JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 71, NO.

21, 2018

ª 2018 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

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JACC STATE-OF-THE-ART REVIEW

Chronic Thromboembolic
Pulmonary Hypertension
Evolving Therapeutic Approaches for Operable and
Inoperable Disease

Ehtisham Mahmud, MD,a Michael M. Madani, MD,b Nick H. Kim, MD,c David Poch, MD,c Lawrence Ang, MD,a
Omid Behnamfar, MD,a Mitul P. Patel, MD,a William R. Auger, MDc

ABSTRACT

Chronic thromboembolic pulmonary hypertension (CTEPH), a rare consequence of an acute pulmonary embolism, is a disease
that is underdiagnosed, and surgical pulmonary thromboendarterectomy (PTE) remains the preferred therapy. However,
determination of operability is multifactorial and can be challenging. There is growing excitement for the percutaneous
treatment of inoperable CTEPH with data from multiple centers around the world showing the clinical feasibility of balloon
pulmonary angioplasty. Riociguat remains the only approved medical therapy for CTEPH patients deemed inoperable or with
persistent pulmonary hypertension after PTE. We recommend that expert multidisciplinary CTEPH teams be developed at
individual institutions. Additionally, optimal and standardized techniques for balloon pulmonary angioplasty need to be
developed along with dedicated interventional equipment and appropriate training standards. In the meantime, the
percutaneous revascularization option is appropriate for patients deemed inoperable in combination with targeted medical
therapy, or those who have failed to benefit from surgery. (J Am Coll Cardiol 2018;71:2468–86) © 2018 The Authors.
Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

C hronic thromboembolic pulmonary hyper-

tension (CTEPH), a form of pre-capillary pul-
monary hypertension,
incomplete resolution of pulmonary thromboemboli
results
and formation of a chronic, fibrotic, flow-limiting
organized thrombus within the pulmonary vascular
bed. CTEPH is a relatively rare outcome, developing
in 0.56% to 3.2% of acute pulmonary embolism survi-
vors (1–3), with those patients exhibiting recurrent or
unprovoked pulmonary embolism at a greater risk for
experiencing this outcome (4–9). However, the his-
tory of “acute pulmonary embolism” in this patient
population is debatable because many patients
from
present with signs of chronic disease at the time of
initial diagnosis.
Because the majority of patients with acute pul-
monary embolism do not develop CTEPH, several
additional factors are felt to be contributory (Table 1).
Certain hypercoagulable states including the pres-
ence of antiphospholipid antibodies and elevated
factor VIII levels are more common among patients
with CTEPH, with a prevalence of 20% and 41%,
respectively (10,11). By contrast, levels of anti-
thrombin III, protein C, protein S, or Factor V Leiden
are not different among the general population
and patients with CTEPH (12,13). Alternative

Listen to this manuscript’s

audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aDivision of Cardiovascular Medicine, University of California San Diego, La Jolla, California; bDivision of Cardiothoracic
Surgery, University of California San Diego, La Jolla, California; and the cDivision of Pulmonary and Critical Care Medicine,
Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, California. Dr. Kim has been a consultant for Actelion,
Bayer, and Merck; and has served on the Speakers Bureau for Bayer. Dr. Poch has been a consultant; and has served on the
Speakers Bureau for Bayer. Dr. Auger has served as an advisory board member (uncompensated) for Bayer’s CTEPH Image Expert
Panel; and has received research funding from Bayer for the CTEPH registry. All other authors have reported that they have no
relationships relevant to the contents of this paper to disclose.

Manuscript received December 3, 2017; revised manuscript received March 19, 2018, accepted April 3, 2018.

ISSN 0735-1097 https://doi.org/10.1016/j.jacc.2018.04.009

JACC VOL. 71, NO. 21, 2018
MAY 29, 2018:2468–86
pathophysiological hypotheses include ineffective
endogenous fibrinolysis, fibrin variants resistant to
intrinsic fibrinolysis, and in situ thrombosis due to
pulmonary arteriopathy rather than a thromboem-
bolic basis for disease (14–16). Deficient angiogenesis
and inflammation have similarly been suggested as
playing a role in disease evolution (17). Inflammatory
markers such as C-reactive protein and tumor necro-
sis factor alpha are elevated in CTEPH, and the pres-
ence of inflammatory cytokines also suggests that
failure in endogenous fibrinolysis and thrombus
breakdown could be a consequence of an inflamma-
tory process (18–20). Other infrequent conditions and
clinical disorders associated with the development of
CTEPH include ventriculoatrial shunt, pacemaker
presence, previous splenectomy, a myeloproliferative
disorder, and the presence of chronic inflammatory
disorders such as inflammatory bowel disease and
osteomyelitis (21–23).
CLINICAL PRESENTATION
Patients with CTEPH often present with progressive
dyspnea, exercise intolerance, and nonspecific ab-
normalities on physical examination. As the disease
progresses, there is a high risk of developing pulmo-
nary hypertension and right heart failure. Patients
frequently have New York Heart Association func-
tional class III to IV symptoms (7) and may exhibit
signs and symptoms of right ventricular hypertrophy
or failure, such as jugular venous distension, right
ventricular lift, fixed splitting of the S2 heart sound,
right ventricular S3, exertional angina, syncope,
hepatomegaly, ascites, and peripheral edema (10,24).
The natural history of acute pulmonary embolism is
resolution of emboli within 3 to 6 months in patients
receiving antithrombotic therapy. Therefore, persis-
tent signs and symptoms after this period of anti-
coagulation therapy might signal the presence of
chronic thromboembolic disease (CTED), and an eval-
uation for such is warranted (25). However, CTEPH is
often diagnosed at an advanced stage due to nonspe-
cific symptoms and late appearance of more specific
signs (26). In the European CTEPH registry, it was
observed that over a year (median 14.1 months) passed
from the time of clinical presentation to diagnosis (27).
Data from the same registry revealed that 74.8% of
patients with CTEPH reported a previous history of
acute pulmonary embolism, whereas only 56.1% had a
history of deep venous thromboembolism (27).
DIAGNOSIS
The diagnosis of CTEPH solely based on history and
physical examination findings is challenging, and
Mahmud et al. 2469
Chronic Thromboembolic Pulmonary Hypertension
more common cardiopulmonary conditions ABBREVIATIONS
such as cardiomyopathy, ischemic heart dis- AND ACRONYMS
ease, and obstructive or restrictive pulmonary
BPA = balloon pulmonary
disease, are typically suspected (24,27). Chest angioplasty
radiography and pulmonary function tests
CBCT = cone beam computed
are helpful in excluding possible airway or tomography
parenchymal lung diseases; electrocardiog- CT = computed tomography
raphy may demonstrate findings associated CTED = chronic
with pulmonary hypertension or other cardiac thromboembolic disease
disorders (28–30). For those patients with CTEPH = chronic
suspected pulmonary vascular disease as thromboembolic pulmonary
hypertension
described in the preceding text, additional
LAO = left anterior oblique
evaluative studies need to be considered.
To screen for pulmonary hypertension and mPAP = mean pulmonary
artery pressure
right heart dysfunction, transthoracic echo-
PAH = pulmonary arterial
cardiography should be obtained (31). Doppler
hypertension
estimate of right ventricular systolic pressure,
Pd/Pa = mean distal to
right ventricular and atrial chamber size and proximal arterial pressure ratio
function, and interventricular septal motion PTE = pulmonary
are features discernible with this noninvasive thromboendarterectomy
imaging modality. An echocardiogram pos- PVR = pulmonary vascular
sesses the additional value in assessing resistance
whether there is valvular or left heart disease, RPE = reperfusion pulmonary
edema
either as a comorbid condition or as the
UC = University of California
possible alternative etiology of pulmonary
hypertension. Diagnostic algorithms (25,32) V/Q = ventilation/perfusion
recommend ventilation/perfusion (V/Q) lung imaging
as a pivotal screening test in the evaluation of CTEPH
patients (Table 2, Figure 1).
LUNG VENTILATION-PERFUSION SCINTIGRAPHY.
V/Q lung imaging is the initial screening test for
evaluating patients with pulmonary hypertension
suspected of CTEPH (3,10,24). V/Q scanning is
highly sensitive (96% to 97.4%) in detecting
perfusion abnormalities and therefore suggesting
the possibility of CTED. Furthermore, with its
negative predictive value of nearly 100%, a normal
V/Q scan excludes the diagnosis of CTEPH (33).
Nonetheless, despite the value of lung scintig-
raphy, V/Q scan is under-utilized and data from
the PAH-QuERI (Pulmonary Arterial Hypertension
Quality Enhancement Research Initiative) registry
demonstrate that only 57% of pulmonary arterial
hypertension (PAH) patients undergo V/Q imaging
to exclude CTEPH during their evaluation (34).
However, the nonspecificity of this modality limits
its utility for the diagnosis of CTEPH, and any
abnormal perfusion scan requires additional diag-
nostic imaging. Computed tomographic pulmonary
angiography, magnetic resonance imaging, and/or
catheter-based pulmonary angiography are ulti-
mately required to establish the diagnosis of
CTED.
2470 Mahmud et al. JACC VOL. 71, NO. 21, 2018

Chronic Thromboembolic Pulmonary Hypertension MAY 29, 2018:2468–86

COMPUTED TOMOGRAPHY. Given the near universal

T A B L E 1 Risk Factors for the Development of CTEPH
inclination for evaluating pulmonary vascular anat-
Acute pulmonary embolism
omy with computed tomography (CT) pulmonary
Recurrent pulmonary embolic events
angiography, this imaging modality plays an essential
Large perfusion defect
Higher pulmonary artery pressure at time of initial PE diagnosis
role in evaluating patients with suspected CTEPH. CT
Idiopathic (unprovoked) pulmonary embolus pulmonary angiography may reveal a variety of ab-
Hemostatic risk factors normalities suggesting CTEPH such as recanalized or
Elevated factor VIII, von Willebrand factor, type 1 plasminogen organized thromboembolic material in the pulmonary
activator inhibitor
arteries, bronchial artery collateral flow, and a mosaic
Abnormal fibrinogen structure
perfusion pattern of the pulmonary parenchyma
Antiphospholipid antibodies and lupus anticoagulant
Non–type-O blood groups
(35–38) (Figure 2). Additional benefits of this modality
Elevated lipoprotein(a) are the assessment of possible underlying paren-
Associated medical conditions chymal lung and mediastinal disease. It can also
Splenectomy detect other pulmonary vessel disorders that may
Ventriculoatrial shunt present with perfusion defects on V/Q lung scanning
Infected intravenous catheters/devices
such as pulmonary artery sarcoma, pulmonary veno-
Chronic inflammatory disorders
occlusive disease, or fibrosing mediastinitis, helping
Hypothyroidism
differentiate them from CTEPH. However, potential
Malignancy
difficulties with this imaging modality relate to
CTEPH ¼ chronic thromboembolic pulmonary hypertension; PE ¼ pulmonary the interpretive expertise required and the lower
embolism.
sensitivity for detecting CTED in segmental and sub-
segmental vessels. In a recent report, the ability of
320-slice CT imaging to detect thromboembolic find-
ings in suspected CTEPH patients was evaluated us-
ing digital subtraction pulmonary angiography as the
T A B L E 2 Diagnostic Tests Used for CTEPH
comparative diagnostic method. Although a sensi-
Diagnostic Technique Features and Supportive Findings
tivity and specificity of 97% and 97.1% for CTE related
Chest radiography  Chronic pulmonary embolism: avascular lung areas;
findings was reported in the main and lobar seg-
asymmetric central pulmonary artery enlargement;
evidence of pleural disease ments, a sensitivity of only 85.8% and specificity of
 Pulmonary hypertension: dilatation of main pulmonary
94.6% was observed in the distal vessels (39).
arteries, right atrial or right ventricular enlargement in
advanced disease Another less frequently used diagnostic modality is
Electrocardiography  Right ventricular hypertrophy with right axis deviation cone beam CT (CBCT), which, though not widely
Pulmonary function  Reduction in DLCO available, has the advantage of evaluating organized
tests  Mild restrictive defect due to parenchymal scarring
Echocardiography  Pulmonary hypertension
thrombi in segmental and subsegmental pulmonary
 Right atrial enlargement arteries in greater detail (40). In CBCT, the x-rays are
 Right ventricular hypertrophy
 Increased tricuspid regurgitation velocity
divergent, forming a cone instead of the slices of
V/Q scan  Preferred initial test with high sensitivity traditional CT with the x-ray tube and detector panel
to detect CTEPH rotating around the patient (41). When compared
 Normal ventilation scan with a
wedge-shaped perfusion defect with CT pulmonary angiography, all segmental
CTPA  Lower sensitivity than V/Q scan branches noted with CBCT were detectable with CT
 Right ventricular enlargement pulmonary angiography, but only 69% of sub-
 Recanalized thromboembolic material associated
with attenuated pulmonary arteries beyond segmental branches seen on CBCT could be observed
the obstruction with CT pulmonary angiography (40). Distal pulmo-
 Bronchial artery collateral flow
 Mosaic perfusion of the pulmonary parenchyma nary artery lesion findings on CBCT in CTEPH are
MRI  Evaluation of pulmonary hemodynamics, and right reported to be highly consistent (>90%) with those of
ventricular size and function
 MRA with contrast enhancement has similar
selective angiography.
sensitivity to CTPA
Pulmonary angiography  “Gold standard” technique to assess the location MAGNETIC RESONANCE IMAGING. This imaging
and right heart and extent of disease; more sensitive at segmental
catheterization and subsegmental level than CTPA modality has the advantage of being free of ionizing
 Determine surgical accessibility radiation and has the ability to evaluate pulmonary
 Hemodynamic evaluation to confirm the diagnosis
arterial and parenchymal abnormalities along
CTEPH ¼ chronic thromboembolic pulmonary hypertension; CTPA ¼ computed tomography pulmonary angi- with pulmonary hemodynamics and right ventricular
ography; DLCO ¼ diffusing capacity of the lungs for carbon monoxide; MRA ¼ magnetic resonance angiography;
MRI ¼ magnetic resonance imaging; V/Q ¼ ventilation-perfusion.
disease. It has good agreement with other
imaging techniques in CTEPH (42–44), but remains
JACC VOL. 71, NO. 21, 2018
MAY 29, 2018:2468–86
infrequently used because it is time-consuming,
not as readily available, and requires interpretive
expertise (45).
CATHETER-BASED PULMONARY ANGIOGRAPHY
AND RIGHT HEART CATHETERIZATION. Catheter-
based pulmonary angiography is safe and has been
considered the “gold standard” for imaging in the
evaluation of CTEPH. When combined with right
heart catheterization, it can confirm the presence of
CTE disease to the level of the subsegmental vessels,
exclude other possible diagnoses, accurately localize
or “map out” lesions in the determination of surgical
accessibility, and evaluate pulmonary hemodynamics
and right heart function (46,47). Because diagnostic
angiography is crucial for identifying organized
thromboembolic disease warranting surgical resec-
tion or interventional treatment, image optimization
is critically important.
Biplane subtraction pulmonary angiography re-
quires attention to: 1) patient positioning; 2) flat de-
tector angulation; 3) collimation; and 4) imaging
system settings. When obtaining right pulmonary an-
giograms, the frontal and lateral flat detectors are kept
in straight anterior-posterior and left lateral (or left
anterior oblique [LAO] 90 ) views, respectively.
Left pulmonary angiograms can be performed in
straight anterior-posterior and left lateral views.
Rotation of views 20 leftward (to LAO 20  and LAO
110 , respectively) is traditionally performed to
decrease overlap of the mediastinum and left lung, but
is not necessary with digital subtraction angiography.
Frontal and lateral angiograms are acquired at
4 frames/s during contrast injection, then decreased to
1 frame/s during the levophase. Angiographic imaging
is often prolonged to record levophase pulmonary vein
drainage and exclude pulmonary vein stenosis or
anomalies.
Characteristic pulmonary angiographic findings
suggestive of CTEPH include webs or bands, intimal
irregularities, pouch defects, abrupt vascular nar-
rowing, and complete obstruction of pulmonary
arteries (48) (Figure 3). Though in the past, selective
pulmonary angiography of individual pulmonary
artery segments was unnecessary for identifying
CTED and determining surgical candidacy, the
evolving success of distal vessel thromboendarter-
ectomy and the availability of balloon pulmonary
angioplasty has revived the value of this technique.
With this, a new classification of lesion morphology
based on the lesion opacity and the blood flow distal
to the lesion on pulmonary angiographic images has
been described, as follows: type A, ring-like stenosis;
Mahmud et al. 2471
Chronic Thromboembolic Pulmonary Hypertension
F I G U R E 1 Diagnostic Work-Up of CTEPH
Signs & symptoms of pulmonary hypertension with/without prior
history of venous thromboembolism
Chest radiography, pulmonary function studies
General studies assessing airway or parenchymal lung disease
ECG, echocardiogram
Evaluation for pulmonary hypertension and other cardiac disorders
Ventilation/Perfusion lung scan
Subsegmental or larger unmatched perfusion defects
Normal
CTEPH excluded
Abnormal
Catheter-based pulmonary angiography
• Confirmation of CTE disease
• Assessment of operability
CT pulmonary angiography
• Confirmation of CTE disease
• Assessment of lung parenchyma, mediastinum, cardiac structures
• Exclusion of alternative possible diagnosis (i.e., pulmonary artery
sarcoma, pulmonary veno-occlusive disease, fibrosing mediastinitis)
Magnetic resonance imaging
• Confirmation of CTE disease
Right heart catheterization
Confirmation and assessment of pulmonary hypertension
(i.e., mPAP ≥ 25 mm Hg, PCWP ≤ 15 mm Hg)
Ventilation/perfusion imaging plays a central and key role in the diagnostic work-up of
CTEPH. A normal scan virtually excludes the diagnosis while an abnormal scan requires
additional diagnostic tests including invasive hemodynamic and angiographic evaluation.
CT ¼ computed tomography; CTE ¼ chronic thromboembolism; CTEPH ¼ chronic
thromboembolic pulmonary hypertension; ECG ¼ electrocardiogram; mPAP ¼ mean
pulmonary artery pressure; PCWP ¼ pulmonary capillary wedge pressure.
type B, web lesion; type C, subtotal lesion; type D,
total occlusion; and type E, tortuous lesion (49)
(Figure 4).
MANAGEMENT OF OPERABLE CTED
Both American and European guidelines endorse
surgical therapy in all patients who have accessible
disease and are considered suitable surgical candi-
dates (24,25). Surgery by means of a complete bilat-
eral pulmonary thromboendarterectomy offers the
best chance of improved long-term outcomes. At
experienced centers, disease at segmental and even
subsegmental branches can be removed. After the
introduction of the procedure at the University of
2472 Mahmud et al.
Chronic Thromboembolic Pulmonary Hypertension
F I G U R E 2 CT Pulmonary Angiography in CTEPH
(A) Evolution from acute to chronic thromboembolic disease. Left panel showing acute
pulmonary embolism in the right descending pulmonary artery. One year later, vessel
distortion, web and intimal thickening is seen at the same location (middle panel), with
vessel attenuation distally (right panel). (B) CT pulmonary angiographic features of
chronic thromboembolic disease. Left panel showing right middle lobe vessel
narrowing (open red arrow) with lining thrombus versus intimal thickening involving the
right descending pulmonary artery. Recanalized thrombus is seen in the left descending
pulmonary artery (solid red arrow). Right panel showing marked vessel narrowing from
organized clot in the right descending pulmonary artery (solid white arrow) and web in
a proximal left lower lobe segmental vessel (open arrow). (C) “Mosaic perfusion” in
CTEPH. Segmental regions of hyperperfusion and hypoperfusion. CT ¼ computed to-
mography; CTEPH ¼ chronic thromboembolic pulmonary hypertension.
JACC VOL. 71, NO. 21, 2018
MAY 29, 2018:2468–86
California (UC) San Diego in 1970, the technique has
undergone significant iterative modification and
improvement. This has resulted in reduction of
perioperative mortality from almost 20% in the early
years to <2% at UC San Diego (50).
The techniques of the operation, known as pul-
monary thromboendarterectomy (PTE) or pulmo-
nary endarterectomy, are well established, and
details have been described previously (51,52). The
procedure is performed via median sternotomy and
requires cardiopulmonary bypass with deep hypo-
thermia and total circulatory arrest. Once sternot-
omy is performed and the patient is placed on
cardiopulmonary bypass, the core temperature is
actively cooled to 18  C to 20 C. The head and the
heart are wrapped with special cooling jackets and
are cooled even further. The process of cooling can
take 30 to 75 min depending on the patient’s body
habitus. After appropriate cooling, an aortic cross-
clamp is applied, cardioplegia for myocardial pro-
tection is administered, and the right pulmonary
artery is explored between the superior vena cava
and aorta. The plane of the dissection is carefully
identified, which is typically between the intimal
and medial layer of the artery, but is often distorted
and difficult to establish. The endarterectomy is
then continued into the lobar, segmental, and sub-
segmental branches (Online Video 1). Although
removal of some thromboembolic material is
possible without circulatory arrest, significant
collateral blood flow occurs through the bronchial
arteries, precluding complete endarterectomy.
Therefore, circulatory arrest is essential and pro-
vides a bloodless field for recognition of the plane
of dissection and removal of the thromboembolic
material from the pulmonary vasculature (Figure 5)
(53). Circulatory arrest times are typically limited to
20 min at a time, and complete endarterectomy can
usually be performed within this time period. Once
endarterectomy is completed, the circulation is
restarted and the artery closed; the process is then
repeated for the left side. The patient is then
rewarmed, a process that takes 75 to 120 min. If
indicated, additional cardiac procedures, such as
coronary artery bypass grafting or valve interven-
tion are performed during this rewarming period. At
the conclusion of the procedure, the patient is
taken off cardiopulmonary bypass and the chest is
closed. Generally, these patients require minimal
inotropic support and have significantly improved
hemodynamic parameters immediately after
surgery.
Operating on distal thromboembolic material is
challenging, and patients with lesions located in the
JACC VOL. 71, NO. 21, 2018 Mahmud et al. 2473
MAY 29, 2018:2468–86 Chronic Thromboembolic Pulmonary Hypertension

F I G U R E 3 Pulmonary Angiographic Findings in CTEPH

(A) Abrupt vascular narrowing with intimal irregularity of the right interlobar artery (white arrow). (B) Early contrast phase showing rounded
vascular irregularity, “pouch defect” consistent with recanalized thrombus. (C) Web defect and vessel narrowing (open arrow) of the left
descending pulmonary artery. (D) Value of lateral angiogram: lateral view (LAT) clearly defining the occlusion of the right descending pul-
monary artery beyond the superior segment take off. CTEPH ¼ chronic thromboembolic pulmonary hypertension; PA ¼ posterior-anterior
view.

distal segmental or subsegmental arteries are more area of the vessel and carefully extended until the
likely to be deemed technically inoperable than those diseased areas distally in the segmental and sub-
with more proximal disease. In such patients, the segmental branches are encountered and removed.
plane of dissection is started proximally in the normal This can be challenging because the normal intima is
2474 Mahmud et al. JACC VOL. 71, NO. 21, 2018

Chronic Thromboembolic Pulmonary Hypertension MAY 29, 2018:2468–86

F I G U R E 4 Novel Angiographic Classification of CTEPH Lesions

(A) Type A: ring-like stenosis lesion. (B) Type B: web lesion. (C) Type C: subtotal lesion. (D) Type D: total occlusion lesion. (E) Type E: tortuous
lesion. Type A–D lesions (arrows) are located proximal to the subsegmental pulmonary artery, namely, the segmental and subsegmental
arteries. Type E lesions (arrowheads) are located distal to the subsegmental artery. CTEPH ¼ chronic thromboembolic pulmonary hyper-
tension. Reprinted with permission from Kawakami et al. Circ Cardiovasc Interv 2016;9:e003318 (49).

F I G U R E 5 Surgical Specimen Resected During PTE Surgery

Bilateral pulmonary endarterectomy with resection of proximal level I disease with associated diagnostic pulmonary angiograms. PTE ¼ pulmonary thromboendar-
terectomy. (Online Video 1) Distal vessel pulmonary thromboendarterectomy. The dissection plane between the intimal and medial layers of the proximal pulmonary
artery is identified and the dissection extended distally to the occluded segment. Following this, the chronic thromboembolic material is removed.
JACC VOL. 71, NO. 21, 2018
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F I G U R E 6 Level I to IV Surgical Classification for CTEPH
Surgical resection of proximal to more distal level of disease in CTEPH patients. Technically, level III to IV disease is more challenging to resect
but results in hemodynamic and clinical improvement; however, resection is associated with higher complications. CTEPH ¼ chronic
thromboembolic pulmonary hypertension.
quite fragile and difficult to dissect free. In cases
where the obstructive material is visible distally, an
experienced surgeon may start the plane of dissection
at the segmental level. The goal is to ensure that all
thromboembolic material is removed, and all the
branches have been cleared, before restarting the
circulation.
A recent intraoperative classification of the disease
(levels I to IV) (Figure 6) suggested by the UC San
Diego group categorizes pulmonary thromboembo-
lism in CTEPH as levels, based on the location of the
fibrotic thromboembolic material: level 1, involving
the main pulmonary arteries; level 2, starting at the
lobar branches; level 3, starting at the segmental
branches; and level 4, where disease is only encoun-
tered at the subsegmental branches. In addition,
Level 1C indicates complete occlusion of 1 lung with
total obstruction of the main right or left pulmonary
artery, and level 0 indicates no evidence of CTEPH in
Mahmud et al. 2475
Chronic Thromboembolic Pulmonary Hypertension
the corresponding lung. It is important to note that
this is a surgical classification as encountered at the
time of endarterectomy. As imaging modalities
improve, the ability to predict the level of disease
pre-operatively has improved; however, invariably
more disease is encountered at the time of surgery
than predicted on routine imaging pre-operatively.
Notably, greater technical expertise is required for
level III to IV disease resection with higher compli-
cations, but hemodynamic improvement can still be
expected after successful surgery.
Historically accepted indications for PTE were
a mean pulmonary artery pressure (mPAP)
>30 mm Hg, pulmonary vascular resistance (PVR)
>300 dynes ∙ s ∙ cm 5, and New York Heart Asso-
ciation functional classification of III to IV (54,55).
However, it is also presently indicated for patients
with symptomatic CTED who are dyspneic or
develop pulmonary hypertension only with exercise.
2476 Mahmud et al.
Chronic Thromboembolic Pulmonary Hypertension
T A B L E 3 Pulmonary Hypertension Medical Therapy Used for the Treatment of CTEPH
Drug Class Evidence and Effects
Soluble guanylate  CHEST-1 trial (randomized, double-blind,
cyclase placebo-controlled study) (74);
stimulants Improved pulmonary vascular resistance and 6-min
(riociguat) walk distance after 16 weeks
 CHEST-2 trial (follow-up extension study) (75);
Persistent efficacy for up to 1 yr
Endothelin receptor Macitentan
antagonists  MERIT-1 trial (randomized, double-blind,
(macitentan and placebo-controlled study) (76);
bosentan) Improved pulmonary vascular resistance after 16 weeks
Bosentan
 BENEFiT trial (randomized, double blind,
placebo-controlled study) (77);
Improved pulmonary vascular resistance and cardiac
index after 16 weeks
 Systematic review of BENEFiT and 10
observational studies (78);
Similar results were reported
Phosphodiesterase 5  Randomized, double blind, placebo-controlled pilot study (79);
inhibitors Improvement in World Health Organization
(sildenafil) functional class and pulmonary vascular resistance
after 12 weeks
Prostanoids Epoprostenol
(epoprostenol  Retrospective cohort study in severe inoperable CTEPH (80);
and treprostinil) Improvement in pulmonary vascular resistance,
pulmonary artery pressure, and exercise capacity
after 3 months
Iloporost
 AIR study (randomized, double-blind, placebo-controlled
study) (81); Improvement in New York Heart Association
functional class and 6-min walk distance at 12 weeks
Treprostinil
 Uncontrolled trial in severe inoperable CTEPH (82);
Improved pulmonary vascular resistance after
20 months, and higher 5-yr survival rate
(53% vs. 16% in historical controls)
AIR ¼ Aerosolized Iloprost Randomized trial; BENEFiT ¼ Bosentan Effects in iNopErable Forms of chronIc
Thromboembolic pulmonary hypertension trial; CTEPH ¼ chronic thromboembolic pulmonary hypertension;
CHEST-1 ¼ Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1;
CHEST-2 ¼ BAY63-2521 – Long-term Extension Study in Patients With Chronic Thromboembolic Pulmonary
Hypertension; MERIT-1 ¼ Macitentan for the Treatment of Inoperable Chronic Thromboembolic Pulmonary
Hypertension trial; PAH ¼ pulmonary arterial hypertension.
Surgery results in symptomatic relief and has the
theoretical benefit of preventing disease progression
that might lead to irreversible small vessel changes
and pulmonary hypertension. Operability assess-
ment can be complex and requires a multidisci-
plinary team of CTEPH experts, which includes
representatives from cardiothoracic surgery, pulmo-
nary vascular medicine, interventional cardiology,
and imaging. This assessment accounts for surgical
accessibility, presence of hemodynamic or ventila-
tory impairments, and evaluation of underlying
comorbidities prohibiting PTE (56). Perioperative
mortality is increased with markedly elevated pre-
operative PVR >1,000 dynes ∙ s ∙ cm 5, and to an
even greater extent with residual pulmonary hyper-
tension following PTE (22,50,56–58). Nevertheless,
the severity of pre-operative PVR and the degree of
pulmonary hypertension should not be considered a
JACC VOL. 71, NO. 21, 2018
MAY 29, 2018:2468–86
contraindication to surgical intervention as these
patients may ultimately have the most benefit from
surgery (50,59). Data from an international registry
show that of 679 newly diagnosed consecutive
CTEPH patients, 427 patients (62.9%) were consid-
ered operable (27). Although pre-op PVR >1,500
dynes ∙ s ∙ cm5 and older age were considered
contraindications to surgery in this registry,
currently, these factors do not independently
constitute contraindication to surgery at many
experienced institutions. Furthermore, many of
those initially considered inoperable went on to
have surgery after a second opinion at an expert
center.
POST-PULMONARY ENDARTERECTOMY OUTCOMES. Pa-
tients undergoing PTE may experience various com-
plications similar to other cardiothoracic surgical
procedures such as arrhythmias, pericardial or
pleural effusions, atelectasis, wound infection, and
delirium. Notably, significant reperfusion pulmonary
edema (RPE), a type of noncardiogenic high-
permeability pulmonary edema, occurs in 9.6% of
patients after PTE and can present with mild post-
operative hypoxemia to severe hemorrhagic pulmo-
nary edema (60,61). The risk of RPE is increased
in patients with high pre-operative and persistent
post-PTE pulmonary hypertension while periopera-
tive treatment with methylprednisolone has no effect
on the incidence of lung injury in CTEPH patients
undergoing PTE (62).
Cognitive neurological dysfunction is observed in
only a fraction of patients undergoing PTE due to
either deep hypothermia or circulatory arrest (63,64).
The benefits of maintaining antegrade cerebral
perfusion compared with deep hypothermic circula-
tory arrest was evaluated in a randomized controlled
trial, and no difference in cognitive function was
observed (65). However, there was a significant
crossover to the circulatory arrest group, emphasizing
the need for a bloodless field during complete
endarterectomy.
Due to the small number of specialized centers with
experience in PTE and management of patients with
CTEPH, there are limited reports on long-term out-
comes. The UC San Diego group has reported a 5-year
and 10-year survival of 82% and 75%, respectively,
with in-hospital mortality of only 2.2% (51). Other in-
stitutions also report 5-year survival rates of 75% to
90% (66–70), and 10-year survival rates of 72% (71).
Results from an international prospective registry,
including 679 newly diagnosed CTEPH patients,
showed that patients who underwent PTE surgery had
JACC VOL. 71, NO. 21, 2018 Mahmud et al. 2477
MAY 29, 2018:2468–86 Chronic Thromboembolic Pulmonary Hypertension

C ENTR AL I LL U STRA T I O N CTEPH Treatment Algorithm by the Multidisciplinary UC San Diego CTEPH Team

Mahmud, E. et al. J Am Coll Cardiol. 2018;71(21):2468–86.

Once the diagnosis of CTEPH is confirmed, patients are evaluated for PTE surgery. In cases deemed to be to be inoperable, with persistent symptomatic pulmonary
hypertension after PTE surgery, or with an unacceptable risk-benefit ratio, targeted medical therapy and/or BPA is considered. Often patients undergo combined
medical therapy and BPA for optimal hemodynamic and clinical results. BPA ¼ balloon pulmonary angioplasty; CTEPH ¼ chronic thromboembolic pulmonary
hypertension; PTE ¼ pulmonary thromboendarterectomy; UC ¼ University of California.

improved 3-year survival rates compared with those improvement in functional class, remodeling of the
not undergoing surgery (27). Other benefits that right ventricle resulting in reduced wall thickness,
are typically observed include improvements in he- increased right and left ventricular ejection fractions,
modynamic parameters (reduction in PVR and mPAP), and reduced volumes (51,71,72).
2478 Mahmud et al. JACC VOL. 71, NO. 21, 2018

Chronic Thromboembolic Pulmonary Hypertension MAY 29, 2018:2468–86

with PAH-targeted therapy had no impact on surgical

T A B L E 4 UC San Diego Approach to BPA
outcomes but was associated with a delay in referral
Overall treatment plan
for surgical evaluation (73). Efforts are currently un-
 4 to 6 separate BPA sessions
 Baseline pulmonary angiogram derway to prospectively study the impact of “bridging
 Baseline and intermittent perfusion scanning therapy” or pre-treating patients with PAH therapies
 Baseline and intermittent 6-min walk test, BNP, functional assessment
 Treatment concluded with 1 BPA procedure in each lung before PTE.
Individual BPA procedure steps Riociguat, a soluble guanylate cyclase stimulator,
1. Identify target lung region with largest defect on most recent perfusion scan is the only therapy approved for inoperable CTEPH or
2. Ultrasound-guided right (or left) femoral vein access, 9-F sheath placement
3. Right heart catheterization and hemodynamic measurement within target lung patients with persistent/recurrent pulmonary hyper-
4. 6-F 90-cm sheath advanced over wire into target lung pulmonary artery tension after PTE based on the results of the CHEST-1
5. Anticoagulation using IV unfractionated heparin (goal ACT 200 to 250 s)
6. 6-F 110-cm Judkins right, multipurpose, hockey stick, or extended back-up guide trial (Chronic Thromboembolic Pulmonary Hyper-
catheter advanced over stiff, angled Glidewire into target lung region tension Soluble Guanylate Cyclase–Stimulator Trial 1)
7. Segmental pulmonary angiography is performed with deep breath holds and injection
of 1:1 diluted contrast at 7.5 to 15 frames/s without digital subtraction (74). This was a 16-week multicenter, randomized,
8. Atraumatic, workhorse 0.014-inch guidewire, supported by 2.0-mm rapid exchange double-blind, placebo-controlled study of 261 pa-
balloon catheter used to cross target lesions; avoid polymer-jacketed guidewires
9. For complete occlusions, antegrade wire escalation with a microcatheter and increasing tients with either inoperable CTEPH (determined by a
guidewire tip stiffness; avoid polymer-jacketed guidewires panel of expert CTEPH surgeons) or persistent/
10. Pd/Pa measurements during free breathing or deep breath hold using microcatheter-
based pressure measurements for easy and repeated use during BPA recurrent pulmonary hypertension following PTE.
11. Serial balloon inflation using 2.0- to 4.0-mm semi- and noncompliant balloons with The riociguat group had significant improvement in
serial dilations of undersized balloons to avoid vessel perforation/rupture and injury
12. Selective use of sculpting or scoring balloons for fibrotic recalcitrant lesions 6-min walk distance of 39 m versus a decrease of 6 m
13. Procedure conclusion when 3 to 5 diseased segments are treated during an initial in the placebo group (p < 0.001). The riociguat group
session, 400-ml IV contrast is administered, and/or 2-Gy exposure reached
14. Overnight admission to a monitored bed/IMU also had a decrease in PVR, reduction in N-terminal
prohormone B-type natriuretic peptide, and
ACT ¼ activated clotting time; BNP ¼ B-type natriuretic peptide; BPA ¼ balloon pulmonary angioplasty;
improvement in World Health Organization func-
IMU ¼ intermediate care unit; IV ¼ intravenous; Pd/Pa ¼ mean distal to proximal arterial pressure ratio;
UC ¼ University of California. tional class (74). A long-term extension study
(CHEST-2 [BAY63-2521–Long-term Extension Study in
Patients With Chronic Thromboembolic Pulmonary
MANAGEMENT OF INOPERABLE CTEPH Hypertension]) reported that these favorable results
persisted to 1 year (75).
PAH-targeted therapies are widely used “off label” in More recently, the endothelin receptor antagonist,
the treatment of CTEPH (Table 3). Retrospective data macitentan, was studied in a Phase II randomized,
from a single center suggest that pre-treating patients placebo-controlled trial in 80 patients with

F I G U R E 7 BPA of the Left Lower Lobe

The baseline and final left lower lobe A8 (lateral), A9 (middle), and A10 (medial) segment balloon pulmonary angioplasty (BPA) at a single
treatment session. All 3 segments were occluded and recanalized with 2.0- to 4.0-mm diameter balloons.
JACC VOL. 71, NO. 21, 2018 Mahmud et al. 2479
MAY 29, 2018:2468–86 Chronic Thromboembolic Pulmonary Hypertension

F I G U R E 8 Exemplary BPA Procedure With Sequential Hemodynamic Assessment

Serial balloon pulmonary angioplasty (BPA) was performed in a right lower lobe A8 segment. An initial angiogram (top row, left image) showed diminished upper
branch distal perfusion and lower branch subtotal occlusion. Intravascular hemodynamics (bottom row) were notable for elevated baseline pulmonary artery (PA)
pressure (systolic >60 mm Hg, mean 35 to 40 mm Hg), significantly dampened distal pressure waveform (upper branch), and resting Pd/Pa ratio <0.50. BPA using
2.0-mm and 3.0-mm balloons resulted in immediately improved upper vessel perfusion by angiography (top row, right image) and intravascular hemodynamics (distal
pressure waveform and Pd/Pa >0.50). A repeat procedure 2 months later showed improved angiographic appearance of both A8 branches (middle row, left image),
PA pressure (systolic 50 mm Hg, mean <30 mm Hg), distal pressure waveform (systolic 20 to 25 mm Hg), and resting Pd/Pa >0.60. Repeat BPA using a 4.0-mm
balloon in both branches resulted in immediately improved distal pressure (systolic 25 to 30 mm Hg) and Pd/Pa >0.65. Final angiography following kissing balloon
inflation showed improved flow within both branches. Pd/Pa ¼ mean distal to proximal arterial pressure ratio (purple line).

inoperable CTEPH. In the macitentan-treated group, distance increased in the macitentan-treated group
PVR decreased to 73.0% of baseline, whereas PVR by 35 m compared with an increase of only 1 m in the
decreased to 87.2% of baseline (p ¼ 0.041) in the placebo-treated group. Important distinctions must
placebo-treated group. At 24 weeks, 6-min walk be made between the methods of this study and the
2480 Mahmud et al. JACC VOL. 71, NO. 21, 2018

Chronic Thromboembolic Pulmonary Hypertension MAY 29, 2018:2468–86

T A B L E 5 BPA for CTEPH With Longer-Term (>12 Months) Outcomes

First Total Procedures/ Reduction in Long-Term

Location Author (yrs) N Procedures Patient mPAP (mm Hg) Survival

Boston, Feinstein (1994–1999) 18 47 2.6/patient 43.0  12.1 to 89% at 34.2 months

MA 33.7  10.2 (p ¼ 0.007)
Oslo, Andreassen (2003–2011) 20 73 3.7/patient 45  11 to 85% at 51 months
Norway 33  10 (p < 0.001)
Okayama, Mizoguchi (2004–2011) 68 255 3.8/patient 45.4  9.6 to 97% at 2.2  1.4 yrs
Japan 24.0  6.4 (p < 0.01)
Sendai, Sugimura (2009–2011) 12 — 5/patient 47.8  1.6 to 100% at 12 months
Japan 24.8  4.9 (p < 0.01)
Aoki (2009–2016) 77 424 5.5/patient 38  10 to 98.4% at 5 yrs
25  6 (p < 0.01)
Tokyo, Yanagisawa (2009–2013) 70 — 4/patient (<65 yrs) 42 to 26.0 (<65 yrs), 100% (<65 yrs), 96.8%
Japan 3/patient ($65 yrs) 41 to 23.5 ($65 yrs) ($65 yrs) at 12 months
(both p < 0.05)
Shimura (2009–2014) 110 423 3.8/patient 43 to 26 (p < 0.05) 100% at 1.97 yrs
Inami (2009–2016) 170 649 3.8/patient Values not available 98.8% at 1 yr
98.0% at 3 yrs
95.5% at 5 yrs
Multiple cities, Ogawa (2004–2016) 308 1,408 4.6/patient 43.2  11.0 to 24.3  6.4 96.8% at 1 to 2 yrs
Japan after BPA; 22.5  5.4 at 94.5% at 3 yrs
follow-up (p < 0.05)

mPAP ¼ mean pulmonary artery pressure; other abbreviations as in Tables 1 and 4.

CHEST-1 study. The MERIT (Macitentan for the
Treatment of Inoperable Chronic Thromboembolic
Pulmonary Hypertension) study was smaller in size,
included only patients who were inoperable, and
permitted the use of background PAH therapy (61% of
the patients also using PDE-5 or oral/inhaled prosta-
cyclin) (76).
BENEFIT (Bosentan Effects in iNopErable Forms of
chronIc Thromboembolic pulmonary hypertension), a
double-blind, randomized, placebo-controlled study
of the endothelin receptor antagonist, bosentan, in
inoperable or persistent/recurrent pulmonary hyper-
tension after PTE demonstrated a reduction in PVR by
24% in the bosentan-treated group compared with
placebo (95% confidence interval: 31.5% to 16.0%;
p < 0.0001) at 16 weeks (77). However, the trial failed
to demonstrate a difference in 6-min walk distance at
16 weeks, which was a coprimary endpoint. There is
no obvious explanation for the differences observed
in the outcomes between the BENEFIT and MERIT
trials and could include trial size, design, and prop-
erties of the specific endothelin receptor antagonist
studied. Other PAH-targeted therapies, including
prostacyclins and PDE-5 inhibitors, have shown some
benefits in small case-controlled studies or subgroups
of larger PAH randomized controlled trials (78–82).
However, the subgroup of PTE patients pre-treated
with PAH therapies had no significant advantage
over those without medical therapy. Instead, the
medically treated group had a significant time delay
in referral for surgery compared with the rest.
PERCUTANEOUS INTERVENTIONAL THERAPY
Balloon pulmonary angioplasty (BPA), also known as
percutaneous transluminal pulmonary angioplasty,
was initially studied as an alternative treatment for
selected patients with inoperable CTEPH almost 2
decades ago (83,84), but the approach was abandoned
due to the frequency of major complications. Over the
past 5 years, the procedure has undergone refinement
with promising outcomes and safety data from
various centers around the world. Contemporary BPA
aims to disrupt organized, flow-limiting obstructions
and improve pulmonary vascular blood flow.
Unlike coronary artery and peripheral vascular in-
terventions, where symptomatic relief can be expe-
rienced after revascularization of a single vessel,
clinical improvement following BPA is typically
observed after revascularization of multiple diseased
segments and regions. In recognition of the success of
BPA, the 2015 European Society of Cardiology/Euro-
pean Respiratory Society guidelines for the diagnosis
and treatment of pulmonary hypertension have rec-
ommended BPA in CTEPH patients who are techni-
cally inoperable or carry an unfavorable risk-benefit
ratio for PTE (recommendation Class IIb, Level of
Evidence: C) (25).
BPA has been performed in the majority of
patients for symptomatic, inoperable CTEPH (85–93)
or for persistent/recurrent pulmonary hypertension
following PTE (94–96). Rescue BPA has also been re-
ported as a transitional or bridging treatment option
JACC VOL. 71, NO. 21, 2018
MAY 29, 2018:2468–86
in rapidly deteriorating CTEPH patients for stabiliza-
tion before PTE (95,96). BPA can also be combined
with PTE in selected CTEPH patients with surgically
accessible disease for one lung and inoperable disease
affecting the contralateral lung (97).
PATIENT SELECTION FOR BPA. BPA is still reserved
for patients with inoperable CTEPH. Because opera-
bility assessment is complex and multifactorial, a
multidisciplinary team approach consisting of pul-
monary vascular medicine specialists, interventional
cardiologists, PTE surgical experts, and imaging spe-
cialists is recommended for evaluating and identi-
fying appropriate patients with CTEPH for BPA
(Central Illustration). Surgical inoperability
contentious issue and highly dependent on local
surgical expertise, patient comorbidities, proximal
versus distal pulmonary segmental disease, and pa-
tient preference (25). At experienced centers around
the world, segmental and subsegmental resection can
be performed to great effect, whereas at less experi-
enced centers, resection may be limited to disease
located at the level of the main and lobar vessels.
Once a patient has been deemed inoperable a sec-
ondary assessment is made to determine if the pa-
tient is suitable for BPA. Once again, an assessment
must be made regarding the degree of observed
vascular obstruction, hemodynamic impairment and
symptoms. In addition, assessment of the specific
lesion types must be made as certain lesion types
confer greater procedural risk and lower success
rates (49).
TECHNIQUE OF BALLOON PULMONARY ANGIOPLASTY.
In the absence of a consistent and agreed upon
technique for the performance of BPA, we describe
the approach undertaken at UC San Diego (Table 4). A
complete treatment course usually involves 4 to 6
separate BPA procedures, spaced apart by 3 to 7 days,
and concluded by a final treatment in each lung.
Target vessels are identified based on noninvasive
lung perfusion scans with the goal to revascularize
the areas with the largest perfusion defects. Inter-
mittent perfusion scans are repeated to observe
overall changes in lung perfusion from baseline and
reprioritize diseased regions. Six-min walk tests are
performed at baseline and repeated at intervals to
follow the clinical response to treatment. Right heart
catheterization and hemodynamic measurements
before each BPA procedure monitor the cumulative
effect of treatment on cardiopulmonary hemody-
namics. Any single procedure is limited to no more
than 2 Gy of radiation exposure and/or 400 ml of
administered contrast.
Mahmud et al. 2481
Chronic Thromboembolic Pulmonary Hypertension
Target lesion c h a r a c t e r i z a t i o n . Characteristic
pulmonary angiographic findings suggestive of
CTEPH include webs or bands, intimal irregularities,
pouch defects, abrupt vascular narrowing, and com-
plete obstruction of pulmonary arteries (48). How-
ever, contemporary imaging modalities, including
intravascular ultrasound, optical coherence tomog-
raphy, and CBCT have been used in CTEPH for
adjunctive lesion characterization and BPA guidance
(85,87,98,99). Webs and slit-like lesions in distal
segments are usually the main targets for the BPA
procedure. More severely obstructed lesions may also
be approached provided antegrade or collateral flow
past the lesion is confirmed (99). At our center, the
is a
primary anatomic imaging modality to identify
optimal targets for BPA remains segmental pulmo-
nary angiography.
To help avoid vascular injury, 0.014-inch work-
horse guidewires with soft, atraumatic, spring-coil
tips are used. Even when treating occluded vessels,
using an atraumatic wire in conjunction with a
balloon or microcatheter support and judicious use of
antegrade wire escalation with increased guidewire
tip stiffness leads to the safest outcomes. Caution
should be exercised in the use of polymer-jacketed
guidewires because early experience for us and
others suggests increased risk of vascular injury and
pulmonary hemorrhage (92). In general, our approach
has been to treat 1 to 2 pulmonary lobes in the same
lung during any single BPA procedure.
The majority of distal pulmonary vascular lesions
can be initially treated using 2.0-mm diameter bal-
loons, whereas proximal segment angioplasty is
performed with sequential balloon inflations using
larger-diameter, noncompliant balloons typically
ranging between 2.5 and 4.0 mm (Figure 7). In some
instances, lesion modification using specialty de-
vices such as the Chocolate (TriReme, Pleasanton,
California) or AngioSculpt (Spectranetics, Colorado
Springs, Colorado) balloon catheters can be attemp-
ted with prolonged balloon inflation, whereas more
aggressive approaches using cutting balloons or
atherectomy catheters increase the risk of vessel
injury and should be avoided. Deployment of
covered stents for catastrophic rupture is possible.
Although data for long-term pulmonary artery
patency following BPA are limited, restenosis is
considered uncommon (87), and stenting to prevent
restenosis after balloon angioplasty is not recom-
mended considering significant pulmonary vascular
mobility during the respiratory cycle (85–87). How-
ever, significant lesion recoil after balloon angio-
plasty is occasionally observed and could potentially
2482 Mahmud et al.
Chronic Thromboembolic Pulmonary Hypertension
be addressed by a thin bioresorbable
developed for this vascular bed.
F u n c t i o n a l a s s e s s m e n t . Prediction of obstructive
pulmonary artery disease is difficult by angiography
alone, and relatively normal-appearing vessels within
pulmonary segments underperfused by noninvasive
imaging warrant intravascular functional assessment
(Figure 8). Measuring distal pressure
microcatheter-based manometer (Navvus
Catheter, Acist, Eden Prairie, Minnesota) that can be
advanced over any guidewire is an effective strategy.
There is no standardized protocol or numerical cut-
point for pressure measurement or subsequent ther-
apy. In 1 study, the BPA procedure was continued
with the aim of achieving a mean distal to proximal
arterial pressure ratio (Pd/Pa) >0.80 unless the
baseline mPAP was >35 mm Hg (100). Investigators
reported a very low rate of procedure-related adverse
events using this strategy and were able to avoid RPE
in the majority of patients. Our strategy has been to
use a Pd/Pa ratio for treatment guidance with
values <0.75 prompting additional balloon dilation
(larger balloons, higher pressures, or scoring bal-
loons/guidewires). Frequently, the ratio only changes
marginally and improves over time. Interval nonin-
vasive perfusion scans between therapy sessions are
also useful to evaluate perfusion within treated seg-
ments and support repeat intervention for areas with
persistent hypoperfusion.
COMPLICATIONS OF BPA. In recent series, BPA
periprocedural mortality ranged from 0% to 10% (85–
93). The 2 most common complications of BPA
include RPE and pulmonary vascular injury, with rare
episodes of vessel perforation/rupture. Despite the
advances and improvement of the procedure, RPE
remains a frequent complication of BPA with an
incidence as high as 53% to 60% as reported in some
older studies (86,87). Several factors associated with
RPE following BPA include first procedure, severity of
baseline pulmonary hypertension, and a high level of
plasma B-type natriuretic peptide (84,86). CTEPH
patients with underdeveloped bronchial arteries are
more likely to develop RPE following the BPA pro-
cedure (101). Inami et al. (102), in a study of 150
consecutive BPA procedures in CTEPH, proposed the
Pulmonary Edema Predictive Scoring Index as a
product of PVR before BPA and the sum of changes in
pulmonary flow grades with the procedure, to predict
the risk of RPE following BPA. In their study, this
scoring index was the strongest factor among study
variables correlating with the occurrence of RPE (p <
0.0001) and was a marker of the risk of RPE (cutoff
value 35.4, negative predictive value 92.3%).
JACC VOL. 71, NO. 21, 2018
MAY 29, 2018:2468–86
scaffold The combined approach of pressure wire guidance
to measure gradients across stenosis and the Pulmo-
nary Edema Predictive Scoring Index might be useful
in reducing the risk of RPE and vascular complica-
tions (100). This approach to finishing each BPA ses-
sion using the scoring index with the goal of
scores <35.4 and the guidance of pressure wire to
using a achieve a distal mean pulmonary arterial
Micro- pressure <35 mm Hg in each target lesion resulted in
similar hemodynamic improvements as BPA without
this guidance, but was associated with fewer numbers
of BPA procedures and treated target lesions, and
absence of RPE. However, no definitive data exist to
support this approach.
Pulmonary artery perforation/rupture is a serious
complication of BPA and is reported in 0% to 7% of
procedures (86–88,103). Some measures suggested
to decrease the risk of pulmonary artery perforation
include proper wire positioning, knuckle-wire tech-
nique, appropriate balloon sizing, and avoidance of
occluded segments without distal flow (99). Nonin-
vasive positive-pressure ventilation with supple-
mental oxygen, and in more severe situations
mechanical ventilation and extracorporeal mem-
brane oxygenation, should be considered as the first
therapeutic strategy for severe lung injury or
vascular rupture following BPA to maintain
oxygenation and preserve blood pressure (104).
Immediate balloon tamponade of the perforated/
ruptured vessel, cessation/reversal of anti-
coagulation, covered stent implantation, Gelfoam
injection, and transcatheter coil embolization are
suggested bailout techniques in these situations
(87,104).
CLINICAL OUTCOMES OF BPA. In the short term, the
procedure is associated with improvements in car-
diopulmonary hemodynamics, pulmonary perfusion,
exercise tolerance, World Health Organization func-
tional class, and 6-min walk distance (85,87–90,105).
Hemodynamic improvements, such as decrease in
mPAP and PVR, are proportional to the number of
treated vessels (86–90). Pulmonary hypertension
does not resolve immediately during or following a
BPA session, and it can take a few weeks to observe
the positive impacts of the procedure (87–106).
Studies have shown improvement in the quality of
life and symptom resolution disproportionate to the
degree of reduction in pulmonary hypertension (107).
Although the available data on long-term outcomes of
BPA in CTEPH are limited (Table 5), persistence of
hemodynamic benefit (reduction in PVR and pulmo-
nary artery pressure) of the BPA procedure at a me-
dian of 2.8 years after procedural completion (91) has
JACC VOL. 71, NO. 21, 2018
MAY 29, 2018:2468–86
been observed. Recently, cumulative data from 7
centers in Japan for outcomes of over 308 inoperable
CTEPH patients treated with BPA (from 2004 to 2016;
1,408 procedures) was reported with 3-year survival
of 94.5%, and a 44% reduction in mPAP (43.2 
11.0 mm Hg to 24.3  6.4 mm Hg after final BPA) (93).
Complications including pulmonary injury (17.8%),
hemoptysis (14.0%), and pulmonary artery perfora-
tion (2.9%) were not infrequent.
The initial experience at UC San Diego confirms the
efficacy and safety of the procedure. Using the tech-
nique described in this paper, we have treated 38
patients (183 procedures) without any major compli-
cations (0%) but procedure-related minor hemoptysis
of 6.6%. In the 20 patients who have completed 1-year
follow-up, we have observed improvement in func-
tional class, a 26% reduction in mPAP (39.1 
8.9 mm Hg to 28.8  6.0 mm Hg) and 90% survival,
with both deaths being unrelated to the BPA proced-
ure. Although difference in patient selection and
technique could be contributing to the differences in
outcomes between the various centers, it is clear that
the technique is effective with short-term efficacy
and long-term durability.
Improvement in right ventricular function has
been observed after BPA (103,108,109). Improved
hemodynamics after BPA may lead to right ventricu-
lar reverse remodeling, improved systolic function,
and reduced subclinical myocardial injury with
reduced high-sensitivity troponin T level (110). Sec-
ondary positive effects of BPA on renal function have
also been reported (111,112). A study of 9 CTEPH pa-
tients with gradually deteriorated PVR at 4.1 (2.7 to
7.9) years after PTE reported significant improvement
in PVR of 4.2 (2.8 to 4.8) Wood units (p < 0.05) at 1.9
(1.3 to 3.3) years after subsequent BPA procedure(s)
(92). Safety and efficacy of the procedure has also
been demonstrated in elderly patients (age $65 years)
compared with younger patients, with similar change
of hemodynamics, rate of periprocedural complica-
tions, length of intensive care unit and in-hospital
stay, and all-cause mortality (113).
CONTEMPORARY TREATMENT STRATEGIES
FOR CTEPH
CTEPH is a disease that is underdiagnosed, and sur-
gical PTE remains the preferred therapy. However,
determination of operability can be challenging, re-
quires an expert team, and availability of surgical
expertise is limited. There is growing excitement for
the percutaneous treatment of inoperable CTEPH
with data from multiple centers around the world
Mahmud et al. 2483
Chronic Thromboembolic Pulmonary Hypertension
showing the clinical feasibility of BPA for the treat-
ment of CTEPH. Riociguat remains the only approved
medical therapy and is an important adjunct for
treatment in patients deemed inoperable or with
persistent pulmonary hypertension after PTE.
In order for this disease to be appropriately
treated, we recommend that expert CTEPH teams
including surgical specialists be developed at indi-
vidual institutions. It is our opinion that BPA be
offered at CTEPH centers as a part of a multidisci-
plinary approach to treatment decisions. Addition-
ally, optimal and standardized techniques for BPA
need to be developed along with dedicated inter-
ventional equipment and appropriate training stan-
dards. The majority of interventional outcomes data
have been self-reported without adjudication, with
heterogeneous techniques and paucity of long-term
outcomes. In order to adequately evaluate the suc-
cess of this procedure as compared with surgical
endarterectomy, more rigorous and standardized
data collection are required. The cumulative benefit
and adverse effect of multiple procedures, especially
on patient radiation exposure and renal contrast
effects, must be determined. A multicenter evalua-
tion with objective adjudication for short-term suc-
cess along with evaluation of long-term outcomes of
BPA are required before true equipoise can be
established for randomized comparisons of BPA
versus PTE for patients with segmental/sub-
segmental CTEPH. In the meantime, the percuta-
neous revascularization option is appropriate for
patients deemed inoperable in combination with
targeted medical therapy, or those who have failed
to benefit from surgery. Whether BPA could poten-
tially allow for discontinuation of targeted medical
therapy is unknown and should be carefully studied.
The ongoing RACE trial (Riociguat Versus Balloon
Pulmonary Angioplasty in Non-operable Chronic
thromboEmbolic Pulmonary Hypertension;
NCT02634203) is addressing the question of the
comparative benefit of riociguat versus BPA for
inoperable CTEPH, and its results are eagerly
awaited.
CONCLUSIONS
There have been remarkable improvements in treat-
ment options for CTEPH patients over the past
decade. PTE remains the only definitive and poten-
tially curative therapy. Recent advancements in sur-
gical techniques and instruments now allow distal
endarterectomy, making surgery the treatment of
choice even in patients with segmental or distal
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Chronic Thromboembolic Pulmonary Hypertension MAY 29, 2018:2468–86

disease. On the basis of positive randomized clinical
trial data, we also have targeted medical therapy to
fill an unmet need for those deemed inoperable.
Furthermore, BPA with the introduction of new
techniques and technologies now offers an alterna-
tive interventional treatment to PTE for select CTEPH
patients not amenable to surgery. However, despite
the recent advances with BPA, there is no standard
technique for global adoption, and patient selection
remains a significant challenge. We still lack adequate
prospective long-term data after BPA, which high-
lights the need for future registries and carefully
conducted studies to determine the safety, efficacy,
and durability of the procedure.
Due to these uncertainties, and with the evolving
management approaches, CTEPH patients should be
referred to an advanced center experienced in the
evaluation and care of this unique patient population.
The optimal treatment for any CTEPH patient re-
quires a comprehensive review by a multidisciplinary
team capable of providing all current treatment
modalities.
ADDRESS FOR CORRESPONDENCE: Dr. Ehtisham
Mahmud, University of California San Diego, Sulpizio
Cardiovascular Center, 9434 Medical Center Drive, La
Jolla, California 92037. E-mail: emahmud@ucsd.edu.
Twitter: @UCSDHealth.

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KEY WORDS balloon pulmonary
angioplasty, BPA, chronic thromboembolic
pulmonary hypertension, CTEPH, PTE,
pulmonary thromboendarterectomy
AP PE NDIX For a supplemental video and
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