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Original Research: Pulmonary Vascular Disease |

Diastolic Pulmonary Vascular Pressure GradientDiastolic Gradient and Prognosis: A Predictor of Prognosis in “Out-of-Proportion” Pulmonary Hypertension FREE TO VIEW

Christian Gerges; Mario Gerges, MD; Marie B. Lang; Yuhui Zhang, MD; Johannes Jakowitsch, PhD; Peter Probst, MD; Gerald Maurer, MD; Irene M. Lang, MD
Author and Funding Information

From the Department of Internal Medicine II, Division of Cardiology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.

Correspondence to: Irene Lang, MD, Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria; e-mail: irene.lang@meduniwien.ac.at


Funding/Support: This research was supported by the Austrian fellowship grant Medizinisch-Wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien [Project No. 08080-2009] and by an educational grant from United Therapeutics Corporation.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(3):758-766. doi:10.1378/chest.12-1653
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Background:  Left-sided heart disease (LHD) is the most common cause of pulmonary hypertension (PH). In patients with LHD, elevated left atrial pressure causes a passive increase in pulmonary vascular pressure by hydrostatic transmission. In some patients, an active component caused by pulmonary arterial vasoconstriction and/or vascular remodeling superimposed on left-sided pressure elevation is observed. This “reactive” or “out-of-proportion” PH, defined as PH due to LHD with a transpulmonary gradient (TPG) > 12 mm Hg, confers a worse prognosis. However, TPG is sensitive to changes in cardiac output and left atrial pressure. Therefore, we tested the prognostic value of diastolic pulmonary vascular pressure gradient (DPG) (ie, the difference between invasive diastolic pulmonary artery pressure and mean pulmonary capillary wedge pressure) to better prognosticate death in “out-of-proportion” PH.

Methods:  A large database of consecutive cases was analyzed. One thousand ninety-four of 2,351 complete data sets were from patients with PH due to LHD. For proof of concept, available lung histologies were reviewed.

Results:  In patients with postcapillary PH and a TPG > 12 mm Hg, a worse median survival (78 months) was associated with a DPG ≥ 7 mm Hg compared with a DPG < 7 mm Hg (101 months, P = .010). Elevated DPG was associated with more advanced pulmonary vascular remodeling.

Conclusions:  DPG identifies patients with “out-of-proportion” PH who have significant pulmonary vascular disease and increased mortality. We propose a diagnostic algorithm, using pulmonary capillary wedge pressure, TPG, and DPG in sequence to diagnose pulmonary vascular disease superimposed on left-sided pressure elevation.

Figures in this Article

The most common subset of pulmonary hypertension (PH) is PH due to left-sided heart disease (LHD), resulting from left ventricular dysfunction (systolic and/or diastolic) and/or valvular disease. According to the definition, mean pulmonary capillary wedge pressure (mPCWP) > 15 mm Hg discriminates the important distinction between precapillary and postcapillary disease. PH due to pulmonary vascular disease affects mainly the precapillary arteriolar compartment, whereas postcapillary disease originates distal to the pulmonary venules and entails morphologic changes in the precapillary compartment only after a significant pressure increase in the venous compartment. The backward hemodynamic consequences of LHD are thought to progress from venous leakage to pulmonary capillary leakage,1 enlarged and thickened pulmonary veins, pulmonary capillary dilatation, fragmentation of the alveolar-capillary membrane, alveolar hemorrhage involving impaired Ca2+ signaling and cytoskeletal reorganization,2 arteriolar changes comprising medial hypertrophy and intimal fibrosis, similar to the changes seen in idiopathic pulmonary arterial hypertension. These vascular changes are thought to represent the substrate for an increase of transpulmonary gradient (TPG) > 12 mm Hg3 or > 16 mm Hg,4 and they support the definition of “reactive” or “out-of-proportion” PH.3 By contrast, TPGs ≤ 12 mm Hg have been classified as passive PH (ie, PH due to pressure transmitted across the capillary bed of the lung), implying a lack of significant anatomic changes in the precapillary vessels. In addition, the difference between diastolic pulmonary arterial pressure (dPAP) and mPCWP has been used to distinguish pulmonary vascular from cardiac disease.5,6

PH due to LHD is common7 and increasingly prevalent,8 and it confers a worse outcome,9,10 similar to PH in other disease states.1113 To define risk in this population, we queried a large database of patients undergoing right-sided and left-sided heart catheterization to analyze whether a simple calculation (ie, the difference between invasive dPAP and mPCWP5,6) was useful to predict prognosis in “out-of-proportion” PH.3

Patients and End Points

Between May 1996 and March 2003, 3,107 patients underwent a first diagnostic right-sided heart catheterization (RHC) at the Medical University of Vienna, a national PH referral center (Fig 1). In 2,524 patients (81.2%), the procedure was combined with a left-sided heart catheterization. Catheterizations were performed for various indications, mostly for the diagnosis of elevated systolic pulmonary arterial pressure (sPAP) at echocardiography, in patients with chronic heart failure and patients with suspected PH, but also prior to valve replacements, percutaneous interventions, and surgical procedures. The database comprises measurements derived from prospective studies of patients with pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension (CTEPH),14 and PH due to LHD,3 and from a retrospective sample of patients with “non-PH” (mean pulmonary arterial pressure [mPAP] < 25 mm Hg) and PH due to LHD. All lung tissues for histologic analysis were screened within the observation period, taking advantage of the practice of the institutional pathology department to preserve tissues at every autopsy and to store lung tissue from patients receiving lung transplants.

Figure Jump LinkFigure 1. Patient disposition. Twenty-eight patients with PH showed a combination of diagnoses (“multiple conditions”). CHD = congenital heart disease; CTEPH = chronic thromboembolic pulmonary hypertension; DPG = diastolic pulmonary vascular pressure gradient; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension.Grahic Jump Location

For hemodynamic assessment, a 7F Swan-Ganz catheter (Baxter Healthcare Corp) was inserted from a femoral or jugular approach. mPAP, mean right atrial pressure (mRAP), mPCWP, and respective oxygen saturations, including the inferior and superior vena cava, were measured. Left atrial pressure was measured transseptally when indicated. Pressures were recorded as averages of eight measurements over eight recorded heart cycles using CathCorLX (Siemens AG). mPCWP was recorded as the average of eight time-pressure integral derivations resulting from wedging the inflated Swan-Ganz balloon catheter into a middle-sized pulmonary artery. Cardiac output was assessed by thermodilution and by the Fick method and was expressed in liters/minute. TPG was calculated by subtracting mPCWP from mPAP; pulmonary vascular resistance (PVR) was calculated by dividing TPG by cardiac output and was expressed in Wood units (mm Hg/min/L). Diastolic pulmonary vascular pressure gradient (DPG) was calculated as the difference between dPAP and mPCWP5,6 during a pull-back. Details of the measurement technique are described in Figure 2A.

Figure Jump LinkFigure 2. Measurements and hemodynamic cutoffs. A, Methods for measuring mPCWP, mPAP, and DPG. The figure illustrates salient examples. A1, Measurement in the setting of severe mitral regurgitation (with a large “V” wave) in a patient with a flail posterior leaflet and a negative DPG (arrow down). A2, Measurements in a patient with severe PAH, without mitral regurgitation and a very high DPG (arrow up). Mean pressures were recorded as medians of eight time-pressure integral derivations over eight recorded heart cycles using CathCorLX (Siemens AG). Accordingly, dPAP was the median of dPAP measurements of eight consecutive beats. The tracings represent typical pull-backs from the pulmonary capillary wedge pressure position to the pulmonary artery position after deflation of the balloon. B, TPG as a predictor of death in patients with pre- and postcapillary pulmonary hypertension. The vertical line marks a change in the slope of the regression line at 12 mm Hg. Dashed lines mark CIs of the hazard function. C, ROC curves of TPG, DPG, PVR, mPAP, and mRAP for the discrimination between precapillary and postcapillary “passive” pulmonary hypertension. Cutoffs were determined by maximizing the Youden index: TPG of 12 mm Hg, DPG of 7 mm Hg, PVR of 3.5 WU, mPAP of 41 mm Hg, and mRAP of 27 mm Hg. AUC = area under the curve; dPAP = diastolic pulmonary arterial pressure; mPAP = mean pulmonary arterial pressure; mPCWP = mean pulmonary capillary wedge pressure; mRAP = mean right atrial pressure; PAP = pulmonary arterial pressure; PVR = pulmonary vascular resistance; ROC = receiver operating characteristic; TPG = transpulmonary gradient; WU = Wood unit. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

An external auditor (P. P.) reviewed 50 randomly selected tracings to analyze the dispersion of DPG values across the line of zero. Negative DPG measurements occurred occasionally.

Ventilation-perfusion lung scintigraphies, multislice CT scans, lung function tests including spirometry and diffusion capacity measurement, and pulmonary angiographies were performed to diagnose CTEPH, COPD, and interstitial lung disease. Creatinine clearance (CrCl) was calculated according to Cockcroft and Gault.15 Deaths were determined after a median of 137 months (25th and 75th percentile, 116 and 154 months) by querying large public Austrian databases (Sterberegister Wien and Österreichisches Zentrales Melderegister) on March 31, 2011. All deaths occurring within Austria are captured within 1 day by both databases. Deaths of Austrian citizens that occur abroad are reported within 1 week to the Sterberegister Wien. Overall survival was measured from the date of diagnostic RHC to the date of death from any cause. The ethics committee of the Medical University of Vienna approved data (No. 617/2011) and tissue (No. 1177/2011) analyses.

Definitions and Subset Classification

The guidelines3 distinguish the following hemodynamic definitions during measurements at rest, without nitric oxide and oxygen: (1) “non-PH” with mPAP < 25 mm Hg, (2) “precapillary PH” with mPAP ≥ 25 mm Hg and mPCWP ≤ 15 mm Hg, and (3) “postcapillary PH” with mPAP ≥ 25 mm Hg and mPCWP > 15 mm Hg. Postcapillary PH was subdivided into (1) “passive” PH with mPAP ≥ 25 mm Hg, mPCWP > 15 mm Hg, and TPG ≤ 12 mm Hg and (2) “reactive” or “out-of-proportion” PH with mPAP ≥ 25 mm Hg, mPCWP > 15 mm Hg, and TPG > 12 mm Hg. Moderate and high-grade echocardiographic ventricular and valvular dysfunctions were classified as probable causes of PH. Cases of pulmonary arterial hypertension associated with connective tissue disease or portal hypertension as well as CTEPH or PH due to interstitial lung disease (moderate to severe) and/or COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] III or IV), diagnosed in association with LHD, were classified as having a combination of diagnoses (“multifactorial PH”) (Fig 1).

Tissues and (Immuno-) Histochemical Assessments of Pulmonary Vascular Disease

Lung samples were available in 10 patients with idiopathic pulmonary arterial pressure undergoing bilateral lung transplant and in 43 patients with PH due to LHD (from 27 autopsies, five lung biopsies, and 11 surgical lung resections). Several 2-μm sections from different lung areas were Trichrome stained and were stained with von Willebrand factor and smooth muscle α actin antibodies.16 Three independent observers counted vessels with medial hypertrophy, vessels with intimal and adventitial fibrosis, and numbers of myocytes, occluded vessels, and plexiform lesions.17

Statistical Analysis

Quantitative variables were described with mean and SD. The strength of association between quantitative variables was measured with Pearson rank correlation coefficient. Qualitative variables were described with counts and percentages, and the χ2 test was used to assess group differences.

The potential of mPAP, mPCWP, cardiac output, cardiac index, PVR, TPG, mRAP, and DPG to distinguish precapillary from “passive” PH was assessed with receiver operating characteristic (ROC) curves. The method of DeLong was used to compare the areas under two ROC curves.18 Cutoff values were determined by maximizing the Youden index, which is the sum of sensitivity and specificity minus one.

Univariate and multiple Cox proportional hazards regression models were used to examine the effects of several variables on patients’ survival. Age-, sex-, stable ischemic heart disease (SIHD)- and CrCl-adjusted survival curve estimates of PVR, DPG, and PH groups were derived with stratified Cox models. The corresponding tests for group comparison, however, were performed with common Cox models.

Restricted cubic splines were used to assess the functional form of the potential influence of a continuous covariate on patient survival in the Cox model.19 Median follow-up time was computed according to the method of Schemper and Smith.20

Data were analyzed with SPSS Statistics (version 19; IBM) and SAS for Windows (version 9.2; SAS Institute). All P values result from two-sided tests, with significance at .05.

Patients

Two thousand three hundred fifty-one complete data sets were collected in 3,107 patients (Fig 2). Fourteen patients were lost to follow-up. At inclusion, 30.6% of patients were in World Health Organization functional class 1, 34.3% in class 2, 25% in class 3, and 10.1% in class 4. One thousand three hundred eighty-nine patients were diagnosed as having PH (mPAP ≥ 25 mm Hg). Cases with PH associated with congenital heart disease (n = 130), and cases with multifactorial PH (n = 28) (Fig 2) were not included in the analysis.

Diagnosis of Precapillary and Postcapillary PH

Nine hundred sixty-two patients were classified as normal (“non-PH”; mPAP < 25 mm Hg, Fig 2). Thirty-eight percent of the patients classified as “non-PH”had a history of hypertension, 34.3% had SIHD, and 20.7% had atrial fibrillation. Patients with PH (n = 1,259) were grouped into diagnostic subsets according to the Dana Point Classification21 (Fig 2). Group 1 patients were younger (47.6 ± 14.5 years vs 62.6 ± 12.5 years) and less likely to be men (35.1% vs 61.5%), had a lower BMI (23.5 ± 3.8 kg/m2 vs 26.3 ± 4.5 kg/m2), were less likely to have a history of hypertension (22.8% vs 41.5%) or SIHD (12.3% vs 43.9%), and showed a rare occurrence of atrial fibrillation (3.5% vs 11.1%), compared with group 2 patients. Hemodynamics are shown in Table 1, and the characteristics of patients with “out-of-proportion” PH are listed in Table 2.

Table Graphic Jump Location
Table 1 —Age and Hemodynamic Characteristics

DPG = diastolic pulmonary vascular pressure gradient; LHD = left-sided heart disease; OOPPH = “out-of-proportion” pulmonary hypertension; PH = pulmonary hypertension; WU = Wood unit.

Table Graphic Jump Location
Table 2 —Severity and Causative Characteristics of Patients With OOPPH

Data are presented as No. (%). GOLD = Global Initiative for Chronic Obstructive Lung Disease; NYHA = New York Heart Association; WHO = World Health Organization. See Table 1 for expansion of other abbreviations.

a 

P = .01.

b 

P = .014.

TPG and DPG

First, flexible hazard ratio functions for survival corrected for sex, age, SIHD, and CrCl < 60 mL/min were constructed for mPAP, mPCWP, cardiac output, cardiac index, PVR, TPG, mRAP, and DPG of patients with pre- and postcapillary PH. TPG, DPG, PVR, mRAP, and mPAP were associated with a significant increase of hazard ratios for death (all P < .001). TPG demonstrated a threshold of 12 mm Hg (Fig 1B, vertical line), beyond which the hazard ratio function increased, in accordance with PH guidelines.3

As a next step, ROC analyses were performed to differentiate between precapillary (n = 120) and “passive” PH (n = 604), imputing TPG, DPG, PVR, mRAP, and mPAP according to the results derived from the flexible hazard ratio functions. This analysis identified a TPG of 12 mm Hg with the highest Youden index (0.97) and an area under the curve (AUC) of 0.98 (Fig 1C). For DPG, the greatest Youden index (0.91) and AUC of 0.97 were found at a threshold of 7 mm Hg (Fig 1C), followed by PVR with the greatest Youden index (0.84) and AUC of 0.96 at a threshold of 3.5 Wood units (Fig 1C). AUCs for TPG, DPG, and PVR were significantly larger than AUCs derived from mRAP and mPAP (all P < .001).

Based on the ROC curves, risk analysis in PH due to LHD was performed in a stepwise fashion. First, PH due to LHD was classified according to a TPG > and ≤ 12 mm Hg, followed by a stratification by a DPG ≥ and < 7 mm Hg (Fig 3). A final stratification by PVR did not further separate the groups.

Figure Jump LinkFigure 3. Hemodynamic algorithm. Hemodynamic algorithm for the diagnosis of a high-risk subgroup of “out-of-proportion” PH. The gray shaded area indicates conditions where pulmonary vascular disease is expected. LHD = left-sided heart disease. See Figure 1 and 2 legends for expansion of other abbreviations.Grahic Jump Location
Survival Analysis in Patients With “Out-of-Proportion” PH Due to LHD

Overall survival of patients with “out-of-proportion” PH and a DPG ≥ 7 mm Hg (n = 179; median, 25th and 75th percentiles: 78 months, 11-145 months) was shorter than of those with a DPG < 7 mm Hg (n = 311; 101 months, 29-173 months) (P = .010) (Fig 4). Table 2 illustrates the hemodynamic and clinical characteristics of patients with “out-of-proportion” PH. Survival of patients with “out-of-proportion” PH and a DPG ≥ 7 mm Hg was similar to that of precapillary PH (P = .908) but different from that of “non-PH” (P < .001), “passive” PH (P < .001), and “out-of-proportion” PH (P = .010) (Fig 4).

Figure Jump LinkFigure 4. Survival curves illustrating a population of “non-PH” group (dashed-dotted line) patients with precapillary PH (closed line), “passive” PH (dashed line), OOPPH (thin closed line), and OOPPH with a DPG ≥ 7 mm Hg (dotted line), all adjusted for age, sex, stable ischemic heart disease, and creatinine clearance < 60 mL/min. Symbols indicate significance levels: †P = .908; *P < .001; ‡P = .010. OOPPH = “out of proportion” PH. See Figure 1 and 2 legends for expansion of other abbreviations.Grahic Jump Location
Semiquantitative Morphometric Analysis of Pulmonary Vascular Remodeling

The median time interval between the first diagnostic catheterization and autopsy, lung biopsy, or other occasion during which pathologic samples were obtained was 11.7 months (−0.5 to 156 months). In patients with PH due to LHD, TPG and DPG correlated with the mean number of myocytes/vessel wall (r = 0.76 and r = 0.74). Compared with “passive” PH (Fig 5A) and “out-of-proportion” PH with a DPG < 7 mm Hg (Fig 5B), patients with “out-of-proportion” PH and a DPG ≥ 7 mm Hg had more vessels with medial hypertrophy (Fig 5C, arrowheads), more vessels with intimal and adventitial fibrosis, more occluded vessels, and more myocytes/vessel wall (Table 3).

Figure Jump LinkFigure 5. Histologic analyses of lung specimens. Representative Trichrome stains of lung sections from individual patients. A, From a patient with PH due to LHD and a TPG of 3 mm Hg. B, From a patient with PH due to LHD with a TPG of 15 mm Hg and a DPG of 5 mm Hg. C, From a patient with PH due to LHD with a TPG of 30 mm Hg and a DPG of 13 mm Hg. D, From a patient diagnosed with idiopathic pulmonary arterial hypertension. Arrowheads point to the smooth muscle cell layer of the respective vessel walls. See Figure 1 to 3 legends for expansion of abbreviations.Grahic Jump Location
Table Graphic Jump Location
Table 3 —Semiquantitative Morphometric Analysis of Pulmonary Vascular Lesions

iPAH = idiopathic pulmonary arterial hypertension; TPG = transpulmonary gradient. See Table 1 for expansion of other abbreviations.

PH due to LHD is a common entity and carries a poor outcome.22,23 Today, in developed countries, it is mainly due to systolic24 and diastolic left ventricular dysfunction10 and less commonly due to valvular heart disease.25 Chronic sustained elevation of pressure in pulmonary capillaries leads to vascular remodeling that resembles the classic pulmonary arteriopathy of precapillary PH.26 However, PH due to LHD is less frequently associated with intimal proliferation and plexiform lesions, and is characterized by fibrosis and myofibroblast proliferation.27 Our data confirm that this condition is more common in mitral stenosis28 and less likely in aortic stenosis (Table 2). Two hemodynamic phenotypes appear to reflect whether pulmonary vascular disease has developed: One has been labeled “passive” PH with elevation of mPAP in the presence of mildly elevated TPG, and the other has been labeled “reactive” PH and is characterized by an increase in TPG that is “out of proportion” to the hydrostatic pressure transmitted by the elevation of left ventricular filling pressures. “Reactive” PH (or “out-of-proportion” PH),3 defined by mPAP ≥ 25 mm Hg, mPCWP > 15 mm Hg, and TPG > 12 mm Hg or PVR > 3 Wood units, has recently been found to be an independent predictor of 6-month mortality in a heart failure population.9 The authors identified 40% of their patients as having “reactive” PH, which is in concordance with our data (45%) and confers a worse prognosis than does passive PH (Fig 4). However, they admitted that patients may have been misclassified using these criteria. It is a common clinical observation that patients with LHD and a TPG > 12 mm Hg may normalize their pulmonary hemodynamics after cardiac transplant or with an infusion of nitroprusside or even only diuretics. Therefore, there is a need for a more precise definition of pulmonary vascular disease in the context of elevated left ventricular filling pressures.

The normal pulmonary circulation is a low resistance circuit, with little or no resting vascular tone, and a constant relationship between PVR and pulmonary arterial compliance expressed as a time constant of 0.6 to 0.7. Under normal conditions, dPAP represents a surrogate of left atrial pressure. The most important factors influencing mPAP are alveolar gases, intraalveolar pressure, hydrostatic pressure, and left atrial pressure. sPAP is generally more flow dependent than is dPAP and is correlated with mPCWP,29 flow, and the overall fluid load. Under diuretic treatment, sPAP and mPAP may decrease in parallel to pulmonary capillary wedge pressure, whereas dPAP remains relatively unaffected. In LHD, pulmonary arterial compliance decreases proportionally more than PVR increases because increased left atrial pressure triggers pulmonary arterial stiffening and a decrease in PVR.30 Therefore, the time constant (PVR × pulmonary vascular compliance) in PH due to LHD is shorter than in other types of PH.30 The disproportionate decrease of compliance in the presence of increased left atrial pressure may be a cause of increased TPG without any pulmonary vasoconstriction or remodeling. Although pulmonary capillary wedge pressure is driven mainly by left-sided filling pressures, elevated dPAP in precapillary PH was associated with vessel occlusions when lung sections were examined under a light microscope.17 A normal gradient between pulmonary arterial diastolic and wedge pressure is between 0 and 5 mm Hg,5,31,32 whereas an increased gradient denotes pulmonary vascular disease. Even though one can argue about distinguishing normal from abnormal on the basis of a prognostic impact, a DPG ≥ 7 mm Hg defines patients with postcapillary PH and significant pulmonary vascular disease more accurately than does TPG alone and appears reasonable in an elderly population.31 However, prediction of survival cannot separate the diagnostic merits of TPG vs DPG. All that can be said is that DPG more specifically addresses the effects of pulmonary vascular remodeling on prognosis in LHD.32 Histologic analyses served as proof-of-concept for pulmonary vascular disease in patients with “out-of-proportion” PH and elevated DPG. Medial hypertrophy was most frequently observed in “out-of-proportion” PH and DPG ≥ 7 mm Hg (Fig 5, Table 3). Backward pressure transmission in PH due to LHD appears to be a powerful trigger of myofibroblast proliferation.

Limitations

Fluid loading and vasoreactivity testing were not performed systematically during catheterizations. Survival data may have been biased by treatments, and the sample of patients with available lung histologies is small and possibly biased to advanced cases. One must also consider the possibility that “out-of-proportion” PH may have been due to vasoconstriction, particularly in less advanced cases.

The algorithm shown in Figure 3 aids the interpretation of hemodynamic data in PH due to LHD. However, we were relying on recorded diagnoses and on a selection based on the clinical indications for RHC, as well as on the individual operators’ judgments, which contain a possible bias against a more general interpretation of our results applying to all patients with PH due to LHD. In a next step, a validation of our clinical prediction rule should ensure that its repeated use leads to the same results by other investigators.33

DPG is a simple hemodynamic parameter identifying a high-risk group of patients with PH due to LHD and a TPG > 12 mm Hg who suffer from pulmonary vascular disease.

Author contributions: Dr Lang is the guarantor of the entire manuscript.

Mr Gerges: contributed to the database, statistical analyses, histology, and writing of the manuscript.

Dr Gerges: contributed to the database, statistical analyses, histology, and writing of the manuscript.

Ms Lang: contributed to the database, statistical analyses, and approving the manuscript.

Dr Zhang: contributed to the histology and histological images and proofread the manuscript.

Dr Jakowitsch: contributed to the figures, database, statistical analyses, and drafting the manuscript.

Dr Probst: contributed as an external auditor and did a critical-read the manuscript.

Dr Maurer: contributed to the design of the study.

Dr Lang: contributed to the study design, hemodynamic measurements, database, histology, and writing of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Lang has relationships with drug companies including AOP Orphan Pharmaceuticals AG; Actelion Pharmaceuticals Ltd; Bayer Schering Pharma; AstraZeneca; Servier; Cordis Corporation; Medtronic; GlaxoSmithKline; Novartis AG; Pfizer, Inc; 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. Mr Gerges, Drs Gerges, Zhang, Jakowitsch, Probst, and Maurer, and Ms Lang have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: Medizinisch-Wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien [Project No. 08080-2009] paid a minimum amount of support to C. G. and M. G. during their diploma work. Currently, M. G.’ s PhD thesis is supported by an educational grant from United Therapeutics Corporation.

Other contributions: The authors thank Harald Heinzl, PhD, for assistance with statistics and Dontscho Kerjaschki MD, who provided lung specimens on behalf of the Clinical Institute of Pathology, Medical University of Vienna.

AUC

area under the curve

CrCl

creatinine clearance

CTEPH

chronic thromboembolic pulmonary hypertension

dPAP

diastolic pulmonary arterial pressure

DPG

diastolic pulmonary vascular pressure gradient

LHD

left-sided heart disease

mPAP

mean pulmonary arterial pressure

mPCWP

mean pulmonary capillary wedge pressure

mRAP

mean right atrial pressure

PH

pulmonary hypertension

PVR

pulmonary vascular resistance

RHC

right-sided heart catheterization

ROC

receiver operating characteristic

SIHD

stable ischemic heart disease

sPAP

systolic pulmonary arterial pressure

TPG

transpulmonary gradient

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Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. [CrossRef] [PubMed]
 
Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355(3):251-259. [CrossRef] [PubMed]
 
Damy T, Goode KM, Kallvikbacka-Bennett A, et al. Determinants and prognostic value of pulmonary arterial pressure in patients with chronic heart failure. Eur Heart J. 2010;31(18):2280-2290. [CrossRef] [PubMed]
 
Manzano L, Babalis D, Roughton M, et al;; SENIORS Investigators SENIORS Investigators. Predictors of clinical outcomes in elderly patients with heart failure. Eur J Heart Fail. 2011;13(5):528-536. [CrossRef] [PubMed]
 
Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. J Am Coll Cardiol. 1997;29(1):153-159. [CrossRef] [PubMed]
 
Rich S, Rabinovitch M. Diagnosis and treatment of secondary (non-category 1) pulmonary hypertension. Circulation. 2008;118(21):2190-2199. [CrossRef] [PubMed]
 
Kapanci Y, Burgan S, Pietra GG, Conne B, Gabbiani G. Modulation of actin isoform expression in alveolar myofibroblasts (contractile interstitial cells) during pulmonary hypertension. Am J Pathol. 1990;136(4):881-889. [PubMed]
 
Tandon HD, Kasturi J. Pulmonary vascular changes associated with isolated mitral stenosis in India. Br Heart J. 1975;37(1):26-36. [CrossRef] [PubMed]
 
Capomolla S, Febo O, Guazzotti G, et al. Invasive and non-invasive determinants of pulmonary hypertension in patients with chronic heart failure.J Heart Lung Transplant. 2000;19(5):426-438.
 
Tedford RJ, Hassoun PM, Mathai SC, et al. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation. 2012;125(2):289-297. [CrossRef] [PubMed]
 
Chemla D, Castelain V, Herve P, et al. Haemodynamic evaluation of pulmonary hypertension.Eur Respir J. 2002;20(5):1314-1331.
 
Harvey RM, Enson Y, Ferrer MI. A reconsideration of the origins of pulmonary hypertension. Chest. 1971;59(1):82-94. [CrossRef] [PubMed]
 
McGinn TG, Guyatt GH, Wyer PC, Naylor CD, Stiell IG, Richardson WS; Evidence-Based Medicine Working Group Evidence-Based Medicine Working Group. Users’ guides to the medical literature: XXII: how to use articles about clinical decision rules. JAMA. 2000;284(1):79-84. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Patient disposition. Twenty-eight patients with PH showed a combination of diagnoses (“multiple conditions”). CHD = congenital heart disease; CTEPH = chronic thromboembolic pulmonary hypertension; DPG = diastolic pulmonary vascular pressure gradient; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension.Grahic Jump Location
Figure Jump LinkFigure 2. Measurements and hemodynamic cutoffs. A, Methods for measuring mPCWP, mPAP, and DPG. The figure illustrates salient examples. A1, Measurement in the setting of severe mitral regurgitation (with a large “V” wave) in a patient with a flail posterior leaflet and a negative DPG (arrow down). A2, Measurements in a patient with severe PAH, without mitral regurgitation and a very high DPG (arrow up). Mean pressures were recorded as medians of eight time-pressure integral derivations over eight recorded heart cycles using CathCorLX (Siemens AG). Accordingly, dPAP was the median of dPAP measurements of eight consecutive beats. The tracings represent typical pull-backs from the pulmonary capillary wedge pressure position to the pulmonary artery position after deflation of the balloon. B, TPG as a predictor of death in patients with pre- and postcapillary pulmonary hypertension. The vertical line marks a change in the slope of the regression line at 12 mm Hg. Dashed lines mark CIs of the hazard function. C, ROC curves of TPG, DPG, PVR, mPAP, and mRAP for the discrimination between precapillary and postcapillary “passive” pulmonary hypertension. Cutoffs were determined by maximizing the Youden index: TPG of 12 mm Hg, DPG of 7 mm Hg, PVR of 3.5 WU, mPAP of 41 mm Hg, and mRAP of 27 mm Hg. AUC = area under the curve; dPAP = diastolic pulmonary arterial pressure; mPAP = mean pulmonary arterial pressure; mPCWP = mean pulmonary capillary wedge pressure; mRAP = mean right atrial pressure; PAP = pulmonary arterial pressure; PVR = pulmonary vascular resistance; ROC = receiver operating characteristic; TPG = transpulmonary gradient; WU = Wood unit. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 3. Hemodynamic algorithm. Hemodynamic algorithm for the diagnosis of a high-risk subgroup of “out-of-proportion” PH. The gray shaded area indicates conditions where pulmonary vascular disease is expected. LHD = left-sided heart disease. See Figure 1 and 2 legends for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Survival curves illustrating a population of “non-PH” group (dashed-dotted line) patients with precapillary PH (closed line), “passive” PH (dashed line), OOPPH (thin closed line), and OOPPH with a DPG ≥ 7 mm Hg (dotted line), all adjusted for age, sex, stable ischemic heart disease, and creatinine clearance < 60 mL/min. Symbols indicate significance levels: †P = .908; *P < .001; ‡P = .010. OOPPH = “out of proportion” PH. See Figure 1 and 2 legends for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5. Histologic analyses of lung specimens. Representative Trichrome stains of lung sections from individual patients. A, From a patient with PH due to LHD and a TPG of 3 mm Hg. B, From a patient with PH due to LHD with a TPG of 15 mm Hg and a DPG of 5 mm Hg. C, From a patient with PH due to LHD with a TPG of 30 mm Hg and a DPG of 13 mm Hg. D, From a patient diagnosed with idiopathic pulmonary arterial hypertension. Arrowheads point to the smooth muscle cell layer of the respective vessel walls. See Figure 1 to 3 legends for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Age and Hemodynamic Characteristics

DPG = diastolic pulmonary vascular pressure gradient; LHD = left-sided heart disease; OOPPH = “out-of-proportion” pulmonary hypertension; PH = pulmonary hypertension; WU = Wood unit.

Table Graphic Jump Location
Table 2 —Severity and Causative Characteristics of Patients With OOPPH

Data are presented as No. (%). GOLD = Global Initiative for Chronic Obstructive Lung Disease; NYHA = New York Heart Association; WHO = World Health Organization. See Table 1 for expansion of other abbreviations.

a 

P = .01.

b 

P = .014.

Table Graphic Jump Location
Table 3 —Semiquantitative Morphometric Analysis of Pulmonary Vascular Lesions

iPAH = idiopathic pulmonary arterial hypertension; TPG = transpulmonary gradient. See Table 1 for expansion of other abbreviations.

References

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Patel NM, Lederer DJ, Borczuk AC, Kawut SM. Pulmonary hypertension in idiopathic pulmonary fibrosis. Chest. 2007;132(3):998-1006. [CrossRef] [PubMed]
 
Thabut G, Dauriat G, Stern JB, et al. Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation. Chest. 2005;127(5):1531-1536. [CrossRef] [PubMed]
 
Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis. 2003;62(11):1088-1093. [CrossRef] [PubMed]
 
Lang I, Gomez-Sanchez M, Kneussl M, et al. Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension. Chest. 2006;129(6):1636-1643. [CrossRef] [PubMed]
 
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Bonderman D, Jakowitsch J, Redwan B, et al. Role for staphylococci in misguided thrombus resolution of chronic thromboembolic pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2008;28(4):678-684. [CrossRef] [PubMed]
 
Du L, Sullivan CC, Chu D, et al. Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med. 2003;348(6):500-509. [CrossRef] [PubMed]
 
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Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. [CrossRef] [PubMed]
 
Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355(3):251-259. [CrossRef] [PubMed]
 
Damy T, Goode KM, Kallvikbacka-Bennett A, et al. Determinants and prognostic value of pulmonary arterial pressure in patients with chronic heart failure. Eur Heart J. 2010;31(18):2280-2290. [CrossRef] [PubMed]
 
Manzano L, Babalis D, Roughton M, et al;; SENIORS Investigators SENIORS Investigators. Predictors of clinical outcomes in elderly patients with heart failure. Eur J Heart Fail. 2011;13(5):528-536. [CrossRef] [PubMed]
 
Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. J Am Coll Cardiol. 1997;29(1):153-159. [CrossRef] [PubMed]
 
Rich S, Rabinovitch M. Diagnosis and treatment of secondary (non-category 1) pulmonary hypertension. Circulation. 2008;118(21):2190-2199. [CrossRef] [PubMed]
 
Kapanci Y, Burgan S, Pietra GG, Conne B, Gabbiani G. Modulation of actin isoform expression in alveolar myofibroblasts (contractile interstitial cells) during pulmonary hypertension. Am J Pathol. 1990;136(4):881-889. [PubMed]
 
Tandon HD, Kasturi J. Pulmonary vascular changes associated with isolated mitral stenosis in India. Br Heart J. 1975;37(1):26-36. [CrossRef] [PubMed]
 
Capomolla S, Febo O, Guazzotti G, et al. Invasive and non-invasive determinants of pulmonary hypertension in patients with chronic heart failure.J Heart Lung Transplant. 2000;19(5):426-438.
 
Tedford RJ, Hassoun PM, Mathai SC, et al. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation. 2012;125(2):289-297. [CrossRef] [PubMed]
 
Chemla D, Castelain V, Herve P, et al. Haemodynamic evaluation of pulmonary hypertension.Eur Respir J. 2002;20(5):1314-1331.
 
Harvey RM, Enson Y, Ferrer MI. A reconsideration of the origins of pulmonary hypertension. Chest. 1971;59(1):82-94. [CrossRef] [PubMed]
 
McGinn TG, Guyatt GH, Wyer PC, Naylor CD, Stiell IG, Richardson WS; Evidence-Based Medicine Working Group Evidence-Based Medicine Working Group. Users’ guides to the medical literature: XXII: how to use articles about clinical decision rules. JAMA. 2000;284(1):79-84. [CrossRef] [PubMed]
 
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