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Chronic thromboembolic obstruction of the major pulmonary
arteries is an underrecognized sequela of acute pulmonary
embolism. Depending on the burden and location of thrombus,
as well as on the duration of vessel obstruction, chronic
thromboembolic disease may lead to pulmonary hypertension
and cor pulmonale. Chronic thromboembolic disease affects
an esti-mated 500 to 2500 patients each year in the United
States, roughly 0.1 to 0.5 percent of patients who survive
acute pul-monary embolism. Consequently, while this disease
is uncommon, chronic thromboembolic pulmonary hypertension
(CTEPH) is not rare, and should be considered in patients
with unexplained dyspnea, as it is potentially correctible
with pulmonary thromboendarterectomy.1
Epidemiology and Pathophysiology
Since most patients with CTEPH present late in their disease
course, the early natural history of this disease process
is poorly understood. However, current evidence suggests
that an acute thromboembolism is likely the precipitating
event even when the patient has no documented history
of acute venous thromboembolism. Studies have documented
not only that symptomatic pulmonary embolism is often
overlooked or misdiagnosed, but that pulmonary embolism
may be asymptomatic.2 Complete anatomic and hemodynamic
resolution is also probably less common than previously
appreciated. Although serial angiographic studies are
limited to small numbers of patients, only partial resolution
is visible in many patients as long as 21 days after an
acute pulmonary embolic event.3 When serial lung perfusion
scans have been performed several months after the primary
embolic event, up to 66% of patients show persistently
abnormal perfusion patterns, reflecting incomplete resolution.
4 These figures may actually underestimate the degree
of residual thromboembolic disease since perfusion scanning
often understates the extent of angiographic obstruction
in chronic thromboembolic disease.5
It is still unclear why acute emboli fail to resolve
in a subset of patients who subsequently develop pulmonary
hypertension. An identifiable hypercoagulable state is
found in only a minority of patients. A lupus anticoagulant
is present in 10% to 20% of patients with CTEPH.6,7 Inherited
deficiencies of protein C, protein S, and antithrombin
III, as a group, can be identified in up to 5% of this
population.8 Efforts to identify abnormalities in the
fibrinolytic pathway or within the pulmonary endothelium
that would account for incomplete thrombus dissolution
have been unrevealing.9-11
The inability to adequately lyse a pulmonary embolus
in the proximal pulmonary arteries can result in a reduction
in the cross sectional area of the pulmonary vascular
bed. If significant, patients may be left with residual
dyspnea after the acute embolism. However, many patients
may remain asymptomatic for months or years following
their initial embolic event. While hemodynamic decline
may be due to recurrent thromboembolic events or in situ
thrombosis with extension of organized thrombus, clinical
experience and analysis of sequential perfusion scans
in a large number of CTEPH patients suggest that an alternative
process may contribute to the hemodynamic deterioration
in this population. The development of a pulmonary hypertensive
arteriopathy, similar to that seen in patients with other
forms of pulmonary hypertension, has been documented in
unobstructed lung regions as well as in vessels distal
to partially or completely occluded proximal pulmonary
arteries.12 These small-vessel changes therefore appear
to be a significant contributor to the hemodynamic progression
seen in many of these patients.
Without surgical intervention, survival of CTEPH patients
is poor and is inversely related to the degree of pulmonary
hypertension at the time of diagnosis. Riedel et al found
a 5-year survival rate of 30% among patients with a mean
pulmonary artery pressure greater than 40 mmHg at the
time of diagnosis and 10% in those whose pressure exceeded
50 mmHg.13 In another study, a mean pulmonary artery pressure
as low as 30 mmHg was identified as a threshold for poor
prognosis.14
Clinical Manifestations
Similar to patients with other forms of pulmonary hypertension,
patients may present with subtle or nonspecific symptoms.
The most common symptoms in patients with CTEPH are progressive
exertional dyspnea and exercise intolerance. These symptoms
are secondary to elevated dead space ventilation and a
limitation in cardiac output from obstruction of the pulmonary
vascular bed. As the disease progresses, additional symptoms,
such as edema, chest pain, light-headedness and syncope
may develop. Early in the course of thromboembolic disease,
physical findings may be limited to an accentuated P2,
which may be easily overlooked during the physical exam.
With progression of the disease, physical findings compatible
with the presence of pulmonary hypertension and right
ventricular failure develop. Meticulous auscultation of
the lungs may provide a clue to the etiology of the pulmonary
hypertension. Short systolic bruits may be audible over
the lung fields in 30% of patients with CTEPH. They are
high pitched and blowing in quality and are auscultated
over the lung fields rather than the precordium. More
audible during an end-inspiratory breath-holding maneuver,
these bruits are caused by turbulent flow through larger
pulmonary arteries partially occluded by thrombus. They
may also be present in other disease states that cause
narrowing of the pulmonary arteries such as large-vessel
arteritis, tumors of the pulmonary artery and congenital
branch stenosis. However, they have not been described
in primary pulmonary hypertension, a common competing
diagnosis.15 A delay of two to three years from the onset
of symptoms to confirmation of the correct diagnosis is
common.16
A delay is most common when there is no history of acute
thromboembolism. The nonspecific symptoms of this disease
as well as the subtle physical findings early in its natural
history contribute to the delay in correct diagnosis.
Symptoms are frequently erroneously attributed to deconditioning,
advancing age, psychogenic dyspnea, or more commonly occurring
cardiopulmonary diseases such as obstructive lung disease
or coronary artery disease. A lack of awareness of the
disease entity by physicians also plays a role in the
difficulty of achieving the correct diagnosis.
Diagnostic Evaluation
Pulmonary vascular disease must always be considered in
the differential diagnosis of unexplained dyspnea. The
diagnostic evaluation serves three purposes: to establish
the presence and severity of pulmonary hypertension, to
determine its etiology, and, if thromboembolic disease
is present, to determine whether it is surgically correctible.
Routine laboratory tests may be normal early in the disease.
The development of right ventricular dysfunction may result
in abnormal liver function stud-is from hepatic congestion
and elevation of blood urea nitro-gen, creatinine, and
uric acid from a reduction in renal blood flow. Long standing
hypoxemia may lead to secondary polycythemia. The presence
of a lupus anticoagulant may be suggested by an elevated
activated partial thromboplastin time and may be accompanied
by a low platelet count.
Chest radiography may be unrevealing in the early stages
of CTEPH. However, several radiographic abnormalities
may be seen with progression of pulmonary hypertension
and cor pulmonale. The lung fields are typically clear
in the absence of coexisting lung disease or may demonstrate
peripheral opacities suggestive of scarring from previous
infarction. Careful inspection may reveal areas of hypoperfusion
or hyperperfusion with a prominent interstitial pattern.
Cardiomegaly with dilation and hypertrophy of the right-sided
chambers and dilation of the central pulmonary arteries
are radiographic signs of long standing pulmonary hypertension.
Asymmetric enlargement of the central pulmonary arteries
is suggestive of chronic thromboembolic occlusion of major
vessels. This radiographic finding may be mistaken for
adenopathy, which is important to exclude.
Pulmonary function tests are often obtained in the evaluation
of dyspnea and serve to exclude the presence of obstructive
airways or parenchymal lung disease. There are no characteristic
spirometric changes diagnostic of CTEPH. Approximately
20% of patients will have a mild to moderate restrictive
defect that is caused by parenchymal scarring.17 The single
breath diffusing capacity for carbon monoxide (DCO) may
be normal, mildly or moderately reduced; a severe reduction
in DCO should alert the physician to other diseases that
severely compromise the small pulmonary vascular bed.
Arterial blood oxygen levels can be normal even in the
setting of significant pulmonary hypertension. With exertion,
many will experience a decline in pO 2 . When present,
hypoxemia in the setting of CTEPH is due to ventilation-perfusion
inequalities, a reduction in cardiac output causing a
decline in mixed venous oxygen saturation, and right-to-left
shunting of blood through a patent foramen ovale.18
Transthoracic echocardiography is commonly the first
study to provide objective evidence of the presence of
pulmonary hypertension. An estimate of the pulmonary artery
systolic pressure can be provided by Doppler evaluation
of the tricuspid regurgitant envelope. Additional echocardiographic
findings vary depending upon the stage of the disease
and include enlargement of the right-sided chambers, leftward
displacement of the interventricular septum, and encroachment
of the enlarged right ventricle on the left ventricular
cavity with abnormal systolic and diastolic function of
the left ventricle.19 Contrast echocardiography may demonstrate
a patent foramen ovale or septal defects.
Once the diagnosis of pulmonary hypertension has been
established, distinguishing between major-vessel obstruction
and small-vessel pulmonary vascular disease is the next
critical step. Radioisotope ventilation-perfusion (V/Q)
lung scanning plays a central role in determining whether
pulmonary hypertension has a thromboembolic origin. The
V/Q scan typically shows one or more mismatched, segmental
or larger defects in CTEPH. This is in contrast to the
normal or “mottled” perfusion scan seen in patients with
primary pulmonary hypertension or other small-vessel forms
of pulmonary hypertension 20 (Figure 1).
It is important to note that during the process of reorganization,
thromboemboli may recanalize or narrow the vessel lumen
so that macroaggregated albumen may pass beyond the point
of partial vessel obstruction. This results in relative
areas of hypoperfusion which appear as “gray zones,” a
finding frequently observed on the V/Q scans of patients
with CTEPH. One consequence of this partial recanalization
is that the magnitude of the perfusion defects with CTEPH
frequently underestimates the actual degree of pulmonary
vascular obstruction as determined by angiography or surgery
5 (Figure 2). Even a single mismatched
segmental defect in a patient with pulmonary hyper-tension
should raise the suspicion of chronic thromboembolic disease.
Furthermore, mismatched segmental perfusion defects are
not specific for thromboembolic disease and may be seen
with other processes that result in obstruction of the
central pulmonary arteries, such as mediastinal adenopathy
or fibrosis, large-vessel arteritis, pulmonary vascular
or bronchogenic tumors, and pulmonary veno-occlusive disease.
Therefore, additional imaging studies may be required
to establish the correct diagnosis.
Cardiac catheterization provides essential information
in the evaluation of patients with suspected pulmonary
hypertension. Right heart catheterization provides data
that allow for quantification of the severity of pulmonary
hypertension and an assessment of cardiac function. Hemodynamics
during symptom limited exercise should be obtained when
there is evidence of only modest pulmonary hypertension
at rest, especially when the patient’s symptoms seem out
of proportion to the degree of resting pulmonary hypertension
or the extent of thromboembolic obstruction. Measurement
of oxygen saturations in the vena cava, right heart chambers
and the pulmonary artery may document previously undetected
left-to-right shunting. Coronary angiography and left
heart catheterization provide additional information in
those at risk for coronary artery disease and in patients
in whom left ventricular dysfunction or valvular heart
disease is suggested by echocardiography. This information
is crucial in the preoperative risk assessment of patients
deemed candidates for pulmonary thromboendarterectomy.
Pulmonary angiography continues to be the gold standard
for defining the pulmonary vascular anatomy and is performed
to identify whether chronic thromboembolic obstruction
is present, to determine its location and surgical accessibility,
and to rule out other diagnostic possibilities. Despite
concerns regarding the safety of performing pulmonary
angiography in patients with pulmonary hypertension, with
careful monitoring and modification of standard angiographic
procedures, pulmonary angiography can be performed safely
even in patients with severe pulmonary hypertension.21
Biplane imaging is preferred, offering the advantage of
lateral views that provide greater anatomic detail compared
with the overlapped and obscured vessel images often seen
in the anterior-posterior view. Interpretation of these
angiograms can be difficult in large measure because the
appearance of chonic thromboemboli bears little resemblance
to the well-defined, intraluminal filling defects of acute
pulmonary embolism. Maturation and organization of clot
results in vessel retraction and partial recanalization
resulting in several angiographic patterns suggestive
of chronic thromboembolic disease: (1) pouch defects;
(2) pulmonary artery webs or bands; (3) intimal irregularities;
(4) abrupt narrowing of major pulmonary vessels; and (5)
obstruction of main, lobar, or segmental pulmonary arteries,
frequently at their point of origin 22 (Figure
3). However, competing diagnoses exhibit angiographic
findings similar to those encountered with chronic thromboembolic
disease. For instance, areas of focal vessel narrowing,
or “bands,” can be seen as a feature of congenital stenosis
of the pulmonary arteries as well as of medium- or large-vessel
arteritis. Total obstruction or abrupt narrowing of the
central pulmonary arteries can be a feature of an intravascular
process such as pulmonary vascular tumors or extravascular
compression from lung carcinoma, hilar or mediastinal
adenopathy, or mediastinal fibrosis. Since chronic thromboembolic
disease is usually bilateral, the presence of unilateral
central pulmonary artery obstuction should always prompt
consideration of one of these rival diagnoses.
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