Chronic thromboembolic pulmonary hypertension.

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Chronic Thromboembolic Pulmonary Hypertension
Marius M. Hoeper, MD; Eckhard Mayer, MD; Gérald Simonneau, MD; Lewis J. Rubin, MD
C
severe pulmonary hypertension. The disease is notoriously
underdiagnosed, and the true prevalence is still unclear.
CTEPH is characterized by intraluminal thrombus organiza-
tion and fibrous stenosis or complete obliteration of pulmo-
nary arteries.1The consequence is an increased pulmonary
vascular resistance resulting in pulmonary hypertension and
progressive right heart failure. Vascular disobliteration by
pulmonary endarterectomy (PEA) is the preferred treatment
for patients with CTEPH,2but not all patients are eligible for
surgery. Recent research has provided evidence suggesting
that the mechanistic view of CTEPH as a disease caused
solely by obliteration of central pulmonary arteries due to
organized thrombi may have been too simplistic. Pulmonary
embolism, either as a single episode or as recurrent episodes,
is thought to be the initiating event followed by progressive
pulmonary vascular remodeling. This concept explains the
clinical observation that CTEPH patients may have severe
pulmonary hypertension out of proportion to the pulmonary
vascular obliteration seen on a pulmonary angiogram. Thus,
treatment of CTEPH often requires a multidisciplinary ap-
proach and may involve surgery, medical treatment, or both.
However, many aspects of the pathogenesis of CTEPH are
poorly understood, the diagnostic approach to these patients
has not been standardized, and neither randomized controlled
trials nor guidelines have been published in this field.
In July 2005, a group of international experts met in
Zurich, Switzerland, for a comprehensive discussion of
CTEPH. The members of this group are listed in the Appen-
dix (in the online-only Data Supplement). This report will
review the issues surrounding CTEPH that were discussed
during that meeting: its etiology and pathogenesis, epidemi-
ology, diagnosis, treatment options, and associated prognosis.
Current issues, including challenges in assessing surgical
candidacy and predicting postoperative outcome, will be
introduced. Finally, potential ways of resolving uncertain and
controversial issues, such as the role of medical therapy and
the requirement for randomized controlled trials, will be
discussed. Algorithms for the diagnosis and management of
CTEPH will be proposed.
hronic thromboembolic pulmonary hypertension
(CTEPH) has emerged as one of the leading causes of
Epidemiology
The true incidence and prevalence of CTEPH are unknown.
Originally, it was believed that 0.1% to 0.5% of patients who
survive an episode of acute pulmonary embolism develop
CTEPH.3–5However, in a prospective follow-up study of 78
survivors of acute pulmonary embolism, echocardiographic
findings suggestive of persistent pulmonary hypertension
and/or right ventricular dysfunction were present in 44% of
the patients after 1 year.6Four patients (5.1%) developed
definite CTEPH, and 3 of these subsequently underwent
successful PEA. The only identifiable risk factors for persis-
tent pulmonary hypertension were an age ?70 years and a
systolic pulmonary artery pressure ?50 mm Hg at the initial
presentation. An echocardiogram at week 6 after diagnosis of
an acute pulmonary embolism was capable of distinguishing
between patients with persistent pulmonary hypertension and
those with complete recovery. In another prospective
follow-up study of 223 patients who presented with acute
pulmonary embolism, the incidence of symptomatic CTEPH
was 3.1% at 1 year and 3.8% at 2 years.7Risk factors for
CTEPH were previous episodes of acute pulmonary embo-
lism, larger perfusion defects at the initial presentation, and a
younger age. The incidence of CTEPH in both studies was
higher than expected, and it is possible that some of the
patients had preexistent unidentified CTEPH when they present-
ed with the clinical picture of acute pulmonary embolism.
Defining the true incidence of CTEPH is hampered by the
observation that up to two thirds of these patients have no
history of clinically overt acute pulmonary embolism.8Thus,
the only way to define the true incidence and prevalence of
CTEPH will be a combination of large-scale multicenter
studies prospectively following patients after pulmonary em-
bolism in combination with subtle case studies of patients
without a history of acute pulmonary hypertension in whom
a diagnosis of CTEPH is made during a diagnostic workup
for unexplained pulmonary hypertension.
Natural History
The natural history of untreated CTEPH must be determined
from historical data because today most patients will be referred
for surgery or medical treatment. In 1982, ie, before PEA
From the Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany (M.M.H.); Department of Cardiothoracic and Vascular
Surgery, Johannes Gutenberg University, Mainz, Germany (E.M.); Centre of Maladies Vasculaires Pulmonaires, Hôpital Antoine Béclère, Clamart,
France (G.S.); and Pulmonary Vascular Program, University of California, San Diego (L.J.R.).
The online-only Data Supplement, which contains the Appendix, can be found at http://circ.ahajournals.org/cgi/full/113/16/2011/DC1.
Correspondence to Marius M. Hoeper, MD, Department of Respiratory Medicine, Hannover Medical School, 30623 Hannover, Germany. E-mail
hoeper.marius@mh-hannover.de
(Circulation. 2006;113:2011-2020.)
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.602565
2011
Contemporary Reviews in Cardiovascular Medicine

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became widely available, Riedel et al9published a series of 26
patients with CTEPH who were followed up for up to 15 years.
Patients who had a mean pulmonary artery pressure
?30 mm Hg at the initial presentation invariably had progres-
sive pulmonary hypertension. Survival at 2 years was ?20%
when the mean pulmonary artery pressure was ?50 mm Hg.
Another study of 49 CTEPH patients treated only with antico-
agulants reported a 3-year mortality of 90% when the mean
pulmonary artery pressure was ?30 mm Hg.10In contrast, a
similar follow-up study from Japan of 48 CTEPH patients with
mean pulmonary artery pressures of 50 mm Hg found a mean
survival of 6.8 years after the diagnosis.11Despite these conflict-
ing data, it is clear that most patients who present with persistent
pulmonary hypertension after pulmonary embolism will have
progressive disease despite adequate anticoagulation and that
these patients carry a high risk of dying from right heart failure
if left untreated.
Pathophysiology
It has been appreciated for many years that CTEPH may not
be explained simply by pulmonary vascular obliteration due
to unresolved thrombemboli.12Persistent obstruction of pul-
monary arteries may result in elevated pulmonary artery
pressures and high shear stress in those areas of the pulmo-
nary vasculature that were spared from thromboembolic
occlusion. In that scenario, acute pulmonary embolism would
be the initiating event, but progression of pulmonary hyper-
tension would result from progressive pulmonary vascular
remodeling, ie, small-vessel disease. This concept was pro-
posed by Drs Kenneth Moser and Nina Braunwald after Dr
Braunwald’s first surgical PEA at the University of California
at San Diego in 1971.12Moser and Braunwald noted that the
patient had “a two compartment pulmonary vascular bed.”
The open pulmonary arteries had marked structural changes
of chronic pulmonary hypertension, whereas the vascular bed
distal to the obliterated segments, which had not been
exposed to high pressure and high shear stress, appeared to be
completely normal. This observation was later confirmed by
clinical and histological studies revealing changes in the
pulmonary microvasculature very similar to other forms of
severe pulmonary hypertension including the formation of
plexiform lesions.13–17Both the extent of proximal occlusion
of pulmonary arteries and secondary small-vessel arteriopa-
thy contribute to the elevated pulmonary vascular resistance
(Figure 1). The more pronounced the distal vascular changes
are, the higher is the risk of surgery and the less likely is
hemodynamic improvement after surgery.2,18
When attempting to elucidate the mechanisms driving the
development of CTEPH, one must distinguish between fac-
tors that prevent complete recanalization of pulmonary arter-
ies after acute pulmonary embolism and those that are
involved in the remodeling of small pulmonary vessels. The
reasons for incomplete resolution of pulmonary emboli have
not been identified. The normal pulmonary vascular bed
carries a high fibrinolytic potential, but alterations in the
fibrinolytic system have not yet been identified in patients
with CTEPH. Secretion by pulmonary vascular endothelial
cells of tissue plasminogen activator and plasminogen acti-
vator inhibitor-1 is not different between lungs from CTEPH
patients and donor lungs.19,20Interestingly, thrombophilia
resulting from mutations in protein C, protein S, antithrom-
bin, prothrombin, or factor V has not been associated with
CTEPH.21,22The only factors that have been linked to
CTEPH thus far are anticardiolipin antibodies, which are
found in 10% to 20% of these patients,22and elevated levels
of factor VIII,23but similar findings have been reported in
patients with other forms of pulmonary hypertension.24
Several risk factors for the development of CTEPH have
been identified, including chronic inflammatory disorders,
myeloproliferative syndromes, the presence of a ventricu-
loatrial shunt, and splenectomy.25The association with these
distinct conditions suggests that chronic infection and/or
chronic inflammatory processes are involved in the pathogen-
Figure 1. Pulmonary angiogram (capillary phase) of the right lung
of a patient with CTEPH. The right middle and upper lobe arteries
are almost completely obstructed by central thromboemboli, which
are not directly visible on this radiograph. The peripheral arteries
and arterioles in these areas (arrows) are not perfused, resulting in
protection from high intravascular pressures and high shear stress.
The peripheral vessels in these areas usually appear normal on
histological examination (not shown). In contrast, the right upper
lobe is exposed to high intravascular pressures and receives
almost the complete blood flow of the right lung. High pressure,
high shear stress, inflammation, and an imbalance of vasoactive
mediators result in vascular remodeling including the formation of
plexiform lesions (inlet).
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esis of CTEPH. This hypothesis is supported by numerous
experimental findings showing that inflammation may cause
a prothrombotic state and impair resolution of pulmonary
thrombemboli.26–29
ThehighproportionofsplenectomizedpatientsintheCTEPH
population has gained considerable attention.30–32The interval
between splenectomy and diagnosis of CTEPH ranges between
2 and 34 years, and the pathogenetic link between these
conditions remains unclear. Current hypotheses include pro-
thrombotic activity of abnormal erythrocytes, interactions be-
tween abnormal erythrocyte membranes and the pulmonary
vasculature, or abnormal platelet activation.25,32,33
Despite the overwhelming evidence linking CTEPH to
previous events of pulmonary embolism, an alternative hy-
pothesis of the pathogenesis of CTEPH disputes the role of
acute or recurrent pulmonary embolism but suggests a pri-
mary arteriopathy of pulmonary vessels and secondary in situ
thrombosis as causes of pulmonary vascular occlusion.34This
hypothesis is driven by pathophysiological considerations
and experimental data raising doubts that a single episode
of pulmonary embolism or even recurrent events may result
in pulmonary vascular obliteration sufficiently severe to
cause pulmonary hypertension. In fact, in situ thrombosis of
pulmonary vessels is a well-recognized complication in
patients with severe pulmonary hypertension of other etiolo-
gies.35The observation of different risk constellations for
acute venous thromboembolism and CTEPH has fueled this
discussion. It has also been argued that venous thrombosis
can be found in ?50% of patients with CTEPH,2although
this number is similar to the rate of detectable venous
thrombosis in patients presenting with acute pulmonary
embolism.36,37The vast majority of experts agree that there is
compelling evidence supporting the concept of pulmonary
embolism, either overt or occult, triggering a cascade of
events that eventually result in CTEPH.36However, distin-
guishing patients with idiopathic PAH and in situ thrombosis
of peripheral vessels from patients with a distal type of
CTEPH may be impossible, and there may be an overlap
between both disorders.
Some but clearly not all of the mechanisms involved in
pulmonary vascular remodeling after acute or recurrent pul-
monary emboli have been identified. The system is complex
and consists of a large spectrum of biological molecules. As
in other forms of pulmonary hypertension, it is widely
believed that some patients are genetically susceptible to
developing this complication, but genetic variants associated
with a heightened risk of CTEPH have yet to be determined.
Mutations in bone morphogenetic protein receptor type 2
(BMPR-2) have been found in familial and idiopathic pul-
monary arterial hypertension.38,39These mutations have been
linked to vascular remodeling because they promote smooth
muscle cell proliferation. Similar mutations have not been
described in CTEPH. In fact, it has been shown that BMPR-2
expression is not diminished in lungs from CTEPH patients.40
However, expression of BMPR-1A, a transmembrane protein
required for BMPR-2 signaling, is markedly downregulated
in lungs from patients with CTEPH as well as other forms of
pulmonary hypertension.40Angiopoetin-1, a signaling mole-
cule involved in angiogenesis and smooth muscle cell prolif-
eration that has been experimentally linked to pulmonary
hypertension,41is upregulated in the lungs from CTEPH
patients. Angiopoetin-1 shuts off BMPR-1A expression and
thereby blocks BMPR-2 signaling even in the absence of
germline BMPR-2 mutations. This mechanism seems to play
a role in several forms of pulmonary hypertension including
but not restricted to CTEPH.40
Inflammatory mechanisms have also been implicated in the
pathogenesis of CTEPH. Plasma levels of the proinflamma-
tory cytokine macrophage chemoattractant protein-1 are ele-
vated in patients with CTEPH and correlate with the magni-
tudeofpulmonary hypertension.42
proinflammatory molecules have also been reported in pa-
tients with idiopathic pulmonary arterial hypertension.43–46
As in other forms of severe pulmonary hypertension, the
endothelin system is activated in patients with CTEPH and
may contribute to pulmonary vasoconstriction as well as
vascular remodeling. Plasma levels of endothelin-1 are ele-
vated in this group of patients, and upregulation of type B
endothelin receptors on pulmonary arterial smooth muscle
cells has been demonstrated.47In a canine model of chronic
pulmonary embolism, pulmonary vascular remodeling was
attenuated by bosentan, an endothelin receptor antagonist that
blocks both ETAand ETBreceptors.48
Taken together, the molecular mechanisms involved in
pulmonary vascular remodeling in CTEPH appear to be
similar to those seen in severe pulmonary hypertension of
other etiology. However, further studies are required for a full
understanding of the sequence of events that eventually result
in pulmonary vascular remodeling.
Elevationsof
Clinical Presentations and Diagnosis
The symptoms and signs of pulmonary hypertension have
been reviewed elsewhere.49–51Patients with CTEPH typically
present in either of 2 scenarios: patients may complain of
progressive dyspnea on exertion, hemoptysis, and/or signs of
right heart dysfunction including fatigue, palpitations, syn-
cope, or edema after a single episode or recurrent episodes of
overt pulmonary embolism. A “honeymoon period” between
the acute event and the development of clinical signs of
CTEPH is common and may last from a few months to many
years. However, up to 63% of patients have no history of
acute pulmonary embolism.8In these patients, progressive
dyspnea on exertion, rapid exhaustion, and fatigue are the
most common symptoms, and the clinical course is often
indistinguishable from other forms of severe pulmonary
hypertension, especially idiopathic pulmonary arterial hyper-
tension. Physical findings are often subtle and may include a
left parasternal heave, a prominent pulmonary component of
S2, and a systolic murmur of tricuspid regurgitation. Signs of
right heart failure, ie, extended neck veins, edema, ascites,
and acrocyanosis, occur late in the course of the disease and
may signal a life-threatening situation. A rare clinical finding
that is virtually pathognomonic for CTEPH is bruits over
peripheral lung fields,52typically over the lower lobes, which
result from turbulent blood flow in partially occluded areas.
According to most experts, these bruits can be found in
?10% of patients with CTEPH, making this sign one of low
sensitivity but probably very high specificity.
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As outlined below, the therapeutic approach to CTEPH
differs substantially from that to pulmonary arterial hyperten-
sion. Thus, it is crucial to clarify the presence or absence of
CTEPH in any patient presenting with unexplained pulmo-
nary hypertension. The fact that many CTEPH patients have
no history of acute pulmonary embolism together with
uncertainties about the appropriate diagnostic approach to
these patients contributes to a substantial rate of diagnostic
misclassifications in this patient population. However, the
most promising means to improve the diagnosis of CTEPH is
increased awareness by physicians.
Echocardiography is widely used as the initial diagnostic
tool when pulmonary hypertension is suspected, and routine
echocardiography 6 weeks after pulmonary embolism has
been suggested to identify patients at risk for developing
CTEPH.6However, the ideal timing of echocardiography, the
need for long-term follow-up in symptomatic or asymptom-
atic patients, and the cost-effectiveness of wide-scale echo-
cardiographic screening of patients after acute pulmonary
embolism remain to be determined.
Imaging technologies including ventilation-perfusion scan-
ning, computed tomography (CT), MRI, and pulmonary
angiography are a fundamental part of the diagnostic workup
of patients with suspected CTEPH. No prospective studies
have evaluated the most appropriate diagnostic approach to
CTEPH, and ventilation-perfusion scanning as well as CT
angiography may underestimate clot burden. Nevertheless,
ventilation-perfusion scanning is a useful tool to start search-
ing for possible CTEPH. There is consensus among experts
that a normal ventilation-perfusion scintigram practically
rules out the presence of CTEPH.3,53–56In contrast, the
presence of multiple bilateral perfusion defects makes
CTEPH the most likely diagnosis, although other conditions
including pulmonary veno-occlusive disease, pulmonary cap-
illary hemangiomatosis, fibrosing mediastinitis, pulmonary
vasculitis, or sarcomas of the pulmonary arteries may cause
similar findings.3,57–60
If scintigraphy shows indeterminate results, ie, whenever
the perfusion scan is not completely normal or reveals
findings suggestive of CTEPH, the next diagnostic step is
usually CT angiography, which may reveal eccentric throm-
botic material within the pulmonary arteries, subpleural
densities, and a characteristic mosaic attenuation of the
pulmonary parenchyma (Figure 2).61–64It is important to note
that patients with pulmonary arterial hypertension can de-
velop secondary thrombosis of the central pulmonary arteries,
a condition mimicking CTEPH.35In addition, neoplasms
involving the pulmonary arteries or pulmonary large-vessel
vasculitis may present with a similar CT picture.59,60,65In
these cases, ventilation-perfusion scanning usually does not
show the typical bilateral segmental and subsegmental per-
fusion defects but rather normal findings, an inhomogeneous
perfusion pattern, or unilateral abnormalities. Large bronchial
artery collaterals are typically visible in patients with CTEPH
and may be of diagnostic value because these collaterals are
rarely found in other forms of pulmonary hypertension except
for some cases associated with congenital heart disease.66–68
Of note, the absence of visible lesions in central pulmonary
arteries does not exclude the presence of CTEPH, especially
not with older imaging technology. Sensitivity and specificity
of new-generation multidetector row scanners have not yet
been sufficiently evaluated.
MRI may also provide a clear diagnosis of CTEPH, but this
technique is infrequently used for this indication.69–72How-
ever, contrast-enhanced magnetic resonance angiography
may be very useful in discriminating central thromboembolic
lesions from tumors because the latter are enhanced with
gadolinium, whereas the former are not.73
Pulmonary angiography remains a standard diagnostic tool
in the assessment of patients with probable or definite
CTEPH both to establish the diagnosis and to assess opera-
bility (Figure 3).74–76Pulmonary angiography is often per-
formed in conjunction with a diagnostic right heart catheter-
ization, which is required to confirm the diagnosis of
pulmonary hypertension, rule out pulmonary venous hyper-
tension, and establish the degree of hemodynamic impair-
ment. In many centers it has become a standard procedure to
perform the right heart catheterization first and then to use the
same introducer sheath for pulmonary angiography, thereby
Figure 2. CT scans of the lungs of patients with CTEPH show-
ing eccentric thrombotic material within the pulmonary arteries
(arrows) (A) and a characteristic mosaic attenuation of the pul-
monary parenchyma with the darker areas corresponding to the
hypoperfused lung sections (B).
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minimizing risks and inconveniences for the patient. Both
right heart catheterization and pulmonary angiography should
be performed by experienced staff. The use of nonionic
contrast media, right and left main branch selective injec-
tions, serial pictures, and multiples views is recommended. If
PEA is considered, pulmonary angiography might best be
done at the institution where surgery would be performed.
A proposed algorithm for the diagnostic workup of patients
with potential CTEPH is shown in Figure 4.
Treatment
CTEPH patients should receive lifelong anticoagulation ad-
justed to a target international normalized ratio between 2.0
and 3.0. The rationale for anticoagulation is the prevention of
recurrent thromboembolic events; once CTEPH is fully es-
tablished, one should not expect significant regression of
pulmonary hypertension from anticoagulation.
It is unclear how to proceed with patients presenting with
mild pulmonary hypertension and no or only mild clinical
impairment and normal right ventricular function after in-
complete resolution of pulmonary emboli. Although some
surgeons advocate early surgery in those patients to prevent
progressive pulmonary vascular remodeling, the natural his-
tory of these patients has never been studied prospectively.
Thus, anticoagulation and watchful waiting with regular
clinical assessment and echocardiographic monitoring is an
acceptable alternative to immediate surgery.
Patients presenting with systolic pulmonary artery pres-
sures ?50 mm Hg at the time of acute pulmonary embolism
are very likely to suffer from CTEPH even if the diagnosis
has not been established earlier. If these patients are in a
stable condition, anticoagulation and watchful waiting for a
period of 3 months is appropriate. Hemodynamic improve-
ment sometimes occurs during this period. In addition,
surgery may be much more difficult and less successful if
thromboemboli have not been completely organized. If per-
sistent pulmonary hypertension is present after 3 months, a
full diagnostic workup is warranted. However, in patients
Figure 3. Pulmonary angiographies of 2 patients with CTEPH.
The first patient (A) has extensive central pulmonary vascular
obliterations and a pulmonary vascular resistance of ?900
dyne · s · cm?5that is fully attributable to the visible lesions,
making PEA the treatment of choice. The therapeutic decision is
much more difficult in the second patient (B), who also has typi-
cal lesions of chronic thromboembolic pulmonary hypertension
with a more distal distribution and a pulmonary vascular resis-
tance of 2000 dyne · s · cm?5. With this constellation, the risk of
surgery is markedly elevated, and the optimal treatment is
uncertain (see text for details).
Figure 4. Proposed algorithm for the diagnostic approach to
patients with CTEPH. Ventilation-perfusion scanning is the recom-
mended screening procedure because a normal perfusion scan
virtually rules out CTEPH. When perfusion scans show indetermi-
nate results or bilateral segmental and subsegmental perfusion
defects, CTEPH is the most likely diagnosis, and further imaging of
the pulmonary vascular tree is required. *Pulmonary angiography
should be performed only if PEA is considered a potential thera-
peutic option. A center experienced in PEA should be contacted
before pulmonary angiography because most of these centers pre-
fer to have pulmonary angiography performed at their institution.
To plan the therapeutic concept, right heart catheterization with
assessment of hemodynamics is often performed in conjunction
with pulmonary angiography. †CTEPH despite a normal or nearly
normal perfusion scan has been reported on rare occasions. Thus,
further diagnostic workup may be warranted if there is a high clini-
cal suspicion of CTEPH.
Hoeper et alChronic Thromboembolic Pulmonary Hypertension
2015