Diagnosis and Treatment of Secondary (NonCategory 1) Pulmonary Hypertension

Stuart Rich and Marlene Rabinovitch

Circulation. 2008;118:2190-2199
doi: 10.1161/CIRCULATIONAHA.107.723007
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Pulmonary Vascular Diseases

Diagnosis and Treatment of Secondary (NonCategory 1)
Pulmonary Hypertension
Stuart Rich, MD; Marlene Rabinovitch, MD

ulmonary hypertension occurs commonly in cardiopulmonary disease. In 1998, a new clinical classification was
proposed that divided pulmonary hypertension into 5 categories on the basis of the presumed underlying etiology of the
pulmonary vascular disease1 (Table 1). Although it was never
intended that this classification be used as a guideline to
determine appropriate therapy, somewhat surprisingly, the
regulatory authorities decided that all medications that were
clinically tested and approved for patients with idiopathic
pulmonary arterial hypertension (PAH) and patients with
pulmonary hypertension associated with connective tissue
diseases be applied to all category 1 patients.2 The wisdom of
this can be debated at a later date. However, it has left
clinicians somewhat confused about the utilization of
therapies to treat patients who fall outside of category 1
pulmonary hypertension, often referred to as secondary
pulmonary hypertension.
There are 3 classes of approved therapies for PAH, all of
which are considered to be pulmonary vasodilators: endothelin receptor blockers, phosphodiesterase-5 inhibitors,
and prostacyclins.3 Their clinical efficacy has been based
on a short-term improvement in exercise tolerance, as
measured by a 6-minute walk test. In all of the clinical
trials, an improvement in walk was apparent within the
first 4 weeks of use, allowing a judgment about efficacy to
be made quickly.4 Hemodynamically, their effects are
modest, but they tend to raise cardiac output with little
effect on pulmonary artery pressure. This has important
implications when they are considered for unapproved use.
We review the distinctive features of these causes of
pulmonary hypertension and the data on the evidence that
supports or refutes the use of these therapies in non
category 1 pulmonary hypertension.

Category 2: Pulmonary Venous Hypertension

Patients with pulmonary venous hypertension have elevated
pulmonary venous pressure (as reflected in the pulmonary
capillary wedge pressure), most frequently as a consequence
of either mitral valve disease5 or left ventricular (LV)
diastolic dysfunction.6 Although mitral stenosis was the most
common cause of this entity decades ago, LV diastolic
dysfunction is the most common cause of pulmonary venous

hypertension seen in our referral practice.7 It is presumed that

the mechanism of both is similar. Specifically, a chronic
elevation in the diastolic filling pressure of the left heart
causes a backward transmission of the pressure to the
pulmonary venous system, which triggers vasoconstriction in
the pulmonary arterial bed.8
Histologically, abnormal thickening of the veins and
formation of a neointima are seen.9 The latter can be quite
extensive (Figure 1). As secondary features, medial hypertrophy and, with time, thickening of the neointima on the
arterial side of the pulmonary circulation occur as well.
There is great potential for reversibility of these changes
with improvement in the cause of the venous hypertension
(see below). The variability in the response of the pulmonary arterial circulation to the elevated venous pressure
indicates that genetic factors also dictate the potential
reversibility of the disease. We have shown experimentally
that insulin resistance, frequently observed in association
with impaired LV diastolic function, is independently
linked to the development of PAH.10 We also know that
when pulmonary venous hypertension is not the result of
LV diastolic dysfunction or obstruction at the level of the
mitral valve, (ie, pulmonary veno-occlusive disease), the
genetic etiology may be similar to that of idiopathic
pulmonary hypertension.11
The clinical profile of LV diastolic dysfunction has been
studied extensively and is characteristically observed in an
older patient with hypertension, diabetes, coronary artery
disease, and/or obesity.12 The clinical signs and symptoms
characteristic of pulmonary venous hypertension include
dyspnea with effort and eventually right ventricular (RV)
failure with edema, similar to category 1 PAH. However,
important and distinctive symptoms are orthopnea and
paroxysmal nocturnal dyspnea, which are not features
of PAH.13
Clinical tests will often reveal findings that suggest that the
patient likely has pulmonary venous hypertension and not
PAH (Table 2). The ECG may show LV hypertrophy rather
than RV hypertrophy. The chest x-ray will often show
pulmonary vascular congestion, pleural effusions, and, on
occasion, pulmonary edema. High-resolution chest computed
tomography can be helpful because it will often reveal

From the University of Chicago Pritzker School of Medicine, Chicago, Ill (S.R.); Stanford University School of Medicine, Stanford, Calif (M.R.); and
Pulmonary Vascular Research Institute, Chicago, Ill (S.R., M.R.).
Correspondence to Stuart Rich, MD, University of Chicago, Section of Cardiology, 5841 S Maryland Ave, MC 2016, Chicago, IL 60637. E-mail
srich@medicine.bsd.uchicago.edu
(Circulation. 2008;118:2190-2199.)
2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.107.723007

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Rich and Rabinovitch

Table 1. Current Clinical Classification of Pulmonary
Hypertension1
Category 1: PAH
Idiopathic
Familial
Pulmonary hypertension associated with:
Collagen vascular disease
Congenital systemic-to-pulmonary shunts
Portal hypertension
Drugs/toxins
HIV infection
Other (Gauchers, hereditary hemorrhagic telangiectasia,
hemoglobinopathies, splenectomy)
Associated with significant venous or capillary involvement
Pulmonary veno-occlusive disease
Pulmonary capillary hemangiomatosis
Persistent pulmonary hypertension of the newborn
Category 2: Pulmonary venous hypertension
Category 3: Pulmonary hypertension associated with disorders of the
respiratory system and/or hypoxemia
Category 4: Pulmonary hypertension due to chronic thrombotic and/or
embolic disease
Category 5: Pulmonary hypertension due to miscellaneous disorders directly
affecting the pulmonary vasculature, eg, sarcoidosis, histocytosis X,
lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor,
fibrosing mediastinitis)

ground-glass opacities and a mosaic perfusion pattern consistent with chronic pulmonary edema.
Essential in the evaluation of these patients is an echocardiogram, which readily allows the assessment of LV systolic
function. It has been emphasized that the differentiation
between systolic and diastolic dysfunction cannot be made on
the basis of the history, physical examination, or chest
x-ray.14 Pulmonary hypertension occurring in the setting of a
reduced LV ejection fraction has been well described and
appears to be one of the most powerful predictors of prognosis for patients with LV failure.15 The echocardiogram will
also detect any significant underlying mitral or aortic valve
disease.16,17 Doppler echocardiography is widely used to
assess diastolic dysfunction in patients with both normal and
reduced LV systolic function.18 However, because pulmonary
hypertension itself produces diastolic filling abnormalities in
the LV, Doppler echocardiography cannot be relied on to
distinguish between category 1 and category 2 pulmonary
hypertension.19
Demonstration of an elevated pulmonary capillary wedge
pressure at cardiac catheterization should secure the diagnosis
of pulmonary venous hypertension. However, this determination is often imprecisely made20 because it is frequently
difficult to get an accurate wedge pressure. Obtaining a blood
sample for determination of oxygen saturation can be helpful
in confirming that the catheter is in the wedged position.21 We
have found that measurement of LV end-diastolic pressure
(LVEDP) at the time of initial diagnosis is very helpful in

Secondary Pulmonary Hypertension

2191

confirming the wedge pressure measurement. In patients with

severe RV failure, the effect of pericardial constraint and
transmission of elevated RV filling pressure across the
intraventricular septum may also be a factor. Some patients
can have a markedly augmented a wave that can raise the
LVEDP above the pulmonary capillary wedge pressure. An
accurate assessment of LVEDP or pulmonary capillary
wedge pressure can only be made at end expiration; using
a digitally derived mean pulmonary capillary wedge pressure will generally yield erroneous information and often a
misclassification of the patient as having normal filling
pressures22 (Figure 2).
Two hemodynamic profiles have been described that are
common in these patients. Some patients will have an
elevation in pulmonary arterial pressure with only a minimal
increase in the transpulmonary gradient (mean pulmonary
arterial pressurepulmonary capillary wedge pressure), as a
reflection of the passive increase in pulmonary arterial
pressure necessary to overcome the increased downstream
resistance (Figure 3A). Indeed, a preserved right ventricle
must generate high systolic pressures to ensure adequate
forward blood flow in these patients, and thus moderate
degrees of pulmonary hypertension are not only characteristic
but also favorable. However, a subset of these patients will
have reactive pulmonary vasoconstriction, resulting in
marked elevations in pulmonary arterial pressure beyond that
which is necessary to maintain cardiac output. These patients
are frequently distinguished by a marked elevation in pulmonary arterial diastolic pressure (Figure 3B). This has been
studied extensively in patients with mitral stenosis and is less
well characterized in patients with LV diastolic dysfunction.
It is believed that these patients have a permissive genotype
that, when exposed to high pulmonary venous resistance,
develops reactive pulmonary hypertension with more severe
arterial changes, including neointima formation, than the
other subgroup.23
A normal LVEDP at rest may, however, still be present in
patients with LV diastolic dysfunction.24 When this occurs in
the setting of reactive pulmonary hypertension, it is very
difficult to know whether these patients have PAH or pulmonary venous hypertension. Using exercise,25 a vasodilator
challenge,26 or an inotropic challenge27 at the time of diagnostic cardiac catheterization to increase the cardiac output
may be helpful. If a significant increase in cardiac output is
unaccompanied by an increase in pulmonary capillary wedge
pressure, the patient more likely has PAH. On the other hand,
if the increase in cardiac output is accompanied by an
increase in pulmonary capillary wedge pressure, the patient
likely has pulmonary venous hypertension. Interestingly,
experimental studies indicate that an elevation in mean
pulmonary arterial pressure may actually precede an elevation in pulmonary venous pressure.28 Thus, there may be no
definitive way to identify pulmonary venous hypertension
hemodynamically in some patients.
Treatment of these patients remains uncertain. Lessons
learned from treating patients with mitral stenosis can be
instructive. Patients with mitral stenosis who present with
pulmonary edema will respond to the use of diuretics as a
temporizing measure before the definitive therapy of mitral

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Figure 1. Pulmonary occlusive venopathy. A, Septal veins with nearly occluded

lumens by fibrous intimal thickening
(asterisk), marked lymphatic dilation
(arrow), and congested alveolar capillaries. Verhoeffvan Gieson stain; magnification 50. B, Obstructive fibrous intimal thickening and recanalization
channels in a septal vein; pulmonary
microvasculopathy. Magnification 200.
C, Focal thickening of alveolar septa by
proliferated capillaries. Hematoxylineosin stain; magnification 20. D, Nodular capillary proliferation, hemosiderinladen alveolar macrophages, and type II
pneumocytes (arrows); pulmonary
venous disease. Hematoxylin-eosin
stain; magnification 300. Reprinted
from Pietra et al,79 with permission from
Elsevier. Copyright 2004, American College of Cardiology Foundation.

valve repair or replacement. Several clinical studies have

shown that removing the mitral valve gradient, either surgically or percutaneously, will result in an immediate fall in the
pulmonary artery pressure.29 32 The magnitude of the fall,
however, can be quite variable, with some patients achieving
normal hemodynamics within 24 hours, and others taking
many months to improve. The magnitude and rate of improvement may be related to the severity of the vascular
disease dictated by both the duration of the pulmonary
hypertension and genetic factors that either induce more
severe vascular disease or impede regeneration and remodeling after removal of the mitral valve obstruction. It is likely
that these same issues are relevant to pulmonary hypertension
in patients with LV diastolic dysfunction.
A review of the management of LV systolic failure in
patients with coexisting pulmonary hypertension is beyond
the scope of this article. However, a few important points are
worth mentioning. Regarding the approved treatments for
category 1 pulmonary hypertension, bosentan has been demonstrated to be ineffective in patients with systolic heart
failure,33 and epoprostenol was associated with increased
mortality in patients with systolic heart failure.34 In contrast,
patients with systolic heart failure and elevated pulmonary
capillary wedge pressures tolerate the acute administration of
sildenafil with a trend toward beneficial hemodynamic
changes.35 Sildenafil has also been shown to be associated
with improvement in measures of exercise performance when
added to existing therapy in patients with systolic heart
failure and pulmonary hypertension.36
Chronic pulmonary vasodilator therapy has not been successful in patients with mitral stenosis and is unlikely to be

beneficial in patients whose pulmonary hypertension is a

result of LV diastolic dysfunction. Because the major hemodynamic effect of these therapies is to raise cardiac output, it
will predictably cause a worsening of pulmonary edema if the
pulmonary venous obstruction is not being relieved. There are
multiple reports of rapid deterioration and death when pulmonary vasodilators are used in the presence of pulmonary
venous hypertension.3739
There are no randomized clinical trials of pulmonary
vasodilator therapy for patients with pulmonary venous hypertension associated with normal LV systolic function, and
no treatment has yet been shown to favorably affect patients
with pulmonary hypertension associated with LV diastolic
heart failure. Our approach to treating these patients has been
to use medical measures to lower LV filling pressures (such
as nitrates, diuretics, and aggressive treatment of systemic
hypertension). When successful, we have found that the
pulmonary arterial pressure will also fall, and the cardiac
output will increase. Given the expense of the approved
treatment with pulmonary vasodilators and the potential for
clinical deterioration, we believe that these treatments should
only be considered in the setting of a supervised clinical trial.

Category 3: Patients With Pulmonary

Hypertension Associated With Lung Disease
Pulmonary hypertension occurs in patients with lung disease.
However, because it would be inappropriate to characterize
all cardiac disease associated with pulmonary hypertension as
similar, it would be equally inappropriate to characterize all
lung diseases associated with pulmonary hypertension as

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Table 2.

Diagnosis of Category 2 Pulmonary Hypertension

Clinical Assessment
Symptoms

Features of Pulmonary Venous

Hypertension
Orthopnea
Paroxysmal nocturnal dyspnea

Signs

Elevated jugular venous

pressure
Edema

ECG

RV hypertrophy may be absent

LV hypertrophy may be present

Chest x-ray

Pulmonary vascular congestion

Pulmonary edema
Pleural effusions

Chest CT scan

Mosaic perfusion pattern

Ground-glass opacities

Echocardiogram

RV enlargement
Elevated pulmonary arterial
pressure by Doppler
Aortic or mitral valve disease
Reduced or normal LV ejection
fraction

Cardiac catheterization

With reduced LV systolic

function
Normal or elevated PCWP
Normal or reduced cardiac
output
Features of aortic or mitral
valve disease
With normal LV systolic
function
Elevated PCWP
Normal PCWP and normal
cardiac output (consider
challenge with exercise or
short-acting pulmonary
vasodilator)
Normal PCWP and reduced
cardiac output (consider
challenge with exercise or
inotropic agents)

CT indicates computed tomographic; PCWP, pulmonary capillary wedge

pressure.

similar. The most commonly encountered lung disease,

chronic obstructive pulmonary disease (COPD), has quite
different clinical manifestations than interstitial lung disease
(ILD). In both COPD and ILD, there are changes in the distal
pulmonary arterial vessels related to hypoxia similar to those
observed in experimental animals40 and in high-altitude
dwellers, as well as changes due to the loss of lung parenchyma.41 Hypoxia induces muscularization of distal vessels
and medial hypertrophy of more proximal arteries as well as
a loss of vessels, which is compounded by a loss of lung
parenchyma in the setting of lung disease. Neither neointima
formation nor the development of plexiform lesions is observed.42 However, in patients with mild COPD in association

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with smoking, severe fibroproliferative neointimal formation

can be observed (Figure 4).
Clinically, patients with COPD will present with dyspnea
and signs of right heart failure, usually in the setting of
marked hypoxemia. Pulmonary function tests and chest
computed tomographic imaging are helpful in making a
diagnosis in these patients. At cardiac catheterization, the
level of the pulmonary hypertension typically is relatively
mild. Indeed, the mean pulmonary arterial pressure seen in
these patients is usually lower than the mean pulmonary
arterial pressure obtained in patients with PAH who respond
favorably to pulmonary vasodilator therapy.43 The fact that
these patients are clinically failing may indicate that it is not
the severity of the pulmonary hypertension but the degree of
hypoxemia that is determining their clinical symptomatology.44 When RV failure occurs at this level of pulmonary
hypertension, it is probable that the RV in these patients is
adversely affected by the hypoxemia and behaves more like
an ischemic RV than a pressure-loaded RV.45 Pulmonary
hypertension in COPD patients can also be affected by
additional factors, including acidemia, hypercarbia, compression of pulmonary vessels by high lung volume, loss of small
vessels in the vascular bed of regions of emphysema and lung
destruction, and increased cardiac output and blood viscosity
from polycythemia secondary to hypoxia.46
Although relatively mild, the level of the PAH is predictive
of prognosis in patients with COPD.44,47,48 Nonetheless, there
has never been a clinical trial showing a sustained beneficial
effect of any pulmonary vasodilator in these patients. Worsening ventilation-perfusion mismatch from vasodilators has
been demonstrated with short-term use and is justification for
why these medications are not used.49 The only effective
treatment for patients with COPD and pulmonary hypertension has been supplemental oxygen, with several studies
showing an improvement in morbidity and mortality.50,51
Clinicians also need to monitor the level of hemoglobin in
these patients. Patients with hypoxemia should have reactive
polycythemia as a basic biological mechanism to compensate
for their cardiopulmonary disease. A hemoglobin level in the
low-normal range, although well tolerated in patients with
normal oxygenation, may not be tolerated in patients with
hypoxemia and pulmonary hypertension.
There is a subset of patients with COPD (5%) who
develop severe PAH (mean pulmonary arterial pressure
45 mm Hg).52 Their clinical characteristics have been
described. These patients have a distinctive pattern of cardiopulmonary abnormalities with mild to moderate airway obstruction, severe hypoxemia, hypocapnia, and a very low
diffusing capacity for carbon monoxide. These observations
suggest that a different biological mechanism results in
changes in the pulmonary vascular bed in susceptible patients
and that severe pulmonary hypertension occurs in the presence of lung disease rather than as a result of the lung disease.
For example, a genetic predisposition to pulmonary hypertension in COPD patients as a result of a 5-HTT polymorphism has been described, which may predispose to more
severe pulmonary hypertension in hypoxemic patients.53
These patients have a hemodynamic profile more typical of
PAH with a dramatic increase in pulmonary arterial pressure,

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Figure 2. Pulmonary capillary wedge tracing in a patient with respiratory variation. The correct pressure is measured at end expiration.
In this case, the digitally derived mean pressure, 7 mm Hg, is 50% of the actual end-expiratory wedge pressure of 15 mm Hg.

normal pulmonary capillary wedge pressures, and markedly

elevated pulmonary vascular resistance. There are no data
regarding whether pulmonary vasodilators have any clinical
benefit in this subset of patients.
ILD can also be associated with pulmonary hypertension.54
The majority of these patients will have an underlying
connective tissue disease. Patients without diagnostic findings of a connective tissue disease are considered to have
idiopathic pulmonary fibrosis. Patients with connective tissue
disease (eg, scleroderma) represent an additional diagnostic
challenge.55 Approximately 20% of those who have pulmonary fibrosis will have pulmonary hypertension, and 20%
of those without pulmonary fibrosis will also have pulmonary
hypertension.56 This makes it often uncertain if the pulmonary hypertension is due to the lung disease, pulmonary
vascular disease, or both.57 Most series show that a marked
reduction in diffusing capacity for carbon monoxide is a
consistent feature of the patients with connective tissue
diseases who have pulmonary hypertension,58,59 but it does
not correlate with the degree of pulmonary fibrosis.
The hemodynamic profile of patients with ILD (without
scleroderma) and pulmonary hypertension is quite distinct
from that of patients with idiopathic PAH.60 62 It is rare for
the mean pulmonary arterial pressure ever to be 40 mm Hg
in these patients, whereas it is rare for the mean pulmonary
arterial pressure ever to be 40 mm Hg in patients with
idiopathic PAH. Consequently, the combination of an abnormality consistent with ILD on the chest computed tomographic scan and mild pulmonary hypertension should point
to the diagnosis of pulmonary hypertension associated with
ILD and not idiopathic PAH.

Most therapies for ILD have been directed toward halting

progression or inducing regression of the interstitial disease
process with immunosuppressive and anti-inflammatory
agents.63 Overall, the results of these trials have been disappointing, which makes the treatment of any associated pulmonary hypertension an attractive therapeutic target. However, although pulmonary vasodilator therapy has been
available for decades, there are no randomized clinical trials
showing benefit of these agents in ILD. One rationale for
their use has been to reduce the effects of chronic hypoxic
vasoconstriction. In hypoxic rabbits, it has been demonstrated
that sildenafil can prevent the development of RV hypertrophy, and iloprost was able to prevent the development of
PAH.64 One clinical study compared the acute effects of
inhaled nitric oxide, intravenous epoprostenol, and oral sildenafil in 16 patients with pulmonary fibrosis in which
improved gas exchange was noted with the oral sildenafil but
not the intravenous prostacyclin.65 Recent results of a randomized clinical trial with bosentan showed no effect on the
primary end point, the 6-minute walk test.66 Given their
potential to cause worsening gas exchange, we strongly
caution against their anecdotal use in any patient until more
definitive data support their chronic use. To date, lung
transplantation is the only intervention proven to improve
survival.67

Category 4: Chronic Thromboembolic

Pulmonary Hypertension
Chronic thromboembolic pulmonary hypertension (CTEPH)
is a very distinctive disorder that has been well characterized.68 Although the physiological trigger (procoagulant state,
inadequate thrombolytic system, antecedent deep vein throm-

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Figure 3. Simultaneous pulmonary arterial and LV pressures. A, Patient with LV diastolic dysfunction. In this patient, the LVEDP is elevated, and the pulmonary arterial diastolic pressure equals the LVEDP. The increase in pulmonary arterial pressure (PAP) is directly
related to the elevated LV filling pressure. B, In contrast, the simultaneous pulmonary arterial and LV pressures are shown in another
patient with LV diastolic dysfunction. In this patient, there is a substantial gradient between the pulmonary arterial diastolic pressure,
which is 35 mm Hg, and the LVEDP, which is 20 mm Hg. In this situation, it is believed that changes in the pulmonary arteriolar bed
occur from reactive pulmonary vasoconstriction, which contributes further to the severity of the pulmonary hypertension.

bosis) can be quite variable, these patients characteristically

present similar to those with idiopathic PAH. They have a
slowly progressive onset of dyspnea with effort and ultimately develop signs and symptoms of right heart failure.
Hypoxemia is very common. A perfusion lung scan is always

abnormal, although the perfusion scan will often underestimate the severity of the underlying thromboembolic disease.
Spiral computed tomographic scanning is the favored imaging modality to determine the presence, severity, and proximal extent of thromboembolic disease and is essential in

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Figure 4. Histological stains of serial sections of a pulmonary

muscular artery from a patient with COPD. a, Orcein stain; b,
Massons trichrome stain; c, Alcian blue stain. Observe the
abundant amount of elastin (a) and collagen (b) within the intimal layer, with a scarce proportion of proteoglycans (c). Internal
scale bar100 m. Observe the abundant amount of elastin (a)
and collagen (b) within the intimal layer, with a scarce proportion of proteoglycans (c). Internal scale bar100 m. Reprinted
from Santos et al.80

determining whether the patients would be surgical candidates for pulmonary thromboendarterectomy.
The pathology of CTEPH has features that usually can
distinguish it from idiopathic PAH69 (Figure 5). The lesions
are frequently more variable, ie, there are arterial pathways
that appear relatively unaffected by vascular disease and
others that typically show recanalized vascular thromboses.
However, the involvement of distal microvessels, particularly
when the thromboses have occurred in subsegmental arteries,
often indicates a worse prognosis. In these cases, the pathology may more closely resemble that of IPAH with associated
plexiform lesions.70,71

Hemodynamically, these patients are indistinguishable

from patients with category 1 PAH. However, because there
is no way for the clinician to know whether the vessel that is
utilized to obtain the wedge pressure tracing has distal
thrombus, we recommend direct measurement of LVEDP at
the time of diagnosis if there is any doubt. Interestingly, some
patients will have a reactive component to their pulmonary
hypertension believed to be a response to the increase
pulmonary resistance created by the thromboembolic disease.
It has been suggested that pulmonary vasoconstriction is
occurring in the vasculature that is uninvolved with pulmonary thromboemboli. One clinical dilemma involves the
patient with a documented solitary pulmonary embolism who
develops pulmonary hypertension. Whether this represents
coincidence, a cause-and-effect phenomenon, or a subset of
genetically susceptible individuals may be impossible to
resolve.
The definitive therapy of these patients is pulmonary
thromboendarterectomy.72 In specialized centers, these patients can have a dramatic improvement in their symptoms,
hemodynamics, and survival, and this is the treatment of
choice. However, some patients will have extensive disease
that is either inoperable or only partially amenable to surgical
removal. The use of pulmonary vasodilators has been tested
in open-label acute and short-term studies with some success.73,74 One study tested sildenafil over 6 months in 12
patients who were deemed inoperable and found a modest
reduction in pulmonary arterial pressure that was associated
with a 54-m increase in the 6-minute walk.75 Another trial
used bosentan in 16 patients who were inoperable and
showed a 92-m improvement in the 6-minute walk but
without hemodynamic monitoring.76 Because there have
never been any prospective randomized trials of vasodilators
in CTEPH, it remains unknown whether these changes will
translate into a clinically meaningful and sustained improvement in the patients. Nonetheless, in patients with inoperable
CTEPH, a clinical trial of pulmonary vasodilator therapy may
be warranted, with the goal of improving the patients
symptomatology and quality of life.

Category 5: Miscellaneous Causes

This category includes uncommon causes of pulmonary
hypertension such as sarcoidosis, schistosomiasis, histocytosis X, and lymphangiomatosis. The pathology between these
entities is quite diverse, and their clinical presentations are
highly variable. There have never been controlled trials of
pulmonary vasodilator therapy, and thus there is no way to
know their potential efficacy. Open-label trials have demonstrated favorable effects of intravenous epoprostenol in patients with sarcoidosis and severe pulmonary hypertension.77,78 However, given the lack of established benefit of
these drugs for other secondary forms of pulmonary hypertension, we urge caution before attempting to use them in
these patients.
Because the diagnosis of pulmonary hypertension is
being made more frequently in patients with coexisting
cardiac and lung diseases, the following guidelines may be
helpful:

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Figure 5. Schematic representation of 3

mechanisms of small-vessel disease in
CTEPH. A Obstructions of small, elastic,
subsegmental arteries not amenable to
surgical treatment. B, Pulmonary arteriopathy in small muscular arteries and
arterioles distal to unobstructed elastic
vessels (medial thickening, intimal proliferation, and plexiform and colander
lesions are shown). C, Pulmonary arteriopathy in small muscular arteries and
arterioles distal to obstructed large elastic vessels (virtually identical changes to
those in B). Reprinted from Galie et al,71
with permission from the American Thoracic Society. Copyright 2006, American
Thoracic Society.

In distinction from category 1 pulmonary hypertension, in

which the treatment is focused on lowering the pulmonary
arterial pressure, in non category 1 pulmonary hypertension, the treatment should focus on treating the underlying
disease.
The use of conventional therapies (diuretics, oxygen)
should be tried initially to correct related clinical problems.
Exercise testing may be helpful to uncover exerciseinduced hypoxemia, which may benefit from treatment.
The acute testing of short-acting pulmonary vasodilators
with hemodynamic guidance is recommended to evaluate
the potential for beneficial or adverse effects before pulmonary vasodilators are considered as chronic therapy:
inhaled nitric oxide (20 to 40 ppm).
intravenous adenosine (50 to 200 g/kg per minute).
intravenous epoprostenol (2 to 6 ng/kg per minute).

Patients who respond favorably to pulmonary vasodilators

should manifest unequivocal improvements within 4 to 6
weeks:
symptoms related to the pulmonary hypertension
should improve by 1 functional class.
echocardiography should show a reduction in RV
enlargement.
exercise testing should demonstrate substantial increases (20%) that correlate with the patients
symptoms.
catheterization should document an important reduction
in pulmonary arterial pressure and pulmonary vascular
resistance (20%).
Patients who fail to improve or who demonstrate
worsening clinical findings (tachycardia, hypoxemia,
hypotension, or worsening edema) should have the
pulmonary vasodilator therapy promptly discontinued.

In conclusion, pulmonary hypertension is a common clinical feature of cardiac and pulmonary diseases. Making a
secure diagnosis can be clinically challenging, and at times it

can be impossible to distinguish patients with coexisting

PAH. In all series, the development of pulmonary hypertension portends a worse prognosis. However, the use of
pulmonary vasodilators as a chronic therapy remains largely
unproven.

Disclosures
None.

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Medical therapy for pulmonary arterial hypertension: updated ACCP
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KEY WORDS: heart failure
heart disease

hypertension

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pulmonary

pulmonary