CLASSIFICATION AND PROGNOSIS OF PULMONARY

HYPERTENSION IN ADULTS

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Literature review current through: Dec 2017. | This topic last updated: Oct 27, 2017.

INTRODUCTION — Pulmonary hypertension (PH) is defined as an elevated mean arterial

pressure ≥25 mmHg at rest . PH has several etiologies and can be a progressive, fatal
disease, if untreated.

The classification and prognosis of PH are reviewed here. The epidemiology, pathogenesis,
clinical features, diagnostic evaluation, and treatment of PH are discussed separately.

CLASSIFICATION — The World Health Organization (WHO) has classified PH based

upon etiology into the five groups listed below :

●Group 1 – Pulmonary arterial hypertension (PAH)

●Group 2 – PH due to left heart disease

●Group 3 – PH due to chronic lung disease and/or hypoxemia

●Group 4 – PH due to chronic thromboembolic pulmonary

hypertension

●Group 5 – PH due to unclear multifactorial mechanisms

PAH refers to group 1 PH. PH refers to any of group 2 through group 5 PH, and is also used
when referring to all five groups collectively.

PH can also be classified as pre- or post-capillary PH. Pre-capillary PH is due to a primary

elevation of pressure in the pulmonary arterial system alone (eg, PAH) while post-capillary
PH is that due to elevations of pressure in the pulmonary venous and pulmonary capillary
systems (pulmonary venous hypertension; eg, group 2) . In practice, some patients have
mixed pre-and post-capillary features.

Group 1 pulmonary arterial hypertension (PAH) — Patients in this class have PAH due to
the following conditions:

●Idiopathic and heritable PAH – PAH due to an unknown mechanism

(idiopathic PAH [IPAH]) and heritable genetic defects (heritable
PAH [HPAH]) are often clinically indistinguishable.

●Drugs and toxins – Several drugs are either definite or possible risk factors for the
development of PAH.
 ●Connective tissue diseases – Systemic sclerosis (also called
scleroderma) and several other connective tissue diseases (eg,
rheumatoid arthritis, systemic lupus erythematosus, Raynaud disease,
mixed connective tissue disease) can be associated with PAH.

●Human immunodeficiency virus (HIV) – PAH occurs in a small

percentage of HIV-infected patients.

●Portal hypertension – PAH associated with portal hypertension

(most often due to chronic liver disease) is referred to as portopulmonary
hypertension.

●Congenital heart disease – This class includes patients with PH due

to left to right intracardiac or extracardiac shunts (atrial,
ventricular, and great artery defects) including those who develop PAH
following closure. Patients with PAH due to congenital inflow/outflow tract obstruction
and congenital cardiomyopathies are not included in this group. Other forms of PAH
due to congenital heart disease (eg, corrected transposition of the great arteries, and
those with atrial redirection surgery) cannot be classified underscoring the need for
assessment of patients with all forms of congenital heart disease and PAH/PH at a center
with the expertise in PH.

●Schistosomiasis – PAH can develop in patients infected with

schistosomiasis species, particularly those with hepatosplenic
involvement.

Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis,

and persistent pulmonary hypertension of the newborn (PPHN) are designated as separate
categories, 1' and 1'' respectively, because these entities have more differences than
similarities with PAH 2.

●PVOD (Group 1') – Unlike PAH which involves the small muscular
pulmonary arterioles, PVOD is characterized by extensive diffuse
occlusion of the pulmonary veins resulting in tortuous dilation of the pulmonary
capillaries. The resulting appearance mimics that of pulmonary capillary
hemangiomatosis. PVOD is a rare cause of PH and is discussed separately.

●PPHN (Group 1'') – PPHN due to abnormal pulmonary vasculature

development in term or late preterm infants is discussed
separately.

Group 2 PH (left heart disease) — PH due to left heart disease (LHD) is characterized by
PH associated with an elevated left atrial pressure (eg, mean LA pressure >14 mmHg)
resulting in pulmonary venous hypertension (ie, post-capillary PH).

●Etiologies – Common causes of left atrial hypertension include

left ventricular systolic or diastolic dysfunction, and mitral and
aortic valve disease [3]. Less common causes include restrictive
cardiomyopathy, constrictive pericarditis, left atrial myxoma, congenital or
acquired inflow/outflow tract obstruction, and congenital cardiomyopathies.

While PH due to left ventricular systolic heart failure is evident, heart failure with
preserved ejection fraction (HFpEF; diastolic dysfunction) is a growing cause of WHO
group 2 PH [3]. Patients with HFpEF are characterized by chronic elevation of left atrial
and pulmonary venous pressure. The pulmonary artery pressure increases in proportion
to the elevated pulmonary venous pressure (passive elevation; post-capillary PH). If the
pressure remains elevated, over time the small pulmonary arteries and arterioles can
remodel resulting in an occlusive vasculopathy similar to that seen in patients with
WHO group 1 PAH (post-capillary and pre-capillary PH).

Patients with obesity can also develop an extreme form of diastolic dysfunction
sometimes referred to as an "obesity-associated restrictive cardiomyopathy" . It is
characterized by fatty infiltration of cardiac myocytes, restrictive physiology, and
marked elevation in left and right heart filling pressures. These patients can also
progress to severe pulmonary hypertension secondary to an occlusive vasculopathy of
the small pulmonary arteries and arterioles [6].

●Pathogenesis – Multiple factors contribute to LHD-PH, including

chronic pulmonary venous congestion, recurrent transient
hypoxemia, and sleep-disordered breathing [7]. PH initially develops in
those with left atrial hypertension due to a proportional increase in pulmonary artery
systolic pressure (post-capillary PH) that is required to maintain an adequate driving
force across the pulmonary vasculature. Ultimately, the magnitude of PH that results
from any given level of left atrial hypertension varies greatly due to individual
differences in the vasoconstrictive and vascular remodeling responses such that patients
may have elements of both post-capillary and pre-capillary PH.

●Epidemiology – The true prevalence of LHD-PH is unknown. Estimates

have been hampered by inaccurate methodology in measurement and by heterogeneity
in the study populations, such that reported rates range from 25 to 100 percent .

•Patients with left ventricular systolic dysfunction can develop PH . The exact
incidence varies with the population studied. As an example, in a study of 108
patients with dilated cardiomyopathy, 26 percent had an estimated pulmonary
artery systolic pressure (PASP) above 40 mmHg, measured by echocardiography
[9]. This was associated with a greater likelihood of death or hospitalizations (89
versus 32 percent), compared with those with a PASP ≤40 mmHg.

•Left ventricular diastolic dysfunction is also associated with PH. As an example,

in an observational study of 244 patients with HFpEF, a high estimated PASP
predicted mortality (unadjusted hazard ratio 1.3 per 10 mmHg increment of PASP)
[12].
 •The importance of mitral regurgitation as a cause of PH was shown in a study of
41 patients with isolated severe mitral regurgitation [14]. PH was identified in 76
percent of patients, of which 17 percent had a PASP >70 mmHg on right heart
catheterization.

Group 3 PH (lung disease) — PH due to lung diseases and/or hypoxemia is discussed

separately.

Group 4 PH (thromboembolic disease) — Chronic thromboembolic pulmonary

hypertension (CTEPH) is discussed separately.

Presentation — Patients with chronic thromboembolic pulmonary

hypertension (CTEPH) usually present with progressive dyspnea and exercise intolerance
[22]. Occasionally, a patient will have waited to seek medical attention despite these
symptoms and will report additional symptoms and signs related to right ventricular
dysfunction, such as peripheral edema, exertional chest pain, syncope, or near-syncope.

History — All patients with CTEPH have dyspnea. The dyspnea initially occurs during
exertion only, but then progresses to occur at rest and becomes more severe [23]. Dyspnea
and exercise intolerance are usually more troubling to patients who are active and, therefore,
such patients tend to be evaluated earlier than patients who live a sedentary lifestyle.

Many patients provide a history consistent with an acute venous thromboembolic event (eg,
pleuritic chest pain, lower extremity discomfort, or a prolonged atypical pneumonia) months
to years prior to the onset of the dyspnea, although a documented history of venous
thromboembolism may be absent in as many as 38 percent of patients with surgically-
accessible CTEPH [24]. Alternatively, they may describe a hospitalization or surgical
procedure from which they never fully recovered. The absence of a diagnosis of venous
thromboembolism is not surprising since venous thrombosis and pulmonary embolism are
frequently overlooked in the population at large [25]. The absence of a documented history
of acute venous thromboembolism should not dissuade a clinician from considering this
diagnosis in patients with unexplained dyspnea.

As the CTEPH progresses, patients may begin to report symptoms or signs related to
progressive pulmonary hypertension complicated by right ventricular dysfunction. This may
include lower extremity edema, exertional chest pain, near-syncope, or syncope [23].

Physical examination — Findings on physical examination may be subtle early in the

course of CTEPH. As an example, the only abnormalities may be narrowing of the aortic-
pulmonic splitting of the second heart sound or subtle accentuation of the pulmonic
component.

More obvious physical findings become apparent once significant right ventricular
hypertrophy or overt right ventricular failure develops. Findings include a right ventricular lift,
jugular venous distension, prominent A and V wave venous pulsations, fixed splitting of the
second heart sound, a right ventricular S3, murmurs of tricuspid regurgitation or pulmonic
insufficiency, hepatomegaly, ascites, and peripheral edema. The peripheral edema may be a
result of chronic lower extremity venous outflow obstruction related to the venous
thromboembolic disease or right ventricular failure related to the progressive pulmonary
hypertension.

A unique physical finding in some patients with CTEPH is the presence of flow murmurs over
the lung fields. These subtle bruits appear to originate from turbulent flow through partially
obstructed or recanalized pulmonary arteries. They are high pitched and blowing in quality,
heard over the lung fields rather than the precordium, accentuated during inspiration, and
frequently heard only during periods of breath-holding. They have not been described in
patients with other types of pulmonary hypertension.

DIAGNOSTIC EVALUATION

Initial evaluation of symptoms — Chronic thromboembolic pulmonary hypertension

(CTEPH) is rarely suspected when a patient presents with progressive dyspnea and
exercise intolerance and, therefore, diagnosis is typically delayed [22,26,27]. More often,
common conditions are suspected (eg, coronary artery disease, cardiomyopathy, chronic
obstructive airways disease, asthma, interstitial lung disease, or deconditioning) and the
patient is evaluated with echocardiography, pulmonary function testing, and/orchest
radiography. In patients with CTEPH, these studies often suggest pulmonary hypertension:

●Echocardiography – The tricuspid regurgitant velocity and estimated systolic

pulmonary artery pressure are usually increased. Right atrial enlargement and right
ventricular hypertrophy with reduced systolic function may be apparent . There may
also be leftward displacement of the septum, which can impair left ventricular filling and
performance.

●Pulmonary function tests – Most patients have a reduction in the single breath
diffusing capacity for carbon monoxide (DLCO), which is out of proportion to any
abnormalities in spirometry. A mild restrictive or obstructive defect may be present,
although spirometry is often normal. The restrictive defect may be related to
parenchymal scarring [29], while the obstructive defect may be due to mucosal
hyperemia caused by bronchial arterial collateral circulation. For those patients who
have an arterial blood gas performed as part of their pulmonary function tests, an
increased alveolar-arterial (A-a) oxygen gradient and a decline in the arterial oxygen
tension (PaO2) with exercise are typical. The resting PaO2 may be normal.

●Chest radiography – Chest radiography may demonstrate abnormalities related to

either pulmonary embolic disease or pulmonary hypertension. Pulmonary embolic
disease may cause areas of hypoperfusion or hyperperfusion, as well as evidence of
old unilateral or bilateral pleural disease. Pulmonary hypertension can cause
enlargement of both main pulmonary arteries, asymmetry in the size of the central
pulmonary arteries, right atrial enlargement, or right ventricular enlargement. Right
ventricular enlargement is suggested by encroachment into the normally empty
retrosternal space on a lateral radiograph.
Group 5 PH (multifactorial) — PH with unclear multifactorial mechanisms include patients
with PH caused by chronic hemolytic anemia (eg, sickle cell disease [SCD], beta-
thalassemia, or spherocytosis), myeloproliferative disorders, systemic disorders (eg,
sarcoidosis, lymphangioleiomyomatosis, pulmonary Langerhans histiocytosis X), metabolic
disorders (eg, glycogen storage disease), chronic kidney disease, or miscellaneous causes. PH
is, in general, an uncommon manifestation of these disorders. Among them, SCD is the best
studied. The most frequent cause of PH in SCD is left-sided heart disease but some patients
also have disease that mimics group 1 PAH and group 4 PH, highlighting the multifactorial
nature of PH in this group.

NATURAL HISTORY AND PROGNOSIS — Pulmonary hypertension (PH) is

progressive, and sometimes fatal, if untreated. National surveillance data reported that
mortality rates from PH have increased from 5.2 to 5.4 per 100,000 over a 22 year period
(1980 to 2002), with the greatest increase reported in African-Americans and women.
Mortality rates were reported as 7.3 per 100,000 in African-Americans, 5.3 per 100,000 in
Caucasians, 5.5 per 100,000 in women and 5.4 per 100,000 in men. These data may reflect
increased physician awareness and changes in diagnosing and reporting PH over the time
period of the study. In the same study, the most common cause of death was chronic lower
respiratory disease from 1980 until 1999. Although PH itself was the most common cause of
death after 1999, the experience of the authors is that reasons for death in this population are
highly variable.

The prognosis of PH is highly variable and depends upon the etiology and severity of PH.

●Etiology of PH – In general, in the absence of therapy, those with

group 1 PAH have worse survival than groups 2 through 5.
However, with therapy, patients with chronic thromboembolic PH
(CTEPH; group 4), particularly surgically correctable CTEPH tend to have the best
survival. As an example, in the Giessen Pulmonary Hypertension Registry, patients with
CTEPH had the best one- three- and five-year survival rates of 89, 77, and 67 percent,
respectively . Compared with those who had PAH, those with chronic lung disease
associated PH (group 3) had worse survival at one year (80 versus 88 percent), three
years (52 versus 72 percent), and five years (38 versus 59 percent). Patients with group 2
PH had similar survival rates to those with PAH.

●Severity of PH – In general, severe PH (eg, mean pulmonary arterial

pressure ≥35 mmHg), and/ or evidence of right heart failure have a poor prognosis.

Group 1 PAH — The natural history and prognosis of group 1 pulmonary arterial
hypertension (PAH) is better studied than that of groups 2 through 5.

Prognosis without therapy — Without therapy, the prognosis of patients in group 1 PAH is
poor. Data from the Registry to Evaluate Early and Long-term PAH Disease Management
(REVEAL registry) reported that, from the time of diagnostic right heart catheterization,
patients with PAH had one-year survival rate of 85 percent, three-year survival of 68 percent,
five-year survival of 57 percent, and seven-year survival rate of 49 percent [17].
The one-year survival of patients with newly diagnosed group 1 PAH may be predicted using
a risk score derived from REVEAL registry data. The risk score is the sum of points derived
from clinical data including group 1 subgroup, demographics, and comorbidities; functional
class, vital signs, six-minute walk test, and brain natriuretic peptide level; echocardiogram,
pulmonary function tests, and right heart catheterization findings. Data were prospectively
collected from 504 patients with a mean six-minute walk distance of 308 m, 62 percent of
whom were classified as World Health Organization (WHO) functional class III . One-year
survival correlated with risk score: 1 to 7 (95 percent), 8 (92 percent), 9 (89 percent), 10 to 11
(72 percent), and ≥12 (66 percent). This risk score calculates survival only and should
not be used to make decisions for treatment. This and other models (eg, The French
Pulmonary Hypertension Network [FPHN] registry) require prospective validation before
they can be routinely used in clinical practice .

Prognosis was reported using data derived from the COMPERA (Comparative, Prospective
Registry of Newly Initiated Therapies for Pulmonary hypertension) database . Patients were
risk stratified using a model that incorporated World Health Organization functional class, six
minute walk distance, brain natriuretic peptide levels, right atrial pressure, cardiac index, and
mixed venous oxygen saturation. Mortality rates in patients at one year after diagnosis was 3
percent for low risk patients, 10 percent for intermediate-risk patients and 21 percent for high
risk patients .

Among the etiologies of group 1 PAH, compared to idiopathic PAH (IPAH), symptomatic
patients with PAH associated with another disease (eg, liver disease, systemic sclerosis)
generally have a worse prognosis; an exception is patients with PAH due to Eisenmenger's
syndrome, who have a better prognosis than patients with IPAH [21-23]. The prognosis of
patients with disease-associated PAH, is discussed in the following sections:

●Systemic sclerosis

●Human immunodeficiency virus

●Portopulmonary hypertension

●Congenital heart disease

●Schistosomiasis

●Pulmonary venoocclusive disease

●Pulmonary hypertension of the newborn

Effect of treatment — Treatment of PAH consistently improves hemodynamic measures,

WHO functional class, and the six-minute walk test distance . It also appears to improve
survival. A meta-analysis of 21 randomized trials (3140 patients) found that therapy with a
prostanoid, an endothelin receptor antagonist, or a phosphodiesterase-5 inhibitor improves
mortality compared to controls (1.5 versus 3.8 percent, risk reduction 0.57, 95% CI 0.35-
0.92. However, the average duration of treatment was 14 weeks. Further details regarding the
effect of PAH-directed therapy on survival are provided separately.
The same survival benefits may not apply to all patient subgroups within group 1 PAH. For
example, although survival from systemic sclerosis-associated PAH has improved in the era
of PAH-directed therapy, it is worse than that for IPAH, and the mortality remains high,
particularly when PH is associated with coexistent interstitial lung disease.

Prognostic factors — Data from prospective trials have described factors that portend a poor
prognosis in patients with PAH . While these factors indicate poor prognosis when PAH is
newly diagnosed, some may not be reliable for ongoing assessment of prognosis during
follow-up.

Factors associated with poor prognosis include:

●Age >50 years

●Male gender

●WHO functional class III or IV

●Failure to improve to a lower WHO functional class during treatment

●Indices of right ventricle dysfunction:

•Echocardiographic findings of a pericardial effusion, large right atrial size,

elevated right atrial pressure, or septal shift during diastole

•Poor right ventricular contractile reserve determined by an increase in pulmonary

artery systolic pressure of <30 mmHg with exercise during stress echocardiography

•Low right ventricle fractional area change and oxygen pulse during exercise on
stress echocardiography

•Low right ventricular ejection fraction <25 percent on planar radionuclide

angiography

•Increased N-terminal pro-brain natriuretic peptide level (NT-proBNP)

•Prolonged QRS duration

•Supraventricular arrhythmia (eg, persistent atrial fibrillation or atrial flutter)

●Decreased pulmonary arterial capacitance (ie, the stroke volume divided by the
pulmonary arterial pulse pressure)

●Hypocapnia

●Comorbid conditions (eg, COPD, diabetes)

●PAH associated with connective tissue disease

●Selective serotonin reuptake inhibitors

 ●Low von Willebrand factor levels

●Bone morphogenetic protein receptor type 2 (BMPR2) mutations

Increased age and male gender are frequently cited as factors that are associated with worse
survival . The reason for this is unknown but thought to be due to age- and gender-related
differences in cardiopulmonary hemodynamics . In addition, the worse prognosis in older
patients may reflect the presence of multifactorial disease or the presence of comorbidities
that impact survival.

●A registry in the United Kingdom and Ireland of patients with PAH diagnosed between
2001 and 2009 found that compared to patients less than 50 years of age, individuals
over 50 years had worse survival at one year (90 versus 95 percent), three years (76
versus 91 percent), five years (57 versus 87 percent), and seven years (44 versus 75
percent)

●Data from the REVEAL registry found that, among individuals with PAH who were
older than 60 years, men had a lower two-year survival than women (64 versus 78
percent, hazard ratio 1.67, 95% CI 1.3-2.2) . In contrast, there was no difference in
survival among men and women with PAH who were 60 years or younger (84 versus 86
percent).

Indices of severe PAH including poor functional class and evidence of right heart failure are
poor prognostic signs. As an example, patients with severe PAH or right heart failure die
sooner without treatment (usually within one year) than patients with mild PAH or no right
heart failure. Patients with IPAH and a mean right atrial pressure ≥20 mmHg have a
median survival of approximately one month .

The circulating factors, such as hepatoma-derived growth factor, remain investigational as a

potential biomarker or predictor of prognosis .

Cause of death — The main cause of death in patients with PAH is thought to be right heart
failure with circulatory collapse and superimposed respiratory failure. A similar course of
circulatory collapse can occur when these patients are placed on mechanical ventilation or
undergo anesthesia or conscious sedation. Patients with PAH who experience cardiac arrest
rarely survive. In a retrospective study of 132 patients with PAH who required
cardiopulmonary resuscitation (CPR) for circulatory arrest, CPR was unsuccessful in 80
percent and only 6 percent survived more than 90 days without residual neurologic deficit .

While early studies in the 1990s reported a high prevalence (73 to 84 percent) of death from
circulatory collapse due to right heart failure, analyses done during the era of PAH-specific
therapies report lower rates (44 to 50 percent), suggesting that although right heart failure and
circulatory collapse remains important causes of death in patients with PAH, it may be
declining with evolving trends in therapy. As examples:

●One prospective analysis from a single-center cohort of 84 patients with PAH reported
that 44 percent of deaths were directly due to right heart failure or sudden death. In
another 44 percent, PH contributed to, but was not the direct cause of, death. In 8
 percent, PH played no role in the cause of death, and in 4 percent, the cause of death
could not be determined . Most deaths were in a healthcare environment with the vast
majority on prostanoid therapy (76 percent) and less than half had advance care
directives.

●Another small retrospective case series from a single center cohort reported that death
from right ventricular failure (32 percent) or sudden death (18 percent) occurred in
patients with PAH and a variety of other causes were identified in the remainder .

●In our clinical experience, it is not uncommon to have success treating PAH in patients
with systemic sclerosis (SSc) or liver disease, only to have the patients then die of other
SSc-related complications or progression of their cirrhosis.

A multicenter prospective study is required to establish the true prevalence of conditions that
contribute to death in patients with PAH.

Groups 2 to 5 — The prognosis of other groups with PH likely varies with the prognosis of
the underlying disease, severity of the PH, and response to therapy. These are discussed
separately:

●Patients with PH due to left heart disease (group 2)

●Patients with PH due to lung disease and/or hypoxemia (group 3)

●Chronic thromboembolic pulmonary hypertension (group 4)

●Sickle cell disease (group 5)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines

from selected countries and regions around the world are provided separately.

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SUMMARY AND RECOMMENDATIONS

●Pulmonary hypertension (PH) is defined as an elevated mean arterial pressure ≥25

mmHg at rest.
●The World Health Organization (WHO) classifies PH into five groups . Pulmonary
arterial hypertension (PAH) refers to group 1 PH, while PH refers to any of group 2 PH
through group 5 PH. PH is also used to refer to all five groups collectively. Pre-capillary
PH is due to a primary elevation of pressure in the pulmonary arterial system alone (eg,
PAH) while post-capillary PH is that due to elevations of pressure in the pulmonary
venous and pulmonary capillary systems (pulmonary venous hypertension; eg, group 2
PH)

●Group 1 PAH may be idiopathic; additional causes include PAH due to heritable
genetic defects, drugs and toxins, connective tissue diseases, human immunodeficiency
virus infection, portal hypertension, congenital heart disease, and schistosomiasis. PH
can also be due to left heart disease (group 2), lung disease and/or hypoxemia (group 3),
chronic thromboembolic disease (group 4), and unclear multifactorial mechanisms
(group 5).

●PH is a progressive disease that may be fatal, if untreated. However, the rate of
progression is highly variable and depends upon the type and severity of the PH. In
general, patients with group 1 PAH who are not on therapy and patients with severe PH
have a poor prognosis.

●Survival rates among patients in group 1 PAH have been reported as 85 percent at one
year, 68 percent at three years, 57 percent at five years, and 49 percent at seven years.
PAH-directed therapy may improve mortality. Factors associated with poor prognosis
include age older than 50 years, male gender, functional class III or IV, failure to
improve functional class with therapy, indices of right ventricular failure, connective
tissue disease-associated PAH, and others. Many patients die from circulatory collapse
from right heart failure (44 to 50 percent).

●The prognosis of patients on group 2 through 5 likely varies with the prognosis of the
underlying disease, severity of the PH, and response to therapy.