The Imaging of Pulmonary Hypertension

Aletta Ann Frazier, MD,*, and Allen P. Burke, MD

Pulmonary hypertension (PH) is the remarkable hemodynamic consequence of widespread
structural and functional changes within the pulmonary circulation. Elevated pulmonary
vascular resistance leads to increased mean pulmonary arterial pressure and, ultimately,
right ventricular dysfunction. PH carries a poor prognosis and warrants timely and accurate
diagnosis for appropriate intervention. The 2008 Dana Point classification system provides
the categorical framework currently guiding therapy and surveillance. Radiologic imaging is
an essential tool in the detection and diagnostic evaluation of patients with PH. Echocardiography, ventilation-perfusion scintigraphy, multidetector computed tomography, and
cardiac magnetic resonance imaging provide insights into vascular morphology, pulmonary
parenchymal status, cardiac function, and underlying etiology of the disorder. Emerging
techniques of functional pulmonary and cardiac imaging hold great promise for the assessment and monitoring of these patients in the future.
Semin Ultrasound CT MRI 33:535-551 2012 Elsevier Inc. All rights reserved.

ulmonary hypertension (PH) is not a specific disease entity but represents the final hemodynamic consequence
of widespread vascular injury to the pulmonary circulation. It
may be driven by a variety of inciting factors, comorbidities,
and genetic susceptibilities. An interplay of vasoconstriction,
inflammation, medial and intimal proliferation, angiogenesis, apoptosis, endothelial dysfunction, and vaso-occlusion
orchestrate the critical vascular morphologic changes.1,2 PH
is a diagnostic challenge: it typically has an insidious clinical
onset, but tempo and severity vary depending on the underlying pathophysiology and coexistent disease. PH is generally
defined as a resting mean pulmonary artery pressure (mPAP)
exceeding 25 mm Hg measured at right heart catheterization
(normal range, 8-20 mm Hg). The pulmonary capillary
wedge pressure (PCWP) may be normal or increased. Pulmonary arterial hypertension (PAH) implies a more specific and
more severe classification of the disease, with the additional
parameter of a PCWP 15 mm Hg (thus excluding left-sided
heart disease). This distinction is important because prognosis and treatment strategies differ between pre- and postcapillary causes of PH. Initial screening for PH includes electro-

*Department of Diagnostic Radiology, University of Maryland Medical System, Baltimore, MD.

Division of Cardiovascular Radiology, American Institute for Radiologic
Pathology, A Program of the American College of Radiology, Silver
Spring, MD.
Department of Pathology, University of Maryland Medical System, Baltimore, MD.
Address reprint requests to Aletta Ann Frazier, MD, Department of Diagnostic Radiology, University of Maryland Medical System, 22 South Greene
Street, Baltimore, MD 21201. E-mail: afrazier@acr.org

0887-2171/12/$-see front matter 2012 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1053/j.sult.2012.06.002

cardiography and Doppler transthoracic echocardiography

(TTE), but right heart catheterization is required for definitive diagnosis.3-5
The most important prognostic indicator of PH is the
degree of right ventricular dysfunction and morphologic
change, termed cor pulmonale. Hypertrophy of the right ventricle (RV) may eventually lead to right-sided chamber dilatation, tricuspid valve incompetency, interventricular septal
reversal, and, ultimately, right ventricular reduced contractility and failure. Optimal assessment parameters for right
ventricular function include right ventricular volume and
ejection fraction. Doppler echocardiography is an excellent
noninvasive modality for this purpose, but changes in right
heart anatomy and function are best evaluated with cardiac
magnetic resonance (MR) imaging.4-6
PH develops across an impressive spectrum of clinical conditions. Although rare, idiopathic pulmonary hypertension
(IPAH) is one of the most severe expressions of PH, with a
relentless and rapid clinical course. Congenital heart disease
(CHD) with long-standing systemic-to-pulmonary shunt
may transition to Eisenmenger syndrome and irreversible
PAH. Widespread vaso-occlusion secondary to conditions
such as chronic thromboembolic disease, tumor thromboembolism, or intravenous (IV) talcosis may lead to PH. Lung
disease and sustained hypoxic states such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and obstructive sleep apnea are associated with PH.
Connective tissue disease, diffuse interstitial lung disease,
and human immunodeficiency virus (HIV) infection may
each be complicated by PAH. Often mistaken for IPAH, pulmonary veno-occlusive disease (PVOD) and pulmonary cap535

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536

Figure 1 Phases of lesions in pulmonary arterial hypertension (PAH). (A) Normal intra-acinar artery. (B) Intra-acinar
artery with markedly thickened media, presumably caused by extension of proliferating smooth muscle cells into distal
vessels. (C) Concentric intimal thickening, cellular (laminar) type. (D) Plexiform lesion. There is a proliferation of small
vessels with surrounding ectatic vessels filled with blood (arrowheads). The lesion is adjacent to a bronchiole (arrow).

illary hemangiomatosis (PCH) are enigmatic overlapping disorders affecting the capillaries, venules, and veins of the
pulmonary circulation. Finally, left-sided ventricular or valvular cardiac disease is overall the most common cause of PH.
The most recent reclassification of PH was conducted in
2008 at the Fourth World Symposium in Dana Point, CA.
Adjustments to the 2003 Venice Classification reflect an
emerging appreciation that many forms of PAH share the
pathophysiologic and clinical manifestations of IPAH, including PVOD and PCH. Schistosomiasis and chronic hemolytic anemia were also added as new disease categories within
PAH. The role of therapeutic regimens, including emerging
PH-specific medications and the indications for lung/heart
and lung transplantation, is covered extensively elsewhere
and is beyond the scope of this article.4,5,7

Pathophysiology
PAH represents a spectrum of idiopathic and associated diseases that result in vascular remodeling primarily of preacinar and intra-acinar muscular arteries with an external diameter of 50-400 m.8,9 PAH is characterized by an increase in
vascular smooth muscle cells with medial proliferation and
smooth muscle cell extension into intra-acinar arterioles.
Functionally, there are endothelial dysfunction and vasoconstriction, mediated in part by inflammation and defects in
apoptosis.10 Resistance to apoptosis, proliferation of vascular
smooth muscle cells, and a cancer-like metabolic shift from

mitochondrial glucose oxidation toward glycolysis have been

termed the Warburg effect.11
Classically, the pathogenesis of PAH has centered on molecular pathways governing vasoconstriction, cell proliferation, and thrombosis, and therefore, involves a wide and
diverse set of molecules.12 Cell proliferation has focused primarily on smooth muscle cells but involves vascular endothelial growth factor and endothelial cells as well. Increases in
endothelin, serotonin, and thromboxane A2 with decreased
prostaglandins and vasoactive intestinal polypeptide have
been implicated as causative for PAH and have been primary
targets for therapy.12
Inflammation modulates the vascular proliferative process
in PAH, and is manifested histologically as the accumulation
of perivascular macrophages, dendritic cells, lymphocytes,
and mast cells, with a necrotizing arteritis rarely occurring. A
variety of cytokines are elevated in patients sera.10 In a subset
of patients, autoimmunity may play a role in the inflammation and vascular proliferation, as it has long been appreciated that serum autoantibodies, even in the absence of overt
connective tissue diseases, are associated with PAH.13
The pathologic findings of PAH include nonspecific features of intimal thickening, medial hypertrophy, and extension of media into acinar arterioles, all of which may be a
secondary reaction to localized fibrosis or inflammation of
any etiology.14 When diffuse, or if accompanied by plexiform
lesions, these changes are characteristic of PAH (Fig. 1). Histologic studies focusing on plexiform lesions have shown that

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537

the affected arteries in IPAH are pulmonary (without contribution of bronchial arteries) and most frequently 50-100 m
in diameter.8 Plexiform lesions occur at branch points of axial
arteries (so-called supernumerary arteries), intralobular arteries associated with bronchioles, or more distal intra-acinar
arterioles (unassociated with airways).9,14 Arteritis and dilatation lesions are also in the spectrum of PAH with plexiform
lesions.14
Recanalized thrombi within distal pulmonary arteries
400 m in diameter have long been appreciated to occur in
PAH (Fig. 2), and even characterized a form of PAH lacking
plexiform lesions previously termed primary thrombotic
pulmonary hypertension.15,16 The characteristic lesion of recanalized thrombus in a distal vessel has been described as a
colander lesion (Fig. 2B).14 Patients with clinically documented chronic thromboembolic pulmonary hypertension
(CTEPH) who have been treated with proximal thromboendarterectomy have been shown to have the full range of peripheral arterial lesions, including plexiform lesions.17
Recently, PCH and PVOD have been included as a subset
of PAH, although these entities were previously considered
capillary or post-capillary forms of PH.5,18 Familial PVOD
has been described, as well as a family with mutations in the
bone morphogenetic protein receptor type 2. In addition,
precapillary changes typical of IPAH have been described in
PVOD, although plexiform lesions have not. The histopathologic features of PCH and PVOD show significant overlap,
suggesting that they represent a spectrum of the same disease
(Fig. 3).19
A large component of the morbidity of PH of any cause is
right heart failure secondary to prolonged PH. With increased afterload, the right ventricular myocardium undergoes a metabolic transformation with a shift toward glycolysis
and re-expression of fetal-type contractile proteins.20,21 In
chronic PH, there is progressive hypertrophy with dilatation
occurring as right heart failure ensues (Fig. 4). The morphologic features of chronic cor pulmonale are similar whether
the cause of the PH is postcapillary (eg, mitral stenosis) or
precapillary as in IPAH. There is evidence that some of the
metabolic changes of right ventricular hypertrophy in PH are
reversible and that there is an element of myocardial hibernation.21

The Imaging of PH
The PH-induced alterations of pulmonary vasculature truly
reflect the underlying mural architecture of the vessels.22,23
The central pulmonary arteries coursing to the level of the
segmental bronchi are formed of multiple parallel elastic laminae and therefore dilate in the face of elevated pulmonary
vascular resistance. These vessels gradually transition to muscular arteries along the distal segmental and subsegmental
airways. With a media of tightly packed smooth muscle cells,
the muscular arteries are highly responsive to circulating factors as well as local stresses. As described previously, the
muscular arteries are typically the focal point of vasoconstriction, vascular remodeling, and vaso-occlusion in PAH.22

Figure 2 Recanalized thrombi. (A) Small muscular artery with

eccentric intimal thickening and recanalized channels. Eccentric
thickening is often secondary to thromboembolism. Elastin
stain. (B) Multiple small dilated arteries with relatively evenspaced recanalized channels (so-called colander lesion). Vascular channels within the artery are filled with blood, separated by
pale-green collagenized intima (arrowheads). Elastin stain. (C)
Peripheral artery with compressed central channels, from a patient with antiphospholipid syndrome.

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538

Figure 3 Pulmonary capillary hemangiomatosis (PCH) and pulmonary veno-occlusive disease (PVOD). (A) PCH,
low magnification, shows circumscribed area of capillary thickening with hemorrhage (arrows). (B) A higher
magnification of PCH demonstrates capillary proliferation on both sides of capillary walls. Elastin stain. (C) PVOD
is characterized by diffuse septal thickening (arrows). There is an occluded vein in the center (arrowhead). (D)
Higher magnification of PVOD demonstrates a recanalized vein within the fibrotic interlobular septum.

Chest Radiography
Chest radiography demonstrates morphologic cardiovascular changes only late in the disease course. The main pulmonary arterial segment is prominent, the central hilar vessels
are dilated, and the peripheral vascularity is diminished (Fig.
5). Atherosclerotic calcifications lining the central arteries
may develop in severe long-standing PAH. A dilated right

heart in cor pulmonale partly fills the retrosternal clear space

on lateral view.

Echocardiography
Echocardiography is an excellent noninvasive tool for screening of PH by measuring systolic pulmonary arterial pressure
using peak tricuspid regurgitant jet velocity. Doppler TTE
has a sensitivity of 79%-100% and a specificity of 68%-98%
for the detection of moderate PH. This modality also has the
advantage of detecting underlying causes or comorbidities,
such as left-sided cardiac disease, abnormal ejection fraction,
valvular abnormality, chamber mass, or intracardiac shunt.4-6

Multidetector Computed Tomography

Figure 4 Cor pulmonale in a case of idiopathic pulmonary hypertension (PH). Short-axis section from autopsy heart: the right ventricle
(RV) is thickened up to 6 mm in the posterior wall (arrows). In
addition, there is marked dilatation of the RV indicative of failure.
The left ventricle (LV) is relatively normal.

Multidetector computed tomography (CT) is an essential tool

to characterize both the cardiovascular and parenchymal
changes of PH. Even more importantly, this modality may
provide clues regarding the cause or related condition of PH;
examples of these more specific findings will be further discussed under individual sections in the following text. In PH,
an enlarged CT-determined mean pulmonary artery (PA) diameter of 29 mm has 87% sensitivity and 89% specificity
for PH (Fig. 6); specificity reaches 100% when this increased
main PA diameter is accompanied by a segmental artery-tobronchus ratio of 1:1 in 3 of 4 pulmonary lobes on axial CT
images.24 PH is also highly likely if the ratio of CT-measured
main PA transverse diameter (P) to that of ascending aorta (A)

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539

Figure 5 Radiographic findings of PH. (A) Posteroanterior chest radiograph shows marked enlargement of the main
pulmonary artery (PA), prominent right interlobar artery, and relative paucity of peripheral vascularity. (B) Lateral
chest radiograph shows filling of retrosternal clear space by an enlarged RV.

is greater than 1 (rPA: 1) with a 96% positive predictive

value.25 Despite these helpful imaging parameters, even if the
main PA diameter is normal and/or the rPA is 1, clinically
significant PH may still be present.
Changes in the muscular arteries on CT are evident as
abruptly diminished peripheral pulmonary vessels (pruning) (Fig. 7) and, occasionally, corkscrew-like vessels.22,26
Mosaic attenuation on CT is reported in many PH conditions,
including chronic thromboembolic disease, IPAH, PCH,
PVOD, and CHD. Although mosaic attenuation is nonspecific, a primary vascular cause is suggested by increased arterial vessel caliber in geographic areas of increased attenuation (hyperemia) compared with diminutive vessels within
zones of low attenuation (oligemia)27 (Fig. 8). As an addi-

Figure 6 Dilatation (29 mm) of the main PA measured transversely

at the level of PA bifurcation on contrast-enhanced axial computed
tomographic (CT) image (mediastinal window). Note additional
feature of PH: the ratio of PA diameter to ascending aorta diameter
exceeds 1 (rPA 1). Wide-based intravascular soft-tissue filling
defect narrows the right main PA, compatible with chronic thromboembolic PH.

Figure 7 Vascular pruning in an adult with uncorrected atrial septal

defect. Axial CT image (lung window) demonstrates abrupt narrowing or cut-off of multiple peripheral vessels on a background of
mosaic attenuation.

540
tional clue, end-expiratory CT will not elicit air trapping
when mosaic attenuation is due to a vascular disorder.28
Dilatation of segmental and subsegmental bronchi has
been observed in PH and may reflect interaction between
pulmonary airways and vessels in response to local tissue
hypoxia23 (Fig. 9). Minimum intensity projection CT technique improves detection of the mosaic attenuation pattern, whereas maximum intensity projection (MIP) images
highlight variations in vessel caliber.22,26 MIP CT images
are also excellent for demonstration of bronchial and chest
wall arterial collaterals that develop through anastomotic
channels in PH22,26,29 (Fig. 10).
The CT features of cor pulmonale include right ventricular
wall thickening, right heart chamber dilatation, and reversal
of the interventricular septum. The RV is normally thin
walled (4-5 mm) and less than one-third the thickness of the
left ventricle (LV).30 Interventricular septal reversal and a
ratio of RV cavity width to LV cavity width on axial CT 1 are
regarded as the most valuable CT signs of right ventricular
dysfunction31 (Fig. 11). Recent investigations show that CTderived ventricular volume ratios are more accurate than
simple diameter measurements for the detection of right ventricular dysfunction. A ratio of right ventricular volume to left
ventricular volume 0.9 correlates with moderately elevated
pulmonary artery pressure (PAP) and increased mortality.32,33 Pericardial thickening or pericardial effusion on CT is
associated with moderate-to-severe PH.34 In the face of high
pressures within the right heart, IV contrast may reflux into
the inferior vena cava and hepatic veins (Fig. 12).

Cardiac MR Imaging
Cardiac MR imaging in PH allows direct demonstration of
right ventricular morphology, chamber volume, interventricular septal motion, tricuspid valve motion, and ejection fraction. Right ventricular hypertrophy in PH is an adaptation to
chronic pressure overload. Short-axis MR views reveal a morphologic transition of the RV from crescentic to round-shaped,

Figure 8 Mosaic attenuation due to vascular etiology on axial CT

image (lung window) in chronic thromboembolic PH. Patchy geographic areas of ground-glass attenuation contain dilated vessels
(hyperemia), whereas areas of decreased attenuation show minimal
vascularity (oligemia).

A.A. Frazier and A.P. Burke

Figure 9 Bronchiectasis in PAH. Coned axial CT image (lung window) shows mild bronchiectasis, pulmonary arterial dilatation, and
mosaic perfusion in an adult patient with uncorrected atrial septal
defect.

Figure 10 Contrast-enhanced coronal maximum intensity projection

(MIP) CT image demonstrates dilated bronchial arterial collateral
vessels within the mediastinum and along the surface of the occluded right interlobar artery (arrows) in chronic thromboembolic
disease.

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541
and hypoxic states), group 4 (chronic thromboembolic disease), and group 5 (multifactorial or unusual scenarios, eg,
sarcoidosis, mediastinal fibrosis) are regarded as primarily
precapillary disorders (with the exception of PVOD and
PCH). Group 2 (left-sided heart disease) is a distinct category
of postcapillary PH owing to pulmonary venous hypertension with elevated PCWP. Imaging of the chest and heart is
essential for the appropriate assignment of a patients condition within the Dana Point World Health Organization
classification scheme. This system of categorization dictates the appropriate therapeutic program and sets the
baseline for disease surveillance. The following discussion
illustrates selected conditions within each of the Dana
Point categories.4,5,39

Idiopathic PAH
and Heritable PAH
Figure 11 Contrast-enhanced coned axial CT image (mediastinal
window) of right ventricular dysfunction in PH shows dilatation of
the RV (RV:LV ratio 1) and abnormal bowing of the interventricular septum toward the left ventricular cavity. The right atrium is
also dilated and tricuspid valve geometry consequently altered.

associated with concentric myocardial thickening as the LV

chamber becomes progressively compromised (Fig. 13A). RV
dilatation further changes the shape of an often hypertrophied
interventricular septum, which gradually flattens or reverses its
curve toward the LV (Fig. 13A, B).30,35 Septal bowing on cine
MR correlates with severe PAH (often 67 mm Hg), functional
deterioration of the RV, and impaired LV filling.30,36 Severe right
ventricular dysfunction also produces delayed gadolinium hyperenhancement at the junction (insertion points) of the RV to
the interventricular septum (Fig. 13C); focal fibrosis and inflammation are seen histologically at these sites.37 Increased right
ventricular end diastolic and end systolic volumes, decreased
stroke volume, and decreased right ventricular ejection fraction
on MR further suggest unfavorable prognosis and treatment failure.6 The alterations in right heart chamber geometry can lead to
tricuspid valve incompetence, and high pressures in the main
PA can lead to regurgitant flow across the pulmonary valve.
Pulmonary arterial flow information using MR angiography,
gated spin-echo images, and phase-contrast velocity mapping
are additional tools for hemodynamic assessment, including abnormal intravascular signal and regional perfusion variation.6,35
Overall, MR is an excellent tool for initial RV evaluation as well
as serial therapeutic assessment.35,38

Idiopathic PAH (formerly termed primary PH) (group 1) is a

severe and sporadic form of PH with no identifiable risk
factor or familial association. The prevalence of IPAH is about
6 persons per million and has clear female predominance
(almost 2:1) with mean age 37 years. Heritable PAH (formerly termed familial PH) (group 1) is distinguished from
IPAH only by the presence of germline mutations, chiefly in
the bone morphogenetic protein receptor type 2 gene with an
autosomal dominant pattern of inheritance. The inherited
form accounts for up to 10% of patients with PAH. Prognosis
has been historically poor in both idiopathic and heritable
forms of PAH, but survival rates are slowly improving with
advances in medical therapy. There are no distinct radiologic

A Spectrum of Diseases
It is important for radiologists to recognize the diagnostic
framework of the Dana Point Symposium classification,
which organizes this broad spectrum of diseases into 5
groups. Group 1 (identifiable conditions of PAH with high
pulmonary vascular resistance), group 3 (pulmonary disease

Figure 12 Contrast-enhanced coned axial CT image (mediastinal

window) demonstrates contrast reflux into the dilated inferior vena
cava and hepatic veins in a patient with Eisenmenger physiology
due to uncorrected ventricular septal defect.

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542

Figure 13 Cardiac magnetic resonance imaging of PH and cor pulmonale. (A) Slightly oblique short-axis cine image
shows right ventricular hypertrophy (arrow), dilated RV chamber and interventricular septum curved toward compressed LV. Note regurgitant jet from incompetent pulmonary valve (arrowhead). (B) Steady-state free precession
image, 4-chamber view, shows dramatic dilatation of right atrium (RA), mildly dilated RV, and slight reversal of
interventricular septum (arrow). (C) Delayed contrast-enhanced image (short-axis view) shows hyperenhancement of
anterior and inferior insertion points (arrowheads) of RV to interventricular septum.

features to distinguish IPAH or heritable PAH from other

causes of PAH; they are clinical and radiological diagnoses of
exclusion.3-5,39,40

Congenital Heart Disease

PAH complicates CHD with systemic-to-pulmonary shunts
(group 1). Without correction, a ventricular septal defect
(VSD), an atrial septal defect (ASD), a patent ductus arteriosus, or a truncus arteriosus may relentlessly assault the pulmonary arterial circuit with high flow volume and systemic
arterial pressure. Cascades of vasoconstriction, shear stress,
intimal injury, angiogenesis, thrombosis, and vascular remodeling ensue. As vascular resistance meets systemic levels,
Eisenmenger syndrome manifests with either bidirectional
flow or shunt reversal. This is one of the most severe and
irreversible forms of PAH. Eisenmenger syndrome is only
avoided if surgical repair is performed by age 2, but outside
developed countries, only 2%-15% of patients receive this
intervention. The prevalence of PAH in CHD with systemicto-pulmonary shunts is almost 12.5 cases per million adults,
and 25%-50% will develop Eisenmenger syndrome. Half of
all patients with large (1 cm) VSDs will develop PAH; sinus
venosus ASD with partial anomalous pulmonary venous return causes PAH in 12% of cases, versus 4% of secundum
ASD cases.
On CT and chest radiograph, the central pulmonary arteries may be outlined by linear calcifications representing atheromatous plaque (Fig. 14A). Dilated central pulmonary arteries may develop chronic thrombus due to sustained
turbulent flow. The central pulmonary arteries may become
so large that they produce airway compromise. Echocardiography identifies most intracardiac shunts (ASD, VSD), but CT
with its larger field of view and anatomic detail can reveal
septal defects as well as a sinus venosus defect, patent ductus
arteriosus, or anomalous pulmonary venous return (Fig.
14B). Bronchial arterial collateral vessels and peripheral nod-

ular neovascularity are occasionally evident as angiocentric

pulmonary nodules4,5,41-43 (Fig. 14C).

Thromboembolic
Vaso-Occlusion
Chronic Thromboembolic PH
CTEPH (group 4) is not easily discerned clinically from other
causes of PAH, including IPAH. Approximately 4% of acute
pulmonary embolism cases may progress to CTEPH within 2
years. Risk factors include elevated factor VIII, antiphospholipid antibodies, malignancy, chronic inflammatory disease,
previous splenectomy, and hypothyroidism. CTEPH appears
to be instigated by incomplete resolution of acute pulmonary
embolism followed by vascular inflammation, fibroblast migration, obstruction, recanalization, and segmental vessel
contraction. The disease has an additional critical dimension,
a distal small-vessel vasculopathy, which mirrors the histology of IPAH. Prognosis of CTEPH is poor without surgical
treatment. Pulmonary endarterectomy provides potential
cure, but 15%-50% of postoperative patients experience ongoing functional limitations due to persistent central vessel
stiffness, residual distal small-vessel remodeling, and/or incomplete right ventricular recovery.44-49
Ventilation-perfusion (VQ) scintigraphy and CT are complementary modalities for the detection of CTEPH. The diagnosis is evidenced by wedge-shaped perfusion defects on VQ
scintigraphy. CT may reveal broad-based soft-tissue filling
defects in central pulmonary arteries (Fig. 15A), as well as
more distal findings of abrupt vascular contraction, webs, or
obliteration. CT MIP images often delineate compensatory
enlarged bronchial and nonbronchial chest wall collateral
vessels (Fig. 15B). Mosaic perfusion reveals alternating zones
of oligemia and hyperemia due to patchy vaso-occlusion (Fig.
15C, D). Peripheral linear scars reflect healed pulmonary infarcts. MR imaging may be used for preoperative and postoper-

The imaging of pulmonary hypertension

543
ative assessment of the pulmonary circulation and right ventricular function. For example, MR demonstrates the restoration of
right ventricular modeling and function after successful thromboendarterectomy in CTEPH.50 MR angiography and phasecontrast imaging demonstrate vascular patency and pulmonary
arterial flow dynamics.6,26,46,51,52

Tumor Thromboembolism
Tumor thromboembolism (group 5) is found in at least 30%
of patients dying of malignancies, including renal cell carcinoma, hepatocellular carcinoma, breast carcinoma, gastric
carcinoma, prostate carcinoma, melanoma, and choriocarcinoma. Intravascular tumor cells may occlude and expand
distal vessels, and are often associated with lymphangitic carcinomatosis. In rare cases, tumor emboli may incite a widespread rapidly progressive obliterative fibrointimal proliferation termed tumor thrombotic microangiopathy. Fatal right
heart failure follows onset of dyspnea in a matter of weeks.
This condition is recognized postmortem in at least 3% of
patients dying with adenocarcinoma (up to 25% incidence in
gastric carcinoma) but is usually missed during its aggressive
clinical course. CT findings suggestive of tumor thromboembolism and tumor thrombotic microangiopathy include
beading and focal dilatation of lobar and segmental arteries,
tree-in-bud opacities, and occasionally peripheral wedgeshaped opacities (evolving pulmonary infarction) (Fig. 16A,
B). The tree-in-bud opacities, representing centrilobular vessels expanded with tumor thromboembolism, are a rare
mimic of bronchiolitis.26,53,54

IV Talcosis

Figure 14 Congenital heart disease and PAH. (A) Posteroanterior

chest radiograph in an adult with uncorrected atrial septal defect
shows cardiomegaly with massive dilatation of central pulmonary arteries outlined by linear calcifications. (B) Contrast-enhanced coned axial CT image (mediastinal window) in a young
adult with PAH shows a ventricular septal defect (arrowhead)
and right ventricular hypertrophy (arrow). (C) Axial CT image
(lung window) in same patient as (B) shows faint nodular densities in peripheral lung (arrows) suggesting neovascularity or
peripheral collateral vessels.

IV talcosis (group 5) is observed in drug addicts. The IV

injection of crushed oral pharmaceutical tablets containing
talc as a binding agent incites a vigorous foreign body granulomatous response within the distal pulmonary arteries.
The occlusive talc emboli promote in situ thrombosis and
perivascular granuloma formation, ultimately leading to elevated peripheral vascular resistance. Unusual cases progress
to interstitial fibrosis, parenchymal emphysema, and right
heart failure. CT manifestations comprise diffuse centrilobular and subpleural micronodules and diffuse ground-glass
opacities (Fig. 17A). Bilateral high-density perihilar masses,
pulmonary architectural distortion, and lower-lobe emphysema are seen in advanced disease (Fig. 17B). The CT appearance of IV talcosis mimics sarcoidosis, silicosis, and granulomatous infection.55-57

Pulmonary Interstitial
Disease and Hypoxic States
In the setting of many obstructive or restrictive interstitial
lung diseases, associated PH significantly diminishes patient
functional status and survival. This is well recognized in
COPD and IPF. Additional pulmonary diseases associated in
this category include chronic bronchiectasis, cystic fibrosis, pul-

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544

Figure 15 Imaging of chronic thromboembolic PH. (A) Contrast-enhanced axial CT image (mediastinal window) shows
dilated main PA and broad-based, partly calcified, intravascular soft-tissue density with obtuse angles to the intimal
surface compromising the right main PA (arrows). (B) Contrast-enhanced axial MIP CT image (mediastinal window)
shows an enlarged main PA, peripheral endovascular webs (arrows), tortuous bronchial arterial collaterals in the
mediastinum, and peripheral corkscrew vessels (arrowheads) in the left lower lobe. (C) Coronal minimum intensity
projection CT image (lung window) confirms the presence of mosaic attenuation. (D) Matching coronal MIP CT image
(mediastinal window) confirms regional variations in vascular perfusion, bronchial arterial collaterals (arrows), and
endovascular webs (arrowheads).

monary Langerhans cell histiocytosis, idiopathic nonspecific interstitial pneumonia (NSIP), and smoking-related pulmonary
fibrosis. PH related to sleep disordered breathing, chronic hypoventilation syndromes, and high altitude exposure is also included in group 3. As a general rule, the degree of underlying PH
is mild to moderate in this category, even with advanced lung
disease. However, a small subset of disproportionate PH exists
when the hemodynamic derangement and right heart strain approach the severity of IPAH and clearly outweigh the apparent
extent of pulmonary disease. These cases are enigmatic, given
that the pulmonary vascular disease is largely regarded as a consequence of the parenchymal disease. Most clinical investigators
suggest that comorbidities such as left ventricular disease, coincident obstructive sleep apnea, and thromboembolic disease are
at least contributory in cases of disproportionate PH, and that

such potential factors should be rigorously sought for directed

treatment.4,5,39,58-62

Chronic Obstructive Pulmonary Disease

COPD (group 3) with underlying mild PH is common, but
only 5%-10% of COPD patients develop an accelerated clinical course with mPAP 40 mm Hg and right ventricular
dysfunction (prevalence: 2-6/1000). It is well recognized
that the presence of PH in COPD is associated with reduced survival. Proposed mechanisms for PH in COPD
range from hypoxic-induced vasoconstriction to irreversible vascular remodeling with diminished distensibility.
Contributory factors include tobacco exposure, endothelial dysfunction, pulmonary hyperinflation, and lung destruction. It is important to note that the presence and

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545

Figure 16 Tumor thromboembolism and PAH. (A) Renal cell tumor thromboembolism with expanded bead-like
configuration of a right middle lobe PA (arrow) on coned axial CT image (lung window). (B) Tumor thrombotic
microangiopathy in a patient with gastric carcinoma and rapid development of cor pulmonale shows prominent
peripheral branching arteries (arrows) dilated by intravascular tumor and fibroproliferative tissue on coned axial CT
image (lung window). (Courtesy of Tomas Franquet, MD.)

severity of PH in COPD does not correlate with the extent

of parenchyma emphysema.59,63-65

relate with severity of parenchymal disease: significant hemodynamic derangement can exist in the absence of overt
clinical or radiologic lung abnormalities.39

Idiopathic Pulmonary Fibrosis

The prevalence of PH in IPF (group 3) ranges widely (8%85%) with increased morbidity and mortality. Factors contributing to the development of PH include vasoconstriction
(due to chronic or intermittent nocturnal hypoxia), imbalance of mediators controlling angiogenesis and angiostasis,
pulmonary inflammation, and interstitial fibrosis. CT findings of classic IPF include decreased lung volumes, reticulation, ground-glass opacities, traction bronchiectasis,
and subpleural bibasilar honeycombing. Unfortunately,
neither the severity of pulmonary fibrosis nor the CTderived main PA diameter correlates with the measure of
elevated mPAP in IPF patients. Pulmonary function variables are more reliable as a screening tool for PH in IPF
than CT-derived findings. Diffusion lung capacity for carbon monoxide correlates inversely with PH, and may be
the most critical parameter overall to assess status and
prognosis in IPF complicated by PH.58,66-70

Associated Systemic Disorders

This section describes a group of diseases strongly associated with PAH. Although a clear cause currently eludes
researchers, the PAH is currently regarded as multifactorial and results from variable measures of autoimmunity, vasculitis, vasoconstriction, hypercoagulability, cardiac disease, and
pulmonary parenchymal disease. It is again notable that
the presence and severity of PAH does not uniformly cor-

Connective Tissue Disease-Associated PAH

Connective tissue disease-associated PAH (CTD-PAH) (group
1) is most strongly documented in female patients with systemic
sclerosis (scleroderma), and its presence significantly worsens
patient prognosis. The prevalence of scleroderma-associated
PAH ranges from 7% to 26%. Patients with systemic lupus
erythematosus develop PAH with a lower prevalence (0.4%14%) and have a better 3-year survival rate than scleroderma
(78% vs 47%). PAH develops much less frequently in polymyositis, dermatomyositis, and rheumatoid arthritis, with
lower severity and impact. Patients with CTD-PAH tend to
show a mild restrictive defect with significantly reduced diffusion lung capacity for carbon monoxide. It is important to
note that although CTD-PAH is usually associated with a CT
pattern of NSIP, severe PAH may exist in the absence of
pulmonary parenchymal disease. CT clues for CTD-PAH include ground-glass opacities, reticulation and bronchiectasis
in the absence of significant honeycombing (ie, NSIP),
esophageal dilatation, degenerative bony disease, and/or softtissue calcifications. Pleural effusions are frequently present
(about one-third of patients) and correlate closely with right
heart failure. Pericardial effusions are also common.1,39,62,71,72

Chronic Hemolytic Anemias

Chronic hemolytic anemias (group 1), including sickle cell
disease (SCD), thalassemia, hereditary spherocytosis, and

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546

monary infarcts, band-like scars, thickened septal lines,

and ground-glass opacities. Dilated central pulmonary arteries, right ventricular hypertrophy, and/or left-sided cardiomegaly may be present.3,23,26,39,73-76

Sarcoidosis
Sarcoidosis (group 5) is a systemic granulomatous disorder
complicated by PH in 5%-74% of patients, most often in
those awaiting lung transplantation. PH in this setting is an
independent predictor for increased mortality. Sarcoidosisassociated PH has an estimated 5-year survival of 59% and
correlates strongly with increased oxygen requirements and
lowered spirometric and diffusing capacity measurements.
Right ventricular failure is identified in almost 30% of sarcoid-related deaths. Although the majority of sarcoidosis patients with PH demonstrate stage IV disease, at least 50% of
those with stage III disease also manifest elevated PAP (25
mm Hg), and 40%-60% of sarcoidosis patients with PH have
no radiographic evidence of pulmonary fibrosis. This suggests additional vasculopathic factors are active, including
granulomatous inflammation (including vasculitis), thrombosis, vasoconstriction, sarcoid-related veno-occlusive disease, and autoimmunity. Compressive lymphadenopathy
and left ventricular disease may further complicate the disorder. Radiologic findings of stage IV sarcoidosis with PH include an enlarged main PA with perihilar fibrosis, upward
hilar traction, cysts, honeycombing, and emphysema. Cardiac MR imaging may reveal right ventricular hypertrophy,
chamber dilatation, and altered ejection fraction.77-81

HIV-Related PAH
Figure 17 Intravenous talcosis and PAH. (A) Coronal reformat thinsection CT image (lung window) shows diffuse miliary and groundglass nodular opacities, subtle mosaic attenuation, and mildly dilated pulmonary arteries. (B) Coronal reformat thin-section CT
image (mediastinal window) in a more advanced stage of IV talcosis
shows dense perihilar masses containing chronic granulomatous
inflammation and coalescent talc particles.

microangiopathic hemolytic anemia, are among the most

common causes of PAH. Mild PAH (detected at TTE) affects
20%-50% of SCD patients and 10%-75% of thalassemia patients. It is a major independent risk factor for morbidity and
mortality. The pathogenesis is likely multifactorial and comprises vasoconstriction, hemolysis, thrombosis, anemia,
asplenia, chronic liver disease, and cardiac dysfunction.
Investigators also propose vascular insensitivity to mediators of vasodilation and angioproliferation. In SCD, PH
has a hemodynamic profile of mild PAP elevation (30-40
mm Hg) occasionally accompanied by postcapillary (venous) hypertension and left ventricular diastolic dysfunction. During episodes of acute chest syndrome, mPAP further elevates and increases the risk of death as sickle cells
impact distal arteriolar and capillary vessels. CT in SCD
may show evidence of evolving or healed subpleural pul-

HIV-related PAH (group 1) has a prevalence of 0.5%, essentially unchanged since the early 1990s. As antiretroviral therapies improve long-term survival in HIV patients, noninfectious complications, such as PAH, remain constant. The
3-year survival rate of HIV-related PAH is 70%. A history of
IV drug use appears to increase the risk of developing PH in
HIV-positive patients. HIV-related PH may have an aggressive clinical course irrespective of the stage of HIV disease,
but may be more severe in HIV/AIDS. The mechanism is not
well understood, but chronic inflammation, immune activation, viral proteins, and elaboration of growth factors
may be important. Imaging findings may show an enlarged
main PA along with evidence of underlying HIV-related
disease, such as opportunistic infection, lymphoma, or
pulmonary Kaposis sarcoma.82-85

Schistosomiasis
Schistosomiasis (group 1), one of the worlds ancient and
most prevalent infectious diseases, is complicated by PH in
1%-5% of the 200 million people chronically infected by the
causative parasite Schistosoma mansoni. In Brazil, a 15%
3-year mortality for schistomiasis-related PAH is reported,
with a clinical severity similar to IPAH. The cascade of vascular injury includes a subacute immune-complex hypersensitivity response accompanied by embolization of Schistosoma ova throughout the pulmonary circulation via

The imaging of pulmonary hypertension

547

hepatosplenic disease. There is consequent periovular

granulomatous vasculitis and perivascular fibrosis. Underlying portal hypertension is contributory. Acute schistosomiasis (Katayama syndrome) may manifest with bilateral nodular lung consolidations, but chronic parasitic
infection is characterized on CT by septal thickening, diffuse or mosaic ground-glass opacity, and nodules that are
occasionally calcified.26,86,87

PVOD and PCH

PVOD and PCH are rare and aggressive idiopathic subgroups
of PAH that typically manifest in young to middle-aged adult
patients. PVOD is defined by widespread occlusive intimal
fibrosis of the small pulmonary veins and venules. PCH is
characterized by multiple nodular lesions of capillary proliferation. Both diseases produce severe elevations of mPAP
with rapid clinical progression over months to a few short
years, and both are difficult to discern from IPAH. Lung
biopsy is required for definitive diagnosis but generally regarded as high risk in these patients.

Pulmonary Veno-Occlusive Disease

PVOD (group 1) presents with a confusing picture of PAH,
normal PCWP, and normal left-sided cardiac and valvular
function despite radiologic signs of pulmonary edema. The
PCWP is usually normal in PVOD because this technique
measures pressure within the larger pulmonary veins and left
atrium, neither of which is directly affected by PVOD. Annual
incidence is approximately 0.1-0.2 cases per million persons,
with male and female patients affected equally. Patients suffer
almost 75% mortality within 1 year of diagnosis, higher than
IPAH. No causative agent is yet identified, but reported associations include chemotherapy, bone marrow transplantation,
pregnancy, HIV infection, and tobacco exposure. Owing to similarities in clinical presentation and tempo, at least 5%-10% of
cases initially diagnosed as IPAH are actually PVOD. PVOD also
shares immune characteristics of IPAH, with autoantibodies detected in 33%. Recognition and discernment of PVOD from
IPAH is essential to avoid potentially fatal florid pulmonary
edema induced by inappropriate administration of PAH-specific
therapies, especially epoprostenol. Clinical and hemodynamic
parameters may assist in this differentiation.

Figure 18 PVOD in a young adult male. Coned axial CT image (lung

window) shows geographic ground-glass densities, extensive thickened septal lines (arrowheads), and enlarged peripheral pulmonary
arteries. Note the CT correlation with PVOD pathology of septal
thickening and fibrosis (Fig. 3C, D).

Chest radiography in PCH shows PAH along with faint diffuse

or fine nodular opacities. On CT, central PA enlargement is
accompanied by widespread centrilobular ground-glass nodules, often mixed with lobular zones of ground glass (Fig. 19).
Less commonly, thickened septal lines, pleural effusion, lymphadenopathy, and/or pericardial effusion are present. The shared
CT findings of PVOD and PCH support overlap in these disorders. CT findings that help to distinguish these disorders from
IPAH include the presence of septal lines and ground-glass nodular or geographic opacities.88-92

Pulmonary Capillary Hemangiomatosis

PCH (group 1) is an even more rare diagnosis of multifocal
angiomatous capillary proliferation leading to critical PAH. It
usually occurs in young adults (mean age: 30 years). There is
both clinical and histologic overlap in PCH and PVOD.88-92
Chest radiography in PVOD shows main PA enlargement,
prominent septal (Kerley B) lines, pleural effusion, and normal left heart contour. CT demonstrates dilated central pulmonary arteries, centrilobular or geographic ground-glass
opacities, and smoothly thickened interlobular septa in the
presence of a normal-sized left atrium (Fig. 18). Occasionally,
diminutive pulmonary veins, peribronchial cuffing, mediastinal
lymphadenopathy, and/or pericardial effusion also are evident.

Left-Sided Cardiac Disease

PH Secondary to
Left-Sided Cardiac Disease
PH secondary to left-sided cardiac disease (group 2) reflects
retrograde transmission of elevated pressure across the postcapillary circulation and capillary bed. PH in this scenario is
defined as an mPAP of 20 mm Hg with a pulmonary wedge
pressure of 15 mm Hg. The distinction between PAH and
pulmonary venous hypertension due to left heart disease is crucial because treatment and prognosis are different. Myocardial
disease with systolic or diastolic failure, valvular disorders,

548

A.A. Frazier and A.P. Burke

appears to be an immune-mediated fibroinflammatory disease provoked by sarcoid-related lymphadenitis or previous
mycobacterial or fungal infection, most commonly Histoplasma capsulatum in North America. Proliferative fibrous tissue narrows central pulmonary arteries and/or draining pulmonary veins, potentially impacting both sides of the

Figure 19 PCH in a young adult female. Coned axial CT image (lung

window) demonstrates multiple ground-glass nodules (arrowheads) and a few thickened septal lines. Note the CT correlation
with PCH pathology of multifocal, circumscribed lesions of alveolar
capillary proliferation (Fig. 3A, B).

pericardial constriction, or left-sided chamber masses, all

may critically impede pulmonary venous return. The prevalence of PH is 40%-70% in isolated diastolic dysfunction,
60% in left ventricular systolic dysfunction, and up to 100%
in severe left-sided valvular disease. Treatment is targeted to
the underlying cardiac condition, most often identified at
TTE or CT.4,5,41,93
CT evidence of pulmonary venous dilatation and smoothly
thickened septal lines are clues to pulmonary venous congestion
and a left-sided cardiac etiology for PH. CT findings of underlying mitral valve disease include leaflet thickening, calcifications,
and left atrial chamber dilatation. Aortic valve calcification and
left ventricular myocardial thickening suggest the presence of
aortic stenosis. An unsuspected left atrial chamber mass compromising pulmonary venous return (eg, thrombus, myxoma)
may be discovered on CT, TTE, or MR imaging.41

Extravascular Constriction
Any lesion that encases central pulmonary vessels can produce PH by extrinsic vasoconstriction. Central lung neoplasm, fibrosis after radiation therapy, and mediastinal fibrosis can each produce secondary PH, and its presence
negatively impacts prognosis. Mediastinal fibrosis (group 5)

Figure 20 Mediastinal fibrosis and PH. (A) Contrast-enhanced axial

MIP CT image (mediastinal window) shows a dilated main PA and a
partly calcified right hilar soft-tissue mass (arrow) severely constricting the right main PA. Tortuous corkscrew peripheral vessels
are noted in the left lower lobe. (B) Axial MIP CT image (lung
window) in the same patient shows that this calcified soft-tissue
mass (arrow) also obliterates the atrial orifice of the right inferior
pulmonary vein. The right lung demonstrates pulmonary venous
hypertension, including ground-glass opacity and thickened septal
lines. The left lung demonstrates pulmonary arterial dilatation (reflecting redistribution of blood flow and possible underlying vasculopathy) with mosaic attenuation.

The imaging of pulmonary hypertension

pulmonary circulation. Clinical presentation of dyspnea,
cough, and hemoptysis mimics chronic thromboembolic disease. Ultimately, biopsy may be necessary in the absence of
convincing diagnostic criteria.
VQ scintigraphy in constrictive mediastinal fibrosis mirrors CTEPH with unilateral or bilateral unmatched perfusion
defects. CT typically shows a focal right-sided and coarsely
calcified hilar soft-tissue density (Fig. 20A). Axial CT as well
as 3-dimensional reconstructed images (including contrastenhanced MIPs) facilitate direct visualization and extent of
vessel encasement as well as redirected blood flow to the
contralateral lung or through collateral bronchial, intercostal,
and internal mammary arteries. With direct venous obstruction, lung parenchymal changes on CT include dilated pulmonary veins, thickened interlobular septa, prominent bronchial walls, ground-glass opacities, and paraseptal venous
infarcts, which all reflect significant pulmonary venous congestion (Fig. 20B). Positron emission tomography scans
show increased metabolic activity within active inflammatory
lesions. CT imaging clues may help distinguish this entity
from CTEPH or neoplasia and may be used to determine
surgical resectability, vascular stent placement, and clinical
response to anti-inflammatory or antifungal therapies.80,94-98

Conclusions
PH is a critical hemodynamic derangement of the pulmonary
circulation driven by complex cascades of inflammation, vasoconstriction, embolic phenomena, and vascular remodeling. Extrinsic agents, systemic diseases, idiopathic disorders,
congenital lesions, hypoxic states, and comorbidities comprise the spectrum of PH. Often a relentlessly progressive
condition of insidious onset, PH warrants early detection and
diagnostic categorization according to the recent Dana Point
classification system. This task is essential to determine
timely and appropriate therapeutic intervention and prognosis. In cases of disproportionate PH, it is also important to
exclude any contributory disorder requiring additional directed treatment, such as left heart disease or mediastinal
fibrosis.
Radiologic imaging provides an essential tool for the comprehensive analysis of the pulmonary vasculature, lung parenchyma, and cardiac morphology and function in PH.
Chest radiography, VQ imaging, and CT help to localize the
primary site of disease as either precapillary or postcapillary,
and further may provide insight into the underlying etiology
of PH. Cardiac structural and functional assessment directed
to the RV, the most important prognostic factor in PH, should
be performed with echocardiography and cardiac MR imaging. In the future, radiological imaging may become widely
used in the functional and physiologic evaluation of the cardiopulmonary system in PH for meaningful therapeutic surveillance.

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