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Original Research
PULMONARY VASCULAR DISEASE
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
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
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759
Results
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 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.
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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
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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.
Out-of-Proportion PH
Severity/Characteristic
NYHA/WHO functional class
I
II
III
IV
Coronary artery disease
Systolic dysfunction
Diastolic dysfunction
Aortic stenosis
Aortic regurgitation
Mitral stenosis
Mitral regurgitation
COPD
GOLD I
GOLD II
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.
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Original Research
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
0
35.1 38.5
34.7 19.2
13.8 35
12.5 23.1
7.4 16.9
0
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.
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