Recent Advances in Pulmonary Hypertension

Clinical Diagnosis of Pulmonary Hypertension

Jonathan D. Rich, MD; Stuart Rich, MD

T here has been an increased recognition of pulmonary

hypertension (PH) in clinical practice over the past 30
years. It is likely that this rise in PH diagnoses is attribut-
Doppler echocardiography. On the other hand, despite a per-
ceived increased recognition of the disease in recent years, the
time between patient-reported onset of symptoms and a PAH
able to multiple factors, including increased awareness by diagnosis remains considerably delayed.6
clinicians, the routine use of diagnostic tools such as Doppler The NIH registry conducted in the 1980s of incident
echocardiography, and the availability and marketing of the PAH cases demonstrated that patients were predominantly
many PH-specific drugs.1 Although the increased awareness young (mean age of 36 at presentation) and female (1.7:1)
of the disease should be viewed as a favorable development, and had idiopathic, familial, or anorexigen-associated PAH.
the unintended consequences include overdiagnosis, mis- The observed 1-, 3-, and 5-year survival of 67%, 45%, and
classification, and at times indiscriminate use of expensive, 37%, respectively represented the natural history of the dis-
PH-specific drugs. In this review, we address the epidemi- ease untreated, because no therapies for PAH existed at that
ology, prognosis, and updated clinical classification of PH. time.5,7 The patients in the modern PAH registries are older
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We then focus on the diagnostic approach to the patient with (mean age at presentation ranging from 48–53 years old) and
suspected PH with an emphasis placed on highlighting key have better survival rates, but the contemporary cohorts are
pearls for the clinician to consider. Finally, we review an predominated by prevalent cases of PAH, which introduces
evolving conceptual framework of viewing the pulmonary a survivor bias.4,8 The French PAH registry enrolled 674
vasculature and the right ventricle as a single, coupled car- newly and previously diagnosed patients over a 1-year period
diopulmonary unit. commencing in October 2002, with patients treated with the
currently available therapies. The estimated 1- and 3-year
Epidemiology and Prognosis survival rates of the subgroup of patients with IPAH, familial
The exact prevalence of PH in both the United States and the PAH, or anorexigen-associated PAH for whom 3-year follow-
world is not known. The most common cause of PH in the up results were reported were 82.9% and 58.2%, respectively.
United States is left heart failure (including both heart failure The modestly improved survival compared with the original
with preserved and reduced systolic function) and, depending NIH registry likely reflects better treatment, but may also
on the definition of PH used, PH may be present in upwards of reflect a predominance of prevalent PAH cases. Regardless,
83% of patients with heart failure.2 Pulmonary arterial hyper- it also demonstrated that the mortality in PAH remains unac-
tension (PAH) on the other hand remains a generally rare ceptably high (Figure 1). Similar to the French registry, the
disease with estimates of prevalence ranging from between 5 Registry to EValuate Early And Long-term pulmonary arte-
to 15 cases per 1 million adults.3,4 Clinical practice suggests rial hypertension disease management (REVEAL) Registry
that there has been an evolution in the phenotype of patients from the United States also reports an older patient population
referred to specialty centers for the diagnosis and manage- (mean age 53 years) but found a higher proportion of women
ment of PH of all types, including PAH. Registries have (4.1:1) compared with the French and original NIH registries
provided important information about the epidemiology and (1.9:1 and 1.7:1, respectively). One-year survival in this pre-
changes in the PAH phenotype that have been observed over dominantly prevalent PAH cohort was 91%.8,9
the past decades. These include changes in age, sex, comor-
bidities, and survival. One explanation may be the increased Classification of Pulmonary Hypertension
awareness for PAH in the modern management era, as effec- The modern classification for PH was established in 1998.10
tive therapies are now available.1 Because primary or idio- The intention of the classification was to group patients who
pathic PH (IPAH) was considered a rare disease that affected appeared to share common mechanisms of disease. What
young women at the time of the initial National Institutes of emerged was a schema that classifies PH diagnoses into 5
Health (NIH) registry,5 it is likely that older patients and men distinct groups: PAH (Group 1); PH secondary to left heart
were often not considered for the diagnosis at that time. Other disease (Group 2); PH secondary to lung disease (Group 3);
factors potentially contributing to biased enrollment included chronic thromboembolic PH (Group 4); and PH secondary to
a lack of familiarity of PH among nonexperts in the commu- unclear or multifactorial mechanisms (Group 5). Since then,
nity and unavailability of widespread screening tools such as modifications to that classification have been made every 5

From the Department of Medicine, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL (J.D.R.); and the
Department of Medicine, Section of Cardiology, University of Chicago Pritzker School of Medicine, Chicago, IL (S.R.).
Correspondence to Jonathan D. Rich, MD, Assistant Professor of Medicine, Northwestern University Feinberg School of Medicine, 676 North St. Clair,
Chicago, IL 60611. E-mail [email protected]
(Circulation. 2014;130:1820-1830.)
© 2014 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.114.006971

1820
 Rich and Rich   Diagnosis of Pulmonary Hypertension   1821

Table 1.  Updated Classification of Pulmonary Hypertension

1. Pulmonary arterial hypertension
 1.1 Idiopathic PAH
 1.2 Heritable PAH
  
1.2.1 BMPR2
  1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3
  
1.2.3 Unknown
 1.3 Drug and toxin induced
 1.4 Associated with:
  1.4.1 Connective tissue disease
Figure 1. Kaplan–Meier survival estimates in the combined
  1.4.2 HIV infection
population of patients with pulmonary arterial hypertension
(PAH; black line). When the predictive modeling approach of the   1.4.3 Portal hypertension
National Institutes of Health (NIH) registry was used, the esti-   1.4.4 Congenital heart diseases
mated survival (gray line) was 10% lower than what was actually
observed. Adapted from Humbert et al4 with permission of the   
1.4.5 Schistosomiasis
publisher. Copyright ©2010, Lippincott Williams & Wilkins.  1' Pulmonary veno-occlusive disease or pulmonary capillary
hemangiomatosis
 1'' Persistent pulmonary hypertension of the newborn (PPHN)
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years.11,12 Although the 5 Groups of PH have remained the

same, some of the lesser understood subgroups have been 2. Pulmonary hypertension due to left heart disease
reassigned to different categories. The most recent changes  2.1 Left ventricular systolic dysfunction
to the classification system were made during the 5th World  2.2 Left ventricular diastolic dysfunction
Symposium of PH in Nice in 201313 (Table 1). The main  2.3 Valvular disease
change was to withdraw persistent PH of the newborn from
 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and
Group 1 because this entity carries more differences than congenital cardiomyopathies
similarities with the other PAH subgroups. Thus, in the cur-
3. Pulmonary hypertension due to lung diseases or hypoxia
rent classification, persistent PH of the newborn is now des-
 3.1 Chronic obstructive pulmonary disease
ignated number 1". Additional changes include moving PH
associated with chronic hemolytic anemia from Group 1 PAH  3.2 Interstitial lung disease
to Group 5 (unclear/multifactorial mechanism). It was also  3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
decided to add specific items related to pediatric PH to cre-  3.4 Sleep-disordered breathing
ate a comprehensive, common classification for both adults  3.5 Alveolar hypoventilation disorders
and children. As a result, congenital or acquired left-heart  3.6 Chronic exposure to high altitude
inflow/outflow obstructive lesions and congenital cardiomy-  3.7 Developmental lung diseases
opathies have been added to Group 2, and segmental PH has
4. Chronic thromboembolic pulmonary hypertension (CTEPH)
been added to Group 5. Also, over the last 5 years, new drugs
5. Pulmonary hypertension with unclear multifactorial mechanisms
have been identified and listed as probable or suspected risk
factors for PAH.  5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative
disorders, splenectomy
Contrary to popular belief, the classification scheme for
PH was never intended to serve as a guide to direct therapy,  5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis,
lymphangioleiomyomatosis
because important differences exist in the subgroups within
each Group. Nonetheless, the current PAH-specific therapies  5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid
disorders
have been given approval for the entire class of Group 1 PAH
by the regulatory authorities.14  5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure,
segmental PH.

Clinical Assessment of the Patient With BMPR indicates bone morphogenic protein receptor type II; CAV1, caveolin-1;
ENG, endoglin; HIV, human immunodeficiency virus; and PAH, pulmonary
Suspected Pulmonary Hypertension arterial hypertension.
History Adapted from Simonneau et al13 with permission of the publisher. Copyright
©2013, Elsevier.
Because the earliest symptoms in patients with PAH are
manifest with exercise, PAH can have an insidious presen-
tation, but usually includes dyspnea with exertion.15 This flow to a markedly hypertrophied right ventricle (RVH).16 As
should be distinguished from a complaint of fatigue, which cardiac output becomes fixed and eventually falls, patients
though also a nonspecific symptom, is not suggestive of PAH may have episodes of syncope or near-syncope, an ominous
in the absence of shortness of breath. With the onset of right symptom requiring prompt medical attention. Patients with
ventricular failure, lower extremity edema or complaints of PH related to left ventricular systolic or diastolic dysfunc-
abdominal distention or early satiety secondary to venous tion, the most common cause of PH, may have orthopnea
congestion are characteristic. Angina is also common, likely or paroxysmal nocturnal dyspnea. Hemoptysis is relatively
reflecting demand ischemia from impaired coronary blood uncommon in patients with PH and may be associated with
 1822  Circulation  November 11, 2014

underlying thromboembolism and pulmonary infarction, and ● Abdominal and peripheral examination: When right
with advanced mitral stenosis. heart failure occurs, manifestations of elevated right
sided filling pressures are often readily apparent by
Physical Examination physical examination, which includes the presence of
Bedside cardiovascular findings reliably reflect the severity of hepatomegaly, ascites, and lower extremity edema. A
the PH and right heart failure if the examination is done care- palpable liver may be present in the setting of severe
tricuspid regurgitation. The presence of clubbing is not
fully.15 Some of these bedside pearls include the following:
typical of IPAH but may be present in Eisenmenger syn-
drome and hypoxic lung disease.
● Vital signs: Blood pressure is frequently low but toler-
ated, representing what has been referred to as warm
shock. Peripheral vasodilation is increased by the use of Even though the physical examination can provide a wealth
vasodilator drugs. An increased resting heart rate from of information about the presence and severity of PH, there
baseline without another explanation is a sensitive sign is an increasing reliance on diagnostic tests to do the same.
of impending or overt decompensated right ventricular Although comprehensive reviews of the diagnostic testing
(RV) failure and should alert the clinician that adjust- evaluation have been published,17,18 some helpful clues and
ments of treatments are needed. pearls from these tests are listed below. Figure 2 provides a
● Pulse oximetry: The resting arterial oxygen saturation generalized algorithmic approach to the diagnostic evaluation
in PAH can vary from normal to low. One distinction of the patient with possible PH.
between Eisenmenger syndrome and other forms of
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PAH is the presence of cyanosis. Pulse oximetry at rest Laboratory Tests

and with exercise is a useful way to uncover a missed In IPAH, the complete blood count is normal. If chronic arte-
intracardiac shunt because marked desaturation with rial oxygen desaturation exists, a reactive polycythemia should
exercise in IPAH is not typically observed in early be present. Thus, patients with a normal pulse oximetry at
stages of the disease. Patients with bidirectional shunt- rest and polycythemia should be retested with exercise. An
ing may have normal resting pulse oximetry which will elevated platelet count (or polycythemia from any cause) is a
fall during exercise, reflecting shunt reversal. The mag- risk factor for PH, whereas a low platelet count may reflect an
nitude of the fall may be helpful in deciding how to
associated autoimmune disease, hypersplenism, or even occult
intervene.
cirrhosis with associated portopulmonary hypertension. A his-
● Jugular venous pressure and waveform: Jugular venous
tory of arterial or venous thrombosis warrants thrombophilia
pressure (JVP) is commonly elevated, with an increased
‘a’ wave from loss of RV compliance which accompanies screening including antiphospholipid antibodies, such as lupus
RVH. Attention to the effects of breathing will allow one anticoagulant and anticardiolipin antibodies. Measurement of
to detect an adaptive, compensated state where the JVP brain natriuretic peptide (BNP) levels is reasonable as BNP
collapses with inspiration, from a maladaptive, decom- levels are often elevated in patients with PH, loosely cor-
pensated state where the JVP does not collapse or even relate with the severity of RVH, and are predictive of clini-
increases with inspiration (Kussmaul’s sign). As the RV cal outcomes.19,20 Specifically, BNP values <50 (NT-proBNP
dilates, the JVP may change waveform and reflect an <300) are markers of enhanced survival, whereas BNP >180
elevated ‘v’ wave from worsening tricuspid regurgita- (NTproBNP >1500) has been associated with worse survival.21
tion. In this scenario, the jugular venous pulsation will Uric acid levels are elevated in patients with PH and inversely
often be stronger and may be confused with the carotid correlate with pulmonary vascular resistance. Although the
arterial pulsation. Assessment of carotid volumes should mechanism is uncertain, it may relate both to overproduction
be routinely performed because it is a useful surrogate of and impaired uric acid excretion caused by the low cardiac out-
stroke volume. put state and tissue hypoxia.22 There is an increased incidence
● Palpation and auscultation: A parasternal RV heave is of thyroid disease in patients with PAH, which can be confused
often palpable at the left lower sternal border while the with symptoms of RV failure. Consequently, it is advised that
closure of the pulmonic valve (palpable P2) is approxi- thyroid function tests be monitored serially in all patients.23
mately at the level of the left second intercostal space. Screening for antinuclear antibodies is important because all
The intensity of the P2 is a representation of the PA sys- of the connective tissue diseases have been associated with
tolic pressure. A right-sided S4 should parallel the ‘a’ the development of PAH. Although scleroderma is the leading
wave of the jugular venous waveform. A right-sided S3 cause of death in patients with PAH secondary to connective
is uncommon unless the patient is in a shock-like state.
tissue diseases, PAH has also been described in patients with
The murmur of tricuspid regurgitation becomes increas-
systemic lupus erythematosus, mixed connective tissue dis-
ingly apparent when the RV dilates. Its loudness is
ease, polymyositis, dermatomyositis, rheumatoid arthritis, and
affected both by the malcoaptation of the TV leaflets and
Sjogren’s syndrome. Because connective tissue diseases may
the contractility of the RV, with accentuation of the mur-
mur occurring with inspiration. Pulmonic insufficiency have an insidious onset and a slowly progressive course, early
may be appreciated in patients with a dilated main pul- recognition of the symptoms of PH may be difficult.24
monary artery, which usually represents longstanding
elevated pressures, most prominent in congenital heart Chest Radiography
disease, long-term survivors from effective therapies, or A chest radiograph will typically show enlargement of the
chronic thromboembolic PH. main pulmonary artery and its major branches, with pruning
 Rich and Rich   Diagnosis of Pulmonary Hypertension   1823
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Figure 2. Diagnostic approach to the patient with a clinical suspicion of pulmonary hypertension. BGA indicates blood gas analysis;
CHD, congenital heart disease; CTD, connective tissue disease; CTEPH, chronic thromboembolic PH; DLCO, diffusing capacity for car-
bon monoxide; HIV, human immunodeficiency virus; PAP, pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; PCH,
pulmonary capillary hemangiomatosis; PEA, pulmonary endarterectomy; PFT, pulmonary function test; PH, pulmonary hypertension;
PVOD, pulmonary veno-occlusive disease; PVR, pulmonary vascular resistance; RHC, right heart catherization; RV, right ventricle; V/Q,
ventilation/perfusion; and WU, Woods Units. Adapted from Hoeper et al54 with permission of the publisher. Copyright ©2013, Elsevier.

of peripheral arteries as distal vessels become occluded and dilation is not easily discernible on a plain chest radiograph.
reabsorbed. This phenomenon is nicely illustrated in pul- Encroachment of the retrosternal air space on the lateral
monary angiograms obtained from a patient with PAH com- film is a suggestive sign that the enlarged silhouette is a
pared with a patient without pulmonary vascular disease result of right ventricular dilation. The lung fields in PAH
(Figure 3). Dilation of the right ventricle gives the heart a should be clear and often appear darkened from the rela-
globular appearance, but right ventricular hypertrophy or tive oligemia in the presence of a low cardiac output state
 1824  Circulation  November 11, 2014

hypertension rather than PAH. When coupled with a mark-

edly thickened interventricular septum, an infiltrative process
should be considered. Doppler echocardiographic estimates of
right ventricular systolic pressures can be obtained by measur-
ing the velocity of the tricuspid regurgitant jet and using the
modified Bernoulli formula. Although Doppler measurements
correlate with right ventricular systolic pressure, they are rel-
atively imprecise (±30 mm Hg) and are not a substitute for
catheterization if a correct measurement of pulmonary artery
pressure is needed.30,31

Normal IPAH for 6 months Pulmonary Function Tests

Although pulmonary function in patients with PAH is often
Figure 3. Left, Pulmonary arteriogram from a healthy adult.
completely normal, reductions in lung volumes of 20% are
Right, Pulmonary arteriogram from a patient with idiopathic pul-
monary arterial hypertension (IPAH) who died within 6 months of common, making the differentiation from interstitial lung
her first symptom. Extensive peripheral pruning is seen uniformly disease on the basis of pulmonary function tests difficult.32
throughout the lung in the patient with idiopathic pulmonary A significant obstructive pattern is not characteristic and
arterial hypertension. Adapted from Reid62 with permission of
the publisher. Copyright ©1986, American College of Chest should suggest obstructive airways disease. In patients with
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Physicians. idiopathic PAH, the diffusing capacity for carbon monoxide

(DLCO) is typically reduced to ≈60% to 80% of predicted.
coupled with the extensive vascular structural changes that Severe reductions in DLCO may also occur, but this tends to
occur in this disease. be more commonly seen in PAH associated with scleroderma.
The presence of mild to moderate arterial hypoxemia is often
Electrocardiography caused by ventilation-perfusion mismatch or reduced mixed
The detection of RVH on the ECG is highly specific but has venous oxygen saturations resulting from low cardiac output.
too low of a sensitivity to exclude PAH.25 T wave inversion, A severe reduction of arterial oxygen saturation is suggestive
representing the repolarization abnormalities associated with of right-to-left intracardiac or intrapulmonary shunts.
RVH, is usually seen in the anterior precordial leads, may
extend into the inferior leads, and is sometimes mistaken Lung Scintigraphy
for anteroseptal or inferior ischemia. Atrial fibrillation and Patients with PAH may reveal a relatively normal perfusion
absence of right axis deviation on the ECG should increase the pattern or diffuse, patchy, perfusion abnormalities. A nor-
suspicion for pulmonary venous hypertension. On the other mal perfusion lung scan will reliably rule out patients who
hand, atrial flutter is not an uncommon arrhythmia in PAH and have PH secondary to chronic pulmonary thromboembolism.
when discovered, should prompt consideration for cardiover- We have noted perfusion lung scans with multiple perfusion
sion or ablation. defects along with a contrast enhanced CT scan showing no
evidence of pulmonary embolism in some patients with pul-
Echocardiography monary veno-occlusive disease (PVOD). Although it remains
Echocardiography usually demonstrates enlargement of the reasonable to obtain a perfusion lung scan specifically to
right ventricle and atrium with normal or small left ventricu- exclude distal thromboembolic disease in the face of a normal
lar dimensions. Right ventricular size and function may be contrast enhanced computed tomorgraphy (CT) scan, as high-
difficult to measure precisely echocardiographically, but the resolution, modern-day 256-slice CT scanners become more
position and curvature of the interventricular septum provide widely available, this may eventually no longer be necessary.
an indication of right ventricular afterload. Echocardiographic
findings that portend a poor prognosis include presence of a Computed Tomography
pericardial effusion, a markedly diminished left ventricular Contrast enhanced chest CT scans are essential in diagnos-
cavity, and RV dysfunction.26 Tricuspid annular plane systolic ing chronic thromboembolic PH. In addition to visualization
excursion (TAPSE) is frequently impaired and its baseline of thrombi in the pulmonary vasculature, a mosaic pattern
value is predictive of PH survival, yet, interestingly, the mea- of variable attenuation compatible with irregular pulmonary
sured TAPSE may not change significantly over time (even perfusion can be seen in the nonenhanced CT scan. Marked
in those who continue to develop progressive RV failure) and variation in the size of segmental vessels is also a specific fea-
thus may not be a sufficiently reliable marker of RV function ture of chronic thromboembolic PH. If left ventricular (LV)
to measure serially.27,28 An emerging echocardiographic tool diastolic heart failure is suspected, a high-resolution chest CT
is the use of speckle-tracking to perform RV strain analysis.29 can be helpful because it will often reveal ground-glass opac-
Although the use of RV strain in PAH provides another way ities consistent with chronic pulmonary edema, and a mosaic
to characterize global RV performance, whether it ultimately perfusion pattern. Pulmonary capillary hemangiomatosis, a
proves superior to other modalities to evaluate RV function very rare cause of PH, has characteristic findings on high-res-
in PAH remains to be determined. Left atrial enlargement olution CT scan with diffuse bilateral thickening of the inter-
on the echocardiogram also suggests pulmonary venous lobular septa, and small centrilobular, poorly circumscribed,
 Rich and Rich   Diagnosis of Pulmonary Hypertension   1825

Figure 4. Simultaneous pulmonary capillary wedge pressure (PCWP) and left ventricular end diastolic pressure (LVEDP) measurements
in a patient with biopsy-proven pulmonary veno-occlusive disease (PVOD). In the face of severely diseased, often obstructed pulmonary
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venules in PVOD, a pressure gradient is expected between the pulmonary arterioles (PCWP) and the left atrium/left ventricle (LVEDP) as
can be seen in this illustration. Note also that all pressure measurements are made at end-expiration.

nodular opacities. Pulmonary capillary hemangiomatosis findings hold promise for the increased use of CMR protocols
may occur in isolation or as an overlapping syndrome with in both clinical trials and practice.38
PVOD.33 High-resolution CT is also helpful to diagnose inter-
stitial lung disease. It has a high degree of specificity, but its Positron Emission Tomography Scanning
relatively low sensitivity is often underappreciated. Patients Although not an accepted standard test to diagnose PH, non-
with PAH without coexisting lung disease should have nor- invasive molecular imaging using positron emission tomog-
mal lung parenchyma. Thus, although the CT scan tends to raphy (PET) offers the potential for monitoring cellular and
under-represent the extent of the disease, the presence of any biochemical events in otherwise inaccessible tissue. Lung
interstitial abnormality should suggest that some degree of parenchymal glucose uptake, measured by 18FDG-PET, has
interstitial lung disease is underlying the PH. A high-resolu- been reported to be increased in IPAH patients compared with
tion CT scan of the chest is also a useful means of detecting healthy controls.39 The observation of inter-/intravariability in
emphysema and may occasionally demonstrate emphysema lung 18FDG measurements in IPAH patients aligns with our
even in patients with little or no abnormality detected by pul- current understanding of the disease, both in terms of the mor-
monary function tests.34 In such instances, one should suspect phological heterogeneity within individual lungs and between
the possibility of mixed interstitial and obstructive lung dis- lungs from IPAH patients. 18FDG-PET merits further evalua-
ease, particularly in the presence of a reduced DLCO. tion as a clinical tool to deep phenotype patients with IPAH in
studies exploring efficacy and dose-response relationships of
Cardiac MRI new PAH targeted treatments. Additionally, the assessment of
Although echocardiography is the mainstay in the imaging of RV uptake of FDG and changes in FDG uptake with disease
the right heart in clinical practice, advances in cardiac MRI progression or response to therapy may develop as a clinically
(CMR) technology have led to the development of more pre- useful tool to track RV metabolism.40,41
cise techniques for the assessment of hemodynamics in the
pulmonary circulation and identification of right ventricular Exercise Testing
morphological changes. CMR is now regarded as the refer- The use of a symptom-limited exercise test should be part of
ence standard in the assessment of RV structure and function the evaluation of patients with PH. The 6-minute walk test
via the measurement of RV volumes and ejection fraction, is commonly used in clinical trials as an end point for effi-
which makes CMR an attractive modality for serial follow- cacy of therapy in patients with PH. It has been correlated
up in PAH management to determine treatment response.35 In with workload, heart rate, oxygen saturation, and dyspnea
addition, CMR offers the possibility to quantify regurgitant response. However, it has many drawbacks that include the
volumes, use delayed gadolinium enhancement as a marker fact that anthropometric factors such as gait speed, age,
for focal scar burden, and to assess myocardial strain, coro- weight, muscle mass, and length of stride can affect the test
nary perfusion, and pulmonary pulsatility.36 One recent study results. In addition, any encouragement from the tester can
was able to predict survival in patients with PAH based on cause large variations in the result.42 Treadmill testing using
the RV ejection fraction computed from CMR.37 A more the Naughton-Balke protocol avoids many of these limitations
recent multicenter study demonstrated the feasibility of using and provides an estimate of work because the program cre-
CMR to track changes in RV size and function in response ates incremental increases in work of 1 metabolic equivalent
to 12 months of PAH-specific therapy. Taken together, these at 2-minute stages.43 Cardiopulmonary exercise testing using
 1826  Circulation  November 11, 2014

either a treadmill or an upright bicycle with measurements of The diagnosis of PH relies on establishing an elevation
gas exchange has the potential to grade the severity of exercise in pulmonary artery pressure above normal. The upper limit
limitation in patients with PH noninvasively and can be per- of normal for pulmonary artery mean pressure at rest is 19
formed serially to follow changes in functional capacity that mm Hg. However, this assumes that there are no abnormalities
often accompany disease progression.44 in downstream pressures of the left atrium or left ventricle, or
an increased cardiac output. That is why a patient can have PH
Hemodynamic Assessment of PH from the standpoint of an elevated pulmonary artery pressure,
but normal pulmonary vascular resistance. Parameters for
Cardiac Catheterization
normal pulmonary arterial systolic pressure derived by echo-
In addition to confirming the diagnosis of PAH and excluding cardiographic Doppler studies suggest that the upper limit of
other PH causes, cardiac catheterization also establishes the normal of pulmonary arterial systolic pressure in the general
severity of disease and allows an assessment of prognosis.7,45 population may be higher than previously appreciated.50
By definition, patients with PAH should have a low or nor-
mal pulmonary capillary wedge pressure (PCWP). Because
this is a critical measurement in distinguishing a patient with
Vasodilator Testing
Several vasodilators are of value in the assessment of pulmo-
PAH from one with pulmonary venous hypertension, qual-
nary vasoreactivity in patients with PAH (Table 2). All appear
ity measures must be established in the cardiac catheteriza-
tion laboratory to ensure that correct values are obtained. to have similar efficacy in identifying patients who are vaso-
Pressures should not be determined by the electronically reactive. However, although adenosine and epoprostenol are
vasodilators at low doses, they possess inotropic properties
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integrated mean pressure from the laboratory’s computer

displayed on the catheterization laboratory monitor, because that become manifest at higher doses, whereas nitric oxide has
these measurements ignore respiratory influences and may little effect on cardiac contractility at any dose. An increase
lead to erroneous measurements.46 Instead, measurements of in cardiac output with no change in pulmonary arterial pres-
all pressures should be properly made at end-expiration to sure will result in a reduction in calculated pulmonary vascular
avoid incorporating negative intrathoracic pressures. Direct resistance, and may be erroneously interpreted as a vasodilator
measurement of LV end-diastolic pressure is advised when response. Changes in PCWP can also have important influences
a reproducible wedge pressure cannot be obtained.47 In cer- on the calculation of pulmonary vascular resistance. A rising
tain cases, administering a volume load of saline may reveal PCWP secondary to increased cardiac output may be a sign of
abnormal LV filling pressures that had previously normalized left ventricular diastolic failure or an adverse effect of a drug,
in patients with mild states of dehydration and unmask the whereas the calculated pulmonary vascular resistance may be
presence of pulmonary venous hypertension.48 Interestingly, lower and suggests a beneficial effect. It is imperative that all
the PCWP in patients with PVOD is often found to be normal. patients with newly diagnosed PAH undergo vasodilator test-
This is likely attributable to the heterogeneity among cases ing to determine the presence or absence of vasoreactivity and
of PVOD, differences in procedural practices, and a lack of possible candidacy for calcium channel blocker therapy.51 The
consideration of PVOD in the differential diagnosis. In cases currently accepted criteria for the presence of vasoreactivity is
in which there is a suspicion of PVOD, we advocate simul- the demonstration of ≥10 mm Hg reduction in mean PA pres-
taneous PCWP and LV end-diastolic pressure measurements sure to a value of <40 mm Hg and without a reduction in cardiac
with the PCWP measurements obtained from multiple lung output, but these criteria have never been formally validated.18
segments. Unfortunately, this is not frequently done in many
clinical practices, which underscores the benefit of referral of Screening of Select High-Risk Patient Populations
these complex cases to highly specialized, experienced cen- Although unproven, it is widely held that earlier detection of
ters. If PVOD is present, one may find an elevated PCWP to PAH would allow earlier treatment and better outcomes. For
LV end-diastolic pressure ratio in some segments, with nearly these reasons the screening of populations at increased risk of
equal values in others49 (Figure 4). developing PAH has been recommended. Particular attention

Table 2.  Agents Used for Determination of Acute Pulmonary Vasoreactivity

Agent Administration Dosage Advantages Drawbacks
Epoprostenol Intravenous 2 ng/kg/min Affects pulmonary arterial pressure and Systemic hypotension
(stepwise increase every 15–30 min), cardiac output, can be used as a chronic Dramatic side effects
maximum dose 10 ng/kg/min therapy
Adenosine Intravenous 50 μg/kg/min increased Affects pulmonary arterial pressure and Bradycardia
by 50 μg/kg/min every 2 min, cardiac output, rapid onset and rapid
maximum dose of 500 μg/kg/min washout
Nitric oxide Inhaled 5–20 ppm for Affects pulmonary arterial pressure alone, Rebound pulmonary hypertension in few
10 min rapid onset and washout cases
Iloprost Inhaled 2.5–5.0 Affects pulmonary arterial pressure Potential dosing variability depending on
μg/inhaled dose selectively with minimal effects on cardiac investigator experience, inhalation device
output. Can be used as chronic therapy and breathing pattern of the patient
Adapted from Rich13 with permission of the publisher. Copyright ©2012, Saunders.
 Rich and Rich   Diagnosis of Pulmonary Hypertension   1827

has been given to patients with the scleroderma spectrum of patients will dictate their candidacy for liver transplantation.
diseases, advanced liver disease, and a family history of heri- Although not prospectively validated, current portopulmo-
table PAH. nary hypertension screening recommendations endorsed by
Because of the high prevalence of PH in patients with the American Association for the Study of Liver Disease
scleroderma spectrum of diseases, which is a leading cause of are that every patient considered for liver transplant have a
death in these patients, recent guidelines have recommended screening transthoracic echocardiogram to assess for PH and,
regular screening by echocardiography. In an attempt to estab- if suggestive, a confirmatory right heart catheterization.53
lish the best way to screen these patients, the Evidence-based The genetic testing of relatives of patients with heritable
detection of pulmonary arterial hypertension in systemic scle- PAH is controversial.54 Genetic testing will identify presymp-
rosis (DETECT) study developed the first evidence-based tomatic carriers of PAH-causing mutations who are at high
detection algorithm for PAH in the scleroderma patients with- risk of developing PAH. However, because of incomplete
out clinical signs and symptoms.52 A 2-step, internally vali- penetrance of mutations in PAH-predisposing genes, it is cur-
dated detection algorithm for clinical practice was created. rently not possible to identify which carriers of a mutation will
The first step included the clinical assessment for the presence develop PAH.55 In addition, there are no proven effective inter-
of telangiectasia, anticentromere antibodies, pulmonary func- ventions or medications available to prevent the onset of PAH
tion test, and DLCO measurements, an ECG, and NT-proBNP in mutation carriers. Thus, although genetic testing in relatives
and uric acid levels. For those with a high composite score, will identify mutation noncarriers who have no increased risk
the second step included echocardiography and consideration of the heritable disease, it will also identify mutation carriers
of right heart catherization in patients with abnormal findings. who will have to live wondering whether or when they will
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This resulted in a 97% sensitivity and 35% specificity for the develop the disease. Given that the most common presenting
diagnosis of PAH. symptom of PAH is dyspnea with exertional activity, which
The incidence of portopulmonary hypertension in patients is also a feature of normalcy, we agree with the argument that
with advanced liver disease has been reported to be between has been made by others, that the relatives are likely better off
2% to 9%. Although low, the coexistence of PAH in these not knowing their genetic status than living a lifetime of worry.

Figure 5. Right ventricle (RV) pulmonary venous (PV) loop relationship analysis in patients with pulmonary vascular disease. A, Outline of
technique used to measure simultaneous RV pressure and volume. B, Sketch of placement of conductance catheter (Millar Instruments,
Houston, TX) in the RV to obtain PV data. C, Schematic of basic measures of pressure and volume relationships. The end-systolic PV loop
relationship (ESPVR) and end-diastolic PV loop relationships (EDPVR) define the boundaries of the PV loops for a given contractile state
of the ventricle. Changing the preload (as shown with dashed lines) or afterload will change the shape and position of the loops, but the
end-systolic and end-diastolic points will always fall on the ESPVR and EDPVR. This is the reason why the ESPVR and EDPVR are used
as load-independent measures of contractility. The ratio of end-systolic pressure (Pes) to stroke volume has the dimension of elastance
(mm Hg/mL) and is called the arterial elastance (Ea) because it is linked to the afterload, which is determined by the arterial system and
is represented in the PV loop by the slope of the line that links Pes and end-diastolic volume. D, Representative tracings of RV PV loops
in borderline pulmonary arterial hypertension (PAH) with preserved ESPVR and stroke volume (left) and late PAH with higher RV end-
diastolic pressure, end-diastolic volume, and RV end-systolic pressure with a lower stroke volume and decreased contractility (shifted
ESPVR to the right). Adapted from Champion et al56 with permission of the publisher. Copyright ©2009, Lippincott Williams & Wilkins.
 1828  Circulation  November 11, 2014

Ventriculoarterial Coupling and the innovative modalities such as PET and measurements of ven-
Cardiopulmonary Unit triculoarterial coupling are encouraging developments to more
The clinical assessment of PH requires an evaluation of the comprehensively assess and follow RV function. However,
status of both the pulmonary vasculature and the right ven- cost limitations and the lack of routine availability of these
tricle, and such characterizations should ideally be made and tests outside of specialized, tertiary care centers may con-
considered as an integrated cardiopulmonary unit (see reviews tinue to limit their routine implementation. For these reasons
in references 56 and 57 for an in depth discussion of this topic). we believe that a careful and detailed physical examination
Indeed, the RV and PA are inextricably linked or coupled both will continue to provide the clinician with useful information
in health and in disease. In normal people, the RV pumps into about the severity and response to therapy in most patients.
a high capacitance pulmonary arterial circuit. Under these
circumstances, the oscillatory components of arterial load Disclosures
are generally minor and therefore expression of RV after- Dr Jonathan D. Rich reports receiving speaker fees from Bayer. Dr
load purely as a mean pulmonary vascular resistance is usu- Stuart Rich has no disclosures.
ally adequate. In the setting of pulmonary vascular diseases
such as PAH, however, the RV is confronted with a diseased References
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 Clinical Diagnosis of Pulmonary Hypertension
Jonathan D. Rich and Stuart Rich

Circulation. 2014;130:1820-1830
doi: 10.1161/CIRCULATIONAHA.114.006971
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