Pulmonary hypertension in idiopathic pulmonary fibrosis: a review.
ABSTRACT Pulmonary hypertension (PH) is a common in patients with idiopathic pulmonary fibrosis (IPF) referred for transplantation. When present, PH is associated with increased mortality, and may explain the deterioration of some patients with preserved pulmonary function. PH in IPF may develop as a consequence of, or disproportionate to the underlying fibrotic lung disease. The distinction between these two 'stages' of PH is essential as there are key differences in their pathophysiology, identification, and potential treatment options. Treatment advances in idiopathic pulmonary artery hypertension have focused attention on PH associated with underlying lung disease. We focus on pathogenetic mechanisms, identification of PH, and the potential for therapeutic intervention for PH in IPF. Although vascular ablation, and chronic hypoxia are both important in the aetiology of secondary PH, these mechanisms do not explain the development of disproportionate PH. In these patients, the early development of PH may be associated with increased fibrotic cell mediators, abnormal vasculature or response to hypoxia, seen in IPF. Nocturnal and exercise desaturation are common in IPF, and may precede and contribute to the development PH. Therapeutic options for PH in IPF are limited, and there have been no controlled trials. Successful therapeutic intervention in pulmonary arterial hypertension, has led to suggestions that therapeutic intervention with PH specific therapy may be useful. However, controlled trials are warranted before therapy can be recommended. In the design of such trials, the distinction between secondary and disproportionate PH is essential.
- Arthritis & Rheumatology. 05/2014; 66(8).
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ABSTRACT: Chronic obstructive lung disease (COPD) and diffuse parenchymal lung diseases (DPLD), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis, are associated with a high incidence of pulmonary hypertension (PH), which is linked with exercise limitation and a worse prognosis. Patients with combined pulmonary fibrosis and emphysema (CPFE) are particularly prone to the development of PH. Echocardiography and right heart catheterization are the principal modalities for the diagnosis of COPD and DPLD. For discrimination between group 1 PH patients with concomitant respiratory abnormalities and group 3 PH patients (PH caused by lung disease), patients should be transferred to a center with expertise in both PH and lung diseases for comprehensive evaluation. The task force encompassing the authors of this article provided criteria for this discrimination and suggested using the following definitions for group 3 patients, as exemplified for COPD, IPF, and CPFE: COPD/IPF/CPFE without PH (mean pulmonary artery pressure [mPAP] <25 mm Hg); COPD/IPF/CPFE with PH (mPAP ≥25 mm Hg); PH-COPD, PH-IPF, and PH-CPFE); COPD/IPF/CPFE with severe PH (mPAP ≥35 mm Hg or mPAP ≥25 mm Hg with low cardiac index [CI <2.0 l/min/m(2)]; severe PH-COPD, severe PH-IPF, and severe PH-CPFE). The "severe PH group" includes only a minority of chronic lung disease patients who are suspected of having strong general vascular abnormalities (remodeling) accompanying the parenchymal disease and with evidence of an exhausted circulatory reserve rather than an exhausted ventilatory reserve underlying the limitation of exercise capacity. Exertional dyspnea disproportionate to pulmonary function tests, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation upon exercise are typical clinical features of this subgroup with poor prognosis. Studies evaluating the effect of pulmonary arterial hypertension drugs currently not approved for group 3 PH patients should focus on this severe PH group, and for the time being, these patients should be transferred to expert centers for individualized patient care.Journal of the American College of Cardiology 12/2013; 62(25 Suppl):D109-16. · 15.34 Impact Factor
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ABSTRACT: A significant proportion of patients with idiopathic pulmonary fibrosis have concurrent pulmonary hypertension. In most, elevations in pulmonary pressures are modest, but approximately 10 % have disproportionately elevated pulmonary pressures. Pulmonary hypertension is associated with decreased functional status and increased mortality. The etiology remains incompletely understood, but likely involves a complex interplay of abnormal angiogenesis, vascular ablation, remodeling, and vasoconstriction. Transthoracic echocardiogram, six-minute walk testing, pulmonary function testing and biomarkers may suggest pulmonary hypertension, but none are sensitive or specific enough to rule in or exclude the diagnosis. Right heart catheterization remains the diagnostic gold standard. Supplemental oxygen should be provided if required and sleep-disordered breathing should be addressed. Small trials suggest that vasodilator therapy may improve exercise tolerance, but no mortality benefit has been demonstrated. Patients with disproportionate pulmonary hypertension should be encouraged to enroll in clinical trials of vasodilator therapy so that the role of these agents can be better defined. Ultimately, genetic profiling technology may serve to individualize therapy in such patients.Current Respiratory Care Reports. 12/2012; 1(4).
In idiopathic pulmonary fibrosis (IPF), varia-
tions in disease course and survival limit the accu-
racy of prognostic evaluation. Disease severity and
serial declines in pulmonary function tests are inde-
pendent predictors of subsequent progression (1-4),
but clinical deterioration is not always associated
with overt changes in the severity of interstitial lung
disease. Pulmonary vascular limitation is increas-
ingly recognised as a major complication of the dis-
The reported prevalence of pulmonary hyper-
tension (PH) ranges from 31% to 85% (5-10). The
presence of PH in IPF is associated with higher
mortality (7, 11, 12), and its development con-
Pulmonary hypertension in idiopathic pulmonary fibrosis: a
T.J. Corte1, S.J. Wort1, 2, A.U. Wells1, 2
1 Department of Thoracic Medicine Royal Brompton Hospital, London, UK;2 Imperial College, London, UK
Abstract. Pulmonary hypertension (PH) is a common in patients with idiopathic pulmonary fibrosis (IPF)
referred for transplantation. When present, PH is associated with increased mortality, and may explain the de-
terioration of some patients with preserved pulmonary function. PH in IPF may develop as a consequence of,
or disproportionate to the underlying fibrotic lung disease.The distinction between these two ‘stages’ of PH is
essential as there are key differences in their pathophysiology, identification, and potential treatment options.
Treatment advances in idiopathic pulmonary artery hypertension have focused attention on PH associated with
underlying lung disease. We focus on pathogenetic mechanisms, identification of PH, and the potential for
therapeutic intervention for PH in IPF. Although vascular ablation, and chronic hypoxia are both important in
the aetiology of secondary PH, these mechanisms do not explain the development of disproportionate PH. In
these patients, the early development of PH may be associated with increased fibrotic cell mediators, abnormal
vasculature or response to hypoxia, seen in IPF. Nocturnal and exercise desaturation are common in IPF, and
may precede and contribute to the development PH.Therapeutic options for PH in IPF are limited, and there
have been no controlled trials. Successful therapeutic intervention in pulmonary arterial hypertension, has led
to suggestions that therapeutic intervention with PH specific therapy may be useful. However, controlled trials
are warranted before therapy can be recommended. In the design of such trials, the distinction between sec-
ondary and disproportionate PH is essential. (Sarcoidosis Vasc Diffuse Lung Dis 2009; 26: 7-19)
Key words: Interstitial lung disease, idiopathic pulmonary fibrosis, pulmonary hypertension, pathogenesis,
right heart catheter, echocardiogram, six minute walk test, brain natriuretic peptide, nocturnal desaturation,
Received: 11 February 2009
Accepted after Revision: 7 June 2009
Correspondence: Prof. Athol. U. Wells,
Royal Brompton Hospital, Sydney st,
London SW3 6NP, United Kingdom
Tel. +44 207 3528121
Fax + 44207 3497769
SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2009; 26; 7-19© Mattioli 1885
T.J. Corte, S.J. Wort, A.U. Wells
tributes to the deterioration of IPF patients. PH is
more frequent when underlying fibrosis is severe,but
may occur at any stage of the disease process (7, 13,
14). In the context of advanced fibrosis, PH may be
‘secondary’ to the underlying disease. In milder dis-
ease, the pathogenesis, and clinical implications of
PH may differ from PH in advanced fibrosis.There-
fore, we consider PH in IPF in two ‘stages’: PH sec-
ondary to underlying lung disease, and dispropor-
Historically, the importance of PH in IPF has
been under-recognised. However, treatment ad-
vances in idiopathic pulmonary artery hypertension
(PAH) have focused attention on PH associated
with underlying lung disease. We focus on patho-
genetic mechanisms, identification of PH, and the
potential for therapeutic intervention for PH in
Definition and Classification of Pulmonary
PH is defined by the following hemodynamic
parameters: sustained mean pulmonary arterial pres-
sure (mPAP) ≥25mmHg at rest or ≥30mmHg dur-
ing exercise, pulmonary capillary wedge pressure
≥15mmHg and pulmonary vascular resistance
(PVR) ≥3Wood units.m2.
In the reclassification of PH at the 2003 World
Symposium in Venice (Table 1) (15-17), PH associ-
ated with lung disease was unified as a single group,
based on a perception that it results from chronic hy-
poxia. The prevailing view, based on chronic ob-
structive pulmonary disease (COPD) data, has been
that secondary PH is usually mild (18-21) with mor-
tality determined by the severity of the underlying
lung disease. Importantly, PH in some interstitial
disorders (including sarcoidosis, Langerhan’s cell
Table 1.Venice Classification of Pulmonary Arterial Hypertension (15, 17)
1. Pulmonary arterial hypertension
1.3 Associated with:
1.3.1 Collagen vascular disease
1.3.2 Congenital systemic-to-pulmonary shunts
1.3.3 Portal hypertension
1.3.4 HIV infection
1.3.5 Drugs and toxins
1.3.6 Other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglo-
binopathies, myeloproliferative disorders, splenectomy)
1.4 Associated with significant venous or capillary involvement
1.4.1 Pulmonary veno-occlusive disease
1.4.2 Pulmonary capillary hemangiomatosis
1.5 Persistent pulmonary hypertension of the newborn
2. Pulmonary hypertension with left heart disease
1.1 Left-sided atrial or ventricular heart disease
2.2 Left-sided valvular heart disease
3. Pulmonary hypertension associated with lung diseases and/or hypoxemia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Sleep disordered breathing
3.4 Alveolar hypoventilation disorders
3.5 Chronic exposure to high altitude
3.6 Developmental abnormalities
4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease
4.1 Thromboembolic obstruction of proximal pulmonary arteries
4.2 Thromboembolic obstruction of distal pulmonary arteries
4.3 Non-thrombotic pulmonary embolism (tumour, parasites, foreign material)
Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumour, fibrosing mediastinitis)
Pulmonary hypertension in idiopathic pulmonary fibrosis
histiocytosis) are included in a separate miscella-
neous subgroup (17), as the link to hypoxemia is less
certain in these conditions. As discussed in this re-
view, the same consideration applies to an important
sub-group of IPF patients, in whom PH is dispro-
portionate to the severity of the underlying lung dis-
Prevalence of PH in IPF
PH is frequent in IPF, especially in severe dis-
ease. Most studies of PH in IPF are in patients re-
ferred for lung transplantation, in which the report-
ed prevalence of PH is 32% to 46% (7-9,13,22,23).
PH develops over time in these patients, as demon-
strated by the rise in prevalence of PH in IPF pa-
tients awaiting transplantation from 33% at initial
assessment to up to 85% immediately prior to trans-
plantation (8,10).However,it is likely that the over-
all prevalence of PH in IPF is lower than in patients
referred for transplantation.
However, PH is not confined to patients with
advanced lung disease. Even in IPF transplantation
referral cohorts, there is no correlation between the
presence or the severity of PH and the extent of dis-
ease on high resolution computed tomography (CT),
the forced vital capacity (FVC) or the composite
physiological index (7, 13, 14, 24). However, the ex-
act prevalence of disproportionate PH is uncertain,
despite its obvious pathogenetic importance. Selec-
tion bias imposes major constraints. Cross-sectional
prevalence studies are needed in IPF,to further char-
acterise the dichotomy between secondary and dis-
proportionate PH. Current studies, which are con-
fined to transplantation cohorts, necessarily fail to
make this essential distinction.
Prognostic Significance of PH in IPF
The presence of PH is a malignant prognostic
determinant in IPF patients (7,11,12). Systolic pul-
monary artery pressure (sPAP) >50mmHg on
echocardiography is associated with a median sur-
vival of 0.7yrs, compared to 4.1yrs for a sPAP of 36-
50mmHg, and 4.8yrs for a sPAP of ≤35mmHg (11).
In another IPF study, five year survival was lower in
patients with mPAP >17mHg (16.7%) than for pa-
tients with mPAP ≤17mmHg (62.2%) (12). PH has
also been associated with a worse outcome in IPF
patients following pulmonary transplantation (25).
These findings have not been universally replicated.
In one study of patients referred for transplant as-
sessment,there was no correlation between hemody-
namic variables and survival (26), although the short
median survival time (5.7 months) in this cohort is
an important limitation. It is also uncertain whether
mild to moderate PH (as opposed to severe disease)
has prognostic significance. No conclusions can be
reached on this point, based on the echocardio-
graphic study of Nadrous (11), as pulmonary pres-
sures tend to be systematically over-estimated by
echocardiography in IPF (23). False positive diag-
noses of PH by echocardiography must necessarily
dilute the prognostic significance of the echocardio-
graphic definition of mild to moderate PH.
Histopathologic findings in PH
Histopathologic changes classic for PAH have
been observed in PH associated with hypoxia (27),
although not specifically studied in IPF. Indepen-
dent of the initial trigger, the structural changes of
the pulmonary bed in PH are often uniform (28,29).
Pulmonary vascular remodelling is complex, involv-
ing all layers of the vessel wall (29).Eccentric intimal
thickening occurs, with fibrotic, plexiform lesions
developing at branch points of ‘muscular’ arterioles,
containing ‘onion-skin’ layers of cells (both myofi-
broblasts and endothelial cells). Eventually, these le-
sions become concentric and encroach on the vessel
lumen.With time,they become less cellular,with ex-
tracellular matrix deposition (30). Smooth muscle
hypertrophy and extracellular matrix expansion are
relatively early findings; with smooth muscle hyper-
plasia playing a more minor role (30). Adventitial
thickness increases as fibroblasts deposit collagen,
inflammatory cells are recruited, and the adventitial
vasa-vasorum develops (31).
Pathophysiology of PH in IPF
The pathophysiology of PH in the context of
IPF is complex. Although multiple mechanisms are
likely to coexist in many cases, a broad pathogenetic
T.J. Corte, S.J. Wort, A.U. Wells
distinction can be made between secondary and dis-
proportionate PH. Fibrotic vascular ablation and
chronic hypoxic vasoconstriction appear to account
for PH secondary to advanced fibrosis but are less
applicable to disproportionate PH, although likely
to play an ancillary role in some cases. In patients
with PH out of proportion to underlying lung dis-
ease, putative aetiological factors have included mol-
ecular mediators common to PH and IPF, perturba-
tion of the balance between angiogenesis and an-
giostasis and intermittent hypoxia (especially during
sleep and exercise).
Secondary Pulmonary Hypertension
Historically, PH secondary to IPF was partially
explained by the fibrotic ablation of pulmonary ves-
sels, and the subsequent elevation in PVR. Vascular
ablation is likely to play a major part in the develop-
ment of PH in end-stage IPF, accounting for a rise
in the prevalence of PH from 33% to 85% over time
in a transplantation referral cohort (10). Plainly, this
mechanism is less relevant to the sub-group of pa-
tients with disproportionate PH.
Chronic hypoxia is important in the develop-
ment of secondary PH in patients with slowly pro-
gressive chronic conditions such as COPD or sys-
temic sclerosis-related fibrotic lung disease. Howev-
er, it does not explain the presence of PH in IPF pa-
tients with limited fibrosis or normoxia (7, 12-14,
24). Even in advanced IPF, chronic resting hypoxia
is a late finding and is, thus, unlikely to play a pri-
mary causative role for PH. However, hypoxia is a
frequent consequence of PH, as shown by a moder-
ate correlation between resting PaO2 and mPAP in
IPF (r=-0.47, p<0.001) (12), and may amplify dis-
ease severity in established PH. Furthermore,
longer-standing intermittent nocturnal hypoxia may
play a crucial role in the development of dispropor-
tionate PH. The mechanisms involved in the pul-
monary vascular response to hypoxia are, therefore,
Disproportionate Pulmonary Hypertension
1. Molecular mechanisms common to PH and IPF
Several cell mediators are involved in the patho-
genesis of both lung fibrosis and PH, suggesting an
overlap in the pathogenesis of these disorders. Pro-
duction of pro-fibrogenic cytokines such as 5-
lipoxygenase (5-LO) and transforming growth fac-
tor-β (TGF-β) are up regulated in both IPF and id-
iopathic PAH (32-34). Increased 5-LO leads, in
turn,to increased production of tumour necrosis fac-
tor-α (TNF-α), platelet-derived growth factor
(PDGF), and fibroblast growth factor, all of which
are important mediators of pulmonary vascular re-
modelling and lung fibrosis.
Prostaglandin-E2 (PGE2) levels are reduced in
the bronchoscopic lavage fluid of IPF patients (32)
and in the pulmonary vessels of patients with idio-
pathic PAH. Reduced PGE2 levels lead to increased
production of TNF-α and TGF-β both of which are
important in interstitial collagen deposition, and
pulmonary vascular remodelling.
Endothelin-1 (ET-1) is clearly important in the
pathogenesis of PH,with several studies showing in-
creased ET gene expression and ET-1 levels in en-
dothelial cells and plexiform lesions of patients with
idiopathic PAH (35).In idiopathic PAH,ET-1 plas-
ma levels (36) correlate with hemodynamic indices
of PH and inversely correlate with survival (37).ET-
1 also acts as a pro-fibrotic mediator. ET-1 levels are
elevated in the airway epithelium of rats with
bleomycin-induced fibrosis (38). Plasma ET-1 levels
are higher in IPF patients, than normal controls (39,
40). In IPF, ET-1 levels are also elevated in the air-
way epithelium, type-2 pneumocytes and pulmonary
vascular endothelial cells (particularly in the pres-
ence of superimposed PH) (40), correlating directly
with mPAP and indirectly with PaO2 (40-42).
ET-1 is produced mainly by endothelial cells,
but also by leukocytes, macrophages, and smooth
muscle cells (43). ET-1 gene expression is induced
by hypoxia, shear stress, and various growth factors
and cytokines (44). ET-1 acts directly on smooth
muscle cells, binding to ETAand ETBreceptors, ac-
tivating phospholipase C, with subsequent influx of
calcium ions, and vasoconstriction (45). It also acts
indirectly to stimulate cytokine and growth factor
production, with resultant extracellular matrix depo-
sition (43). ET-1 also stimulates inflammation and
platelet aggregation (46). It also binds to ETBrecep-
tors on endothelial cells stimulating nitric oxide
(NO) and prostacyclin release leading to endotheli-
um-dependent vasodilation. ET-1 thus has a bi-
modal effect, with an initial mild vasodilation, fol-
lowed by prolonged vasoconstriction (47).
Pulmonary hypertension in idiopathic pulmonary fibrosis
The role of these cell-mediators in both PH and
IPF suggests an underlying link in the pathogenesis
of these disorders, and may offer opportunities for
therapeutic interventions that are relevant to both
2. Angiostasis and Angiogenesis
There is evidence for both angiogenesis and an-
giostasis in the lungs of IPF patients.These conflict-
ing observations have been difficult to reconcile (48,
49). Turner-Warwick first described new vessel for-
mation in fibrotic lungs, with evidence of anasto-
moses between the pulmonary and systemic circula-
tion (50).Both angiogenic and angiostatic
chemokines are present, but despite a net pro-angio-
genic environment (51, 52), there is an overall re-
duction in vessel density (53). Traditionally, this re-
duction in vasculature was explained by fibrotic vas-
cular ablation. However, although total vessel densi-
ty is markedly reduced, vessel redistribution is seen
in areas of fibrosis. Vessels are absent within fibrob-
lastic foci, and microvascular density is decreased in
areas of extensive fibrosis, but increased in areas of
minimal fibrosis, and adjacent to fibroblastic foci
(53, 54). Phenotypically, the new vessels formed in
fibrotic areas are abnormal with an absent elastin
layer (51, 54).
It is unlikely that either angiogenesis or an-
giostasis alone are responsible for the development
of PH in IPF patients. The angiostatic reduction in
vessel density may contribute to elevation of the
PVR. In isolation, angiogenesis should not increase
PVR, as the newly formed thin-walled vessels are
unlikely to vasoconstrict effectively. However, it ap-
pears likely that balance of angiogenesis and an-
giostasis is lost in the IPF lung, with regional imbal-
ance leading to areas of angiogenesis (adjacent to fi-
broblastic foci) (53) and other areas of angiostasis.
One intriguing unifying hypothesis is that wide-
spread angiostasis may represent a homeostatic re-
sponse to focal angiogenesis, amplifying the devel-
opment of PH.
3. Adaptive Response to Intermittent Hypoxia
a) Pulmonary Vascular Response to Hypoxia
Chronic hypoxic pulmonary vasoconstriction
largely occurs in the ‘muscular’ pre-capillary arteri-
oles. This adaptive response allows redirection of
blood flow to better-ventilated lung, minimising
ventilation-perfusion mismatch,and subsequent ar-
terial hypoxia. Significant vasoconstriction occurs
at PAO2< 70mmHg within seconds of exposure to
hypoxic conditions, and reverses completely when
normoxia is restored (55). Multiple mechanisms
underlie the acute hypoxic vasoconstrictive re-
sponse. Initially, hypoxic conditions inhibit voltage-
gated potassium ion channels resulting in an influx
of calcium ions and subsequent vasoconstriction via
calmodulin-mediated myosin activation (55). Mi-
tochondria may play a role in sensing cellular hy-
poxia, although the precise mechanism remains un-
certain (56). Hypoxic vasoconstriction is dependent
on an intact pulmonary vascular endothelium (57),
and endothelium-derived factors, such as ET-1 are
important in its mediation (58). Thus, it is likely
that alveolar hypoxia has both a direct effect on ad-
jacent pulmonary arterioles, as well as an indirect
effect modulated by endothelial vasoactive media-
Chronic alveolar hypoxia leads to a sustained
vasospastic response,associated with pulmonary vas-
cular remodelling (59). Animal studies have shown
attenuation of hypoxia-induced PH by selective and
non-selective ET-1 antagonists, suggesting a key
role for the endothelin pathway in the pathogenesis
of PH (60). Down-regulation of synthesis of the va-
sodilator nitric oxide occurs in chronic hypoxia.
Serotonin, a potent pulmonary vasoconstrictor,
worsens PH in animal models of hypoxic PH (61).
Prolonged hypoxia is associated with an influx of
alveolar macrophages, neutrophils and pro-inflam-
matory cytokines, suggesting inflammation may play
a key role (62). When present, chronic hypoxia is an
important driving mechanism for pulmonary vascu-
b) The role of Intermittent Nocturnal Hypoxia
The prevalence of nocturnal desaturation in IPF
is not widely studied. However, nocturnal desatura-
tion is common in idiopathic interstitial pneumonia,
and is not related to the severity of underlying lung
disease (63). Based on these data, it is likely that the
prevalence of nocturnal hypoxia is high, and under-
recognised in IPF patients.
In a study of interstitial lung disease, nocturnal
desaturation was associated with a significant rise in
arterial ET-1 levels (64). The acute vasospastic re-
sponse to hypoxia occurs within seconds (55) and
T.J. Corte, S.J. Wort, A.U. Wells
ET-1 is an important mediator in vascular remodel-
ling and fibrosis. These factors suggest that pul-
monary vascular remodelling, and in turn, the devel-
opment of PH, might be driven by nocturnal hypox-
We propose that intermittent nocturnal hypox-
ia may precede and contribute to the development
of PH. Repetitive episodes of acute hypoxia result
in an acute rise in PVR (65) and eventually lead to
vascular remodelling (perhaps mediated by ET-1),
the hallmark of PH. Additionally, intermittent hy-
poxia may result in the resetting of peripheral
chemoreceptors, and lowering of patients’ hypoxic
drive, as seen in other nocturnal hypoventilation
syndromes (66, 67). This ‘desensitisation’ to hypox-
ia may make patients more vulnerable to exposure
to daytime and exercise-induced hypoxia, which in
turn, may also contribute to pulmonary vascular re-
c) The role of Intermittent Exercise Induced Hypoxia
Exercise desaturation is frequent in IPF, espe-
cially in severe disease, and is clearly associated with
higher mortality, independent of pulmonary func-
tion (68, 69). IPF patients with six-minute walk test
(6MWT) desaturation to 88% have a higher mortal-
ity, similar the increased mortality seen in IPF pa-
tients with PH (69). As exercise-induced hypoxia is
a feature of established PH, its presence may reflect
the development of PH, in some IPF patients.
However, we suggest that repetitive, exercise-
induced hypoxia may also precede and contribute to
the development of PH in IPF. In a recent study of
IPF patients without resting hypoxia, pulmonary
pressures increased during exercise. Although oxy-
gen desaturation did occur during exercise, oxygen
supplementation did not ameliorate the rise in pul-
monary pressures, suggesting that exercise-induced
hypoxia is not the only mechanism contributing to
the acute rise in pulmonary arterial pressures during
exercise (70). Plasma ET-1 levels rise acutely with
exercise desaturation (71), and may play a role in the
pathophysiology of PH in IPF. Current studies of
transplant populations with severe disease are not
able to accurately assess this process, in which larger
prospective studies of the general IPF population are
warranted, particularly as there are widespread im-
plications for oxygen therapy and pulmonary reha-
Identification of PH in IPF
Currently, the diagnosis of PH rests on the
gold-standard right heart catheter (RHC). Howev-
er, RHC is moderately invasive and resource-limit-
ed, therefore not acceptable as a regular screening
tool for PH. With the potential for therapeutic in-
tervention, ‘screening’ IPF patients for the early
identification of PH is increasingly desirable and
clinically relevant, as PH may develop at any stage
of the underlying disease. Elevated mPAP reflects
the underlying pathology of the pulmonary vascula-
ture but may not accurately represent the patho-
physiology of the smaller pulmonary vessels. A reli-
able investigation reflecting the calibre of the distal
pulmonary vessels is desirable, but yet to be identi-
fied. Peacock and colleagues reviewed the current
end-points available for detecting and monitoring
PH, concluding that they were often inadequate
In IPF in the absence of PH, pulmonary func-
tion testing plays a key role in the assessment of
severity, and monitoring of progression. The ques-
tion remains, however, as to whether particular pul-
monary function profiles predict the presence of PH
in IPF. Routine markers indicative of disease severi-
ty (such as FVC) are not helpful in the assessment of
PH in these patients.This poor association between
FVC and mPAP highlights the uncoupling of dis-
ease severity and PH seen in IPF patients.
Diffusing capacity (DLco), a non-specific
marker, is reduced in both vascular and fibrotic dis-
ease. In IPF, DLco is lower in patients with PH on
RHC (7). The combination of DLco<40% and re-
quirement of supplemental oxygen is more accurate
at predicting PH than pulmonary function parame-
ters alone (sensitivity 65%, specificity 94%). Hama-
da et al confirmed these findings, showing a negative
correlation between DLco % predicted and mPAP
and survival (12). However, Nathan et al demon-
strated that DLco levels, measured in isolation, are
not reliably indicative of PH (13).The additional di-
agnostic value of adjusting DLco for alveolar volume
(KCO) or forced vital capacity (FVC/DLco), in or-
der to identify disproportionate reduction in DLco,
merits further study in IPF.
Pulmonary hypertension in idiopathic pulmonary fibrosis
Patients with both IPF and PH have lower
PaO2levels than patients with IPF alone.It has been
suggested that hypoxemia disproportionate to the
reduction in lung volumes is a useful predictor for
the presence of PH in patients with ILD. Zisman et
al established a model inversely relating mPAP to
SpO2 as well as to FVC%/DLco% (73), and have
validated this model in a second IPF population
(74). Models such as this require further elucidation
and external validation, but may be useful in non-in-
vasive screening for PH.
Despite limitations in visualisation of the right
heart, and operator dependence, trans-thoracic
echocardiography (TTE) is a useful and readily
available tool for evaluation of PH (75). Tricuspid
peak Doppler flow velocity correlates well with he-
modynamic parameters (75, 76) and systolic PAP is
relatively sensitive (79-100%) and specific (60-98%)
for the presence of PH (77, 78). Measurement of
sPAP is not possible in the absence of tricuspid re-
gurgitation, and while this is rarely a problem in se-
vere PH (79) this limits the utility of TTE in the as-
sessment of less severe PH. Despite these limita-
tions, TTE is the recommended tool for screening
and early detection of PH by the American College
of Chest Physicians (80).
In chronic lung disease, the role of TTE for the
identification of PH has been questioned. In patients
awaiting pulmonary transplantation, one study
showed similar median sPAP values by RHC and
TTE. However, measurements differed by
>20mmHg in 17.7%, and correlation between the
two methods was non-significant, suggesting that
echocardiography is unreliable in this patient cohort
(81). In patients awaiting lung transplantation, RHC
and TTE measures of sPAP correlated (r2=0.50), but
the relationship was insufficient to justify the use
TTE alone to identify PH (82). Arcasoy et al studied
patients with advanced lung disease evaluated for
lung transplantation, and found a significant correla-
tion (r=0.69) of sPAP measured by RHC and TTE.
However, 52% of measurements differed by
>10mmHg,and 48% of patients were misclassified as
having PH by echocardiography. TTE tended to
overestimate sPAP in patients with normal pressures,
and underestimate sPAP in those with PH (23).
Novel echocardiographic parameters evaluated
in PH include ‘time to peak pulmonary artery flow
acceleration’ (PAT) which inversely correlates with
PVR (83). RV isovolumic relaxation time (RV
IVRT), negatively correlates with mPAP and can be
used in the absence of tricuspid regurgitation (84).
Measurement of peak tricuspid systolic velocity on
tissue Doppler is simple and reproducible, and cor-
relates with right ventricular dysfunction (85) and
PVR (86). RV IVRT measured by tissue Doppler
correlates better with mPAP than conventional
echocardiography (84). In one study of patients with
pulmonary fibrosis and mild PH, tissue Doppler pa-
rameters of right ventricular (RV) function (such as
RV E/Em index) correlated better with survival than
conventional TTE parameters in one study (87).
Stress echocardiography may be a further
method for the identification of early PH in IPF pa-
tients. In patients with systemic sclerosis, stress
echocardiography revealed that 46% had exercise-in-
duced PH, and that this inversely correlated with
maximal workload achieved (88). Exercise-induced
PH may be a predictor for the development of overt
PH. Stress echocardiography may be a novel screen-
ing tool for patients at risk for the development of
Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance (CMR) imaging is
an excellent technique for determining right ventric-
ular structure and function (89), also providing 3-di-
mensional visualisation of the pulmonary artery. Fur-
thermore, pressure-volume loops can be constructed
to assess RV contractility.CMR is also more accurate
and reproducible than TTE in assessing RV wall mo-
tion abnormalities and systolic function,although as-
sessment of diastolic function is more difficult (90).
CMR has an established role in the diagnosis
and monitoring of patients with PH. RV mass index
correlates with mPAP (91), and RV impairment on
CMR is associated with elevated NT-pro brain na-
triuretic peptide (NT-proBNP) levels (89). In one
study of patients with connective tissue disease and
mild lung fibrosis, early signs of right ventricular
dysfunction on CMR were associated with the de-
velopment of PH (92). There have been no specific
CMR studies in patients with PH in the context of
IPF. However, it is likely that CMR will become an
T.J. Corte, S.J. Wort, A.U. Wells
important tool for the identification of PH in IPF
patients, in whom TTE is somewhat less reliable es-
pecially in mild PH.
Computed tomography is not commonly used
to identify PH as it is neither sensitive nor specific
for this purpose. However, CT does have the advan-
tage of imaging the pulmonary vasculature as well as
the pulmonary parenchyma and cardiac chambers. A
correlation between the diameter of the main pul-
monary artery on CT and mPAP has long been
recognised (93) with a main pulmonary artery diam-
eter >3.32cm being specific (95%), but not sensitive
(59%) for PH (94). A closer correlation with mPAP
was found using the ratio of ‘Pulmonary artery di-
ameter’/‘Ascending aorta diameter’ (95). Few studies
have focused on more peripheral pulmonary arteries,
however Tan et al demonstrated an elevation in the
segmental pulmonary artery size compared to its
corresponding bronchus in patients with PH com-
pared to a control group (96).
There have been few CT studies focusing on
the identification of PH in IPF patients. One study
of 65 patients with advanced fibrosis did not show a
difference between CT measured ‘main pulmonary
artery diameter’/‘aorta diameter’ in patients with or
without PH as measured on RHC (24). In patients
with interstitial lung disease, the main pulmonary
artery diameter, and the ‘main pulmonary artery di-
ameter’/‘aorta diameter’ ratio correlate poorly with
RHC parameters (97).
Right ventricular size can be assessed on con-
trast-enhanced CT. Deviation of the interventricular
septum, and reflux of contrast into the hepatic veins
or inferior vena cava is specific for tricuspid regurgi-
tation in patients with PH (98). Patients with severe
PH often have pericardial thickening or mild to
moderate pericardial effusions (99) however, these
changes are neither sensitive, nor specific for PH.
Pulmonary parenchymal changes, such as mo-
saicism, present in PH, are difficult to visualise in
the presence of lung fibrosis.
Functional Exercise Capacity
Exercise-induced hypoxia occurs commonly in
both IPF and PH and is likely to be multi-factorial,
reflecting ventilation-perfusion mismatching, low
mixed-venous oxygen, oxygen diffusion limitation
and intra-cardiac shunting (100). Exercise-induced
hypoxia occurs in patients with overt PH but may al-
so precede and contribute to the development of PH
in IPF patients (101).
In IPF, the 6MWT is simple, reproducible
(102) and can be performed in severe disease. De-
saturation during 6MWT to 88% is common and
associated with increased mortality, independent of
pulmonary function and resting oxygen saturation
(68). In IPF patients awaiting transplantation,
greater desaturation on 6MWT was present in pa-
tients with PH on RHC (7). The adverse prognos-
tic significance of 6MWT desaturation may reflect
either advanced fibrotic disease or the presence of
early pulmonary hypertension (or pulmonary hyper-
tension on exercise which may precede resting PH
The clinical utility of the six-minute walk dis-
tance (6MWD) in IPF is critically dependent upon
underlying disease severity. In unselected IPF pa-
tients, the 6MWD appears to have little or no prog-
nostic value (68, 102, 103). By contrast, as in idio-
pathic PAH (104, 105), the 6MWD may have an
important role in severe disease, based upon data
from IPF transplantation cohorts (106, 107). A
6MWD of less than 350m was associated with a
higher mortality (106) and in another study, a
6MWD of less than 207m predicted more strongly
than FVC % predicted (with an adjusted mortality
rate ratio of 4.7) (107). A weak but significant cor-
relation between 6MWD and mPAP was demon-
strated in this transplant population (107).
Atrial natriuretic and brain natriuretic peptide
(BNP) are the two main peptides in the natriuretic
system. BNP is secreted by the cardiomyocytes from
both left and right ventricles in response to ventric-
ular stretch (108). Ventricular wall stretch up-regu-
lates BNP gene transcription leading to increased
BNP secretion (109). BNP is the biologically active
prohormone secreted by the cardiomyocytes into the
bloodstream. It has a short half-life, as it is
metabolised by serum endopeptidases releasing the
more stable, but inactive NT-proBNP, which is, in
turn, excreted by the kidneys.
Pulmonary hypertension in idiopathic pulmonary fibrosis
In patients with idiopathic PAH, BNP corre-
lates with right ventricular dysfunction, functional
class, hemodynamic parameters and measures of ex-
ercise capacity (110). BNP levels are elevated PH
secondary to congenital heart disease, systemic scle-
rosis (111), and chronic thromboembolic disease
(112). BNP is useful in longer-term follow up of pa-
tients with PH, with changes in BNP levels corre-
lating with changes in hemodynamic parameters and
6MWD (113, 114).
Instability of BNP in the bloodstream makes
rapid processing of the samples imperative, and as-
says more complicated to perform, compared to the
fully automated analysis of NT-proBNP levels. Ear-
lier studies were done with BNP, however more re-
cently,NT-proBNP has been found to correlate with
echocardiographic and CMR measures of right ven-
tricular impairment (89), hemodynamic indices and
6MWD (115). High initial NT-proBNP is an inde-
pendent predictor of poor prognosis (116). NT-
proBNP is renally excreted,and therefore affected by
impaired renal function. Thus, it may be a more in-
clusive prognostic marker, incorporating poor renal
function, known to be an independent predictor of
poor prognosis.NT-proBNP does not correlate with
hemodynamic parameters in the presence of renal
impairment, and may not be as good as BNP as a
follow-up marker in PH (117).
Limited data are available for the role of natri-
uretic peptides in the identification of PH in chron-
ic lung disease. BNP may be secreted in small
amounts by lung parenchyma (118),but this remains
unconfirmed. Elevated BNP levels in patients with
chronic lung disease are associated with poorer prog-
nosis, and exercise tolerance (119). In this study, el-
evated BNP correlated with hemodynamic measures
for PH, and identified significant PH (sensitivity
85%; specificity 88%). Elevated BNP also predicted
mortality independent of pulmonary function, sug-
gesting that the increased mortality was related to
the development of PH,and that BNP may be a use-
ful screening modality for PH in the context of
chronic lung disease. In a study of 39 IPF patients,
BNP correlated with hemodynamic indices of PH,
but not pulmonary function (120). BNP of
33.3pg/ml was the identified threshold, distinguish-
ing between moderate-high and no-mild PH with a
sensitivity of 100% and specificity of 89%. This
study suggests that plasma BNP is a useful non-in-
vasive measure for the identification of PH in pa-
tients with IPF, but larger prospective studies in IPF
patients (also assessing left ventricular function) are
warranted before natriuretic peptides are used rou-
tinely in clinical practise.
Treatment of PH in IPF
Few clinical trials have been performed specifi-
cally addressing treatment of PH in IPF. Historical-
ly, treatment has focused on reversal of hypoxia and
treatment of the underlying respiratory condition.
Supplemental oxygen is recommended for the treat-
ment of PH at large (17),with no specific data avail-
able in IPF. In light of its likely pathogenetic role,
correction of chronic resting hypoxia with supple-
mental oxygen is important.The benefit of reversing
intermittent hypoxia (at night, or on exercise) is un-
known, and needs further study.
Vasodilators have been used cautiously in IPF
patients, due to the potential risk of worsened gas
exchange and hypoxemia (121). Shunt fraction and
hypoxemia are increased with intravenous
prostaglandin I2, but not with sildenafil (122, 123).
Nitric oxide and sildenafil appear to cause selective
pulmonary vasodilation, with maintained ventilation
perfusion matching and arterial oxygenation.
Limited data in IPF and PH suggest a clinical
and hemodynamic benefit of sildenafil.A single dose
of sildenafil (50mg) acutely improves pulmonary he-
modynamics and gas exchange (122). Furthermore,
echocardiographic parameters and 6MWD im-
proved in three IPF patients treated with sildenafil
for three months (124). A study of 11 IPF patients,
treated with sildenafil for three months demonstrat-
ed a mean improvement in 6MWD of 49m, with
57% patients showing a significant response (125).
Sildenafil was well tolerated with only a single pa-
tient experiencing transient hypotension. Clearly,
larger studies are required to clarify the role of silde-
nafil in this patient group.
The role of endothelin receptor antagonists
(ETRA)s in IPF associated PH has not been widely
studied. As ET-1 thought to be instrumental in the
pathogenesis of IPF and PH, ETRAs may well be a
helpful intervention. The “Bosentan use in Intersti-
tial Lung Disease” (BUILD)-1 study demonstrated
no benefit of bosentan over placebo in IPF patients
(126). However, there was a non-significant trend
T.J. Corte, S.J. Wort, A.U. Wells
towards improvement for patients taking bosentan.
This may reflect the presence of a responsive sub-
group, perhaps those with underlying vascular de-
compensation. The use of bosentan in IPF is cur-
rently being further evaluated in the BUILD-3
study. In a small study of open-label bosentan in 12
IPF patients (some with PH), bosentan was well-
tolerated, but not associated with changes in clinical
or physiological parameters at three months (127).
No controlled studies have addressed the effect of
ETRAs in IPF and PH.
We hypothesise that IPF patients may benefit
from early identification and treatment of PH. It is
clear that markers associated with pulmonary vascu-
lar disease such as exercise desaturation, also predict
mortality. This suggests that vascular decompensa-
tion on exercise may precede the development of
PH on RHC. An algorithm for the identification of
patients at higher risk of developing PH, based on
exercise data and other markers, is required to facil-
itate early intervention. In the same way that an-
giotensin converting enzyme inhibitors, when given
following myocardial events, reduce the long-term
development of cardiac failure (128); early treat-
ment of patients at higher risk may prevent or retard
the development of established pulmonary hyper-
PH is a common complication of IPF. It is as-
sociated with considerable additional morbidity and
mortality. Pathogenetic mechanisms are incomplete-
ly understood although it is likely that both fibrosis
and vascular remodelling share key mediators, such
as ET-1.Whilst RHC remains the gold standard for
diagnosis of PH at present, it is clear that non-inva-
sive measures are desperately needed. Furthermore,
detection of the early development of PH may be of
clinical benefit. Importantly, the development of
agents such as ETRAs for the treatment of idio-
pathic PAH, has raised the possibility of therapy for
patients with both IPF and PH.Clinical trials to test
this hypothesis are clearly warranted.
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Summary of Current Uncertainties
1. PH is common in IPF patients referred for transplantation. However, studies in transplant populations do not capture the prevalence
in IPF overall. Larger studies of the greater IPF population are needed to define the prevalence of PH in IPF, and to determine the
best method(s) for identification of PH in these patients.
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When present,PH is associated with increased mortality,and may explain the deterioration of some patients with preserved pulmonary
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increased fibrotic cell mediators, abnormal vasculature or response to intermittent hypoxia.
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of acute hypoxia result in acute rises in PVR, and eventually lead to vascular remodelling. Intermittent hypoxia may also lead to the re-
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as well as encouraging case-series in patients with fibrotic lung disease, have led to suggestions that therapeutic intervention with PH
specific therapy may be useful. However, controlled trials are warranted before therapy can be recommended. In the design of such tri-
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