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336 PART IV Noncoronary Diseases: Diagnosis and Management
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the acute use of pulmonary vasodilators (intravenous epoprostenol
or treprostinil, inhaled NO, and so on) or up-titration of the
dose of already existing therapies.
If the underlying illness is unrelated to PAH, treatment of
the disease, while optimizing volume status and avoiding PAHtargeted therapy interruptions, is the recommended approach.
Judicious volume replacement, if needed, in patients with PAH
and chronic RV dysfunction is important to avoid both diminished
RV filling and a detrimental increase in RV preload. This is
especially challenging in cases where large amounts of volume
replacement are traditionally recommended, such as in sepsis
or septic shock. Although elective surgical procedures are usually
avoided, the presence of PAH should not exclude patients from
life-saving surgery or interventional procedures. Although
mortality and the perioperative complication rate may be high
144,145
and there are no data on what type of anesthesia to use during
surgery, experts recommend not veering too far from standard
operating procedure.
Avoidance of arrhythmias or their prompt treatment is crucial
in maintaining normal levels of systemic blood pressure and
coronary perfusion. The most common arrhythmias are atrial
tachycardias, atrial flutter, and atrial fibrillation. Due to the
importance of atrial contraction in a dysfunctional RV, rhythm
restoration medically or with electrical cardioversion is most
often pursued.
146
Other treatment measures for the critically ill PAH patient
include avoidance of intubation and negative inotropes; oxygen
supplementation to maintain normoxia; and the treatment of
infections, anemia, or any other condition that may be present.
Treatment in specialized centers is also recommended, based on
the high mortality (≈40%) reported in this patient population.
147
WHO Group 1′
Pulmonary veno-occlusive disease (PVOD) and/or pulmonary
capillary hemangiomatosis (PCH) have both similarities and
differences with PAH, and are therefore considered under a
different group (WHO Group 1′). These are relatively uncommon
conditions and seem to have significant overlap. Specifically, up
to 80% of patients with one disease also have pathologic characteristics of the other; due to other similarities, it has been
proposed that PCH may be an angioproliferative process resulting
from the effect of PVOD on the postcapillary circulation.
epidemiology of these diseases is not well established, but experts
have estimated their incidence at approximately 0.2 cases per
million adults.
149
There is increasing recognition of possible
associated forms of PVOD/PCH related to toxins and other
diseases or risk factors.
150
Unlike PAH, PVOD/PCH is male predominant and has a worse
prognosis.
151
In addition, most of the pulmonary vascular pathology in PAH is within the precapillary circulation, whereas PVOD/
PCH has mostly postcapillary vascular pathology with pulmonary
venule dilatation, proliferation, and occlusion by fibrous tissue.
Although some familial cases of PVOD/PCH have been described,
these are usually not related to BMPR2 mutations, as are most
cases of PAH. Conversely, biallelic mutations of the eukaryotic
translation initiation factor 2 alpha kinase 4 (EIF2AK4)
been described in families with PVOD/PCH.
148
152
The
148
have
The clinical presentation of PVOD/PCH is almost identical
to PAH and their hemodynamic profile is also relatively similar.
Although a lung biopsy is the gold standard for disease confirmation, this is no longer recommended due to increased morbidity
in patients with PH. The most helpful diagnostic modality is a
high-resolution chest computed tomography (CT), which may
show subpleural septal thickening, centrilobular ground-glass
nodules, pleural effusions, and mediastinal lymphadenopathy.
These imaging characteristics together with clinical suspicion
(some cases may present with digital clubbing, crackles on lung
auscultation, or severe hypoxia compared to PAH), a much lower
CO diffusion capacity (DLCO) than expected with PAH, and
possible development of pulmonary edema with PAH-specific
medications help establish the diagnosis.
medical therapies for PVOD/PCH; PAH-specific medications
may result in harmful pulmonary edema,
154,155
154
by experienced providers and with
may be used in some cases
close monitoring. Lung transplantation is the only curative option
currently available.
151
There are no approved
150,151
although they
WHO Group 1″
Pediatric PAH can manifest at any age from infancy to adulthood.
Recent registries describe idiopathic, heritable, or CHD-PAH as
the most common forms of pediatric PAH,
156
with an estimated
incidence and prevalence of idiopathic PAH of 0.5 to 0.7 and
2.1 to 4.4 per million children, respectively,
of CHD-PAH per million children.
157
157,158
or 2.2 and 15.6
PPHN reflects the failure
of the pulmonary vasculature to decrease its PVR during birth,
which allows for the transition from in utero to neonatal life.
This results in sustained elevation of PA pressures and impairment
of pulmonary blood flow and oxygenation. The mechanisms
related to this are not well described and this type of PH can be
associated with multiple neonatal cardiopulmonary diseases.
Its prevalence has been estimated at 1.9 per 1000 live births.
Although mortality has improved in recent years, it is still as
high as 10% and PPHN is linked to a high incidence of neurodevelopmental impairment.
for PPHN
162
; there is controversial evidence regarding maternal
use of SSRIs and an increased risk of PPHN.
161
Preterm status increases the risk
163
WHO Group 2
Pulmonary hypertension due to left heart disease (LHD; WHO
Group 2 PH) accounts for as many as three-quarters of echocardiographically diagnosed PH cases.
dysfunction (systolic or diastolic) and valvular heart disease are
the most common etiologies for this group, although it can also
be seen in more uncommon situations (see Box 32.1). The
presence of PH in LHD has been associated with worse outcomes
and increased symptom severity.
predilection similar to PAH, but affects older individuals with
systemic hypertension, valvular heart disease, or coronary artery
disease.
168
Definition and Epidemiology. Pulmonary hypertension due to
LHD is now defined as mean PAP greater than or equal to 25 mm
Hg, a PAOP greater than 15 mm Hg, and a normal or reduced
cardiac output.
169
Owing to multiple factors—including variable
164
Left ventricular (LV)
165–167
It tends to have a female
151
151,153
159
160
CHAPTER 32 Pulmonary Hypertension 337
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definitions of PH using different echocardiographic values, the
paucity of invasive hemodynamic data, and heterogeneity of the
studied populations—the prevalence of PH in LHD is not clear.
Although it reportedly ranges between 23% and 83%
171,172
170
in left
heart failure patients, when invasive hemodynamics are used, it is
closer to 70%.
173
More specifically, in left heart failure with reduced
ejection fraction (HFrEF), echocardiography-based studies note
a prevalence between 23% and 48% depending on the population studied (EF threshold used to define reduced EF) and the
definition of PH (systolic PAP or RVSP threshold used to define
167,174
PH).
between 62% and 73%.
Right heart catheter-based studies note a prevalence
165,175
In left heart failure with preserved
EF (HFpEF), there is similar variability, with echocardiographic
studies noting a prevalence between 36% and 83%
172,176
and
right heart catheter-based studies noting a prevalence between
47% and 63%.
173,177
The data on PH prevalence in LHD due to
valvular abnormalities have the same issues. Nevertheless, two
studies that looked at right heart catheterization data in patients
with severe aortic stenosis, using the definition of PH presented
earlier, noted a prevalence of 48% to 62%.
178,179
Pathophysiology and Diagnosis. Development of PH in LHD
is mainly related to LV dysfunction resulting in increased filling
pressures, transmitted retrograde from the left heart to the
pulmonary veins, capillaries, and, eventually, the pulmonary
180,181
arteries.
mitral regurgitation may contribute as well.
Decreased left atrial compliance and exercise-induced
182
It is not entirely
clear how, but it has been suggested that the aforementioned
venous congestion may lead to endothelial dysfunction (likely
due to NO and endothelin-1 imbalance)
183
which, in turn, can
induce pulmonary vasoconstriction and permanent vascular
remodeling.
184
The latter may result in further increases of mean
PA pressures that appear to be higher than expected for a given
PAOP. In theory, this could lead to pulmonary vascular disease
with increased RV afterload and subsequent RV failure. Based
on these factors, pulmonary hypertension in LHD can either be
more “passive” exclusively owing to backwards pressure transmission or more “reactive” owing to additional pulmonary vasoconstriction and remodeling. The latter form of LHD-related
PH has also been described as “out of proportion.” These terms
are nebulous, however, as a clear hemodynamic definition is
lacking and are based on the observation that the mean PAP is
higher than would be expected for a given PAOP. This can lead
to confusion in differentiating between WHO Group 2 PH versus
PAH superimposed on LHD, making management decisions
harder and placing patients at risk for inappropriate treatment.
Practically, PH in LHD could be owing to elevated PAOP and
filling pressures without a pulmonary arterial/vascular disease
component, a combination of both, or a pulmonary arterial/
vascular disease component only, unmasked after diuresis-related
PAOP decrease to less than 15 mm Hg. To better elucidate the
latter and define its presence, multiple variables have been
proposed, including PVR, the transpulmonary pressure gradient
(TPG = mean PAP − PAOP) and the diastolic pressure gradient
(DPG = diastolic PAP − PAOP). Since an ideal marker of pulmonary arterial/vascular disease should be as independent as
possible from changes in PAOP, blood flow, stroke volume, and
pulsatility and should reflect changes in the pulmonary circulation,
such as compliance and vessel distensibility,
be the best candidate. Pulmonary vascular resistance, which is
2,170
DPG seems to
frequently used in practice, is calculated based on flow and
pressure, which are interdependent, making it less reliable.
TPG, which has previously been used to identify reactive or
out-of-proportion pulmonary hypertension in LHD when its
value is greater than 12 mm Hg,
169
is also less attractive, as it is
affected by increasing PAOP and stroke volume as well as pulsatil-
181
it y.
In contrast, the DPG is less affected by PAOP changes
for a given stroke volume when compared to systolic PAP or
mean PAP.
181
Normal range for DPG has been reported to be
between 1 and 3 mm Hg for normal subjects and usually stays
below 5 mm Hg in most heart disease patients.
180,181,185
In order to better differentiate disease processes, recent
guidelines
2,170
have moved away from the passive, reactive, and
out-of-proportion terminology, adopting instead the term
“postcapillary PH” to define LHD-related PH (when mean PAP
≥25 mm Hg and PAOP >15 mm Hg). Moreover, based on the
data presented earlier on DPG, a cut-off of less than 7 mm Hg
is used to define “isolated postcapillary PH” (DPG <7 mm Hg)
versus “combined pre- and postcapillary PH” (DPG ≥7 mm
170
Hg).
A PVR of less than 3 Wood units in addition to a DPG
of less than 7 mm Hg was subsequently added in the definition
of isolated postcapillary PH and conversely greater than 3 Wood
units for combined pre- and postcapillary PH.
2,186
This was based
on reports of higher mortality when PVR was greater than 3
Wood units in a population with HFrEF and PH,
185
in order to
be more consistent with other PH definitions,2 and to have an
additional measure that takes TPG and cardiac output into
account.
186
A number of studies since
179,187–189
noted worse
prognosis in cases of LHD-associated PH when the DPG was
greater than 7 mm Hg, with one notable exception.
190
this controversy in the prognostic value of this measure, its
diagnostic value in differentiating between isolated postcapillary
and combined pre- and postcapillary PH is still supported. DPG
greater than or equal to 7 mm Hg and PVR greater than 3 Wood
units, in addition to mean PAP of greater than or equal to 25 mm
Hg and PAOP greater than 15 mmHg are thought to best differentiate combined pre- and postcapillary PH in LHD.
Although exercise testing and fluid loading have been proposed
in order to unmask PH related to LHD in patients with HFpEF,
the evidence is still not adequate for specific recommendations.
This is due to lack of standardized testing methodology and
normative values.
Clinical Presentation. The presentation of PH in LHD is very
similar to the presentation of any form of PH, although there
may be some signs related to left heart dysfunction. These may
include interstitial pulmonary edema, pleural effusions, and
crackles on lung auscultation or murmurs owing to mitral or
aortic valve disease on cardiovascular examination.
Management. When approaching the patient with WHO Group
2 PH, the initial goal of treatment is to address the underlying
disease. In cases of HFrEF, optimizing medical therapy and
addressing volume status are key components of management.
181
180
Despite
186,188
191
338 PART IV Noncoronary Diseases: Diagnosis and Management
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Although there is no strong evidence supporting a similar
approach to PH in HFpEF patients, it is still usually undertaken.
In cases of valvular heart disease, repair or replacement of the
diseased valve is also recommended.
191
A second component of
LHD-PH management is treatment of any concomitant diseases
that can lead to or exacerbate PH, such as COPD or sleep apnea.
Medical treatment of PH-LHD with PAH-specific medications
makes sense from a pathobiologic standpoint. As noted earlier,
there seems to be a component of endothelial dysfunction
183
that can be targeted by both endothelin receptor and NO pathwayrelated medications. Moreover, these medications may have
additional beneficial effects on myocardial function or remodel-
170,192
ing.
Nevertheless, the results of randomized controlled trials
for PAH-specific medical therapy in WHO Group 2 PH have
been equivocal.
In HFrEF, all the trials with endothelin antagonists or pros-
tanoids were negative
193
or increased mortality.
or terminated early owing to side effects
195
PDE5 inhibitor use in HFrEF has been
194
reported to be safe and well tolerated, with improvement in
exercise tolerance (peak VO2) and hemodynamics (mean PAP,
PVR, cardiac output, PAOP).
196–201
A randomized controlled trial
looking into the use of riociguat in HFrEF did not meet its
primary endpoint of improved walk distance, but noted improvement in hemodynamics and was also well tolerated.
202
There are fewer data on the use of PAH-specific therapies in
HFpEF. Trials with PDE5 inhibitors showed no significant
modest improvements
204
in exercise capacity and hemodynamics.
203
or
Riociguat in HFpEF did not seem to affect PAP but showed
some improvement in exploratory hemodynamic parameters
(stroke volume and RV end-diastolic area), was safe, and was
well tolerated.
205
The design of most of these studies could be challenged to
some extent, as patient selection was often not based on an
invasive hemodynamic diagnosis of PH and some of these patients
were not optimized from a volume status perspective prior to
treatment initiation. Moreover, most of these studies were not
stratifying patients based on the presence of isolated postcapillary
PH or combined pre- and postcapillary PH. More recent clinical
trials are taking some of these newer definitions into account.
WHO Group 3
Pulmonary hypertension due to lung diseases and/or hypoxia
can stem from a diverse group of etiologies (see Box 32.1) and
is defined as the presence of PH (mean PAP ≥25 mm Hg) in the
setting of one or more of these conditions. The most common
lung diseases related to the development of PH are interstitial
lung disease (ILD; also referred to as diffuse parenchymal lung
disease), COPD, and combined ILD and COPD (commonly
referred to as combined pulmonary fibrosis and emphysema
[CPFE]).
a common cause for WHO Group 3 PH, the disease seems to
be milder and easier to manage.
Epidemiology. The incidence and prevalence of PH in chronic
lung diseases vary widely. This is a function of varying PH etiologies (ILD includes a large number of pathologies), the different
tools used to recognize PH and how it was defined for the studies,
206
Although sleep breathing disorders (SBD) are also
207,208
and a wide range of underlying disease severity. Based on the
current PH definition noted earlier, between 23% and 50% of
patients with very severe COPD (mean forced expiratory volume
[FEV1] <30% predicted) have PH.
209–211
Similarly, studies looking
at patients with end-stage idiopathic pulmonary fibrosis (IPF)
showed a PH prevalence between 31% and 46%, although patients
with elevated PAOP were not excluded.
212,213
The prevalence of
PH in sleep-related disordered breathing is also relatively high,
with similar variability as seen with the other Group 3 PH etiolo-
214,215
gies.
Although it reportedly ranges between 17% and 42%
in larger studies,
216,217
it is suspected to be closer to 20%. Interestingly, an increased incidence of sleep disordered breathing has
been noted in patients with PAH.
218,219
Pathophysiology. Alveolar hypoxia with subsequent hypoxic
pulmonary vasoconstriction and destruction of the pulmonary
vascular bed are the most widely accepted mechanisms for the
development of PH in chronic lung disease.
220–222
Other mechanisms proposed include respiratory acidosis contributing to
pulmonary vasoconstriction and hypoxia-induced polycythemia
with increase in blood viscosity, which may result in elevated
PA pressures and thrombosis.
222,223
These may lead to endothelial
dysfunction and nonreversible pulmonary vascular remodeling,
which increases PVR and PAP. Although inflammation has been
theorized as a contributing factor, its impact is not clearly defined.
Moreover, the relative effect of each of these mechanisms remains
to be quantified.
222,224
Similar mechanisms, as well as increased
sympathetic activation and dysregulated metabolism, seem to
play a role in sleep-related disordered breathing PH.
225
Clinically, there is accumulating evidence that the development
of PH in end-stage lung disease is associated with worse oxygenation, decreased exercise capacity, and shorter survival.
Whether this is causation or a secondary indicator of worse
underlying disease has not been elucidated and the severity of
PH does not always correlate with the severity of the underlying
lung disease.
209–213,226
Interestingly, from a hemodynamic perspective, patients with COPD-related PH tend to have lower mean
PAP, a slower rate of PAP worsening, preserved cardiac output,
more diastolic RV dysfunction (vs. systolic RV dysfunction) and
are less likely to die from right heart failure compared to PAH.
Clinical Presentation and Diagnosis. WHO Group 3 PH
patients tend to present with symptoms similar to those of other
forms of PH that are also similar to symptoms of their underlying
lung disease. They may also present with lower partial pressure
of arterial CO2 and with disproportionately low DLCO.
diagnostic algorithm is the same as the one used in pulmonary
hypertension in general, including echocardiography and,
ultimately, right heart catheterization. In addition to these and
the other PH studies, lung imaging (chest radiography and
high-resolution CT), pulmonary function testing (spirometry,
body plethysmography, and DLCO), and polysomnography are
crucial to confirm WHO Group 3 PH.
Management. The basis of WHO Group 3 PH management
is treating the underlying hypoxia and chronic lung disease per
best current practices.
206
Multiple attempts have been made to
209,226
211,226
227,228
The
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assess the efficacy of PAH-specific treatments in these patients.
To date, studies with endothelin receptor antagonists
with PDE5 inhibitors
232
in diffuse parenchymal lung disease
229–231
or
have been negative or showed improvement only in dyspnea
and quality-of-life scores. Similarly, in COPD-related PH, trials
with these medications have also been negative or lead to conflicting results.
233–235
Inhaled prostanoid therapy is currently being
investigated in WHO Group 3 PH, whereas a trial of riociguat
in idiopathic interstitial pneumonias was terminated early due
to safety concerns.
Owing to the intricacies of distinguishing WHO Group 3 PH
from the less common PAH with concomitant lung disease, recent
guidelines have attempted to elucidate this. Specifically, if there
is “severe” PH with COPD, ILD, or combination of the two
(defined as mean PAP ≥35 mm Hg or mean PAP ≥25 mm Hg
and a CI <2.0 L/min per m2), there is increased risk of comorbid
PAH superimposed on chronic lung disease.
206
In these cases,
referral to a center with PH expertise would be beneficial for
the patient for more in-depth evaluation of the specific clinical
situation and participation in clinical trials or consideration for
PAH-specific therapy.
WHO Group 4
Pulmonary hypertension due to chronic thromboembolic disease
is categorized as WHO Group 4 pulmonary hypertension. It is
defined as mean PAP greater than or equal to 25 mm Hg in the
presence of organized pulmonary emboli suggested by persistent
perfusion defects on lung perfusion scintigraphy and confirmed
radiographically with catheter-based, CT, or magnetic resonance
(MR) angiography. In addition to having a different pathophysiologic basis relative to other forms of PAH, CTEPH is the only
potentially curable form of pulmonary hypertension with a
pulmonary endarterectomy.
Epidemiology. Though experience suggests that CTEPH is
under-recognized, it is considered a relatively rare outcome in
those patients having survived one or more acute pulmonary
embolic events.
237
Several studies have reported incidence rates
of CTEPH after acute pulmonary embolism (PE) ranging between
0.57% and 8.8%.
238–243
looking at “all comers” (patients with symptomatic PE; n = 1186),
“survivors” (patients with symptomatic PE after 6 month treatment; n = 999), and “survivors without major comorbidities”
(no significant cardiopulmonary, oncologic, or rheumatologic
disease; n = 1175) reported CTEPH incidence of 0.56%, 3.2%,
and 2.8%, respectively. This analysis also revealed that recurrent
thromboembolic events and unprovoked PE were associated with
a higher risk of developing CTEPH.
within a 2-year period after acute PE has been reported at 4.8%.
Moreover, multiple reports note that a large number of patients
with CTEPH do not have a history of PE (25.2%) or deep vein
thrombosis (DVT) (43.9%).
Published data provide a better characterization of patients at
risk for CTEPH.
245,246
Some of these risk factors include the presence of thrombophilic states, such as antiphospholipid antibody
syndromes or lupus anticoagulant
248
VIII
; factor V Leiden
236
A recent meta-analysis of 16 studies
244
The prevalence of CTEPH
245
245–247
249
; and von Willebrand factor.
; elevated levels of factor
248,249
Other
244
241
risk factors associated with higher CTEPH incidence include larger
perfusion defects or higher levels of pulmonary hypertension
at the time of initial PE diagnosis, recurrent PE, splenectomy,
ventriculoatrial shunts, infected pacemakers, non-O blood group,
thyroid replacement therapy, and history of malignancy.
Pathophysiology. CTEPH is thought to evolve from a prior
episode of acute PE, although the acute event may have been
asymptomatic and never diagnosed.
245
Efforts at identifying the
pathophysiologic mechanisms of CTEPH have been focused on
the transition from an acute thromboembolism to a chronic,
endothelialized, endovascular “scar,” though the process is incompletely understood. In addition to a possible genetic predisposition
for inadequate thrombus dissolution, hypotheses include the
concepts of local inflammation, ineffective angiogenesis, and
endothelial dysfunction.
250,251
White blood cell–derived inflammatory infiltrates within the
thrombus/vessel-wall complex may result in a chemokine cascade
that promotes smooth muscle cell proliferation, fibroblast migration and proliferation, apoptosis inhibition, and endothelin-1
production. Although the specifics are unclear, this may lead to
maladaptive vessel-wall remodeling with poor thrombus dissolution and lumen recanalization.
250–253
Moreover, a dysfunctional
endothelium may be responsible for ineffective angiogenesis,
promoting abnormal thrombus contraction and absorption
and resulting in fibroblast proliferation and deregulation of
myofibroblast differentiation. These hypotheses, taken together
with reports of abnormal fragmentation of fibrinogen variants,
provide a plausible mechanism for abnormal thrombus dissolution and maladaptive vessel-wall remodeling, bridging the gap
between acute pulmonary embolus and chronic thromboembolic
disease.
250,255–257
Another pathophysiologic feature of CTEPH is the development of a distal pulmonary vasculopathy, which can occur in
varying degrees in addition to proximal vessel chronic thrombus.
Early observations revealed small-vessel disease with pathologic
changes similar to PAH,
258
whereas more recent observations
report a more complex distal vasculopathy, associated with
bronchial-to-pulmonary venous shunting and collateral blood
259
flow.
Whether this downstream vascular pathology is an
evolution of chronic thromboembolic disease or is provoked by
other factors (i.e., high flow state in the uninvolved vascular bed,
genetic predisposition, an infectious process, or other medical
condition) remains unclear.
250
Clinical Presentation and Diagnosis. The most common
presenting symptoms of CTEPH are similar to other forms of
PH: exertional dyspnea and unexpected exercise intolerance.
Other symptoms related to CTEPH can include cough, hemoptysis, palpitations, or atypical chest pain but tend to be relatively
uncommon and, in cases of advanced disease, symptoms of RV
failure can predominate. Physical examination findings are similar
to PAH and can be very subtle or absent altogether. Additional
physical findings may be related to prior DVT and venous stasis
changes of the extremities, such as varicose veins or skin discoloration. Hypoxia may be present from right-to-left shunt through
a patent foramen ovale, significant RV dysfunction, or severe
238,241,246
254
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Wash in
Post Q
LPO Q
Fig. 32.2 Ventilation perfusion scintigraphy in a case of chronic thromboembolic pulmonary
hypertension, demonstrating large perfusion defects (second and third rows) mismatched to the
ventilation portion of the scan (first row). Ant, Anterior; Equil, equilibrium; LAO, left anterior
oblique; LLAT, left lateral; LPO, left posterior oblique; Post, posterior; Q, perfusion; RAO, right
anterior oblique; RLAT, right lateral; RPO, right posterior oblique; W/O, washout.
Equil
Ant Q
RPO Q
W/O 1 min
LLAT Q
LAO Q
W/O 2 min
RLAT Q
RAO Q
ventilation/perfusion (V⋅/Q⋅) mismatch causing cyanosis.
pulmonary flow murmurs or bruits may be heard when auscultating the lungs due to turbulent blood flow through partially
obstructed or narrowed vessels.
The initial part of the diagnostic algorithm is identical to
other forms of PH. The diverging test in the evaluation of CTEPH
is the lung V⋅/Q⋅ scintigraphy scan, which screens for mismatched
perfusion defects that might reflect the presence of chronic
thromboembolic disease (Fig. 32.2). Despite recent advances in
CT imaging of the pulmonary vascular bed, the V⋅/Q⋅ scan remains
the recommended standard in screening for CTEPH
its greater sensitivity.
262,263
perfusion abnormalities in regions of normal ventilation are
observed in patients with chronic thromboembolic disease and
are distinct from more peripheral, “mottled” perfusion abnormalities sometimes noted in PAH.
scan excludes the diagnosis of operable CTEPH, an abnormal
perfusion scan is not specific for CTEPH.
Catheter-based, digital subtraction pulmonary angiography
(DSA) has been considered the gold standard test for confirming
the diagnosis of CTEPH. Angiographic findings may include
“pouch” defects, complete obstruction of major vessels, pulmonary
260
Finally,
261
due to
Persistent subsegmental or larger
264
Although a normal perfusion
265
artery “webs” or “bands,” pulmonary artery wall irregularities,
and distinct vessel narrowing, occasionally accompanied by
poststenotic dilatation
266
(Fig. 32.3). Other imaging modalities
used include CT pulmonary angiography (CTPA) and MR
pulmonary angiography (MRA), which can play a pivotal role
in the workup of the CTEPH patient.
265
Defining disease severity from a hemodynamic perspective
with right heart catheterization is an essential component of the
evaluation. Hemodynamic data can assist with preoperative risk
stratification, since higher PVR and severe RV dysfunction increase
perioperative mortality.
267–269
Management. The treatment option providing the greatest
opportunity for cure for patients with CTEPH is surgical removal
of the thromboembolic material via pulmonary thromboendarterectomy (PTE) surgery (also known as pulmonary endarterectomy, PEA), followed by life-long anticoagulation. Assessment
of surgical candidacy necessitates a thorough evaluation at an
experienced CTEPH center as to the operability of the chronic
thromboembolic lesions. The fundamental elements of the
procedure have remained relatively unchanged over the past 2
decades,
268,270
necessitating a median sternotomy, cardiopulmonary
CHAPTER 32 Pulmonary Hypertension 341
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A B
Fig. 32.3 Digital subtraction pulmonary angiography demonstrating multiple pulmonary vascular defects.
(A) Posteroanterior view of the right lung showing truncated pulmonary arteries without contrast present
in the apex of the right upper lobe and most of the right lower lobe. (B) Lateral view of the same right
lung depicting lack of contrast of the entire right lower lobe and abnormal contour of pulmonary arteries
with a prominent pouch defect (arrow) where the descending right pulmonary artery terminates abruptly.
bypass, and deep hypothermia (for tissue protection) with circulatory arrest periods in order to provide a bloodless visual field
for optimal resection of organized thrombotic material. The
favorable short- and long-term outcomes of the surgery with
reduction of PA pressures, improvement in RV function and
functional status have been consistently reported by multiple
centers worldwide.
236,268,270–272
become available, the hemodynamic and resultant functional
status improvements are sustained in most patients, along with
a favorable impact on long-term survival.
Treatment options for CTEPH patients deemed not to be
surgical candidates include PH-targeted medical therapy and,
in some centers, balloon pulmonary angioplasty. In patients
with inoperable CTEPH, sildenafil
hemodynamic benefit but without significant improvement of
the primary endpoint (6-minute walk distance). Similar results
were noted in a larger trial with bosentan
with residual pulmonary hypertension following PTE surgery.
A recent randomized controlled trial examining the efficacy of
riociguat in patients with inoperable CTEPH and persistent
pulmonary hypertension following PTE surgery demonstrated
a significant improvement in 6-minute walk distance, pulmonary hemodynamics, and WHO FC, as well as a reduction of
NT-proBNP levels compared to placebo.
confirmed for up to a year in a subsequent open-label long-term
278
trial.
Another recently emerging treatment option is percutaneous
transcatheter balloon pulmonary angioplasty (BPA). Though early
279,280
reports
suggested some pulmonary hemodynamic benefit
in inoperable patients or poor surgical candidates, a resurgence
Moreover, as longer-term data have
273,274
275
showed a pulmonary
276
that included patients
277
These findings were
of this procedure has documented significant hemodynamic
improvements as long as 1 year after BPA.
281–286
The benefits of this
procedure in the treatment of CTEPH patients requires further
study given ongoing questions regarding appropriate patient
selection, long-term outcomes, timing of repeat procedures, and
optimal technique to minimize complications.
287
WHO Group 5
WHO Group 5 PH encompasses many diseases, including a wide
range of hematologic, systemic, and metabolic disorders (see
Box 32.1). Moreover, the relatively low incidence of these primary
pathologies in combination with their significant heterogeneity
has resulted in the acquisition of rather superficial knowledge
regarding the epidemiology, pathogenesis, or prognosis of associated PH. Mechanisms of PH development range from vascular
obliteration and proliferative vasculopathy to extrinsic compression or intrinsic occlusion.
Very little data exist on the use of PAH-specific therapy for
Group 5 PH. The large number of diseases, varying pathophysiology, significant overall heterogeneity and relatively low incidence
of PH in each subgroup of diseases hinders our ability to design
and undertake high-quality clinical trials. In most cases, the
underlying disease should be treated and the patients should be
referred to tertiary centers with PH expertise. Taken together,
there is a clear need for additional research to better understand
how these diseases cause PH and, more important, their clinical
significance and therapeutic options.
The full reference list for this chapter is available at
ExpertConsult.com.
2
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