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Introduction
Because pulmonary hypertension can occur from diverse
etiologies, a classification of the disease has been very
helpful. The original classification, established at a
World Health Organization (WHO) symposium in 1973, classified
pulmonary hypertension into groups based on the known
cause and defined primary pulmonary hypertension (PPH)
as a separate entity of unknown cause. PPH was then classified
into three histopathological patterns: (a) plexogenic
arteriopathy, (b) recurrent thromboembolism, and (c) venoocclusive
disease. In 1998, a new classification for pulmonary
WHO Functional Classification
of Pulmonary Hypertension
A. Class I – Patients
with pulmonary hypertension but without
resulting limitation of physical activity. Ordinary
physical activity
does not cause undue dyspnea or fatigue, chest pain,
or near
syncope.
B. Class II – Patients
with pulmonary hypertension resulting in
slight limitation of physical activity. They are comfortable
at rest.
Ordinary physical activity causes undue dyspnea or
fatigue, chest
pain, or near syncope.
C. Class III – Patients
with pulmonary hypertension resulting in
marked limitation of physical activity. They are comfortable
at
rest. Less than ordinary activity causes undue dyspnea
or fatigue,
chest pain, or near syncope.
D. Class IV – Patients
with pulmonary hypertension with inability
to carry out any physical activity without symptoms.
These
patients manifest signs of right heart failure. Dyspnea
and/or
fatigue may be present even at rest. Discomfort is
increased by
any physical activity. |
hypertension was developed that focused on the biologic
expression of the dis-ease and etiologic factors in an
attempt to group these illnesses on the basis of clinical
similarities.1 This classification serves as a useful
guide to the clinician in organizing the eval-uation of
a patient with pulmonary hypertension and developing a
treatment plan. In addition, a functional classification
(see Table) patterned after the New York Heart
Association Functional Classification for heart disease
was developed to allow comparisons of patients with respect
to the clinical severity of the disease process.
Recently, parameters for normal pulmonary arterial systolic
pressure derived by echo Doppler studies have been published
which suggest that the upper limit of normal of pulmonary
arterial systolic pressure in the general population may
be higher than previously appreciated.2 Importantly, however,
the study characterized changes based on age and found
a mod-est increase in pulmonary arterial pressure with
age similar to what exists in the systemic circulation.
There are patients whose resting hemodynamics are normal,
but in whom marked elevations in pulmonary pressure occur
with exercise. It has been presumed that this represents
an early stage of pulmonary vascular disease. However,
as patients may have a hypertensive response to exercise
with respect to the systemic vasculature, a similar type
of response can occur in the pulmonary vasculature. Thus,
whether exercise induced pulmonary hypertension represents
true pulmonary vascular disease or reduced compliance
of an otherwise normal pulmonary circulation can be difficult
to ascertain.
Pulmonary Hypertension–Diagnostic
Challenges
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Pulmonary Arterial Hypertension
- Primary Pulmonary Hypertension
(a) Sporadic
(b) Familial
- Related to:
(a) Collagen Vascular Disease
(b) Congenital Systemic to Pulmonary Shunts
(c) Portal Hypertension
(d) HIV Infection
(e) Drugs/Toxins
(1) Anorexigens
(2) Other
(f) Persistent Pulmonary Hypertension of the Newborn
(g) Other
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Patients with pulmonary arterial hypertension characteristically
present with effort dyspnea that can have a slowly progressive
course.3 The onset of right ventricular failure, manifest
by a reduction in cardiac output and/or elevation in right
atrial pressure, is usually associated with a marked clinical
deterio-ration and poor prognosis.4 The rapidity in which
this occurs in highly variable and is often related to
the age of onset and associated conditions. Thus, patients
with pulmonary arterial hypertension associated with congenital
heart defects will more commonly have a slow, insidious
onset of symptoms and develop right heart failure after
decades, whereas patients with the CREST syndrome* present
later in life with a progres-sive downhill course.
Primary Pulmonary Hypertension
Patients with primary pulmonary hypertension (PPH) are
sub-categorized into sporadic and familial. The diagnosis
of famil-ial PPH is made through a patient’s family
history, as there are no clinical or pathologic features
that separate these two entities. Although the prevalence
of familial PPH had been published as being 12% at the
time of the NIH Registry, this underestimates the true
familial prevalence. Because of incomplete penetrance
of the gene, it may skip several gener-ations, which would
not be uncovered unless the physician were to take an
in-depth look at the patient’s family medical histories.
The PPH-1 gene, which has been recently described, has
been reported to be present in approximately half the
patients with familial PPH.5 Those without the PPH-1 gene
may have other genetic mutations that have not yet been
discovered or may have a gene that cannot be deter-mined
by current techniques. Patients with sporadic PPH have
also been noted to test positive for the PPH-1 gene in
about 25%. These patients actually may be familial but
mis-characterized as sporadic because of the lack of a
supporting family history, or may indeed represent point
mutations.
Collagen Vascular Disease
Patients with pulmonary arterial hypertension related
to the collagen vascular diseases will have clinical features
repre-senting both entities. It is most common for the
collagen vas-cular disease to manifest itself years before
the onset of pul-monary hypertension, but on occasion
the opposite has occurred. Many patients with PPH will
have elevated titers of antinuclear antibodies.6 Whether
this represents a form fruste of a collagen vascular disease,
or is just a clinical fea-ture of PPH, has been debated.
The high incidence of pul-monary hypertension in patients
with CREST and scleroderma has supported the recommendation
that these patients be screened periodically with echocardiography.
Congenital Heart Disease
Congenital systemic to pulmonary shunts can cause pul-monary
hypertension believed to be related to the increased blood
flow and pressure transmitted to the pulmonary circula-tion.
In most instances this entity is reversible if detected
early and the shunt is corrected. In some instances, however,
pulmonary hypertension develops very rapidly at the early
stages of the disease and precludes any surgical correction.
Some patients present with a remote history of a patent
ductus arteriosis that was ligated, or an atrial septal
defect that was relatively small with coexisting pulmonary
vascular dis-ease. Whether the shunt and the pulmonary
hypertension are related or coincidental has been a matter
of debate.7 Right-to left-shunting through a patent foramen
ovale needs to be dis-tinguished from congenital heart
disease. It is uncommon for a patent foramen ovale to
be associated with significant right-to- left shunting
at rest, but it can contribute to exercise-induced hypoxemia.
When uncertainty exists, transesophageal echocardiography
should distinguish a foramen ovale from an atrial septal
defect. If necessary the distinction can be made during
catheterization by sizing the defect with the balloon
from a pulmonary artery catheter.
Portal Hypertension
The association between liver disease and pulmonary hyper-tension
appears to be related to portal hypertension, and not
to liver disease itself.8 Why portal hypertension leads
to pulmonary hypertension has never been fully understood.
Making the diagnosis of portal hypertension in a patient
with pulmonary hypertension can be problematic. The diagnosis
of portal hypertension, an elevation in portal pressure,
can be made by direct wedge pressure determination of
the portal vein at the time of cardiac catheterization.
An elevation of portal pressure above 10 mmHg from a normal
right atrial pressure defines portal hypertension. It
has never been deter-mined, however, what gradient is
necessary to make this diagnosis in a patient with an
elevated right atrial pres-sure that is commonly found
in patients with pulmonary hypertension. Thus, the clinical
diagnosis of portal hyperten-sion may have to be made
by other indirect determinations such as the presence
of esophageal varices or an abnormal flow pattern in the
hepatic veins determined by Doppler.
HIV Infection
It is well established that the presence of the HIV virus
can induce pulmonary hypertension, probably through activation
of cytokine or growth factor pathways. There has been
no association made between the viral load or the type
of antivi-ral therapy and the severity of the pulmonary
hypertension.9 As antiviral therapy against HIV improves
over time, it will be of interest to note whether or not
the coexisting pulmonary hypertension resolves with treatment.
Drugs/Toxins
Although several drugs and toxins have been associated
with the development of pulmonary hypertension, a causal
relationship with many of these remains uncertain. The
strongest association between drug ingestion and the development
of pulmonary hypertension has been made with the fenflu-ramines.
10 Although the syndrome is indistinguishable from primary
pulmonary hypertension, our experience suggests these
patients tend to have a more aggressive disease with a
poorer prognosis than similar patients with PPH. This
may be a result of the fenfluramines triggering a unique
molecular pathway that produces pulmonary vasculopathy.
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