|
 Reda
E. Girgis, MB, BCh
Assistant Professor of Medicine
Division of Pulmonary and Critical Care Medicine
Johns Hopkins University
Baltimore, Maryland
Since the discovery of hypoxic pulmonary vasoconstriction
six decades ago, respiratory physiologists and clinicians
have been fascinated by pulmonary hypertension in the
setting of chronic lung disease (Table
1). The term “cor pulmonale” indicates
an alteration in right ventricular structure and function
due to parenchymal lung disease. The Third World Symposium
on Pulmonary Arterial Hypertension grouped these conditions
under the heading “Pulmonary Hypertension Associated
with Lung Diseases and/or Hypoxemia.”1 While alveolar
hypoxia likely plays an important role, it has become
increasingly clear that these conditions do not simply
represent chronic hypoxic pulmonary hypertension. Despite
the widespread familiarity with cor pulmonale, its clinical
importance remains poorly characterized and likely underestimated.
This article will provide an overview of the most common
respiratory diseases associated with pulmonary hypertension
and recommendations for the diagnostic evaluation.
Table
1. Respiratory Diseases Causing Pulmonary Hypertension.
|
- Obstructive lung disease
- Chronic obstructive pulmonary disease (COPD)
- Cystic fibrosis/bronchiectasis
- Obliterative bronchiolitis
- Interstitial lung disease
- Connective tissue disease related
- Idiopathic interstitial pneumonias
- Idiopathic pulmonary fibrosis
- Nonspecific interstitial pneumonia
- Others
- Sarcoidosis
- Langerhans cell histiocytosis
- Lymphangioleiomyomatosis
- Others
- Alveolar hypoventilation
- Obesity-hypoventilation syndrome
- Thoracic cage disorders
- Kyphoscoliosis
- Neuromuscular disease
- Sleep-disordered breathing
- Obstructive sleep apnea (OSA)
- Central sleep apnea
- Overlap syndrome (COPD in combination with
OSA)
- Chronic exposure to high altitude
- Developmental abnormalities/neonatal lung
disease
|
Chronic Obstructive Pulmonary
Disease
The exact prevalence of pulmonary hypertension in chronic
obstructive pulmonary disease (COPD) is unclear. In
very advanced disease (GOLD stage IV: FEV1 <30% predicted
or <50% and associated with chronic hypoxemia and/or
hypercapnia), the prevalence may be as high as 66%.2
On average, pulmonary hypertension is mild in severity
(mPAP 25 to 35 mm Hg) with preserved right ventricular
function (Table 2).
Table
2. Pulmonary Hemodynamics in 178 Hypoxemic COPD
Patients.*
|
|
Room Air
|
Oxygen
|
| Right atrial pressure (mm Hg) |
| Rest |
5 (3)
|
6 (3)
|
| Exercise |
13 (6)
|
12 (6)^
|
| Mean pulmonary artery pressure
(mm Hg) |
| Rest |
29 (10)
|
28 (10)^
|
| Exercise |
50 (16)
|
45 (14)^
|
| Pulmonary artery wedge pressure
(mm Hg) |
| Rest |
9 (5)
|
10 (6)
|
| Exercise |
18 (8)
|
17 (9)^
|
| Cardiac index (L/min-m2) |
| Rest |
2.9 (0.6)
|
2.8 (0.6)^
|
| Exercise |
4.1 (0.9)
|
4.0 (0.8)
|
| Pulmonary vascular resistance (dyne.s.cm-5) |
| Rest |
330 (164)
|
323 (174)
|
| Exercise |
367 (182)
|
337 (161)^
|
*Adapted from Timms RM, Khaja FU, Williams GW. Hemodynamic
response to oxygen therapy in chronic obstructive
pulmonary disease. Ann Intern Med.1985;102(1):29-36.
Mean values with standard deviations are in parentheses.
All patients had room air PaO2 </=55 mm Hg or
</=59 in conjunction with signs of right heart
failure or polycythemia. P<.01 for all comparisons
between rest and exercise while breathing room air.
^ P<.01 compared with room air.
|
Vascular Remodeling
Although alveolar hypoxia with resultant pulmonary vasoconstriction
is important, the lack of complete reversibility in
response to oxygen or nitric oxide inhalation indicates
that acute hypoxic vasoconstriction is not the sole
determinant of pulmonary hypertension in these patients.
Chronic hypoxia induces neomuscularization of previously
nonmuscularized pulmonary arterioles and medial hypertrophy
of small muscular pulmonary arteries. A prominent feature
of the vascular remodeling of COPD–related pulmonary
hypertension is intimal thickening by longitudinally
oriented smooth muscle cells with abundant extracellular
deposition of collagen and elastin (intimal fibroelastosis).
These changes have also been described in mild, normoxemic
COPD patients without pulmonary hypertension and in
asymptomatic smokers.3 Small vessel thrombi and/or emboli
may also occur. Medial hypertrophy, on the other hand,
is prominent only in the setting of established pulmonary
hypertension.4 These findings suggest that intimal changes
are not sufficient to produce pulmonary hypertension
at rest, but could contribute to luminal narrowing as
medial hypertrophy develops with progressive disease.
Mechanisms for Vascular Remodeling
Pulmonary arterial rings of COPD patients have impaired
endothelial-dependent vasodilatation5 and expression
of endothelial nitric oxide synthase (eNOS) is reduced
in advanced disease as well as in asymptomatic smokers.3
Exhaled nitric oxide has also been shown to be reduced
in COPD patients with pulmonary hypertension.6 There
may also be a link between certain polymorphisms in
the eNOS or ACE genes and pulmonary hypertension in
COPD.7 Excretion of prostacyclin metabolites is decreased
in COPD patients with pulmonary hypertension.8 Pulmonary
vascular expression of endothelin-1 is increased in
established pulmonary hypertension9, but not in early
disease. 10 Recent studies suggest an important role
for serotonin (5-HT) and its transporter (5-HTT) in
the vascular smooth muscle hyperplasia of pulmonary
hypertension. The 5-HTT LL genotype, which is linked
with greater 5-HTT expression, was associated with significantly
higher pulmonary artery pressure in COPD patients compared
with the other polymorphisms.11 A correlation between
small airway inflammation and vascular remodeling has
also been demonstrated.3 Increased CD8 lymphocytes were
detected in the adventitia of small muscular arteries
of mild COPD patients and smokers and correlated with
intimal thickening and endothelial dysfunction. These
findings raise the possibility that smoking can have
direct effects on the pulmonary vasculature.
Clinical Impact of Pulmonary Hypertension in Chronic
Obstructive Pulmonary Disease
Despite the relatively modest nature of pulmonary
hypertension in COPD, its presence clearly has an adverse
impact on survival. Oswald-Mammosser et al reported
a 5-year survival of 36% among severe COPD patients
whose mPAP exceeded 25 mm Hg compared with 62% in those
without pulmonary hypertension. 12 Pulmonary function
and blood gas variables were not predictive of survival.
Although several studies have demonstrated increased
mortality in COPD patients with pulmonary hypertension,
it remains unclear whether the pulmonary hypertension
is a cause of death or simply a marker of underlying
disease severity.
Interstitial Lung Diseases
Connective Tissue Diseases
Interstitial lung disease is the most common pulmonary
manifestation of scleroderma, or systemic sclerosis.
Patients with systemic sclerosis can develop pulmonary
arterial hypertension as a ¡°primary¡±
vascular process or pulmonary hypertension secondary
to more extensive pulmonary fibrosis. In either case,
the presence of pulmonary hypertension is a poor prognostic
sign in these patients. An abrupt worsening in symptoms,
hypoxemia, and DLCO in a patient with pulmonary fibrosis
should arouse suspicion for pulmonary hypertension.
A recent review of 619 patients by the Johns Hopkins
Scleroderma Center demonstrated that the prevalence
of pulmonary hypertension increased with worsening restrictive
ventilatory defect. Importantly, longterm survival of
patients with combined pulmonary hypertension and interstitial
lung disease was similar to that in patients
with isolated pulmonary hypertension and significantly
worse than that in isolated interstitial lung disease.13
Idiopathic Pulmonary Fibrosis
Limited available data suggest that both the prevalence
and the severity of pulmonary hypertension in idiopathic
pulmonary fibrosis are greater compared with COPD. In
a study of lung transplant candidates, 59% of 106 with
idiopathic pulmonary fibrosis had a pulmonary artery
systolic pressure ¡Ý45 mm Hg compared with
only 18% of 253 COPD patients.14 While exercise-induced
elevation in pulmonary artery pressure is common in
COPD, it appears to be a more consistent finding in
idiopathic pulmonary fibrosis and is not associated
with a rise in pulmonary artery wedge pressure.15 Moreover,
a sizable proportion of unselected idiopathic pulmonary
fibrosis patients have moderate to severe pulmonary
hypertension. Leuchte et al reported that 6 of 28 consecutive
patients had an mPAP >35 mm Hg.16
Pulmonary hypertension is clearly a poor prognostic
factor in idiopathic pulmonary fibrosis. Bishop and
Cross demonstrated that mPAP was the single most important
predictor of mortality. 17 Patients with an mPAP ¡Ý30
mm Hg had a 5-year mortality of 82% compared with 35%
and 26% among those with an mPAP between 20 and 29 mm
Hg and <20 mm Hg, respectively. In another large
study, the presence of signs of pulmonary hypertension
on a plain chest radiograph had equal power in predicting
mortality as a total lung capacity <50% of predicted
or a maximal exercise PaO2 <35 mm Hg. The mechanisms
of pulmonary hypertension in idiopathic pulmonary fibrosis
may differ from those in COPD, reflecting more profound
structural vascular remodeling. Pathologically, the
vasculopathy of idiopathic pulmonary fibrosis differs
from COPD in that the intimal lesion can progress to
Figure 1. Pulmonary hypertension in idiopathic
pulmonary fibrosis. Vascular intimal fibrosis with
luminal obliteration (arrow) in a region involved
by interstitial fibrosis and chronic inflammation.
Courtesy of Dr. Rubin Tuder, Johns Hopkins University.
|
acellular fibrosis with luminal obliteration (Figure
1).19 A weak correlation with PaO2 suggests a relatively
minor role for hypoxia.15 Alterations in vasoactive
mediators similar to what is seen in idiopathic pulmonary
arterial hypertension, such as increased expression
and circulating levels of endothelin-120,21 have also
been demonstrated.
Sarcoidosis, Langerhans Cell Histiocytosis, and
Lymphangioleiomyomatosis
While these diseases are considered interstitial
lung diseases, they have been grouped separately1 because
of the apparent greater frequency and severity of pulmonary
hypertension observed in these groups. Active vascular
granulomatous inflammation and/or healed lesions are
a universal finding in sarcoidosis.22 The extent of
vascular involvement may be related to the degree of
parenchymal disease, corresponding to the clinical observation
that overt pulmonary hypertension is uncommon with stage
0-II disease.
On the other hand, sarcoidosis with significant vascular
involvement has also been noted. In a large review of
lung transplant candidates, Shorr and coauthors reported
mPAP of 34 mm Hg among 289 sarcoid patients, significantly
higher than the average mPAP (25 mm Hg) in their idiopathic
pulmonary fibrosis patients.23 Patients who died awaiting
lung transplantation had an average mPAP of 41 mm Hg
compared with 32 mm Hg among survivors.
A prominent proliferative, inflammatory vasculopathy
with occasional Langerhans cells involving both arteries
and veins is well described in Langerhans cell histiocytosis.
Fartoukh et al reported on 21 consecutive patients referred
for lung transplantation, all with very severe pulmonary
hypertension (mPAP 59 mm Hg).24 Two had clinical manifestations
of venular obstruction. Although advanced parenchymal
disease was present, there was no relationship between
pulmonary function and mPAP. Moreover, vascular remodeling
was observed in regions unaffected by parenchymal lesions
and progressed on serial lung biopsies independent of
the interstitial and bronchiolar processes.
Sleep-Disordered Breathing
The relationship between obstructive sleep apnea and
pulmonary hypertension has recently been reviewed.25
The prevalence has been estimated to be approximately
20% with mostly borderline to mild pulmonary hypertension
(mPAP <25 to 30 mm Hg). Increasing body-mass index
and more severe nocturnal desaturation are linked to
pulmonary hypertension in obstructive sleep apnea, whereas
the apnea-hypopnea index is not. Most studies have failed
to exclude patients with associated
COPD (overlap syndrome) and the obesity-hypoventilation
syndrome, two commonly associated conditions that can
independently cause pulmonary hypertension and augment
the propensity for obstructive sleep apnea to contribute
to pulmonary hypertension.
The Strasbourg group recently reviewed their experience
with these subsets.26 Among 181 patients with pure severe
obstructive sleep apnea (apnea-hypopnea index: 73/h)
without comorbid conditions, mPAP was 15 ¡À
5 mm Hg and only 9% had mPAP ¡Ý20. In contrast,
27 obesity-hypoventilation syndrome patients, defined
as having a body mass index >30 and PaCO2 >45
mm Hg, had mPAP of 23 ¡À 10 mm Hg and 59%
had mPAP ¡Ý20. Overlap patients had intermediate
values. It thus appears that abnormal daytime lung function
and gas exchange are required to develop significant
pulmonary hypertension in the setting of sleep disordered
breathing.
Diagnostic Evaluation of Pulmonary
Hypertension in Lung Disease
Traditionally, clinicians have not aggressively
pursued the diagnosis of pulmonary hypertension in chronic
respiratory diseases, probably because of the lack of
effective therapy. With the increasing array of drugs
for pulmonary arterial hypertension, there is the potential
of treating some of these patients. Existing data on
pulmonary hypertension therapies in this setting are
discussed in an accompanying article. A proper diagnostic
evaluation for pulmonary hypertension is important to:
1) identify other treatable causes for pulmonary hypertension
(eg, left heart disease, chronic thromboembolic disease);
2) help delineate the basis for symptoms; 3) provide
prognostic information that may guide decisions such
as lung transplantation; and 4) guide the aggressiveness
of certain interventions such as oxygen supplementation
and nocturnal positive pressure ventilation.
Routine Clinical Assessments
While difficult to assess, dyspnea and fatigue seemingly
out of proportion to the degree of respiratory impairment
should raise the suspicion of superimposed pulmonary
hypertension. Physical signs may often be obscured by
hyperinflation or obesity. Enlargement of the central
pulmonary arteries on chest radiography increases the
likelihood that pulmonary hypertension is present, but
is not sufficiently accurate to make a confident diagnosis.
With right ventricular enlargement, the heart takes
on a globular appearance and encroaches on the retrosternal
airspace on the lateral view. If severe hyperinflation
is present, this may be difficult to appreciate.
Using computed tomography, a main pulmonary artery
diameter ¡Ý29 mm was a good predictor for
pulmonary hypertension in parenchymal lung disease,
with sensitivity and specificity of 84% and 75%, respectively.27
The combination of main pulmonary artery enlargement
and a segmental artery/bronchus ratio of >1 in 3
lobes increased the specificity to 100%. Electrocardiographic
signs of cor pulmonale are also useful, but have low
sensitivity.
Correlations between the degree of obstructive or restrictive
ventilatory defect and pulmonary hypertension are only
modest. The DLCO, which is mainly determined by the
pulmonary capillary blood volume, is often severely
reduced when pulmonary hypertension complicates lung
disease. Among emphysema patients considered for lung
volume reduction, DLCO was the only pulmonary function
variable that correlated with pulmonary vascular resistance.2
The DLCO corrected for alveolar volume (DL/VA) appears
to be a more sensitive indicator of pulmonary vascular
involvement in idiopathic pulmonary fibrosis.19 Severe
hypoxemia should also raise the suspicion of pulmonary
hypertension. When daytime hypoxemia and moderate to
severe hypercapnia (PaCO2 >50 mm Hg) are present,
some degree of pulmonary hypertension is expected.
Cardiac Imaging
Echocardiography for assessing pulmonary hypertension
in patients with lung disease is problematic.14 Because
of anatomical factors, particularly hyperinflation,
estimation of right ventricular systolic pressure (RVSP)
is not possible in many patients. When RVSP can be estimated,
it is often inaccurate, frequently >10 to 20 mm Hg
different from the measured
value at right heart catheterization. Similar findings
have been observed in emphysema patients evaluated for
lung volume reduction surgery (Figure
2). Estimation of RVSP was possible in only one
third of these patients. In contrast, adequate visualization
of the right ventricle is possible in most patients.
The absence of right ventricular abnormalities had a
negative predictive value of 90%.14 Surprisingly, the
specificity was quite low at 57%, yielding a positive
predictive value of only 39%. Other indices such as
the right ventricular outflow tract acceleration time
and isovolumic relaxation time have been shown to be
useful.28 Cardiac magnetic resonance imaging is gaining
interest as a potentially superior imaging technique
compared with echocardiography, particularly for the
right ventricle, although more data are needed before
cardiac magnetic resonance imaging can be routinely
recommended.
Figure 2. Bland-Altman plot of pulmonary
artery systolic pressure (PASP) in 53 patients in
the National Emphysema Treatment Trial. The x-axis
is the average of the Doppler echocardiogram (DE)
estimate and the right heart catheterization (RHC)
measurement of the PASP and the y-axis is the difference
between the two measurements for each paired observation.
DE, on average, overestimates the measured PASP
(bias = 2.86 mm Hg.) The 95% limits of agreement
were -18.5 mm Hg and 24.2 mm Hg. Courtesy of Dr.
Micah Fisher, Johns Hopkins University (submitted
for publication). |
Cardiopulmonary Exercise Testing
When resting pulmonary hemodynamics are normal,
moderate exercise during right heart catheterization
or echocardiography may uncover exercise-induced pulmonary
hypertension. However, normal values for exercise pulmonary
artery pressure are not well defined and changes in
left heart filling pressures are difficult to gauge.
Moreover, the clinical significance of isolated exercise-induced
pulmonary hypertension is not clear. Oxygen desaturation
with exercise frequently accompanies pulmonary hypertension
associated with lung disease. Formal cardiopulmonary
exercise testing, on the other hand, may be useful in
distinguishing a ventilatory from a cardiovascular limitation
to exercise.
Brain Natriuretic Peptide
The plasma brain natriuretic peptide level appears to
be an emerging tool in detecting pulmonary hypertension
in chronic lung disease. In one study of pulmonary fibrosis
patients, plasma level was 242 ¡À 66 pg/mL
among 11 patients with moderate to severe pulmonary
hypertension (mPAP >35 mm Hg) compared to 24 ¡À
6 in the other 28 subjects.16 Using a cut-off value
of 33 (normal <18), the sensitivity and specificity
for moderate to severe pulmonary hypertension was 100%
and 89%, respectively. Brain natriuretic peptide level
was strongly correlated with pulmonary vascular resistance.
Sleep Study
A polysomnogram should be obtained in patients with
any clinical suggestion of sleep disordered breathing.
Screening for obstructive sleep apnea with portable
devices may be feasible, but has not been studied in
patients with comorbidities. While the importance of
isolated nocturnal desaturation in the pathogenesis
of pulmonary hypertension is controversial, it seems
prudent to consider overnight oximetry in patients with
established pulmonary hypertension and mild daytime
hypoxemia (PaO2 of 60 to 70 mm Hg). Exercise-induced
desaturation cannot be used to predict nocturnal desaturation.29
Right Heart Catheterization
Given the still limited utility of noninvasive techniques,
right heart catheterization is required to confirm a
diagnosis and determine severity of pulmonary hypertension.
Whether or not to perform right heart catheterization
on a patient with lung/respiratory disease is really
dictated by clinical judgment. If one feels that the
pulmonary hypertension is potentially treatable with
specific medications, performance of catheterization
seems reasonable. Although acute vasodilator testing
is recommended in patients with idiopathic pulmonary
artery hypertension, there is no indication for such
a study in patients with pulmonary hypertension and
lung disease.
When Is Pulmonary Hypertension ¡°Out of
Proportion¡± to Degree of Lung Disease?
Given the availability of effective medications
for pulmonary artery hypertension, this is a clinically
important question. The pulmonary vascular response
can vary widely among individuals exposed to similar
insults. From a clinical practice perspective, the question
being posed is: Is the pulmonary hypertension completely
the result of the respiratory condition and, therefore,
treatment should be focused on the latter or is there
to some extent an independent pulmonary vascular process
that can be targeted by specific pulmonary hypertension
therapies? Although no hard answers exist, some general
guidelines can be made based on the reported severity
of pulmonary hypertension in the setting of various
conditions. Pulmonary hypertension can be classified
as follows: mild (mPAP 25 to 34 mm Hg); moderate (mPAP
35 to 44 mm Hg); or severe (mPAP ¡Ý45 mm
Hg or any degree of pulmonary hypertension accompanied
by evidence of right ventricular failure).
Moderate to severe pulmonary hypertension is rare in
pure obstructive sleep apnea. Pulmonary hypertension
complicating COPD is not expected unless the FEV1 is
less than 50% of predicted and is typically mild to
moderate. However, in the presence of profound hypercapnia,
severe pulmonary hypertension is not uncommon. For these
diseases, treating the underlying hypoxemia and sleep
apnea should significantly improve the pulmonary hypertension.
In interstitial lung disease, on the other hand, moderate
to severe pulmonary hypertension usually occurs in the
setting of advanced parenchymal disease: total lung
capacity or forced vital capacity <50% of predicted
or with extensive radiographic changes. For sarcoidosis,
Langerhans cell histiocytosis, and lymphangioleiomyomatosis,
where a prominent obstructive component may exist, an
FEV1 <50% predicted typically accompanies significant
pulmonary hypertension. Advanced pulmonary hypertension
in the presence of underlying lung disease of less severity
raises the possibility of a primary vasculopathy.
Summary
Pulmonary hypertension is a common, yet often overlooked
complication of chronic respiratory diseases. While
often mild and overshadowed by the underlying condition,
pulmonary hypertension and right ventricular dysfunction
can dominate the clinical picture, particularly in certain
interstitial lung diseases. A diagnosis of pulmonary
hypertension has important prognostic implications and
helps delineate the basis for symptoms. Importantly,
newer therapies for pulmonary arterial hypertension
may prove to be useful in this setting. Further research
is needed to improve the diagnostic accuracy of noninvasive
testing and understand the pathogenesis of pulmonary
hypertension associated with lung disease.
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