You are on page 1of 9


Original Research

Diastolic Pulmonary Vascular

Pressure Gradient
A Predictor of Prognosis in Out-of-Proportion
Pulmonary Hypertension
Christian Gerges; Mario Gerges, MD; Marie B. Lang; Yuhui Zhang, MD;
Johannes Jakowitsch, PhD; Peter Probst, MD; Gerald Maurer, MD;
and Irene M. Lang, MD

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 5 .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.
CHEST 2013; 143(3):758766
Abbreviations: AUC 5 area under the curve; CrCl 5 creatinine clearance; CTEPH 5 chronic thromboembolic pulmonary hypertension; dPAP 5 diastolic pulmonary arterial pressure; DPG 5 diastolic pulmonary vascular pressure gradient;
LHD 5 left-sided heart disease; mPAP 5 mean pulmonary arterial pressure; mPCWP 5 mean pulmonary capillary wedge
pressure; mRAP 5 mean right atrial pressure; PH 5 pulmonary hypertension; PVR 5 pulmonary vascular resistance;
RHC 5 right-sided heart catheterization; ROC 5 receiver operating characteristic; SIHD 5 stable ischemic heart disease;
sPAP 5 systolic pulmonary arterial pressure; TPG 5 transpulmonary gradient

most common subset of pulmonary hyperThetension

(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 Ca21 signaling
and cytoskeletal reorganization,2 arteriolar changes


Downloaded From: by a VISN 1 New England Healthcare System User on 07/21/2014

Original Research

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
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.11-13 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
Materials and Methods
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
Manuscript received July 2, 2012; revision accepted August 17,
Affiliations: From the Department of Internal Medicine II, Division of Cardiology, Vienna General Hospital, Medical University
of Vienna, Vienna, Austria.
Funding/Support: This research was supported by the Austrian
fellowship grant Medizinisch-Wissenschaftlicher Fonds des Brgermeisters der Bundeshauptstadt Wien [Project No. 08080-2009]
and by an educational grant from United Therapeutics Corporation.
Correspondence to: Irene Lang, MD, Department of Internal
Medicine II, Division of Cardiology, Medical University of Vienna,
Whringer Grtel 18-20, 1090 Vienna, Austria; e-mail: irene.lang@
2013 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.12-1653

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.
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.
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 sterreichisches
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-mm
CHEST / 143 / 3 / MARCH 2013

Downloaded From: by a VISN 1 New England Healthcare System User on 07/21/2014


sponding 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.

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 5 130), and cases with
multifactorial PH (n 5 28) (Fig 2) were not included
in the analysis.
Diagnosis of Precapillary and Postcapillary PH
Figure 1. Patient disposition. Twenty-eight patients with PH
showed a combination of diagnoses (multiple conditions).
CHD 5 congenital heart disease; CTEPH 5 chronic thromboembolic pulmonary hypertension; DPG 5 diastolic pulmonary
vascular pressure gradient; PAH 5 pulmonary arterial hypertension; PH 5 pulmonary hypertension.

sections from different lung areas were Trichrome stained and

were stained with von Willebrand factor and smooth muscle a 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 x2 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 corre-

Nine hundred sixty-two patients were classified as

normal (non-PH; mPAP , 25 mm Hg, Fig 2). Thirtyeight 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 5 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-ofproportion PH are listed in Table 2.
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


Downloaded From: by a VISN 1 New England Healthcare System User on 07/21/2014

Original Research

Figure 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 5 area under the curve; dPAP 5 diastolic pulmonary arterial pressure; mPAP 5 mean pulmonary arterial pressure; mPCWP 5 mean
pulmonary capillary wedge pressure; mRAP 5 mean right atrial pressure; PAP 5 pulmonary arterial pressure; PVR 5 pulmonary vascular
resistance; ROC 5 receiver operating characteristic; TPG 5 transpulmonary gradient; WU 5 Wood unit. See Figure 1 legend for expansion
of other abbreviation.

As a next step, ROC analyses were performed to differentiate between precapillary (n 5 120) and passive PH (n 5 604), 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
CHEST / 143 / 3 / MARCH 2013

Downloaded From: by a VISN 1 New England Healthcare System User on 07/21/2014


Table 1Age and Hemodynamic Characteristics

Postcapillary PH (PH due to LHD) (N 5 1,094)
OOPPH with
OOPPH with
Precapillary PH
Passive PH DPG , 7 mm Hg DPG 7 mm Hg
(n 5 137)
All (N 5 1,094)
(n 5 604)
(n 5 311)
(n 5 179)

Hemodynamic Variable
Age, y
BMI, kg/m2
Heart rate, beats/min
Cardiac output, L/min
Cardiac index, L/min/m2
Left ventricular ejection fraction, %
Mixed venous oxygen saturation, %
Systemic vascular resistance, WU
Systemic vascular resistance index, WU/m2
Pulmonary vascular resistance, WU
Pulmonary vascular resistance index, WU/m2
Mean right atrial pressure, mm Hg
Pulmonary arterial systolic pressure, mm Hg
Pulmonary arterial diastolic pressure, mm Hg
Mean pulmonary arterial pressure, mm Hg
Mean pulmonary capillary wedge pressure, mm Hg
Transpulmonary gradient, mm Hg
Diastolic pulmonary vascular pressure gradient, mm Hg

51.2 15.4
25.1 4.9
79.5 14.1
4.7 1.6
2.6 0.9
52.7 10.4
60.9 12.8
20.1 7.4
11.3 5
8.8 5.3
5.0 3.3
8.4 5.3
77.5 26.7
30.7 12.4
48.3 16.8
10.1 6.8
36.7 15.7
18.4 12.3

62.6 12.5
26.3 4.5
77.6 15.6
4.8 1.4
2.6 0.7
38.6 20.6
62.6 10.2
19.7 6.1
10.8 4.1
3.0 2.1
1.7 1.3
10.1 5.1
56.4 15.8
25.2 7.7
37.3 9.8
24 7.5
13.4 7.9
1.2 7

62.4 12.7
26.2 4.5
76.3 15.2
4.8 1.4
2.6 0.7
39.8 22.6
62.9 10
19.6 6.2
10.7 4.1
1.8 0.8
1.0 0.5
9.8 4.9
50.3 11.8
23.2 6.2
33.6 7.3
25.4 7.3
8.2 2.9
22.4 4.9

64.3 11.1
26.5 4.2
77.5 15.4
4.9 1.3
2.6 0.7
38.0 18.6
62.9 9.9
19.7 5.6
10.9 3.8
3.7 1.2
2.0 0.8
10.0 5
61.3 14.2
25.1 6.3
39.8 8.1
23.1 7
16.6 3.3
1.9 3.6

60.4 13.8
26.5 5
82.3 16.6
4.7 1.4
2.6 0.7
34.5 14.7
60.9 11
19.7 6.8
11.1 4.6
5.8 3.2
3.3 2.1
11.4 5.8
68.2 19.9
32.5 9.7
45.3 13
20.6 7.8
24.8 9.5
11.9 6.2

DPG 5 diastolic pulmonary vascular pressure gradient; LHD 5 left-sided heart disease; OOPPH 5 out-of-proportion pulmonary hypertension;
PH 5 pulmonary hypertension; WU 5 Wood unit.

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.

Table 2Severity and Causative Characteristics

of Patients With OOPPH

Overall survival of patients with out-of-proportion

PH and a DPG 7 mm Hg (n 5 179; median, 25th
and 75th percentiles: 78 months, 11-145 months)
was shorter than of those with a DPG , 7 mm Hg
(n 5 311; 101 months, 29-173 months) (P 5 .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 5 .908) but different from that of
non-PH (P , .001), passive PH (P , .001), and outof-proportion PH (P 5 .010) (Fig 4).

Out-of-Proportion PH
NYHA/WHO functional class
Coronary artery disease
Systolic dysfunction
Diastolic dysfunction
Aortic stenosis
Aortic regurgitation
Mitral stenosis
Mitral regurgitation

DPG , 7 mm Hg
(n 5 311)

DPG 7 mm Hg
(n 5 179)

11 (3.5)
42 (13.5)
184 (59.2)
74 (23.8)
143 (45.9)
142 (45.7)
170 (54.7)
52 (16.7)
20 (6.4)
24 (7.7)
109 (35)
32 (10.3)
26 (8.4)
6 (1.9)

2 (1.1)
28 (15.6)
105 (58.7)
44 (24.6)
79 (44.1)
78 (43.6)
89 (49.7)
16 (8.9)a
7 (3.9)
26 (14.5)b
67 (37.4)
21 (11.8)
17 (9.6)
4 (2.2)

Data are presented as No. (%). GOLD 5 Global Initiative for Chronic
Obstructive Lung Disease; NYHA 5 New York Heart Association;
WHO 5 World Health Organization. See Table 1 for expansion of
other abbreviations.
aP 5 .01.
bP 5 .014.

Survival Analysis in Patients With

Out-of-Proportion PH Due to LHD

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 (20.5 to 156 months). In patients
with PH due to LHD, TPG and DPG correlated with
the mean number of myocytes/vessel wall (r 5 0.76
and r 5 0.74). Compared with passive PH (Fig 5A)
and out-of-proportion PH with a DPG , 7 mm Hg


Downloaded From: by a VISN 1 New England Healthcare System User on 07/21/2014

Original Research

Figure 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 5 .908;
*P , .001; P 5 .010. OOPPH 5 out of proportion PH. See Figure 1 and 2 legends for expansion of other abbreviations.

Figure 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 5 left-sided heart disease. See
Figure 1 and 2 legends for expansion of other abbreviations.

(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).
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
CHEST / 143 / 3 / MARCH 2013

Downloaded From: by a VISN 1 New England Healthcare System User on 07/21/2014


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 3 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.

Figure 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 hyper-

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,
tension. Arrowheads point to the smooth muscle cell layer of the
respective vessel walls. See Figure 1 to 3 legends for expansion of


Downloaded From: by a VISN 1 New England Healthcare System User on 07/21/2014

Original Research

Table 3Semiquantitative Morphometric Analysis of Pulmonary Vascular Lesions

PH (n 5 10)
Vessel Morphology
Vessels with medial hypertrophy, %
No. myocytes/vessel wall, mean
Vessels with intimal fibrosis, %
Vessels with adventitial fibrosis, %
Vessels occluded, %
Patients with plexiform lesions, No. (%)

Postcapillary PH (n 5 38)

iPAH (n 5 10)

TPG 12 mm Hg
(n 5 20)

OOPPH with
DPG , 7 mm Hg (n 5 9)

OOPPH with
DPG 7 mm Hg (n 5 9)

62.7 31.2
66.7 32
60.4 39
63.9 33.9
44.2 25.8
1 (10)

50.6 40.6
31.3 19.1
3.9 7.5
0.6 2.3
7.5 23.1

35.1 38.5
34.7 19.2
13.8 35
12.5 23.1
7.4 16.9

86.3 21
85.9 55.4
67.7 18.1
25 17.8
25.9 18.2
1 (11.1)

iPAH 5 idiopathic pulmonary arterial hypertension; TPG 5 transpulmonary gradient. See Table 1 for expansion of other abbreviations.

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
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
Brgermeisters der Bundeshauptstadt Wien [Project No. 080802009] 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.

1. West JB, Mathieu-Costello O. Vulnerability of pulmonary
capillaries in heart disease. Circulation. 1995;92(3):622-631.
2. Kerem A, Yin J, Kaestle SM, et al. Lung endothelial dysfunction in congestive heart failure: role of impaired Ca21 signaling and cytoskeletal reorganization. Circ Res. 2010;106(6):
3. Gali N, Hoeper MM, Humbert M, et al; ESC Committee for
Practice Guidelines (CPG). Guidelines for the diagnosis and
treatment of pulmonary hypertension: the Task Force for the
Diagnosis and Treatment of Pulmonary Hypertension of
the European Society of Cardiology (ESC) and the European
Respiratory Society (ERS), endorsed by the International
Society of Heart and Lung Transplantation (ISHLT). Eur
Heart J. 2009;30(20):2493-2537.
4. Mehra MR, Kobashigawa J, Starling R, et al. Listing criteria for heart transplantation: International Society for Heart
and Lung Transplantation guidelines for the care of cardiac
transplant candidates2006. J Heart Lung Transplant. 2006;
5. Buchbinder N, Ganz W. Hemodynamic monitoring: invasive
techniques. Anesthesiology. 1976;45(2):146-155.
6. Stevens PM. Assessment of acute respiratory failure: cardiac
versus pulmonary causes. Chest. 1975;67(1):1-2.
7. Ghio S, Gavazzi A, Campana C, et al. Independent and additive
prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure.
J Am Coll Cardiol. 2001;37(1):183-188.
8. Lam CS, Borlaug BA, Kane GC, Enders FT, Rodeheffer RJ,
Redfield MM. Age-associated increases in pulmonary artery
systolic pressure in the general population. Circulation. 2009;
9. Aronson D, Eitan A, Dragu R, et al. Relationship between
reactive pulmonary hypertension and mortality in patients with
acute decompensated heart failure. Circulation. Heart Fail.
10. Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT,
Redfield MM. Pulmonary hypertension in heart failure with
preserved ejection fraction: a community-based study. J Am
Coll Cardiol. 2009;53(13):1119-1126.
11. Patel NM, Lederer DJ, Borczuk AC, Kawut SM. Pulmonary
hypertension in idiopathic pulmonary fibrosis. Chest. 2007;
12. 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):
13. 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.
CHEST / 143 / 3 / MARCH 2013

Downloaded From: by a VISN 1 New England Healthcare System User on 07/21/2014


14. Lang I, Gomez-Sanchez M, Kneussl M, et al. Efficacy of longterm subcutaneous treprostinil sodium therapy in pulmonary
hypertension. Chest. 2006;129(6):1636-1643.
15. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41.
16. 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.
17. Du L, Sullivan CC, Chu D, et al. Signaling molecules in
nonfamilial pulmonary hypertension. N Engl J Med. 2003;
18. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing
the areas under two or more correlated receiver operating
characteristic curves: a nonparametric approach. Biometrics.
19. Heinzl H, Kaider A. Gaining more flexibility in Cox proportional hazards regression models with cubic spline functions.
Comput Methods Programs Biomed. 1997;54(3):201-208.
20. Schemper M, Smith TL. A note on quantifying follow-up
in studies of failure time. Control Clin Trials. 1996;17(4):
21. Simonneau G, Robbins IM, Beghetti M, et al. Updated
clinical classification of pulmonary hypertension. J Am Coll
Cardiol. 2009;54(suppl 1):S43-S54.
22. 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;
23. 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;

24. Manzano L, Babalis D, Roughton M, et al; SENIORS Investigators. Predictors of clinical outcomes in elderly patients
with heart failure. Eur J Heart Fail. 2011;13(5):528-536.
25. 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.
26. Rich S, Rabinovitch M. Diagnosis and treatment of secondary
(non-category 1) pulmonary hypertension. Circulation. 2008;
27. 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.
28. Tandon HD, Kasturi J. Pulmonary vascular changes associated with isolated mitral stenosis in India. Br Heart J. 1975;
29. Capomolla S, Febo O, Guazzotti G, et al. Invasive and noninvasive determinants of pulmonary hypertension in patients
with chronic heart failure. J Heart Lung Transplant. 2000;
30. Tedford RJ, Hassoun PM, Mathai SC, et al. Pulmonary capillary
wedge pressure augments right ventricular pulsatile loading.
Circulation. 2012;125(2):289-297.
31. Chemla D, Castelain V, Herve P, et al. Haemodynamic evaluation of pulmonary hypertension. Eur Respir J. 2002;20(5):
32. Harvey RM, Enson Y, Ferrer MI. A reconsideration of the
origins of pulmonary hypertension. Chest. 1971;59(1):82-94.
33. McGinn TG, Guyatt GH, Wyer PC, Naylor CD, Stiell IG,
Richardson WS; Evidence-Based Medicine Working Group.
Users guides to the medical literature: XXII: how to use
articles about clinical decision rules. JAMA. 2000;284(1):


Downloaded From: by a VISN 1 New England Healthcare System User on 07/21/2014

Original Research