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Definition of Pulmonary Hypertension, 327
Clinical Presentation, 327
Diagnosis, 329
Classification, Pathophysiology, and Management, 329
WHO Group 1, 329
Epidemiology, 329
Pathophysiology, Pathobiology, and Pathology, 329
Clinical Presentation and Natural History, 331
Management, 333
Management of the Critically Ill Patient With Pulmonary
Arterial Hypertension, 335
WHO Group 1′, 336
WHO Group 1″, 336
WHO Group 2, 336
Definition and Epidemiology, 336
32
Pulmonary Hypertension
Demosthenes G. Papamatheakis, William R. Auger
Pathophysiology and Diagnosis, 337
Clinical Presentation, 337
Management, 337
WHO Group 3, 338
Epidemiology, 338
Pathophysiology, 338
Clinical Presentation and Diagnosis, 338
Management, 338
WHO Group 4, 339
Epidemiology, 339
Pathophysiology, 339
Clinical Presentation and Diagnosis, 339
Management, 340
WHO Group 5, 341
Over the past 2 decades, significant advances have been made
in the understanding of the pathophysiology of pulmonary
hypertension. In addition, dramatic improvements have occurred
in the diagnostic and therapeutic approach of patients afflicted
with this disease. The resulting development of new interventions
for disease management has fundamentally transformed its natural
history and has improved the perception of its various phenotypes.
This has enabled a more detailed classification of the various
pulmonary hypertension subtypes, leading to a more structured
approach to patient care. The purpose of this chapter is to offer
the latest information on disease classification, epidemiology,
and clinical presentation, and to provide guidance for a systematic
approach to both the diagnosis and therapy in patients with
pulmonary hypertensive disorders.
DEFINITION OF PULMONARY HYPERTENSION
Pulmonary hypertension (PH) refers to elevated pressures in
the pulmonary vascular bed and is defined by a mean pulmonary
artery pressure (PAP) greater than or equal to 25 mm Hg
confirmed by right heart catheterization.1 Pulmonary arterial
hypertension (PAH), which is an important PH subtype that
will be discussed extensively in this chapter, also requires a
pulmonary artery occlusion pressure (PAOP) of 15 mm Hg or
less and a pulmonary vascular resistance (PVR) greater than 3
Wood units.
The pulmonary circulation extends from the pulmonic valve
to the left atrium and consists of the pulmonary outflow track;
the right and left main pulmonary arteries; the lobar, segmental,
and subsegmental arteries; the pulmonary arterioles; and the
capillaries, venules, and larger pulmonary veins. PH may refer
to elevated pulmonary artery pressures (precapillary PH), elevated
pulmonary venous pressures (postcapillary PH) or, less frequently,
a combination of the two. The initial classification of PH included
PH without an identifiable cause (primary), and PH with an
identifiable cause (secondary). In the last 15 years, however, there
has been increasing understanding of the different etiologies of
PH, revealing the need for a more nuanced classification scheme.
To better demarcate specific categories of the disease, with similar
pathophysiologic mechanisms, presentation, and therapies, major
changes to the classification of PH were introduced in the 1990s
(Box 32.1).
has been maintained since the introduction of the World Health
Organization (WHO) groups in 1998, multiple classification
updates have been published by various professional societies,
with incremental modifications.
2
Although the general architecture of the classification
3–5
CLINICAL PRESENTATION
The symptoms associated with PH are widely nonspecific and
are, in large part, related to the severity and stage of the disease.
The most common presenting symptoms are dyspnea on exertion
327
CHAPTER 32 Pulmonary Hypertension 327.e1
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Keywords
pulmonary hypertension
pulmonary arterial hypertension
chronic thromboembolic pulmonary hypertension
right heart failure
critical illness in pulmonary hypertension
328 PART IV Noncoronary Diseases: Diagnosis and Management
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BOX 32.1 Pulmonary Hypertension Classification
Group 1: Pulmonary Arterial Hypertension
1.1 Idiopathic
1.2 Heritable
1.2.1 BMPR2 mutation
1.2.2 Other mutations
1.3 Drugs and toxins induced
1.4 Associated with:
1.4.1 Connective tissue disease
1.4.2 Congenital heart disease
1.4.3 Portal hypertension
1.4.4 Human immunodeficiency virus (HIV) infection
1.4.5 Schistosomiasis
Group 1′: Pulmonary Veno-Occlusive Disease and/or
Pulmonary Capillary Hemangiomatosis
1′.1 Idiopathic
1′.2 Heritable
1′.2.1 EIF2AK4 mutation
1′.2.2 Other mutations
1′.3 Drugs, toxins, and radiation induced
1′.4 Associated with
1′.4.1 Connective tissue disease
1′.4.2 HIV infection
Group 1″: Persistent Pulmonary Hypertension of
the Newborn
Group 2: Pulmonary Hypertension Owing to Left Heart
Disease
2.1. Left ventricular systolic dysfunction
2.2 Left ventricular diastolic dysfunction
2.3 Valvular disease
2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital
cardiomyopathies
2.5 Congenital/acquired pulmonary veins stenosis
Group 3: Pulmonary Hypertension Owing to Lung Diseases
and/or Hypoxia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental lung diseases
Group 4: Chronic Thromboembolic Pulmonary
Hypertension and Other Pulmonary Artery Obstructions
4.1 Chronic thromboembolic pulmonary hypertension
4.2 Other pulmonary artery obstructions
4.2.1 Angiosarcoma
4.2.2 Other intravascular tumors
4.2.3 Arteritis
4.2.4 Congenital pulmonary artery stenoses
4.2.5 Parasites (hydatidosis)
Group 5: Pulmonary Hypertension With Unclear and/or
Multifactorial Mechanisms
5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders,
splenectomy
5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid
disorders
5.4 Others: pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis,
chronic renal failure (with or without dialysis), segmental pulmonary
hypertension
Modified from Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension:
The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the
European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society
for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119.
and gradual exercise intolerance. Of note, these symptoms tend
to be progressive with time, resulting in a steady decline of
functional capacity and a worsening in dyspnea. Less common
symptoms include easy fatigability, cough, hemoptysis, hoarseness
(from compression of the left recurrent laryngeal nerve by an
enlarged pulmonary artery), or chest discomfort. In advanced
disease, symptoms related to right ventricular (RV) failure start
to manifest, including lower extremity edema, abdominal distention, shortness of breath at rest, chest pain, and syncope.
On physical examination, most patients with PH exhibit subtle
findings unless they are in RV failure. These include widening
of the S2 heart sound and accentuation of its P2 component.
In more severe or later-stage disease, possible additional findings
include elevated jugular venous pressure, a positive hepatojugular
reflux, a fixed split S2, right-sided S4 and/or S3 heart sounds, a
murmur associated with tricuspid regurgitation or pulmonic
insufficiency, an RV heave, ascites, abdominal distention, hepatomegaly, and/or lower extremity edema. Clubbing is not a
common finding in PH, but can be present in cases of comorbid
parenchymal lung disease or right-to-left shunt. Cyanosis is also
not common unless the above comorbidities are present or in
the presence of right-to-left shunting through a patent foramen
ovale in cases of severe right atrial pressure elevation.
During the evaluation of the patient with PH, a modified
New York Heart Association functional classification is used to
stratify symptoms and function of PH patients. In the WHO
Functional Classification, patients are categorized into four classes
depending on severity of symptoms, as shown in Table 32.1.
6
In
addition to functional class (FC), recent guidelines have suggested
the use of clinical, laboratory, and other testing data (i.e., presence
of syncope, N-terminal pro b-type natriuretic peptide [NTproBNP] plasma levels, 6-minute walk distance, right heart
catheterization hemodynamics) in order to risk-stratify patients
to low-, moderate- or high-risk groups, corresponding to a 1-year
mortality of less than 5%, 5% to 10%, and greater than 10%,
respectively.
2
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TABLE 32.1 World Health Organization
(WHO) Functional Classification in Patients
With Pulmonary Hypertension
WHO
Functional
Class
Class I No significant symptoms with ordinary physical activity
Class II Symptoms with ordinary activity; slight limitation of
Class III Symptoms with less than ordinary activity; marked
Class IV Symptoms with any activity or at rest; unable to perform
Modified from Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and
differential assessment of pulmonary arterial hypertension. J Am Coll
Cardiol. 2004;43:40S–47S.
Symptoms (Increased Dyspnea, Fatigue,
Chest Pain, or Presyncope)
activity
limitation of activity
any physical activity.
DIAGNOSIS
One of the biggest challenges in PH management has been delay
in diagnosis. Registry data indicate a mean time between symptom
onset and diagnosis of PAH (a distinct pulmonary hypertension
subgroup) of between 2.3 and 2.8 years.
have been made to increase awareness of the disease in the medical
community and empower physicians to consider it in unexplained
dyspnea. This could allow for earlier initiation of the appropriate
workup and possible referral to a specialty center with the option
to intervene earlier in the disease process. The latter could be
beneficial, since it could delay disease progression and the
development of right heart failure9 that, in turn, has been associated with worse prognosis and poorer survival.
suspected, a detailed and thorough history and physical examination can assess for specific risk factors and help identify the
possible etiology.
The basis of PH screening is echocardiography and the
cornerstone of PH diagnosis is right heart catheterization.
However, there are several other studies that play a role in the
workup of PH (Fig. 32.1). Echocardiography provides an estimate
of the RV systolic pressure (RVSP) based on the tricuspid
regurgitant jet velocity and the right atrial (RA) pressure estimate.
The tricuspid regurgitant jet velocity can be used to calculate
the pressure gradient between the RV and the RA based on the
Bernoulli principle (gradient is equal to 4 times the squared
regurgitant jet velocity), whereas the RA pressure can, in most
cases, be inferred from the size of the inferior vena cava. Although
there are no published consensus guidelines on the RVSP value
beyond which PH is considered, most echocardiography laboratories use 35 to 40 mm Hg. Moreover, an echocardiogram can
give qualitative information regarding the RA (dilatation) and
RV (enlargement, hypertrophy, or decreased function) that can
indicate right heart dysfunction in the setting of PH.
The recommended diagnostic steps once PH is suspected are
to assess for other respiratory abnormalities (pulmonary function
tests, polysomnography or overnight oximetry, chest radiograph),
an electrocardiogram (ECG) to further evaluate for arrhythmias
or other cardiac pathology, ventilation perfusion scintigraphy to
7,8
Significant efforts
10,11
Once PH is
rule out chronic thromboembolic pulmonary hypertension, and
blood testing for connective tissue diseases (antinuclear antibody,
rheumatoid factor), liver disease (liver function tests), and human
immunodeficiency virus (HIV) infection. The workup culminates
with a right heart catheterization, in which these definitions
are used to confirm PH (mean PAP ≥25 mm Hg) and/or PAH
(mean PAP ≥25 mm Hg, PAOP ≤15 mm Hg, and PVR >3 Wood
units). During the right heart catheterization, a vasodilator or
vasoreactivity challenge is performed, which includes the use
of a vasodilatory agent (most commonly, inhaled nitric oxide
[NO]) to assess acute vasoreactivity. Patients with PAH are
considered to have a positive vasoreactivity test if their mean
PAP decreases by at least 10 mm Hg and to less than 40 mm Hg.6
These vasoreactive patients (~5% of the PAH population) tend
to have a better prognosis and can be managed with calcium
channel antagonists,
12,13
which are not used in nonvasoreactive
patients. Interestingly, approximately 50% of these patients will
stop being vasoreactive within the first 1 or 2 years of diagnosis
and may need additional medical therapy. Fig. 32.1 depicts the
diagnostic algorithm for PH.
CLASSIFICATION, PATHOPHYSIOLOGY,
AND MANAGEMENT
WHO Group 1
WHO Group 1 PH, or PAH, has a distinct pathophysiology,
natural history, and response to treatment. As previously noted,
PAH is PH (mean PAP ≥25 mm Hg) with the additional criteria
of PVR greater than 3 Wood units and PAOP less than or equal
to 15 mm Hg.1 This is in the absence of other causes of precapillary PH, such as chronic thromboembolic pulmonary hypertension (CTEPH), which can fulfill this definition, but also includes
chronic thromboembolic disease. PAH is subcategorized based
on etiology, as shown in Box 32.1. Although these etiologic factors
seem to be inherently heterogeneous, they result in similar
pulmonary vascular pathology, pathobiology, and clinical presentation; thus, they are grouped together.
Epidemiology. The incidence and prevalence of PAH have
been derived from several large registries summarized in Table
7,14–16
32.2.
years,
and the older from Europe and from the United States. All of
the above registries show a clear female predominance, ranging
from 65% to 80%, although this may be less pronounced in the
older populations.
Pathophysiology, Pathobiology, and Pathology. The patho-
physiologic basis of PAH is thought to be multidimensional;
numerous prior reviews and updates have summarized key
findings.
be a disease of excessive pulmonary vasoconstriction, it is now
evident that there are additional pathobiologic components
playing a role, including endothelial dysfunction, abnormal cell
proliferation and apoptosis, shift of cellular metabolism, genetic
predisposition, coagulation dysregulation, and inflammation.
Mean age of onset for PAH has ranged from 36 to 52
14,17
with the younger populations reported from China
18–22
Although PAH was previously thought to primarily
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Signs, symptoms and history suggestive
of pulmonary hypertension (PH)
Echocardiography
Characteristics not
consistent with PH:
other pathology
Characteristics
consistent with PH:
etiological work-up
Possible CTEPH:
Refer to expert
center, RHC and
DS-PA, CT-PA or
MR-PA
PAH likely:
Testing for CTD, CHD,
drugs and toxins,
HIV, liver disease,
schistosomiasis
Fig. 32.1 Diagnostic algorithm for suspected pulmonary hypertension. ABG, Arterial blood gas;
CHD, congenital heart disease; CTD, connective tissue disease; CTEPH, chronic thromboembolic
pulmonary hypertension; CT-PA, computed tomography pulmonary angiography; DLCO, carbon
monoxide diffusion capacity; DS-PA, digital subtraction pulmonary angiography; HIV, human
immunodeficiency virus; HRCT, high-resolution computed tomography; mPAP, mean pulmonary
artery pressure; MR-PA, magnetic resonance pulmonary angiography; PAH, pulmonary arterial
hypertension; PAOP, pulmonary artery occlusion pressure; PFT, pulmonary function testing; PH,
pulmonary hypertension; PSG, polysomnogram; PVR, pulmonary vascular resistance; RHC, right
heart catheterization; RV, right ventricle; VQ: ventilation perfusion scintigraphy; x-ray, radiography.
(Modified from Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis
and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment
of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European
Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital
Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart
J. 2016;37:67–119.)
Mismatched
perfusion defects
present
No mismatched
perfusion defect: RHC
mPAP > 25 mm Hg
–
PAOP < 15 mm Hg
–
PVR > 3 Wood units
VQ scan
No significant heart
or lung disease
PH or RV dysfunction
not present: treat
underlying disease
- Electrocardiogram
- Chest x-ray
- HRCT
- PFT (with DLCO)
- ABG
- PSG
Heart or lung
disease confirmed
PH or RV dysfunction
present: refer to PH
expert center
TABLE 32.2 Summary of Pulmonary Arterial Hypertension Epidemiology Based on
Large Registries
Incidence (Cases Per
Registry
Scottish
7
French
REVEAL
Spanish
Million Adult Population)
14
15
16
Excessive vasoconstriction in PAH has been linked to abnormalities of function or expression of potassium channels located
on pulmonary artery smooth muscle cells,23 impaired production
of vasodilators from the endothelium (i.e., NO from endothelial
NO synthase),
24,25
and overexpression of vasoconstrictors (i.e.,
thromboxane A2, endothelin-1, and serotonin).
factors, together with vascular effector imbalances (frequently,
growth factors—such as platelet-derived growth factor, fibroblast
growth factor, and TGFb),28 impact vascular remodeling by
Prevalence (Cases per
Million Adult Population) Notes
7.1–7.6 26–52 Retrospective; some data based on disease codes
2.4 15 Prospective; hemodynamic and clinical data
2 10.6 Prospective; matched French cohort hemodynamic and clinical data
3.2 16 Mostly retrospective, with 2 years of prospective data
augmenting postapoptotic endothelial cell29 and pulmonary
artery smooth muscle cell proliferation,
29–31
as well as activation
of adventitial fibroblasts32 and metalloproteases.33 Moreover,
these dysregulations can result in an imbalanced prothrombotic
microenvironment,28 causing thrombus formation within the
25–27
Some of these
pulmonary circulation, which further exacerbates pulmonary
vascular obstruction and lumen narrowing.34 The role of inflammation in PAH has been confirmed based on pathologic findings
of perivascular inflammatory components35 and is thought to
CHAPTER 32 Pulmonary Hypertension 331
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be a significant disease factor, albeit not a well-elucidated one.36
Finally, it has been hypothesized that, as seen in cancer biology,37
PAH is characterized by a shift of mitochondrial metabolism
from oxidative to glycolytic.
more resistant to apoptosis, hence allowing overproliferation.
38,39
This is believed to make cells
37
Taken together, the above changes result in thickening of the
pulmonary artery wall and narrowing of the pulmonary artery
lumen, which can eventually be obliterated. These pathologic
changes are only present in the arteries (pulmonary veins are
not usually affected) and tend to appear in vessels approximately
500 µm in diameter or smaller. Pathologic changes include intimal
hyperplasia, medial hypertrophy, and adventitial thickening with
perivascular inflammatory infiltrates.35 End-stage forms of these
changes are the previously described complex/plexiform lesions,
which can also include in situ thrombotic material.
34,35
Clinical Presentation and Natural History. The initial clinical
presentation of PAH does not significantly differ from other
forms of PH. Registry data reveal that patients may go years
with dyspnea on exertion prior to getting the correct diagnosis.8
Symptoms of right heart failure are more common in PAH than
other groups of PH, as the disease severity tends to be higher.
Signs and symptoms of underlying disease processes—such as
chronic liver disease, HIV/AIDS, congenital heart disease, or
connective tissue disease—can also be present. Longer term, PAH
has a worse prognosis in general than most other forms of PH
and a lower survival rate,40 mostly owing to disease progression
leading to RV dysfunction and failure.
Etiologic categories
Idiopathic. Idiopathic PAH, which is usually diagnosed when
other possible causes of PAH have been ruled out, tends to be
sporadic in nature. It is the most common form of PAH in the
Western world, accounting for approximately 40% to 50% of
PAH cases,
7,8,41
and second to congenital heart disease–associated
PAH in China (~35% of PAH cases).17 Idiopathic PAH incidence,
as reported by various registries, is estimated to range between
0.9 and 2.6 cases per million adults.
7,14–16
Idiopathic PAH preva-
lence is estimated to be between 4.6 and 9 cases per million
7,14–16
adults.
Although the earlier registries42 and the ones from
China17 show a younger mean age at diagnosis of idiopathic
PAH (approximately 36 years old), most other registries note a
mean age of diagnosis between 46 and 65 years old. Female
predominance varies depending on the registry but, similar to
PAH, ranges from 62% to 83%.
7,14–17,42
Heritable. Heritable PAH is relatively similar to idiopathic
PAH but has a clear association to a genetic defect and accounts
for approximately 3% to 4% of PAH cases.
7,8,41
Previously known
as familial PAH, heritable PAH has been associated with multiple
genetic mutations that are the focus of ongoing research. The
most common PAH-associated mutations are encoding for the
bone morphogenetic protein receptor type 2 (BMPR2), a member
of the tumor growth factor-β (TGF-β) family. This is usually an
autosomal dominant trait, which is modulated by factors such
as variable expressivity and incomplete penetrance. The latter
is estimated to be approximately 27% for both genders (42% in
females and 14% in males)43 and may be affected by female
hormones. It is estimated that more than 70% of families with
heritable PAH have one of the more than 300 independent BMPR2
mutations.44 Moreover, it is thought that up to 26% of sporadic
and previously thought to be idiopathic cases of PAH can be
attributed to mutations of this gene
45,46
and therefore pose a
hereditary risk to other family members. Two other members
of the TGF-β cell signaling family have also been associated with
heritable PAH (specifically in relation to hereditary hemorrhagic
telangiectasia): activin-like kinase-type 1 (ALK1) and endoglin
(ENG).47 In addition, mutations of the bone morphogenetic
responsive-gene SMAD9 (also known as SMAD8),48 the gene
encoding for a membrane protein of caveloae caveolin-1,49 and
the gene encoding for the potassium channel KCNK3 have also
been implicated in multiple cases of heritable PAH.50 Interestingly,
registry data indicate that patients with heritable PAH tend to
develop the disease at a younger age, are more severely ill at
diagnosis, and have accelerated disease progression51 compared
to idiopathic PAH, although they both retain a female preponderance (~1.8 : 1)42 and have similar pathophysiology and
pathology.
Drug and toxin related. Expert opinion regarding which
drugs and toxins are associated with PAH development has
changed over the years. Based on recently published guidelines,
2,4
these substances are categorized based on the level of evidence
for association with disease development. A “definite” association
is based on large, multicenter epidemiologic studies or an epidemic. A “likely” association is based on multiple case series or
a single-center, case-control study. A “possible” association lacks
any related studies but features substances that have similar
mechanisms of action as the ones in the prior two categories.
Finally, an “unlikely” association is based on negative epidemiologic studies that failed to show a link between the substance
and the development of PAH. The current drugs and toxins with
these defined PAH associations are listed in Table 32.3. Of note,
selective serotonin reuptake inhibitors (SSRIs) have been associated with increased risk of primary pulmonary hypertension of
the newborn (PPHN) when taken by their mothers during
pregnancy.52 Epidemiologic data are lacking regarding this type
of PAH.
Associated. Associated PAH includes PAH in the setting of
connective tissue disease, congenital heart disease, HIV infection,
portal hypertension, or schistosomiasis (see Box 32.1) and
accounts for approximately 50% of all PAH.
7,8,41
Connective tissue disease–associated PAH (CTD-PAH) has
been well described in systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. It can also be seen
with rheumatoid arthritis, dermatomyositis, and Sjögrens syn-
53,54
drome.
million adults
It has an estimated prevalence of 2.3 to 10 cases per
7,14,54
and is the most common form of associated
PAH in the Western world (15%–30% of all PAH), with systemic
sclerosis (particularly the limited cutaneous form) being the
most common diagnosis.
7,15,16,54,55
In China, CTD-PAH is the
third most frequent form of PAH after congenital heart disease–
associated and idiopathic PAH, with systemic lupus erythematosus
being the more common diagnosis rather than systemic sclero-
17,41,53
sis.
Scleroderma-related CTD-PAH has a strong female
predominance (~80% females), a mean age of diagnosis greater
than 60 years, and a shorter survival time compared to idiopathic
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TABLE 32.3 Drugs and Toxins Associated With Pulmonary Arterial Hypertension
Definite Likely Possible Unlikely
Aminorex Amphetamines Cocaine Oral contraceptives
Fenfluramine L-Tryptophan Phenylpropanolamine Estrogen
Dexfenfluramine Methamphetamines St. John’s wort Cigarette smoking
Toxic rapeseed oil Dasatinib Amphetamine-like drugs
Benfluorex Interferon α and β
a
SSRIs
Modified from Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension:
The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the
European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society
for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119.
a
Increases risk of persistent pulmonary hypertension of the newborn in mothers taking SSRIs during gestation.
b
Mostly alkylating agents, such as mytomycin C and cyclophosphamide.
56–58
PAH
despite having similar outcome predictors59 and pathophysiology. The early detection60 and appropriate management
of these patients is very important, as PAH is a leading cause of
death in systemic sclerosis.
61
Congenital heart disease-associated PAH (CHD-PAH) is the
second most common form of associated PAH in Europe and
the United States (10% to 23% of all PAH) after CTD-PAH
7,15
and the most common form of PAH overall in China (43%).17
Chemotherapeutic agents
BOX 32.2 Congenital Heart Disease–
Associated Pulmonary Artery Hypertension
Subclassification
1. Eisenmenger Syndrome
This category includes all large intracardiac and extracardiac defects that
begin as systemic-to-pulmonary shunts and progress with time to severe elevation
of PVR and to reversal (pulmonary-to-systemic) or bidirectional shunting. Cyanosis,
secondary erythrocytosis, and multiple organ involvement are usually present.
Improvement in childhood CHD management has resulted in
2.
a larger number of adult CHD patients with higher disease
complexity. A clinical subclassification of this category of associated PAH is now recommended (Box 32.2) to better characterize
each individual patient.2 Depending on their stratification, these
patients may have different presentations and prognoses. Eisenmenger syndrome, for example, in which the shunt is now right
to left due to high right-sided pressures, can have more dramatic
findings and complications (cyanosis, erythrocytosis, hemoptysis,
cerebrovascular accidents, brain abscesses, and so on) than other
forms. Despite these factors, patients with Eisenmenger syndrome
have improved survival compared to untreated idiopathic PAH.62
Although the reason for this is unclear, RV adaptation since
birth and the possible pressure relief from the right-to-left shunt
in relation to cardiovascular hemodynamics are mechanisms
thought to affect survival.63 On the other hand, the worst survival
in CHD-PAH has been noted in post-CHD repair or PAH patients
with small, coincidental defects.64 Epidemiologic data are not
robust, mostly due to their retrospective nature and the lack of
uniformity regarding PAH definition or diagnosis in CHD
patients. A European survey noted that as many as 28% of CHD
adult patients may have pulmonary hypertension,65 although a
more conservative estimate may be closer to 6%.66 Based on data
extrapolated from international registries, CHD-PAH prevalence
likely ranges between 1.7 and 12 cases per million adults.
7,14
It
is not entirely clear why some patients with CHD will develop
PAH compared to others, but the suspected explanation relates
to increased blood flow through the pulmonary vascular system.
The latter, a direct result from a systemic-to-pulmonary shunt,
PAH Associated With Prevalent
Systemic-to-Pulmonary Shunts
This category includes moderate to large defects, in which PVR is mildly to
moderately increased, systemic-to-pulmonary shunting is still prevalent, and
cyanosis at rest is not a feature. They are divided into correctable (surgically
or with intravascular percutaneous procedure) and noncorrectable.
3.
PAH With Small/Coincidental Defects
This category includes PAH with significant PVR elevation in the presence of
small cardiac defects (usually ventricular septal defects <
defects <2 cm of effective diameter as assessed by echocardiography), which
themselves do not account for the development of the PVR elevation. The
clinical picture is very similar to idiopathic PAH and closing the defects is
contraindicated.
4.
PAH After Defect Correction
This category includes persisting PAH after congenital heart disease repair,
either immediately after correction or developing within months to years after
correction. This is in the absence of any significant postoperative hemodynamic
lesions.
Modified from Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS
Guidelines for the diagnosis and treatment of pulmonary
hypertension: The Joint Task Force for the Diagnosis and Treatment
of Pulmonary Hypertension of the European Society of Cardiology
(ESC) and the European Respiratory Society (ERS): Endorsed by:
Association for European Paediatric and Congenital Cardiology
(AEPC), International Society for Heart and Lung Transplantation
(ISHLT). Eur Heart J 2016;37:67-119.
a
Size applies to adult patients.
PAH, Pulmonary arterial hypertension; PVR, pulmonary vascular
resistance.
leads to increased pressures, endothelial dysfunction, vascular
remodeling, and eventual pulmonary obstructive arteriopathy
as seen in other forms of PAH. The subsequent PVR elevation
results in eventual shunt reversal (pulmonary-to-systemic;
b
a
1 cm and atrial septal
CHAPTER 32 Pulmonary Hypertension 333
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Eisenmenger syndrome) once pulmonary artery pressures start
exceeding systemic pressures.67 The presence of PAH has a
documented negative impact on CHD patient outcomes68 and
there should be a high level of suspicion for PAH development
and for screening of the disease in this population.
4
HIV-associated PAH (HIV-PAH) has a relatively low prevalence
of approximately 0.45%69 and does not seem to have changed
significantly despite the increased use of highly active antiretroviral
therapy (HAART).70 Nevertheless, the incidence of PAH in patients
with HIV may have decreased since the advent of HAART, with
some studies suggesting that it may have beneficial effects on
pulmonary hemodynamics over time.
71,72
Therefore, the stable
prevalence is likely a function of the overall increased survival
of HIV-infected patients. Of note, these patients may also present
with other comorbidities, such as drug or toxin exposure
73,74
or
liver disease, which can also predispose to PH, making determining
disease etiology less straightforward. Although the pathogenesis
of HIV-PAH is unclear, the resulting pathology is similar to what
is seen in idiopathic PAH. There is no evidence that HIV infects
pulmonary endothelial cells or that viral proteins are found in
the pulmonary vasculature of HIV-PAH patients. Prevailing
pathogenetic theories include an indirect role of the virus through
inflammatory or tissue growth pathways and/or a possible genetic
predisposition being unmasked by the virus.
72
Approximately 4% to 6% of patients with portal hypertension
will develop PAH (portopulmonary hypertension [PoPH]).
75,76
It is mostly related to the presence of portal hypertension regardless of the presence of cirrhosis, the level of hepatic impairment,
and the type of liver disease. Although clinically very similar to
other forms of PAH, the pathogenesis of PoPH is not well defined.
High cardiac output and elevated blood flow through the pulmonary vasculature noted in liver disease and portal hypertension
are thought to play a significant role in the development of the
disease, with PoPH patients having higher cardiac index (CI)
and lower PVR than idiopathic PAH patients.
8,77
Survival of
patients with PoPH is similar or even worse than those with
idiopathic PAH,
7,8
and the presence of significant PoPH (in
contrast to mild PoPH with normal PVR) is a major risk factor
for liver transplantation.
78
Schistosomiasis-associated PAH (Sch-PH) is the most common
form of PAH worldwide but is rare in the United States and
Europe.79 This is owing to the very large number of Schistosomainfected individuals found in endemic areas (Sub-Saharan Africa,
South America, the Caribbean, the Middle East, and parts of
Asia).80 One of the challenges of Sch-PH is the lack of a widely
recognized disease definition, although it is most commonly
defined as the presence of PAH in conjunction with active
Schistosoma infection or prior infection/exposure and evidence
of hepatosplenic schistosomiasis, a chronic form of the disease.81
For those reasons and the variable definitions used for PAH in
prior studies,
82,83
the prevalence of Sch-PH is estimated to be
between 8% and 25% of patients with chronic hepatosplenic
schistosomiasis. The latter represents approximately 10% to 25%
of the estimated 20 million people worldwide with chronic
schistosomiasis.79 Sch-PH is now thought to be a reactive
arteriopathy in response to parasitic granulomas with pathologic
changes similar to idiopathic PAH.
Management. In the last 20 years, the knowledge surrounding
PAH management and the available pharmacotherapies have
increased significantly. Initial registries showed a 1- and 5-year
survival of 68% and 34%, respectively, in incident idiopathic
PAH.84 Almost a decade later, although similar survival can be
seen in developing countries,85 developed countries report survival
for all PAH between 79% and 93% for 1 year and 48% and 68%
for 5 years.
10,86–90
Although these changes can be partly attributed
to increased awareness and recognition of the disease at an earlier
stage, inclusion of prevalent and incident cases, analyzing all
forms of PAH, and a possibly shifting disease phenotype (i.e.,
older population),41 some can also be attributed to the advent
of new therapies. The wealth of data derived from multiple
registries has also resulted in several prognostic equations or
calculators for patient risk stratification
validated in subsequent studies.
92–94
10,84,86,91
that have been
Overall, the management
of PAH can be divided into general measures, supportive therapies,
specific PAH-targeted drug treatments and, eventually, lung
transplantation in cases of end-stage disease or atrial septostomy
when the latter is not available.
2,95
General measures are mostly related to recommendations on
basic medical interventions as well as physical and daily living
activities. These include pregnancy avoidance in female PAH
patients, as pregnancy of child-bearing age can result in significant
morbidity and mortality,
ing some level of physical activity. This can be accomplished in
96,97
psychosocial support, and maintain-
the form of cardiopulmonary rehabilitation, which can be
beneficial in PAH patients.
98,99
Other general measures include
medication compliance, infection avoidance and prevention,
hypoxia avoidance, and genetic counseling. Despite the paucity
of evidence regarding their efficacy, these are still recommended
for PAH patient management.
2
Supportive therapies are also based on limited clinical evidence.
Anticoagulation is recommended for idiopathic PAH, heritable
PAH, and anorexigen-associated PAH based on retrospective data
indicating potentially favorable outcomes.
recent registry data
101,102
are less convincing or even conflicting
12,100
On the other hand,
regarding their efficacy. Diuretics have a clear role in the management of PAH, especially in the setting of decompensated RV failure
and volume overload. Although studies are lacking, there is a
symptomatic benefit that has been empirically documented. The
use of oxygen therapy in hypoxic patients attempts to mitigate
hypoxic pulmonary vasoconstriction and comes from studies in
chronic obstructive pulmonary disease (COPD).
103
The use of
digoxin as a positive inotrope for the dysfunctional RV, and managing anemia and iron deficiency (which are common in patients
with PAH) are also therapies that lack long-term evidence.
PAH pharmacotherapy is generally based on inhibiting
proliferation and inducing vasodilation, but there seem to be
other beneficial effects of these specific medications that have
not been clearly defined. Calcium-channel blockers (CCBs) have
mostly a vasodilatory effect and were the cornerstone of PAH
medical therapy prior to the advent of PAH-specific medications.
It is now recognized that they are effective in only a small percentage of patients with idiopathic PAH that are acutely vasoreac-
12,13
tive.
Efficient doses are on the higher end of the spectrum;
patients need to be closely monitored for side effects as well as
334 PART IV Noncoronary Diseases: Diagnosis and Management
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for inadequate response or eventual deterioration, in which case
additional PAH-specific therapy should be implemented. In
nonvasoreactive patients, CCB treatment is not recommended
as there may be side effects without any benefit.
Unlike CCBs, PAH-specific medications work through one
of three distinct pathways, including the prostacyclin, endothelin,
and NO/cyclic-guanosine monophosphate (cGMP) pathways.
These are all thought to work in parallel via pulmonary artery
endothelial and smooth muscle cells to regulate vascular contractility and remodeling.
The prostacyclin pathway has both vasodilator and antiproliferative effects
synthase expression
105
; studies show both a decrease in prostacyclin
106
and endogenous prostacyclin25 in PAH.
Prostacyclin (prostaglandin I2) is produced from arachidonic
acid within the pulmonary artery (PA) endothelial cells and
binds to prostacyclin receptors on the PA smooth muscle cell
wall. Through second messengers, it induces cyclic adenosine
monophosphate production, which leads to smooth muscle cell
relaxation and growth inhibition.
inhibitor of platelet aggregation.
have similar effects and is available for therapeutic purposes.
Epoprostenol requires continuous intravenous (IV) infusion
through a tunneled central venous catheter and has a half-life
of 3 to 5 minutes. In unblinded randomized controlled trials in
various forms of PAH,
109–111
capacity, hemodynamics, and mortality.
epoprostenol analogue that can be administered subcutaneously
and intravenously and has an approximate plasma half-life of
1.5 and 0.5 hours, respectively. The subcutaneous form has been
shown to improve symptoms, exercise capacity, and hemodynamics in a randomized controlled trial.
pharmacokinetics
in both shorter-term
113
and has been shown to be safe and effective
114
and longer-term
tional studies. One randomized controlled trial on IV treprostinil
was stopped early owing to safety reasons and the data are
considered unreliable.
116
Treprostinil is also available in inhaled
form, which has been shown to improve 6-minute walk distance
and quality of life when added to PAH patients on background
therapy.
117
The oral form of treprostinil showed a 6-minute walk
distance improvement in PAH patients when used as a monotherapy,
118
but this improvement failed to reach statistical significance in patients on background PAH therapy.
mostly used as an inhaled formulation, has shown improvements
in exercise capacity, symptoms, pulmonary vascular resistance,
and reduction in clinical events as a PAH monotherapy
improvement in exercise capacity when added on to background
PAH therapy.
122
Finally, selexipag is an oral prostacyclin receptor
agonist that has been shown to reduce the risk of a composite
morbidity and mortality outcome measure in a very large, eventdriven randomized controlled trial.
analogues and prostanoids are similar, including nausea, diarrhea,
headaches, extremity and jaw pain, and flushing.
Activation of the endothelin system includes production of
endothelin-1 from pre-proendothelin and proendothelin sequentially within the PA endothelial cells. Once released, it can bind
with endothelin receptors (ETA and ETB) located on the PA smooth
muscle cell wall. Although ETA is thought to cause sustained
vasoconstriction and vascular smooth muscle cell proliferation
104
107
Of note, it also acts as an
108
Exogenous prostacyclin can
it improved symptoms, exercise
110
Treprostinil is an
112
Its IV form has similar
115
open label, observa-
119,120
Iloprost,
121
and
123
Side effects of prostacyclin
and ETB is thought to induce endothelin clearance as well as to
increase NO and prostacyclin production from endothelial cells,
the end result of their stimulation appears to be pro-proliferative,
pro-fibrotic, and pro-inflammatory.
107
Despite the increasing
evidence that endothelin and activation of its pathway plays an
important role in PAH pathogenesis,
124,125
there are still elements
of its pathobiology that have not been elucidated to date. Currently
there are three endothelin receptor antagonists (ERAs) available
in the United States that block one or both endothelin receptors
and therefore have vasodilatory and antiproliferative effects.
Ambrisentan selectively antagonizes endothelin receptor A and
has shown improvement in exercise capacity, symptoms, hemodynamics, and time to clinical worsening in PAH subgroups in
two large randomized controlled trials.
126,127
Bosentan antagonizes
both endothelin receptors (A and B) and has shown similar
improvements in outcomes in multiple randomized controlled
128–131
trials.
Macitentan also antagonizes both endothelin A and
B receptors and in a very large, event-driven, randomized clinical
trial showed reduction in the composite morbidity and mortality
endpoint, as well as increased exercise capacity.
132
Of note, all
of these medications have shown efficacy with or without
additional PAH therapy and have relatively similar side effect
profiles with some variability in the rate of peripheral edema,
abnormal liver function tests, and anemia.
The NO/cGMP pathway is based on cGMP-mediated
vasodilation and antiproliferation. Intrinsically, endothelial NO
synthase (eNOS) produces NO by catalyzing L-arginine oxidation
to L-citrulline within the endothelial cell of the PA. NO induces
smooth muscle cell relaxation, through soluble guanylate cyclase
(sGC) stimulation and cGMP production. Since continuous
administration of NO is technically difficult, augmentation of
the NO effect can be accomplished by either inhibition of cGMP
degradation (phosphodiesterase 5 [PDE5] inhibitors) or induction
of cGMP synthesis (sGC stimulation with riociguat). Sildenafil
is a selective PDE5 inhibitor that has been shown to improve a
combination of exercise capacity, symptoms, hemodynamics,
and time to clinical worsening in multiple randomized clinical
133–135
trials
as monotherapy or as part of combination PAH therapy.
Similar results were noted in a randomized controlled clinical
trial with tadalafil
trial with vardenafil,
136
and a smaller randomized controlled clinical
137
although the latter is not currently commercially available in the United States. Mild side effects have
been reported with PDE5 inhibitors, mostly related to headaches
or flushing. Riociguat is an sGC stimulator that increases cGMP
and was shown to improve exercise capacity, hemodynamics,
FC, and time to clinical worsening in a large randomized clinical
138
Hypotension, syncope, and hemoptysis were its most
trial.
worrisome side effects; its use in combination with PDE5 inhibitors is contraindicated because of the additive effect of the two
drugs on lowering systemic blood pressure.
Treatment with PAH-specific medications is recommended
for patients with FC II or worse symptoms. There is now increasing evidence that combination therapy may be better at improving
outcomes in patients with PAH when compared with monotherapy.
122,134,136,139
This concept is based on the presence of several
parallel pathways at the level of the pulmonary artery smooth
muscle cell that can be individually targeted by different medications. Combination therapy can be provided either initially or
CHAPTER 32 Pulmonary Hypertension 335
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sequentially and is usually goal oriented. This includes specific
treatment targets, such as achieving WHO FC II or I, improvement
of 6-minute walk distance to greater than 400 meters, normalization of RV function on echocardiography and of cardiac index
on right heart catheterization, and normalization of NT-proBNP
plasma levels.
140
If these targets are not met, therapy is generally
augmented, whereas improvement in these parameters can be
an indicator of better prognosis.
11
A comprehensive description of these treatment strategies is
beyond the scope of this chapter; we encourage consulting the
most recent guidelines.
2,95
In addition to using FC as a guide for
pharmacotherapy, these guidelines promote patient stratification
in low-, moderate-, or high-risk groups based on estimated 1-year
mortalities of less than 5%, 5% to 10%, and greater than 10%,
respectively (Table 32.4).2 In summary, initial monotherapy or
a combination of oral therapies, including an ERA and a PDE5
inhibitor or a sGC stimulator, are recommended for WHO FC II
or low-risk patients. A similar combination or prostacyclin-based
treatment with or without an oral agent is usually recommended
for FC III or moderate-risk patients. Parenteral prostacyclin-based
treatment, with possible additional oral therapies, is recommended
for FC IV or high-risk patients. In the case of inadequate clinical
response, sequential add-on therapy is recommended, including
double or triple combination therapy.
2
When maximal medical therapy fails or disease continues to
progress, lung transplantation is the main therapeutic option.
141
Balloon atrial septostomy can be considered as a bridging therapy
to transplant or as a palliative procedure in cases of FC IV
patients with syncope and refractory RV failure.
142
Nevertheless,
balloon atrial septostomy should be avoided in severe hypoxia
or in patients with significant right atrial pressure elevation.
Extracorporeal membrane oxygenation has also been used for
bridging to transplant in end-stage lung disease, as well as in
cases of severe RV failure and advanced PAH.
143
Management of the Critically Ill Patient With Pulmonary
Arterial Hypertension. In case of critical illness from severe
right heart failure or another underlying disease, patients with
PAH may require intensive care unit (ICU) admission. In these
instances, treatment is focused on reduction of RV preload
and afterload, augmentation of cardiac output, maintenance
of systemic blood pressure, and treating any underlying disease
process if present.
Evaluation of end-organ function through surrogate markers
is recommended in addition to standard vital sign monitoring.
In general, signs of poor cardiac output (low mixed or central
venous oxygen saturation) and poor tissue (elevated lactate) or
kidney (low urine output) perfusion are all poor prognostic
signs and indicators of RV failure.
Patients can present with low systemic blood pressure, acute
kidney injury, volume overload, worse hypoxia together with
worse shortness of breath, lower extremity edema, and/or
abdominal distention. Aggressive diuresis to decrease preload to
the RV is key in managing these patients, often with intravenous
diuretics as decreased gastrointestinal system perfusion can lead
to nausea and vomiting or poor absorption of oral medications.
In cases of low systemic blood pressure, vasopressor support
may be needed to maintain adequate organ and coronary perfusion pressures and avoid cardiovascular collapse. Positive inotropes
(dobutamine, dopamine, milrinone, and the like) may also be
used to increase cardiac output and help with tissue and kidney
perfusion. Afterload reduction of the RV may be achieved with
TABLE 32.4 Pulmonary Arterial Hypertension Patient Risk Stratification and Assessment
Determinants of Prognosis
(Estimated 1-Year Mortality) Low Risk (<5%) Moderate Risk (5%–10%) High Risk (>10%)
Clinical signs of right heart failure Absent Absent Present
Progression of symptoms No Slow Rapid
Syncope No Occasional Repeated
WHO functional class I, II III IV
6-minute walk distance >
Cardiopulmonary exercise testing Peak VO2 >15 mL/min/kg (>65%
NT-proBNP plasma levels BNP <
Imaging RA area <18 cm
Hemodynamics RAP <
Modified from Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension:
The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the
European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society
for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119.
Most variables and cut-off values are based on expert opinion.
BNP, β-natriuretic peptide; CI, cardiac index; NT-proBNP, NT terminal pro-β natriuretic peptide; RA, right atrium; RAP, right atrial pressure; SvO2,
mixed venous oxygen saturation; VE/VCO2, ventilatory equivalents for carbon dioxide; VO2, oxygen consumption; WHO, World Health
Organization.
440 min 165–440 min <165 min
11–15 mL/min/kg (35%–65%
predicted)
VE/VCO
slope <36
2
50 ng/L
NT-proBNP <300 ng/L
No pericardial effusion
8 mm Hg
CI ≥2.5 L/min/m
SvO2 >65%
2
2
Peak VO
2
predicted)
VE/VCO
slope 36–44.9
2
BNP 50–300 ng/L
NT-proBNP 300–1400 ng/L
RA area 18–26 cm
No or minimal pericardial effusion
RAP 8–14 mm Hg
CI 2.0–2.4 L/min/m
SvO2 60%–65%
2
2
Peak VO
predicted)
VE/VCO
BNP > 300 ng/L
NT-proBNP >1400 ng/L
RA area >
Pericardial effusion
RAP >
CI < 2.0 L/min/m
SvO2 <60%
<11 mL/min/kg (<35%
2
slope ≥ 45
2
2
26 cm
14 mm Hg
2
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