SPECIAL ARTICLE

Pulmonary Hypertension
Hemodynamic Diagnosis and Management
Kanu Chatterjee, MB, FRCP; Teresa De Marco, MD; Joseph S. Alpert, MD

H
emodynamic classification of pulmonary hypertension relates to the hemodynamic
mechanisms of pulmonary arterial hypertension, such as abnormalities of pulmo-
nary blood flow, pulmonary vascular resistance, and pulmonary venous pressures.
The therapeutic approaches can be directed to the hemodynamic mechanisms of pul-
monary hypertension. Arch Intern Med. 2002;162:1925-1933

The normal pulmonary arterial systolic
pressure in healthy subjects ranges from
18 to 30 mm Hg and the diastolic pres-
sure ranges from 4 to 12 mm Hg. Pulmo-
nary hypertension is diagnosed when
pulmonary arterial systolic and mean
pressures exceed 30 and 20 mm Hg, re-
spectively.1 The systolic pulmonary arte-
rial pressure exceeding 35 mm Hg and
mean pulmonary arterial pressure ex-
ceeding 30 mm Hg during exercise are
also regarded as abnormal hemodynamic
responses to exercise and indicate pul-
monary hypertension. It should be ap-
preciated that in the elderly population,
pulmonary arterial pressure may be con-
siderably higher, particularly during ex-
ercise in the absence of any discernible
cause. The higher pulmonary arterial
pressure in the elderly is primarily due to
decreased compliance of the pulmonary
artery, although pulmonary vascular re-
sistance (PVR) increases as well with ag-
ing.2 The morphologic changes in the
pulmonary vascular bed related to aging
are increased in the intimal area of the
smallest arteries, which reduce the lu-
men.3 Primary or unexplained pulmo-
nary hypertension is being diagnosed
with increasing frequency in the rela-
From the Chatterjee Center for Cardiac Research (Dr Chatterjee) and the Heart
Failure and Pulmonary Hypertension Program, School of Medicine (Dr De Marco),
University of California, San Francisco; and the Department of Medicine, University of
Arizona Health Sciences Center, Tucson (Dr Alpert).
tively older population. However, age-
related changes in pulmonary arterial
pressure (PAP) should be considered be-
fore such a diagnosis is established.
CLASSIFICATION, ETIOLOGY, AND
PATHOPHYSIOLOGIC MECHANISMS
Pulmonary hypertension is usually clas-
sified as primary or secondary. Second-
ary pulmonary hypertension is diag-
nosed when pulmonary hypertension is
presumed to result from a coexisting dis-
ease, such as collagen vascular disease. In
primary pulmonary hypertension, no ob-
vious cause is recognized. This tradi-
tional classification into primary or sec-
ondary pulmonary hypertension has a
number of limitations and is not all that
useful in clinical practice. The World
Health Organization (WHO) has pro-
posed a new treatment-oriented classi-
fication (Table 1).4 Although this WHO
classification is comprehensive, the he-
modynamic abnormalities in the differ-
ent categories are not obvious. Because pul-
monary hypertension is a hemodynamic
diagnosis, a hemodynamic classification
that has therapeutic and prognostic impli-
cations would seem to be desirable. Pul-
monary arterial pressure is related to pul-
monary blood flow (PBF) and PVR. The
following equations illustrate the hemody-
namic relations between mean pulmo-
nary arterial pressure (MPAP [millimeters

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 nary hypertension). Increased resis-
Table 1. World Health Organization Classification of Pulmonary Hypertension tance may be observed in more than
1 pulmonary vascular segment.
1. Pulmonary Arterial Hypertension In some patients, chronic el-
Primary pulmonary hypertension: (a) sporadic; (b) familial
Pulmonary hypertension related to collagen vascular disease, congenital systemic to
evation of PCWP is associated with
pulmonary shunts (Eisenmenger syndrome), portal hypertension, human immunodeficiency increased PVR (mixed pulmonary
viral infection, drugs/toxins (eg, anorexigens), persistent pulmonary hypertension of the hypertension). The hemodynamic
newborn, and others profiles of these different types of
2. Pulmonary Venous Hypertension pulmonary hypertension are sum-
Left-sided atrial or ventricular heart disease
Left-sided valvular heart disease
marized in Table 2. The clinical
Extrinsic compression of central pulmonary veins: (a) fibrosing mediastinitis; (b) conditions that are usually encoun-
adenopathy/tumors tered in these hemodynamic catego-
Pulmonary veno-occlusive disease ries are summarized in Table 3.
Other
3. Pulmonary Hypertension Associated With Disorders of the Respiratory Systems PRIMARY PULMONARY
and/or Hypoxemia
Chronic obstructive pulmonary disease
HYPERTENSION
Interstitial lung disease
Sleep-disordered breathing Based on the hemodynamic profile,
Alveolar hypoventilation disorders primary pulmonary hypertension is
Long-term exposure to high altitude precapillary pulmonary hyperten-
Neonatal lung disease sion. It is a relatively rare disease with
Alveolar capillary dysplasia
Other
an annual incidence of 1 to 2 per mil-
4. Pulmonary Hypertension Due to Chronic Thrombotic and/or Embolic Disease lion population.5 Most cases of pri-
Thromboembolic obstruction of proximal pulmonary arteries mary pulmonary hypertension are
Obstruction of distal pulmonary arteries: (a) pulmonary embolism; (b) in situ thrombosis; sporadic, but there is a 6% to 12% fa-
(c) sickle cell disease milial incidence, and the familial type
5. Pulmonary Hypertension Due to Disorders Directly Affecting the Pulmonary Vasculature appears to be inherited as an auto-
Inflammatory: (a) schistosomiasis; (b) sarcoidosis; (c) pulmonary capillary hemangiomatosis;
and (d) other
somal trait with incomplete pen-
etrance.6,7 A pattern of genetic an-
ticipation that indicates a worsening
of the disease in subsequent genera-
Table 2. Hemodynamic Profiles of Different Types of Pulmonary Hypertension tions as manifested by greater sever-
ity or earlier onset has also been ob-
1. Precapillary Pulmonary Hypertension served.8 The localization of the gene
Systolic, diastolic, and mean pulmonary arterial pressures are higher than normal; pulmonary for familial primary pulmonary hy-
capillary wedge pressure (mean) is normal. Pulmonary vascular resistance is significantly
elevated; pulmonary arterial end diastolic pressure is significantly higher than the pulmonary
pertension to chromosome 2q33
capillary wedge pressure. has been reported.9,10 A mutation
2. Postcapillary Pulmonary Hypertension in the gene encoding bone morpho-
Systolic, diastolic, and mean pulmonary arterial pressures are higher than normal; pulmonary genetic protein receptor type II
capillary wedge pressure is elevated; pulmonary vascular resistance is normal; pulmonary (BMPR2) that may cause uncon-
arterial end diastolic pressure is equal or within 5 mm Hg of mean pulmonary capillary
wedge pressure.
trolled proliferation of vascular
3. Mixed smooth muscle has been observed
Systolic, diastolic, and mean pulmonary arterial pressures are higher than normal; pulmonary both in patients with primary pul-
capillary wedge pressure is elevated; pulmonary arterial end diastolic pressure is modestly monary hypertension and in other
higher than the mean pulmonary capillary wedge pressure. forms of precapillary pulmonary hy-
4. Selective or Nonselective Increase in Pulmonary Blood Flow pertension.
Systolic, diastolic, and mean pulmonary arterial pressures may be higher than normal;
pulmonary blood flow is increased; pulmonary vascular resistance is normal or slightly
The precise pathogenetic mecha-
increased; pulmonary venous pressure is modestly increased or normal. nisms of primary pulmonary hyper-
tension are not known. Emerging evi-
dence from experimental studies
favors abnormalities of membrane po-
of mercury]), PBF (liters per minute), PBF and PVR are normal (postcapil- tassium channels that modulate cal-
PVR (dynes per second per 5 cm), and larypulmonaryhypertension).Pulmo- cium kinetics as one of the mecha-
pulmonary (PCWP) and mean pul- naryhypertensionmayalsoresultfrom nisms.11 Down-regulation or lack of
monary (MPCWP) capillary wedge selective or nonselective increases in these voltage-dependent potassium
pressures (millimeters of mercury): PBF or may be due to an increase in channels appears to be a common ab-
resistance in the pulmonary circula- normal molecular denominator for
(1) PVR=(MPAPMPCWP)/PBF
tion. The sites of increased resistance many forms of precapillary pulmo-
(2) MPAPPCWP=PVRPBF in the pulmonary vascular bed may be nary arterial hypertension, includ-
(3) MPAP=(PVRPBF)+MPCWP
in the pulmonary arteriolar segments ing primary pulmonary hyperten-
Thus, in pulmonary venous hyperten- and/or the more proximal pulmonary sion. Inhibition or down-regulation
sion, PAP can be increased when both arterialsegments(precapillarypulmo- of these voltage-dependent potas-

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sium channels promotes influx of in-
tracellular calcium in pulmonary ar-
terial smooth muscle cells, which is
associated with vasoconstriction and
smooth muscle cell hypertrophy and
proliferation. Increased production of
vasoconstrictors (eg, thromboxane A2
and endothelin 1) relative to produc-
tion of vasodilators (eg, prostacyclin
[PGI2] and nitric oxide) has also been
demonstrated in patients with pre-
capillary pulmonary hypertension.12
Immunohistochemical studies have
reported that endothelial nitric ox-
ide synthase expression is signifi-
cantly reduced in the large, me-
dium, and small muscular pulmonary
arteries as well as in the elastic pul-
monary arteries in patients with vari-
ous types of precapillary pulmonary
hypertension.13 In addition, hyper-
coagulopathy, expressed as in-
creased levels of plasminogen activa-
tor inhibitor type I and fibrinopeptide
A and decreased levels of tissue plas-
minogen activator, has been sug-
gested as a potential mechanism for
increased PVR resulting from in situ
intravascular thrombosis.14,15 In-
creased levels of serotonin and re-
duced thrombomodulin levels along
with enhanced platelet activity also
suggest a hypercoagulable state in pul-
monary hypertension.
Abnormalities of elastase and
matrix metalloproteinase activity have
been suggested as contributing to the
development of pulmonary hyper-
tension as well. Precapillary pulmo-
nary hypertension can be associated
with connective tissue disorders in-
cluding scleroderma, mixed connec-
tive tissue diseases, and systemic lu-
pus erythematosus.16 In connective
tissue disorders and particularly in pa-
tients with scleroderma, obliteration
of alveolar capillaries resulting from
destruction of the vascular bed due to
a fibrotic process has been suggested
as a mechanism for precapillary pul-
monary hypertension. Transform-
ing growth factor- has been shown
in experimental studies to decrease fi-
brosis in scleroderma. Whether such
therapy will be of any benefit in treat-
ing pulmonary hypertension associ-
ated with this disorder still needs to
be established.
An increased incidence of pul-
monary hypertension has been ob-
served in patients with the human
immunodeficiency virus. 17 The
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Table 3. Clinical Conditions Encountered in the Hemodynamic Categories
of Pulmonary Hypertension
1. Precapillary Pulmonary Hypertension
Primary pulmonary hypertension, pulmonary hypertension associated with collagen vascular
disease, Eisenmenger syndrome, liver disease (portal hypertension), human
immunodeficiency viral infection, appetite suppressants, persistent pulmonary hypertension
of the newborn, high-altitude pulmonary hypertension, neurogenic pulmonary hypertension,
thromboembolic pulmonary hypertension, peripheral pulmonary artery branch stenosis
2. Postcapillary Pulmonary Hypertension
Left ventricular systolic or diastolic failure, aortic stenosis or regurgitation, primary mitral
regurgitation, mitral valve obstruction, pulmonary venoocclusive disease (congenital or
acquired)
3. Mixed
Chronic primary systolic left ventricular failure, aortic stenosis, chronic aortic and primary
mitral regurgitation, mitral valve obstruction
4. Selective or Nonselective Increase in Pulmonary Blood Flow
Atrial septal defect, ventricular septal defect, patent ductus arteriosus, high-output cardiac
failure (thyrotoxicosis), liver disease, chronic anemia
mechanism of pulmonary hyperten- viscosity and PVR. The more severe
sion in these patients remains unclear, the pulmonary hypertension is in pa-
but increased release of endothelin tients with chronic obstructive pul-
1 in response to human immunode- monary disease, the worse is the prog-
ficiency viral infection has been sug- nosis. The average survival of patients
gested as a potential mechanism.12,18 without cor pulmonale is 13.5 years,
Various types of liver disease, includ- but with cor pulmonale, 50% of pa-
ing cirrhosis, portal hypertension, tients die within 7 years.21 In pa-
portal vein thrombosis, and congen- tients with sleep-disordered breath-
ital absence of the portal veins, can ing (obstructive sleep apnea) and
be associated with pulmonary hyper- morbid obesity with hypoventila-
tension.19 However, the incidence of tion syndrome, hypoxemia-medi-
pulmonary hypertension is less than ated pulmonary vasoconstriction ap-
1% in patients with cirrhosis. The pears to be a major contributing
pathophysiologic mechanisms of pul- factor to the development of precap-
monary hypertension associated with illary pulmonary hypertension.
liver disease remains unclear. Possible Various toxins and drugs have
mechanisms include increased lev- been associated with precapillary
els of intestinal vasoactive peptides pulmonary hypertension. Rape-
reaching the lung, leading to altered seed oil (inhaled) and exposure to
pulmonary arterial hemodynamics L-tryptophan and anorectic medi-
such as increased cardiac output and cations such as fenfluramine are
abnormal pulmonary vasodilatory re- well-documented risk factors for
serve. Finally, it has also been sug- pulmonary hypertension. The risk
gested that repeated bouts of pulmo- of developing pulmonary hyperten-
nary thromboembolism might be a sion in patients using anorectic
potential mechanism for pulmonary medications is less than 1% of pa-
hypertension in patients with liver tients exposed.22 However, the risk
disease. of pulmonary hypertension in-
Pulmonary hypertension asso- creases with prolonged (more than
ciated with disorders of the respira- 3 months) exposure to these drugs.
tory system, such as chronic obstruc- The mechanisms of pulmonary hy-
tive pulmonary disease, is the result pertension secondary to anorectic
of hypoxemia-mediated pulmonary drugs remains unclear, although in-
vasoconstriction as well as destruc- creased serotonin release and their
tion of the pulmonary microvascu- inhibitory effect on potassium chan-
lature.20 In patients with chronic ob- nels leading to increased cytosolic
structive pulmonary disease, PAP calcium influx have been proposed
correlates directly with the level of ar- as potential mechanisms.23
terial PCO2 and inversely with the Chronic thromboembolic dis-
level of the arterial oxygen satura- ease or in situ pulmonary arterial
tion. Secondary polycythemia result- thrombotic disease can cause pre-
ing from hypoxemia increases blood capillary pulmonary hypertension.
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Thrombotic in situ occlusion of the
pulmonary circulation can occur in
a number of conditions including
polycythemia, hemoglobin sickle cell
disease, eclampsia, and dissemi-
nated fibromuscular dysplasia. In the
thrombotic diseases, small vessels are
affected diffusely throughout the
lungs. In chronic thromboembolic
disease, occlusion of the larger pul-
monary arteries leads to pulmo-
nary hypertension.24
POSTCAPILLARY PULMONARY
HYPERTENSION
In postcapillary pulmonary hyperten-
sion, PAP increases passively in pro-
portion to increases in PCWP while
PVR remains normal (see equations
1-3).25 In healthy persons, PVR and
transpulmonary pressure gradients
decrease in response to increased
PCWP. However, when there is a sub-
stantial increase in PCWP, there is a
parallel increase in PAP. Postcapil-
lary pulmonary hypertension can be
seen in patients with mitral valve ob-
struction and other valvular heart
diseases such as aortic stenosis and
regurgitation, primary mitral regur-
gitation, and left ventricular failure.
In the mixed hemodynamic form of
pulmonary hypertension, chronic el-
evation of PCWP is associated with
increases in PVR and thus a dispro-
portionate increase in PAP.
The mechanism of vasoconstric-
tion in response to chronic eleva-
tion of PCWP is not clear. About one
third of patients with chronic pul-
monary venous hypertension de-
velop increased PVR. Various mecha-
nisms for this abnormal pulmonary
vascular reactivity have been pro-
posed, including narrowing or clo-
sure of the airways by direct en-
croachment from enlarged venous
vessels or interstitial edema, leading
to worsening ventilation-perfusion
mismatch and hypoxemia, causing
pulmonary vasoconstriction and in-
creased PVR. However, in many pa-
tients with the mixed variety of pul-
monary hypertension resulting from
increased PCWP, arterial oxygen
saturation at rest and during exer-
cise is normal. Thus, hypoxemia can-
not be the only mechanism for pul-
monary hypertension in these latter
patients. It has been demonstrated
that transpulmonary endothelin 1 re-
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lease is significantly increased in pa-
tients with mixed pulmonary hyper-
tension.26 Therefore, endothelial
dysfunction leading to abnormal pul-
monary vasodilatory reserve ap-
pears to be an important mecha-
nism of pulmonary hypertension in
these individuals.
INCREASED PBF
Pulmonary hypertension resulting
from selective and nonselective in-
creases in PBF can be seen in patients
with atrial septal defect, ventricular
septal defect, and patent ductus ar-
teriosus. In patients with high out-
put states such as thyrotoxicosis,
chronic anemia, and liver disease,
moderate pulmonary hypertension
may also be observed. In some pa-
tients with increased PBF there is also
an increase in PVR. It has been sug-
gested that flow-dependent pulmo-
nary vasodilation is abnormal in such
patients, and there may be a modest
increase in PVR as well. With the de-
velopment of Eisenmenger physiol-
ogy, there is a marked increase in PVR
and PAP and a reversal of previously
present left to right shunt.27
CLINICAL EVALUATION OF
HEMODYNAMIC TYPES OF
PULMONARY HYPERTENSION
Symptoms
The most common presenting symp-
tom is exertional dyspnea. With in-
creasing severity of pulmonary hy-
pertension and any associated disease
causing pulmonary hypertension, ex-
ercise tolerance progressively de-
clines, limited by dyspnea and fa-
tigue. Orthopnea may be experienced
by patients with both precapillary (eg,
chronic obstructive pulmonary dis-
ease) and postcapillary (eg, left ven-
tricular failure) pulmonary hyperten-
sion. Paroxysmal nocturnal dyspnea
is, however, diagnostic of pulmo-
nary venous hypertension. Typical ex-
ertional angina is most frequently ob-
served in patients with postcapillary
pulmonary hypertension with left
ventricular systolic failure resulting
from ischemic dilated cardiomyop-
athy. Rarely, typical exertional an-
gina is experienced by patients with
severe precapillary pulmonary hyper-
tension in the absence of coronary ar-
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tery disease (right ventricular angina).
Atypical chest pain, however, is a fre-
quent symptom both in patients with
precapillary and patients with post-
capillary pulmonary hypertension ir-
respective of the cause. Presyncope or
frank syncope, exertional or sponta-
neous, are ominous symptoms in the
patient with pulmonary hyperten-
sion irrespective of hemodynamic
mechanisms. Palpitations and iso-
lated exertional fatigue are nonspe-
cific symptoms.
In the elderly, fatigue and dys-
pnea are frequently attributed to ag-
ing and deconditioning, which may
cause delay in the diagnosis. In elder-
ly patients, presyncope or syncope
maybecausedbyconditionsunrelated
to pulmonary hypertension, such as
conduction system diseases.
Hemoptysis may be a symp-
tom of pulmonary hypertension ir-
respective of its cause. In elderly pa-
tients with hemoptysis, however,
lung cancer should be always ex-
cluded. Rarely, patients with pul-
monary hypertension may develop
hoarseness (Ortner syndrome) due
to compression of the left recurrent
laryngeal nerve by the enlarged pul-
monary artery.28
Physical Examination
Bedside examination is extremely use-
ful for the diagnosis of pulmonary hy-
pertension and its possible cause.29
The increased intensity of the pul-
monic component of the second heart
sound (P2) compared with the aortic
component of the second heart sound
(A2) is the most consistent finding in
pulmonary arterial hypertension ir-
respective of its cause. The transmis-
sion of the P2 to the cardiac apex is
also suggestive of pulmonary hyper-
tension because P2 is normally inau-
dible over the cardiac apex. Eleva-
tion of jugular venous pressure, a right
ventricular heave, signs of tricuspid
regurgitation, pulmonary ejection
sounds, and a pulmonary insuffi-
ciency murmur are secondary find-
ings associated with pulmonary hy-
pertension. A right ventricular S3
gallop indicates right ventricular fail-
ure. Systolic pulsations over the sec-
ond left intercostal space is due to a
dilated pulmonary artery.
During bedside clinical evalu-
ation in a patient with suspected or
established pulmonary hypertension,
some abnormal physical findings may
provide clinical clues to the cause of
pulmonary hypertension. Differen-
tial cyanosis and clubbing (cyanosis
and clubbing of toes but not of fin-
gers) is very suggestive of Eisen-
menger syndrome secondary to a
patent ductus arteriosus. Central cya-
nosis and clubbing and biventricu-
lar hypertrophy with a single second
heart sound but with marked increase
in its intensity suggest Eisenmenger
syndrome resulting from ventricular
septal defect. Wide splitting of the
second heart sound with marked in-
crease in the intensity of P2 in the
absence of complete right bundle
branch block and in the presence of
cyanosis and clubbing suggest Ei-
senmenger syndrome associated
with atrial septal defect.
A sustained outward move-
ment of the left ventricular apical im-
pulse indicates either left ventricu-
lar hypertrophy or reduced left
ventricular ejection fraction, thus in-
directly suggesting postcapillary pul-
monary hypertension. Similarly,
physical findings of mitral or aortic
valve disease or of hypertrophic or
restrictive cardiomyopathy also in-
dicate postcapillary pulmonary hy-
pertension. A left ventricular S3 gal-
lop in patients with suspected or
documented coronary artery dis-
ease, aortic valve disease, or dilated
cardiomyopathy indicates a substan-
tial increase in left ventricular dias-
tolic pressure, which suggests post-
capillary pulmonary hypertension.
Chest Radiography
Chest radiography also provides use-
ful information regarding the cause
of pulmonary hypertension. En-
larged central pulmonary arteries
with rapid tapering of the vessels to-
ward the periphery are appreciated
in patients with severe pulmonary hy-
pertension. The width of the descend-
ing right pulmonary artery is greater
than normal (12.11.2 mm SD).30
Linear calcification of the pulmo-
nary artery indicates severe, long-
standing pulmonary hypertension.
Increased cardiothoracic ratio on a
plain chest radiograph may result
from either right or left ventricular
enlargement. Radiologic findings of
pulmonary plethora suggest Eisen-
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menger syndrome. Substantial left
atrial enlargement and/or evidence of
pulmonary venous congestion indi-
cates postcapillary pulmonary hy-
pertension. In elderly patients, chest
radiography is of limited value ex-
cept in patients with severe pulmo-
nary hypertension.
Electrocardiogram
The electrocardiogram (ECG) is oc-
casionally helpful in assessing the
cause of pulmonary hypertension.
The ECG criteria for right ventricu-
lar hypertrophy are recognized in
most patients with precapillary pul-
monary hypertension. Evidence of left
atrial enlargement in the absence of
left ventricular hypertrophy sug-
gests mitral valve obstruction and
postcapillary pulmonary hyperten-
sion. In patients with postcapillary
pulmonary hypertension due to aor-
tic valve disease or primary left ven-
tricular myocardial disease, ECG evi-
dence of right ventricular hypertrophy
may be absent. Left bundle branch
block or ECG evidence of left ven-
tricular myocardial infarction indi-
cates left ventricular disease and thus
indirectly suggests postcapillary pul-
monary hypertension. In elderly pa-
tients, some of the ECG criteria or
right ventricular hypertrophy may be
present without significant pulmo-
nary hypertension. Also, in the el-
derly, the ECG changes of right ven-
tricular hypertrophy are more
frequently absent due to concomi-
tant left ventricular disease.
Echocardiography
All patients with suspected or estab-
lished pulmonary hypertension
should undergo a comprehensive
echocardiographic evaluation. Right
ventricular systolic pressure is the
same value as pulmonary arterial sys-
tolic pressure in the absence of right
ventricular outflow tract obstruc-
tion. Right ventricular systolic pres-
sure can be assessed by estimating the
velocity of the tricuspid valve regur-
gitant jet. Left and right atrial dimen-
sions and left and right ventricular di-
mensions and function can also be
assessed by echocardiography. The
presence of valvular heart disease and
its severity can be evaluated. Trans-
thoracic, transesophageal, and echo
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1929
Doppler studies are of considerable
value in discerning intracardiac
shunts, including right to left shunts
through a patent foramen ovale as
well as other congenital anomalies
that can be associated with pulmo-
nary hypertension. Exercise echo
Doppler studies are used to assess
changes in exercise-induced pulmo-
nary arterial systolic pressure. Echo-
cardiographic studies are essential in
all patients with suspected or estab-
lished pulmonary hypertension.
Ventilation-Perfusion
Scintigraphy and Computed
Tomography
Ventilation-perfusion scintigraphy is
used in patients with established pre-
capillary pulmonary hypertension to
exclude chronic thromboembolic
disease.5 It should be appreciated,
however, that in some patients with
primary pulmonary hypertension,
ventilation-perfusion scans could be
abnormal. Spiral computed tomo-
graphic studies are being increas-
ingly used in the evaluation of pa-
tients with pulmonary hypertension
to assess pulmonary interstitial dis-
ease and chronic thromboembolic
disease. Magnetic resonance imag-
ing may also be used for diagnosis
of pulmonary embolism.
Pulmonary Function Tests
Pulmonary function tests are per-
formed to assist in the differential di-
agnosis of pulmonary hypertension
secondary to airway or neuromus-
cular diseases. Pulmonary function
tests are also necessary for patients
with precapillary hypertension who
are being considered for lung trans-
plantation surgery. In primary pul-
monary hypertension, pulmonary
function tests may be normal or a re-
strictive defect and decreased diffus-
ing capacity may be observed.5
Other Ancillary Studies
In selected patients, further addi-
tional studies are necessary, such as
polysomnography to exclude sleep-
disordered breathing as the cause of
pulmonary hypertension. Blood tests
including human immunodefi-
ciency virus antibody, antinuclear
antibody, rheumatoid factor, liver
 Table 4. Hemodynamic Patterns in Various Types of Pulmonary Hypertension (Patient Examples)*

PVR, dyne/s
Patient DIAG MPAP, mm Hg MRAP, mm Hg MPCWP, mm Hg CO, L/min per 5 cm
1 PPH 50 16 3 3.1 1192
2 SPPH (echo Doppler: RVSP, 40 mm Hg)
Rest 13 7 12 4.8 101
Exercise 22 10 14 15.0 43
3 IDCM 44/37 17/14 26/25 4.7/8.0 290/89
4 ASD 31 16 14 9.3 (PBF) 146

*DIAG indicates suspected diagnosis before right heart catheterization; MPAP, mean pulmonary arterial pressure; MRAP, mean right atrial pressure; MPCWP,
mean pulmonary capillary wedge pressure; CO, cardiac output; PVR, pulmonary vascular resistance; PPH, primary pulmonary hypertension; SPPH, suspected
primary pulmonary hypertension; RVSP, right ventricular systolic pressure; IDCM, ischemic dilated cardiomyopathy; ASD, atrial septal defect; and PBF, pulmonary
blood flow.
Data for patient 3 are presented as before nitroprusside infusion/after nitroprusside infusion.

function tests, and thyroid func-
tion tests are often performed in pa-
tients with precapillary pulmonary
hypertension based on their clini-
cal presentation. Pulmonary angi-
ography, pulmonary angioscopy,
and magnetic resonance imaging
studies are occasionally used in pa-
tients with suspected thromboem-
bolic pulmonary hypertension.31
Hemodynamics Studies
Right heart catheterization and, oc-
casionally, left heart catheterization
should be performed in a cardiac cath-
eterization laboratory equipped to do
careful hemodynamic studies.32 Ap-
propriate hemodynamic studies are
required not only to establish the di-
agnosis of pulmonary hypertension,
but also to determine its hemody-
namic classification. In patients with
precapillary pulmonary hyperten-
sion, PAP and PVR are elevated and
PCWP is normal. In some patients
with mild to moderate elevation of
pulmonary arterial systolic pressure
as determined by echo Doppler
study, hemodynamic studies at rest
and during exercise should be per-
formed to establish the diagnosis con-
clusively. In patients with precapil-
lary pulmonary hypertension, PAP
and PVR are elevated at rest. During
exercise, PAP increases, but the nor-
mal fall in PVR does not occur. In
healthy subjects, PAP does not in-
crease during exercise despite a sub-
stantial increase in PBF because of a
decrease in PVR. The decrease in pul-
monary resistance results from pul-
monary capillary recruitment and
endothelium-dependent relaxing fac-
tornitric oxidemediated pulmo-
nary vasodilation. In older healthy
subjects, during exercise, the PCWP
may exceed 30 mm Hg and may be
associated with a passive increase in
the MPAP. The rise in PCWP is due
to decreased left ventricular compli-
ance. Thus, in healthy elderly sub-
jects, exercise-induced pulmonary
hypertension is postcapillary and
may be a normal age-related re-
sponse and should not be consid-
ered for aggressive therapy of pul-
monary hypertension.
The hemodynamic profile of a
patient with severe precapillary pul-
monary hypertension and of a pa-
tient with a misdiagnosis of primary
pulmonary hypertension are summa-
rized in Table 4. In patients with es-
tablished precapillary pulmonary hy-
pertension, measurement of the ratio
of peak pulmonary arterial systolic
pressure and the dicrotic notch pres-
sure may provide some clues to the
diagnosis of thromboembolic pulmo-
nary hypertension. In thromboem-
bolic pulmonary hypertension, the di-
crotic notch pressure is closer to the
peak systolic pressure because the re-
sistance in the pulmonary vascular
bed lies in the proximal pulmonary
artery branches. However, pulmo-
nary angiography, spiral computed to-
mography, or magnetic resonance an-
giography must be performed to
establish the diagnosis of chronic
thromboembolic disease. If PCWP is
found to be elevated during hemo-
dynamic studies in patients with pul-
monary hypertension, it is essential
to determine PVR by measuring PBF.
Patients with normal resistance have
postcapillary pulmonary hyperten-
sion. This information has practical
clinical implications: in patients with
refractory left ventricular failure who
are being considered for cardiac trans-
plantation,itisessentialtodemonstrate
thatPVRandpulmonaryhypertension
are reversible. An example of such a
patient is illustrated in Table 4.
In patients with selective in-
creases in PBF causing pulmonary hy-
pertension (eg, atrial septal defect), it
is also important to assess PVR be-
cause surgical or catheter-based
closure of the defects are contraindi-
cated if PVR is equal to or higher than
systemic vascular resistance (Eisen-
menger physiology). Hemodynamic
studies are also required to assess the
severity of pulmonary hypertension
(mild: MPAP, 25-40 mm Hg; moder-
ate: MPAP, 41-55 mm Hg; and se-
vere: MPAP, 55 mm Hg).33 It should
be emphasized that in healthy sub-
jects 60 years or older, MPAP is 22
mm Hg2 SD; the recommended he-
modynamic criteria for the diagno-
sis of severity of pulmonary hyper-
tension are associated with over-
diagnosis and overestimation of the
severity of pulmonary hypertension in
the elderly.34
Treatment
A summary of management strate-
gies for patients based on the hemo-
dynamic categories of pulmonary
hypertension is given in Table 5.
Postcapillary Hypertension. Reduc-
tion of PCWP is the primary thera-
peutic goal for the treatment of pa-
tients with postcapillary pulmonary
hypertension.25 Diuretics and, pre-
dominantly, venodilators (eg, ni-
trates or vasodilators) with mixed ar-
teriolar and venous dilating properties
(eg, angiotensin-converting enzyme
inhibitors) or a combination of an ar-
teriolar dilator (hydralazine) and a

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venodilator such as a long-acting ni-
trate are effective in reducing PCWP
and PVR in patients with postcapil-
lary pulmonary hypertension. Con-
comitant therapy to correct the pri-
mary cause (eg, correction of mitral
valve obstruction or treatment of di-
lated cardiomyopathy) is essential. In
patients with postcapillary pulmo-
nary hypertension with increased
PVR, inhaled nitric oxide and endo-
thelin antagonists may be effective in
reducing PVR and pulmonary hyper-
tension, although such therapy is still
experimental at present.
Pulmonary Hypertension Due to In-
creased PBF. In patients with pul-
monary hypertension due to selec-
tive or nonselective increases in
PBF, the principal mechanism for
reduction of PAP is reduction of
PBF. For example, in patients with
atrial septal defect, PAP declines
with closure of the defect. In pa-
tients with persistent elevation of
PVR despite reduction of PBF, pul-
monary vasodilators have proven
useful.
In hyperthyroidism, pulmo-
nary hypertension results from non-
selective increases in PBF as well as
modest increases in PVR. Pulmo-
nary hypertension in hyperthyroid-
ism is completely reversible with
treatment of thyrotoxicosis.35
Precapillary Pulmonary Hyperten-
sion. Treatment of precapillary pul-
monary hypertension includes
therapy to decrease PVR as well as
specific therapy for the underlying
cause if one is present. In many pa-
tients, pharmacotherapy for right
ventricular failure is also necessary.
Vasodilator Therapy. In the past,
many different vasodilators (ie, hy-
dralazine, diazoxide, isosorbide dini-
trates, -adrenergic blocking agents
and -adrenergic agonists such as iso-
prenaline) have been used in pa-
tients with pulmonary hypertension
but without much success.36 At pres-
ently, calcium channel blockers and
PGI2 analogues are the only effective
vasodilator pharmacotherapy. Among
the various calcium channel block-
ers, long-acting vasoselective dihy-
dropyridines and slow-release, heart
rateregulating calcium channel
blockers are the preferred agents. Be-
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2002 American Medical Association. All rights reserved.
Table 5. Management Strategies for Patients Based on the Hemodynamic Categories
of Pulmonary Hypertension
1. Postcapillary Pulmonary Hypertension
Reduction of pulmonary capillary wedge pressure: diuretics, venodilators (eg, nitrates), mixed
arteriolar and venodilators (eg, angiotensin-converting enzyme inhibitors), combination of
arteriolar and venodilators (eg, hydralazine and nitrates)
Decrease pulmonary vascular resistance: pulmonary vasodilators (nitroglycerin, nitroprusside,
angiotensin-converting enzyme inhibitors, prostacyclin, inhaled nitric oxide, endothelin
antagonists)
Correction of primary cause: correction of valvular heart disease; treatment of cardiomyopathies
2. Pulmonary Hypertension Due to Selective or Nonselective Increase in Pulmonary Blood Flow
Reduction of pulmonary blood flow: correction of the primary cause (eg, repair of the atrial
septal defect and treatment of hyperthyroidism); decrease of the ratio of systemic to
pulmonary vascular resistance (SVR/PVR); predominantly arteriolar vasodilators (eg,
hydrazaline and phentolamine)
3. Precapillary Pulmonary Hypertension
Vasodilators: calcium channel blockers; continuous prostacyclin infusion; endothelin
antagonists
Treatment of right ventricular failure: digitalis, diuretics, angiotensin-converting enzyme
inhibitors, intermittent dobutamine, dopamine, phosphodiesterase inhibitor infusions;
treatment of primary cause, if any
Adjunctive therapy: long-term anticoagulation, supplemental oxygen
Surgical therapy: lung or heart and lung transplantation; atrial septostomy; pulmonary
thrombodendarterectomy
Investigational therapies: prostacylin analogues (iloprost, baroprost, uniprost); endothelin
antagonists; inhaled nitric oxide; nitric oxide donors (L-arginine); gene therapies to enhance
nitric oxide synthase, prostacyclin synthase, bone-morphogenetic protein receptor
Natriuretic peptides and endopeptidase inhibitors
Phosphodiesterase-5 inhibitor and sildenafil
fore long-term calcium channel tors have been shown to delay
blocker therapy is undertaken, it pulmonary vascular remodeling in ex-
seems reasonable to identify the re- perimental animals.39 In isolated pa-
sponders by measuring PAP and PVR tients with cor pulmonale, angioten-
in response to short-acting vasodila- sin-converting enzyme inhibitors have
tors (eg, intravenous adenosine or in- been reported to produce beneficial
haled nitric oxide) or intravenous hemodynamic effects.40 However, ex-
PGI2.37 A positive response is de- perience with angiotensin-convert-
fined as a 10mm Hg or more de- ing enzyme inhibitor therapy is ex-
crease in MPAP with either no change tremely limited in these patients. In
or an increase in cardiac output and/or elderly patients, vasodilator therapy is
a decrease in PVR of approximately associated with increased incidence of
25%. Clinical experience suggests that symptomatic systemic hypotension.
20% or fewer of patients with mod-
erate or severe precapillary pulmo- PGI2 Analogues. Prospective ran-
nary hypertension respond to therapy domized clinical trials have demon-
with calcium channel blockers. strated improved exercise tolerance
It should also be appreciated that and survival in patients with pri-
many patients who respond to cal- mary pulmonary hypertension treated
cium channel blocker therapy re- with epoprostenol.41,42 The survival
quire large doses of these agents (eg, benefit was observed in patients with
diltiazem hydrochloride, up to 720 New York Heart Association (NYHA)
mg/d; nifedipine, up to 300 mg/d).38 functional class III and IV heart fail-
The mechanism of pulmonary vaso- ure resulting from primary pulmo-
relaxation induced by calcium chan- nary hypertension. The beneficial ef-
nel blockers is related to the inhibi- fects of epoprostenol have also been
tory effect on calcium influx into demonstrated in patients with pul-
vascular smooth muscle cells. The ad- monary hypertension due to sclero-
verse effects of calcium channel block- derma. In a substantial number of pa-
ers relate to their negative inotropic tients, continuous epoprostenol
effect. Thus, in patients with overt therapy has been shown to delay the
right ventricular failure, calcium chan- need for lung transplantation
nel blockers should not be used. An- therapy.43 The acute hemodynamic
giotensin-converting enzyme inhibi- response to intravenous PGI2 is char-
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1931
acterized by an increase in cardiac
output, decrease in PAP and PVR, and
an increase in systemic oxygen deliv-
ery. However, such acute beneficial
responses are seldom observed in pa-
tients with severe precapillary pul-
monary hypertension. The lack of an
acute beneficial hemodynamic re-
sponse, however, does not preclude
long-term epoprostenol therapy.37
The mechanism of this beneficial
effect of long-term epoprostenol
therapy without acute response re-
mains unclear. Reversal of pulmo-
nary vascular remodeling has been
suggested. Some of the beneficial ef-
fects may be attributed, in part, to the
antiplatelet properties of PGI2. Pros-
tacylin can also improve endothelial
function and alter hemostasis by de-
creasing P-selectin (a leukocyte ad-
hesion receptor) and increasing
thrombomodulin levels.44,45 It may
also reduce smooth muscle cell pro-
liferation and migration.
The optimal dose of PGI2 in an
individual patient is variable. How-
ever, the dose should be gradually in-
creased according to clinical re-
sponse. Owing to the short half-life
of PGI2, a tunneled venous catheter
is needed for continuous administra-
tion of epoprostenol. Abrupt discon-
tinuation of epoprostenol may be as-
sociated with a rebound increase in
PAP that may lead to acute right ven-
tricular failure and even death. Com-
mon adverse effects include abdomi-
nal discomfort, jaw pain, diarrhea,
flashing, rash, and foot pain. Ad-
verse effects are particularly com-
mon during initiation of therapy.
Endothelin Antagonists. As circu-
lating endothelins and endothelin re-
ceptors activation induce pulmo-
nary vasoconstriction and increase
PVR and PAP, endothelin antago-
nists have been evaluated for long-
term treatment of pulmonary hy-
pertension.46,47 Experimental studies
have reported a substantial reduc-
tion in PVR and PAP in precapil-
lary, postcapillary, and mixed he-
modynamic subsets of pulmonary
hypertension. Recently, bosentan, an
oral nonselective endothelin recep-
tor blocking agent (blocks both en-
dothelin A and B receptors) has been
approved by Food and Drug Admin-
istration for treatment of primary
and scleroderma pulmonary hyper-
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2002 American Medical Association. All rights reserved.
tension. Treatment with bosentan
(80-160 mg twice daily) was asso-
ciated with significant improve-
ment in clinical class and an in-
crease in 6-minute walk distance.
Right ventricular systolic function
improves along with decreased PVR
and PAP. Although long-term sur-
vival benefit is yet to be estab-
lished, bosentan clearly should be
considered in the treatment of pa-
tients with precapillary pulmonary
hypertension with mild to moder-
ately severe heart failure. At pres-
ent, patients in NYHA functional
class IV or requiring urgent intrave-
nous PGI2 therapy are not considered
for bosentan therapy. During bosen-
tan therapy, monitoring of liver and
hematologic functions is necessary.
Newer selective and nonselec-
tive endothelin receptor antagonists
are undergoing clinical trials. It is
likely other endothelin antagonists
will be available for treatment of pul-
monary hypertension.
Other Adjunctive Therapies. Long-
term anticoagulation therapy with
warfarin is recommended in all pa-
tientswithprecapillarypulmonaryhy-
pertension.Long-termanticoagulation
therapy has been shown to reduce
mortality, probably by reducing the
incidence of intravascular thrombo-
sis in situ.48,49 Supplemental oxygen
therapy is of benefit in patients who
arehypoxic.50 Patientswithovertright
ventricular failure should be treated
with diuretics, digitalis, and possibly
angiotensin-convertingenzymeinhibi-
tors.51 Spironolactone appears to be
quite effective in patients with severe
precapillary pulmonary hypertension
and right heart failure with ascites. In-
travenous dobutamine, dopamine, or
phosphodiesterase inhibitors are used
forshort-termtreatmentofsevereright
ventricular failure.37
Investigational Therapies. Prosta-
cyclin analogues that can be admin-
istered nonparenterally are under in-
vestigation.52,53 Iloprost and beroprost
are 2 PGI2 analogues that can be ad-
ministered by inhalation and orally,
respectively. Treprostinil sodium is an
analogue of PGI2 that can be admin-
istered subcutaneously by an insulin
pump and has been approved by the
Food and Drug Administration for
treatment of primary pulmonary hy-
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1932
pertension.54 However, recent stud-
ies have failed to demonstrate ben-
eficial effects during long-term
treatment with iloprost.55,56 Placebo-
controlled studies in Europe have re-
ported improved exercise tolerance
with beroprost in patients with pri-
mary pulmonary hypertension. In-
haled nitric oxide is of some use for
short-term treatment of precapillary
pulmonary hypertension. However,
long-term administration of nitric ox-
ide by inhalation does not appear to
be a viable therapy.
Nitric oxide donors such as L-
arginine have shown some promise
in patients with precapillary pulmo-
nary hypertension. Gene therapies to
enhance the activity of nitric oxide
synthase, PGI2 synthase, potassium
channels, and bone morphogenetic
protein receptors are potential novel
therapeutic approaches that will re-
quire meticulously performed clini-
cal trials. Trials of natriuretic pep-
tides and endopeptidase inhibitors
have been shown to reduce PAP and
PVR in animal models. However,
clinical trials will be necessary to as-
sess the potential beneficial effects of
these agents in the management of
precapillary pulmonary hyperten-
sion. Phosphodiesterase-5 inhibitor
sildenafil (Viagra) attenuates hy-
poxia-induced pulmonary vasocon-
striction and has the potential to be
an effective treatment for pulmo-
nary arterial hypertension.57
Surgical Therapy. Atrial septos-
tomy has been performed as a pallia-
tive procedure in patients with
severe precapillary pulmonary hyper-
tension.37,38,54 However, the risk of
atrial septostomy is considerable in
patients with severe right ventricu-
lar failure, and, therefore, it should
only be performed in institutions with
considerable experience.
Pulmonary endarterectomy is a
surgical technique that has been de-
veloped for the treatment of chronic
thromboembolic pulmonary hyper-
tension. In selected centers, the op-
erative mortality for this procedure is
low, and long-term survival benefit
has been documented even in pa-
tients with severe thromboembolic
pulmonary hypertension. Long-
term anticoagulation therapy is nec-
essary after thromboendarterec-
tomy. Single or double lung transplan-
tation remains the surgical treatment
of choice for refractory precapillary
pulmonary hypertension. One-year
survival after lung transplantation is
approximately 70% to 75% and 5-year
survival is 40% to 45%. However, all
patients with primary pulmonary hy-
pertension should be initially treated
with PGI2, and only those patients
who fail to respond to PGI2 should
be considered for lung transplanta-
tion therapy.
Accepted for publication February 13,
2002.
Corresponding author and re-
prints: Kanu Chatterjee, MB, FRCP,
ChatterjeeCenterforCardiacResearch,
University of California, San Francisco,
1182M,Moffitt-LongHospital,505Par-
nassus Ave, San Francisco, CA 94143
(e-mail: chatterj@medicine.ucsf.edu).
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