 2013;41:217-223 [PubMed]journal. [CrossRef] [PubMed]
 
Gerges C. .Gerges M. .Lang I.M. . Characterization of pulmonary hypertension in heart failure using the diastolic pressure gradient: the conundrum of high and low diastolic pulmonary gradient. JACC Heart Fail. 2015;3:424-425 [PubMed]journal. [CrossRef] [PubMed]
 
Lankhaar J.W. .Westerhof N. .Faes T.J. .et al Quantification of right ventricular afterload in patients with and without pulmonary hypertension. Am J Physiol Heart Circ Physiol. 2006;291:H1731-H1737 [PubMed]journal. [CrossRef] [PubMed]
 
Benza R.L. .Miller D.P. .Gomberg-Maitland M. .et al Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164-172 [PubMed]journal. [CrossRef] [PubMed]
 
Humbert M. .Sitbon O. .Chaouat A. .et al Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156-163 [PubMed]journal. [CrossRef] [PubMed]
 
van de Veerdonk M.C. .Kind T. .Marcus J.T. .et al Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol. 2011;58:2511-2519 [PubMed]journal. [CrossRef] [PubMed]
 
Mahapatra S. .Nishimura R.A. .Sorajja P. .Cha S. .McGoon M.D. . Relationship of pulmonary arterial capacitance and mortality in idiopathic pulmonary arterial hypertension. J Am Coll Cardiol. 2006;47:799-803 [PubMed]journal. [CrossRef] [PubMed]
 
LeVarge B.L. .Pomerantsev E. .Channick R.N. . Reliance on end-expiratory wedge pressure leads to misclassification of pulmonary hypertension. Eur Respir J. 2014;44:425-434 [PubMed]journal. [CrossRef] [PubMed]
 
Kovacs G. .Avian A. .Pienn M. .Naeije R. .Olschewski H. . Reading pulmonary vascular pressure tracings: how to handle the problems of zero leveling and respiratory swings. Am J Respir Crit Care Med. 2014;190:252-257 [PubMed]journal. [PubMed]
 
Hoeper M.M. .Bogaard H.J. .Condliffe R. .et al Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D42-D50 [PubMed]journal. [CrossRef] [PubMed]
 
Simonneau G. .Gatzoulis M.A. .Adatia I. .et al Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34-D41 [PubMed]journal. [CrossRef] [PubMed]
 
McLaughlin V.V. .Gaine S.P. .Barst R.J. .et al Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol. 2003;41:293-299 [PubMed]journal. [CrossRef] [PubMed]
 
Simonneau G. .Barst R.J. .Galie N. .et al Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165:800-804 [PubMed]journal. [CrossRef] [PubMed]
 
Hiremath J. .Thanikachalam S. .Parikh K. .et al Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant. 2010;29:137-149 [PubMed]journal. [CrossRef] [PubMed]
 
Stevens P.M. . Assessment of acute respiratory failure: cardiac versus pulmonary causes. Chest. 1975;67:1-2 [PubMed]journal. [CrossRef] [PubMed]
 
DeLong E.R. .DeLong D.M. .Clarke-Pearson D.L. . Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44:837-845 [PubMed]journal. [CrossRef] [PubMed]
 
Farber H.W. .Miller D.P. .McGoon M.D. .Frost A.E. .Benton W.W. .Benza R.L. . Predicting outcomes in pulmonary arterial hypertension based on the 6-minute walk distance. J Heart Lung Transplant. 2015;34:362-368 [PubMed]journal. [CrossRef] [PubMed]
 
Sitbon O. .Humbert M. .Nunes H. .et al Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780-788 [PubMed]journal. [CrossRef] [PubMed]
 
Fritz J.S. .Blair C. .Oudiz R.J. .et al Baseline and follow-up 6-min walk distance and brain natriuretic peptide predict 2-year mortality in pulmonary arterial hypertension. Chest. 2013;143:315-323 [PubMed]journal. [CrossRef] [PubMed]
 
Savarese G. .Paolillo S. .Costanzo P. .et al Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J Am Coll Cardiol. 2012;60:1192-1201 [PubMed]journal. [CrossRef] [PubMed]
 
Gabler N.B. .French B. .Strom B.L. .et al Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012;126:349-356 [PubMed]journal. [CrossRef] [PubMed]
 
Mlczoch J. .Probst P. .Szeless S. .Kaindl F. . Primary pulmonary hypertension: follow-up of patients with and without anorectic drug intake. Cor Vasa. 1980;22:251-257 [PubMed]journal. [PubMed]
 
Ryan J.J. .Rich J.D. .Thiruvoipati T. .Swamy R. .Kim G.H. .Rich S. . Current practice for determining pulmonary capillary wedge pressure predisposes to serious errors in the classification of patients with pulmonary hypertension. Am Heart J. 2012;163:589-594 [PubMed]journal. [CrossRef] [PubMed]
 
Halpern S.D. .Taichman D.B. . Misclassification of pulmonary hypertension due to reliance on pulmonary capillary wedge pressure rather than left ventricular end-diastolic pressure. Chest. 2009;136:37-43 [PubMed]journal. [CrossRef] [PubMed]
 
Frost A.E. .Farber H.W. .Barst R.J. .Miller D.P. .Elliott C.G. .McGoon M.D. . Demographics and outcomes of patients diagnosed with pulmonary hypertension with pulmonary capillary wedge pressures 16 to 18 mm Hg: insights from the REVEAL Registry. Chest. 2013;143:185-195 [PubMed]journal. [CrossRef] [PubMed]
 
Tedford R.J. .Beaty C.A. .Mathai S.C. .et al Prognostic value of the pre-transplant diastolic pulmonary artery pressure-to-pulmonary capillary wedge pressure gradient in cardiac transplant recipients with pulmonary hypertension. J Heart Lung Transplant. 2014;33:289-297 [PubMed]journal. [CrossRef] [PubMed]
 
Tampakakis E. .Leary P.J. .Selby V.N. .et al The diastolic pulmonary gradient does not predict survival in patients with pulmonary hypertension due to left heart disease. JACC Heart Fail. 2015;3:9-16 [PubMed]journal. [CrossRef] [PubMed]
 
Felker G.M. .Thompson R.E. .Hare J.M. .et al Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000;342:1077-1084 [PubMed]journal. [CrossRef] [PubMed]
 
Pulido T. .Adzerikho I. .Channick R.N. .et al Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809-818 [PubMed]journal. [CrossRef] [PubMed]
 
Guazzi M. .Vicenzi M. .Arena R. .et al Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation. 2011;124:164-174 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 Patient disposition. A, Retrospective cohort. A total of 1,410 patients were classified as having postcapillary PH, 257 as having precapillary PH, and 43 as having Multiple PH. Of these, 38 patients had iPAH. B, Treatment cohort. The cohort consisted of patients who were enrolled in four randomized placebo-controlled trials (gray shading; P01:03 [n = 26], P01:04 [n = 224], P01:05 [n = 246], and TRUST [n = 45]) and one open-label trial (P01:06 [n = 437]) of parenteral treprostinil in PAH. aOf those 283 patients, 238 received SC treprostinil; the remaining 45 patients (who were enrolled in TRUST) were treated with IV treprostinil. Cpc-PH = combined precapillary and postcapillary PH; CTEPH = chronic thromboembolic pulmonary hypertension; iPAH = idiopathic PAH; Ipc-PH = isolated postcapillary PH; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; RHC = right heart catherization; SC = subcutaneous; TRUST = Treprostinil IV for Untreated Symptomatic PAH Trial.Grahic Jump Location
Figure Jump LinkFigure 2 Hemodynamic thresholds discriminating iPAH from isolated postcapillary PH. A, B, Receiver operating characteristic curves of mPAWP, CPA, mRAP, DPG, TPG, and PVR. A, Hemodynamic parameters that are higher in Ipc-PH. B, Hemodynamic parameters that are elevated in iPAH. Cutoffs were determined by maximizing the Youden index: mPAWP of 12 mm Hg, DPG of 7 mm Hg, TPG of 22 mm Hg, PVR of 4.5 WU, CPA of 1.3 mL/mm Hg, and mRAP of 7 mm Hg. AUC = area under the curve; CPA = pulmonary arterial compliance; DPG = diastolic pulmonary vascular pressure gradient; mPAWP = mean pulmonary arterial wedge pressure; mRAP = mean right atrial pressure; PVR = pulmonary vascular resistance; ROC = receiver operating characteristic; TPG = transpulmonary gradient; WU = Wood units. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3 Hemodynamic changes from baseline. Placebo-corrected changes from baseline in mRAP (A), PVR (B) and CPA (C). All values were normally distributed. P values are results of independent-sample t tests between placebo and treprostinil. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4 Hemodynamic predictors of survival/freedom of lung transplantation. A-D, Multivariate flexible hazard ratio functions for mRAP and PVR at baseline (A, B) and follow-up (C, D). Analyses were adjusted for age, World Health Organization functional class, 6-min walk distance, and heart rate. Dashed blue lines mark CIs of the hazard functions. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5 Hypothetical hemodynamic algorithm for the identification of PAH patients who are likely to experience a significant hemodynamic treatment response. Because of the retrospective nature of our study, prospective validation is needed. HFpEF = heart failure with preserved ejection fraction. See Figure 1 and 2 legends for expansion of other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Retrospective Cohort: Clinical and Hemodynamic Characteristics of Patients With Precapillary and Postcapillary PH

iPAH = idiopathic pulmonary arterial hypertension; PH = pulmonary hypertension; WHO = World Health Organization; WU = Wood units.

Table Graphic Jump Location
Table 2 Treatment Cohort: Baseline Clinical and Hemodynamic Characteristics of Patients Receiving Treprostinil or Placebo
a BMI missing for four patients receiving treprostinil.
b 6-MWD available for 283 patients in the treprostinil group.
c Cause missing for two patients in the placebo group.

6-MWD = 6-min walk distance; WU = Wood units. See Table 1 for expansion of other abbreviation.

References

Califf R.M. .Adams K.F. .McKenna W.J. .et al A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1997;134:44-54 [PubMed]journal. [PubMed]
 
Luscher T.F. .Enseleit F. .Pacher R. .et al Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT). Circulation. 2002;106:2666-2672 [PubMed]journal. [CrossRef] [PubMed]
 
Redfield M.M. .Chen H.H. .Borlaug B.A. .et al Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309:1268-1277 [PubMed]journal. [CrossRef] [PubMed]
 
Bonderman D. .Ghio S. .Felix S.B. .et al Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation. 2013;128:502-511 [PubMed]journal. [CrossRef] [PubMed]
 
Bonderman D. .Pretsch I. .Steringer-Mascherbauer R. .et al Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study. Chest. 2014;146:1274-1285 [PubMed]journal. [CrossRef] [PubMed]
 
Vachiery J.L. .Adir Y. .Barbera J.A. .et al Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol. 2013;62:D100-D108 [PubMed]journal. [CrossRef] [PubMed]
 
Hellems H.K. .Haynes F.W. .Dexter L. . Pulmonary capillary pressure in man. J Appl Physiol. 1949;2:24-29 [PubMed]journal. [PubMed]
 
D’Alonzo G.E. .Barst R.J. .Ayres S.M. .et al Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343-349 [PubMed]journal. [CrossRef] [PubMed]
 
Paulus W.J. .Tschope C. .Sanderson J.E. .et al How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007;28:2539-2550 [PubMed]journal. [CrossRef] [PubMed]
 
Gerges C. .Gerges M. .Lang M.B. .et al Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in “out-of-proportion” pulmonary hypertension. Chest. 2013;143:758-766 [PubMed]journal. [CrossRef] [PubMed]
 
Gerges M. .Gerges C. .Pistritto A.M. .et al Pulmonary hypertension in heart failure: epidemiology, right ventricular function and survival. Am J Respir Crit Care Med. 2015;192:1234-1246 [PubMed]journal. [CrossRef] [PubMed]
 
Naeije R. .Vachiery J.L. .Yerly P. .et al The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease. Eur Respir J. 2013;41:217-223 [PubMed]journal. [CrossRef] [PubMed]
 
Gerges C. .Gerges M. .Lang I.M. . Characterization of pulmonary hypertension in heart failure using the diastolic pressure gradient: the conundrum of high and low diastolic pulmonary gradient. JACC Heart Fail. 2015;3:424-425 [PubMed]journal. [CrossRef] [PubMed]
 
Lankhaar J.W. .Westerhof N. .Faes T.J. .et al Quantification of right ventricular afterload in patients with and without pulmonary hypertension. Am J Physiol Heart Circ Physiol. 2006;291:H1731-H1737 [PubMed]journal. [CrossRef] [PubMed]
 
Benza R.L. .Miller D.P. .Gomberg-Maitland M. .et al Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164-172 [PubMed]journal. [CrossRef] [PubMed]
 
Humbert M. .Sitbon O. .Chaouat A. .et al Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156-163 [PubMed]journal. [CrossRef] [PubMed]
 
van de Veerdonk M.C. .Kind T. .Marcus J.T. .et al Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol. 2011;58:2511-2519 [PubMed]journal. [CrossRef] [PubMed]
 
Mahapatra S. .Nishimura R.A. .Sorajja P. .Cha S. .McGoon M.D. . Relationship of pulmonary arterial capacitance and mortality in idiopathic pulmonary arterial hypertension. J Am Coll Cardiol. 2006;47:799-803 [PubMed]journal. [CrossRef] [PubMed]
 
LeVarge B.L. .Pomerantsev E. .Channick R.N. . Reliance on end-expiratory wedge pressure leads to misclassification of pulmonary hypertension. Eur Respir J. 2014;44:425-434 [PubMed]journal. [CrossRef] [PubMed]
 
Kovacs G. .Avian A. .Pienn M. .Naeije R. .Olschewski H. . Reading pulmonary vascular pressure tracings: how to handle the problems of zero leveling and respiratory swings. Am J Respir Crit Care Med. 2014;190:252-257 [PubMed]journal. [PubMed]
 
Hoeper M.M. .Bogaard H.J. .Condliffe R. .et al Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D42-D50 [PubMed]journal. [CrossRef] [PubMed]
 
Simonneau G. .Gatzoulis M.A. .Adatia I. .et al Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34-D41 [PubMed]journal. [CrossRef] [PubMed]
 
McLaughlin V.V. .Gaine S.P. .Barst R.J. .et al Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol. 2003;41:293-299 [PubMed]journal. [CrossRef] [PubMed]
 
Simonneau G. .Barst R.J. .Galie N. .et al Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165:800-804 [PubMed]journal. [CrossRef] [PubMed]
 
Hiremath J. .Thanikachalam S. .Parikh K. .et al Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant. 2010;29:137-149 [PubMed]journal. [CrossRef] [PubMed]
 
Stevens P.M. . Assessment of acute respiratory failure: cardiac versus pulmonary causes. Chest. 1975;67:1-2 [PubMed]journal. [CrossRef] [PubMed]
 
DeLong E.R. .DeLong D.M. .Clarke-Pearson D.L. . Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44:837-845 [PubMed]journal. [CrossRef] [PubMed]
 
Farber H.W. .Miller D.P. .McGoon M.D. .Frost A.E. .Benton W.W. .Benza R.L. . Predicting outcomes in pulmonary arterial hypertension based on the 6-minute walk distance. J Heart Lung Transplant. 2015;34:362-368 [PubMed]journal. [CrossRef] [PubMed]
 
Sitbon O. .Humbert M. .Nunes H. .et al Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780-788 [PubMed]journal. [CrossRef] [PubMed]
 
Fritz J.S. .Blair C. .Oudiz R.J. .et al Baseline and follow-up 6-min walk distance and brain natriuretic peptide predict 2-year mortality in pulmonary arterial hypertension. Chest. 2013;143:315-323 [PubMed]journal. [CrossRef] [PubMed]
 
Savarese G. .Paolillo S. .Costanzo P. .et al Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J Am Coll Cardiol. 2012;60:1192-1201 [PubMed]journal. [CrossRef] [PubMed]
 
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