Download Clinical Insights Into the Pathogenesis of Primary Pulmonary

Clinical Insights Into the Pathogenesis
of Primary Pulmonary Hypertension*
Stuart Rich, MD, FCCP
Because of the lack of adequate animal
models, much of our knowledge of the pathogenesis of
from clinical experiences. The clinical response to
primary pulmonary hypertension
vasodilators, prostenoids, and anticoagulants as treatments appear to correlate with the patho¬
logic changes of medial hypertrophy, intimal proliferation, and thrombosis. Endothelial dysfunc¬
tion, as a primary abnormality in primary pulmonary hypertension, provides an explanation for
the pathologic and clinical expression of the disease in its various forms. Other clinical features
of the disease, such as age of onset and rapidity of progression, may be influenced by triggers of
the disease process and underlying individual genetic susceptibility. As we have been able to
has
come
correlate the spectrum of clinical observations with advances in vascular biology, newer, more
focused and effective therapies should begin to emerge.
(CHEST 1998; 114:237S-241S)
HP he pathogenesis of primary pulmonary hyperten-*- sion (PPH) has been elusive. The disease is rare,
which makes it difficult to study patients who present
with PPH in its various stages. Because there is no
comparable animal model, testing clinical hypothe¬
ses
in the animal
is problematic and forces
laboratory
these
a wealth of
speculation. Despite
obstacles,
information has been obtained from the clinical
experience in diagnosing and treating patients with
PPH that has provided insight into the underlying
of the disease. Although the clinical
pathogenesistends
to raise more questions than an¬
experience
swers, this review will focus on advances in our
current understanding of the pathogenesis of this
disease derived from clinical observations.
Pulmonary Hypertensive Vasculopathy
Medial Hypertrophy
disease that is manifest by a
that has mul¬
pulmonary hypertensive
vasculopathy
One
feature
of PPH is
tiple
expressions.1 pathologic
medial hypertrophy of the pulmonary arterioles that
appears to represent vasoconstriction.2 Although it is
usually seen in conjunction with other lesions, iso¬
lated medial hypertrophy has been described in
several pathologic series of patients dying with PPH
and seems to be more prevalent in children than
PPH
represents
a
*From the Section of Cardiology,
Medical Center, Chicago.
Rush-Presbyterian-St. Luke's
to: Stuart Rich, MD, The Rush Heart Institute,
Correspondence
Center for Pulmonary Heart Disease, Rush-Presbyterian-St.
Luke's Medical Center, 1725 W Harrison St, Suite 020, Chicago,
IL; email: [email protected]
adults.1'3-4 The vessels are characterized by marked
thickening of the media, with only modest amounts
of intimal proliferation.4 It was originally postulated
that this represented uncontrolled growth and con¬
striction of the smooth muscle cells of the pulmonary
arterioles.2 Pulmonary vasoconstriction was believed
to be the cause of pulmonary hypertension.5
Clinically, we test for the presence of pulmonary
vasoconstriction by challenging the patient with a
the response.
short-acting vasodilator and measure
in
a
substantial
fall
Observing
pulmonary artery
pressure and pulmonary vascular resistance (PVR)
characterizes the patient as responsive, and thus
implies reversible pulmonary vasoconstriction.6 The
unresponsive patients, it is assumed, have advanced
vascular changes that preclude the drug from caus¬
ing smooth muscle cell relaxation. Consistent with
this hypothesis, Sitbon and colleagues7 have charac¬
terized patients with PPH as responders or nonre¬
sponders to nitric oxide based on acute reductions in
mean pulmonary artery pressure following inhalation
of the gas. However, Palevsky and colleagues8 com¬
several vasodilators with
pared theinacute effects ofPPH
with
and were unable to
histology patients
correlate the two. Obviously the mechanisms for
vasoconstriction and vasodilation are
pulmonary
more complex than initially thought.
The monocrotaline rat model has been one of the
most widely used animal models to study various
aspects of PPH.9 In that model, monocrotaline is
injected into the rat; this results in medial hypertro¬
phy of the pulmonary arterioles and pulmonary
after approximately 4 weeks. However,
hypertension
close observation of the development of the medial
CHEST / 114 / 3 / SEPTEMBER, 1998 SUPPLEMENT
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21842/ on 05/02/2017
237S
revealed that it is preceded by intense
hypertrophy
metabolic activity and proliferation of the pulmonary
endothelial cell layer.10 Studies such as these suggest
that the development of medial hypertrophy is reg¬
ulated by the endothelium, and that isolated medial
hypertrophy represents an abnormality of endothe¬
lial cell control over pulmonary vascular smooth
muscle. Nitric oxide has been identified as an endothelial-derived mediator that has important regula¬
tory properties over vascular tone.11 It is believed
that nitric oxide, a powerful vasodilator, keeps the
relaxed state.
pulmonary vascular bed in a relatively
One hypothesis is that the loss of normal endothelial
cell production of nitric oxide could result in pulmo¬
nary arterial vasoconstriction and smooth muscle cell
hypertrophy.reduced levels of nitric oxide
synthase in
Recently,
the pulmonary vasculature of patients with PPH
have been characterized, which implicates inade¬
quate local nitric oxide production as part of this
disease process.12 In addition, the more severe the
vascular changes, the lower the levels of
pulmonary
nitric oxide synthase observed. This may account for
the clinical characterization of patients as being
responsive or unresponsive to vasodilator challenge.
Comparing the effects of vasodilators that are
considered to be endothelial dependent, such as
with ones that are endothelial inde¬
acetylcholine,
such
as nitroglycerine or nitric oxide, has
pendent,
been attempted with the hope of characterizing the
endothelial cell dysfunction in a given
degree ofThe
studies suggest a progressive loss of
patient.13
in
vasoreactivity the pulmonary vascular bed that
correlates with the severity of the disease. The
response to any pulmonary vasodilator in PPH will
and the characterization of an
likely be a graded one,
individual patient as being a responder or nonrean attempt to categorize them for selection
sponder
of long-term therapy.
One example is the common practice to categorize
patients with PPH as being responders or nonre¬
However, there is no
sponders to calcium ofblockers.
definition a response to calcium block¬
accepted
ers, with investigators arbitrarily choosing an acute
in PVR that varies between 20% and
change
50%.14-15 In the calcium blocker experience, it is
clear that there is a subset of patients who seem to be
highly responsive, who maintain a sustained fall in
while receiving
pulmonary artery pressure and PVR
As with nitric oxide,
long-term
therapy
indefinitely.16
one would presume that the difference between
these subgroups of patients relates to the severity of
the pulmonary vascular disease.
However, the experience with calcium channel
blockers has raised more questions than it has an¬
swered. If one presumes that the calcium channel
238S
blocker is opposing pulmonary vasoconstriction,
which occurs as a result of endothelial injury, then
one would expect that the long-term effectiveness of
the calcium channel blockers would be limited by
progressive endothelial dysfunction at some point in
time. However, this does not appear to be the case,
as we have patients with PPH receiving calcium
channel blockers with sustained improvement for
>10 years. Whether the calcium channel blockers
affect endothelial cell proliferation or injury is un¬
known. It has also been shown that the vasodilatory
response to calcium channel blockers does not rep¬
resent the maximal extent of pulmonary vasodilator
reserve. For example, patients who are responsive to
calcium channel blockers will have a further fall in
pulmonary artery pressure IVand PVR when a more
potent vasodilator such as adenosine is added.17
Another important question is how to interpret the
more common acute hemodynamic response to cal¬
cium blockers in patients with PPH, namely a rise in
cardiac output and thus a fall in PVR, without any fall
in pulmonary artery pressure.18 The conditions of
some patients will improve with long-term therapy,
whereas others will deteriorate.19 Unfortunately, the
widespread
practice of using calcium blockers in
PPH without documenting beneficial effects hemodynamically has probably led to worsening and death
in many patients.
From clinical
observations, one can conclude that
vascular
smooth muscle cell hypertrophy
pulmonaryto
appears
express marked reactivity early in the
and
disease, that it loses reactivity as endothelial cell
injury progresses. It is possible that pulmonary vaso¬
constriction and smooth muscle cell hypertrophy are
linked to endothelial cell regulation via nitric oxide.
It remains unclear, however, what role the calcium
channel plays in the regulation of pulmonary vascular
tone in normal patients and patients with pulmonary
hypertension.
Intimal Proliferation and Fibrosis
Endothelial proliferation leading to obliteration of
the pulmonary vascular bed has also been character¬
ized in patients with advanced PPH.134 Wagenvoort
and Wagenvoort3 have described this as a manifes¬
tation of advanced disease that follows medial hyper¬
trophy and pulmonary vasoconstriction. However,
severe endothelial proliferation in the absence of
medial hypertrophy and demonstrable clinical vaso¬
constriction has also been described.4 This suggests a
causative role for growth factors, of which endothelin
is a strong possibility, leading to intimal proliferation
with or without vasoconstriction.20 There are endo¬
thelin receptors in the pulmonary vasculature that
interact with G-proteins that regulate intracellular
Pathogenesis of Primary Pulmonary Hypertension
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21842/ on 05/02/2017
calcium and reduce
protein kinase C activity.21 Pa¬
tients with PPH have elevated endothelin levels that
appear to be liberated by the pulmonary vascular
bed.22 A relationship between endothelin levels and
severity of disease has been demonstrated, but it
remains unclear whether endothelin is the cause or
result of PPH.23 Patients with primary and secondary
forms of pulmonary hypertension have markedly
elevated levels of endothelin-like activity in the
vascular endothelium, which raises the
pulmonarythat
endothelin receptor blockers may be
possibility
useful as a treatment of pulmonary hypertension.24
Thromboxane, another growth factor that is pri¬
marily derived from platelets, has received particular
attention in pulmonary hypertension.25 Besides its
effects on platelet aggregation, it also causes vaso¬
constriction and induces intimal proliferation. The
action of thromboxane is opposed by prostacyclin, a
compound that is produced by normal vascular
endothelium and that has vasodilatory and anticoag¬
ulant properties.26 Patients with PPH have been
characterized as having an imbalance in the ratio of
thromboxane to prostacyclin production, suggesting
that overproduction of one or underproduction of
the other might be a factor in the disease.25 Clinical
trials have now shown significant reductions in pul¬
monary artery pressure and PVR when prostacyclin
Glaxo-Wellcome; Research
(epoprostenol [Flolan];
Park, NC) is given to patients with PPH
Triangle
long term.27-30 Prostacyclin is effective even in pa¬
tients who show no acute vasodilatory response from
it, suggesting that it works as an antiproliferative
agent as well.31
Angiotensin-converting enzyme (ACE) inhibitors
have also been tested in patients with PPH. Shortterm studies have been disappointing, as the acute
to be
hemodynamic effects of these drugsfromseem
the effec¬
minimal.32 However, lessons learned
tiveness of ACE inhibitors in heart failure have
us that they also work beyond vasodilation, as
taught
the effect of ACE inhibitors in reducing circulating
neurohormones results in improved exercise toler¬
ance and survival.33 Recently, it has been described
that patients with PPH have increased expression of
ACE in the endothelium and media of the pulmo¬
nary vasculature.34 Elevated neurohormonal profiles
have also been demonstrated in these patients.23
Thus, it might seem that ACE inhibition would be a
the
logical treatment of PPH, not necessarily with but
of causing acute pulmonary vasodilitation,
goal
with the goal affecting the disease process by limiting
vascular proliferation and by lessening the effects of
neurohormonal activation on the pulmonary vascu¬
lature and myocardium.
In summary, intimal proliferation of the pulmo¬
nary arterioles appears to parallel increases in endo¬
thelin levels, implicating endothelin as important in
the pathogenesis of the disease. The severity of the
intimal proliferation seems to reflect the severity and
of the disease. It is possible that the
chronicity
intimal proliferation is reversible, which suggests
that we should also be evaluating drug therapy by
of the disease other than hemo¬
looking at measures
end
as
an
point.
dynamics
Thrombosis In Situ
A third representation of PPH histologically is
thrombosis in situ of the pulmonary arterioles.1'3'4
Vessels with eccentric intimal pads that are pre¬
sumed to be caused by local thrombosis, as well as
recanalized thrombi, are randomly scattered
throughout the pulmonary vasculature of patients
with PPH.4 Although once believed this could rep¬
microembolism, to our knowledge,
pulmonary
of these microemboli in patients with PPH
been demonstrated.4 The current thinking
has
is that this represents local thrombosis of the pulmo¬
nary arteriolar bed. It has been shown that these
patients have elevated levels of fibrinopeptide A,
which reflects the procoagulant environment within
the pulmonary vascular bed.35 Consistent with this
long-term effects of warfarin
hypothesis are the
in improving survival as demon¬
anticoagulation
strated in one retrospective study and one prospec¬
tive study.16'36 As platelet activation is likely part of
thrombosis, it again brings into question the role of
the platelet and its associated growth factors in the
of PPH. The National Institutes of
development
Health Registry on Primary Pulmonary Hyperten¬
sion reported that these thrombotic lesions seem to
be equally prevalent between men and women,
whereas plexiform lesions seem to be more com¬
found in women.4
monly
It is quite possible that in some patients, throm¬
bosis of the pulmonary arterioles may be the only
manifestation of PPH. Warfarin therapy
pathologic
alone has been shown to improve survival and he¬
in some cases.37 Another curiosity is the
modynamics
fact that some patients with PPH can develop exten¬
sive central thrombi that are nonocclusive in nature,
suggesting that the local procoagulant state of the
vascular bed can be quite intense.38
pulmonary
The basis for the in situ thrombosis of the pulmo¬
nary arteriolar bed in PPH is probably endothelial
injury. It is likely that platelet activation and vasoac¬
and this
tive substance release are
resent
a source
never
may
occurring,
either perpetuate or promote the disease
process in many patients. In patients in whom in situ
thrombosis is the predominant lesion, there may be
no demonstration of pulmonary vasoreactivity (since
pulmonary vasoconstriction is not underlying). These
serve
to
CHEST/114/3/SEPTEMBER, 1998 SUPPLEMENT
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21842/ on 05/02/2017
239S
triggers to the disease (such as HIV virus or anorexi¬
gens). Individual genetic susceptibility, combined
with the intensity and duration of exposure to a
trigger, probably influences the histologic manifesta¬
tion of the disease, and hence its clinical expression
SIGNALS
SENSORS
(FigIn 1).
the
MEDIATORS
Vasoactive
Growth
Factors
Substances
Pulmonary Vascular Smooth
Muscle Cell
years to come, we will be looking to identify
the triggers of endothelial injury in these patients
and why some people seem to be predisposed
whereas others are not. However, as we understand
the nature of the vascular abnormality in these
patients and the effects of drugs, more progress in
drug treatment and improved survival will be forth¬
coming.
Figure 1. Based on clinical data, a paradigm can be proposed to
explain pulmonary hypertension as a final common pathway. A
of signals, acting on specific endothelial receptor sites, will
variety
alter endothelial control of the arteriolar microenvironment. The
variations in expression of a pulmonary arteriopathy are likely
explained
by the type and intensity of the signals affecting
endothelial cell function, the mediators that are generated, and
their effect on vascular tone, and the underlying genetic predis¬
position of the patient. In PPH, the signals remain unknown.
References
1 Edwards
WD, Edwards JE. Clinical primary
hypertension:
884-88
2
3
three
pathologic types.
pulmonary
Circulation 1977; 56:
Wagenvoort CA. Vasoconstriction and medial hypertrophy in
pulmonary hypertension. Circulation I960; 22:535-46
Wagenvoort CA, Wagenvoort N. Primary pulmonary hyper¬
a pathologic study of the lung vessels in 156 clinically
diagnosed cases. Circulation 1970; 42:1163-84
Pietra GG, Edwards WD, Kay JM, et al. Histopathology of
primary pulmonary hypertension: a qualitative and quantita¬
tive study of pulmonary blood vessels from 58 patients in the
tension:
patients should benefit substantially from long-term
However, because of the rel¬
anticoagulant therapy.
nature
of these thrombotic lesions
atively ubiquitous
in the lungs of patients with PPH, it is recommended
that all patients be treated with anticoagulant the¬
rapy 39
Endothelial
Injury.The Common Pathway
one does not assume that PPH is three
distinct
diseases, it needs to be underscored
separate
that the three pathologic features of PPH that have
been reviewed are typically seen throughout the
lungs of most patients with PPH. This has been
demonstrated in the National Institutes of Health
Registry on PPH,4 in patients with familial PPH,40 in
patients with pulmonary hypertension secondary to
atrial septal defects,41 and from exposure to toxic
that the hypertensive
rapeseed oil.42thatItis appears
in
seen
PPH
vasculopathy
represents a spec¬
trum that includes medial hypertrophy, intimal pro¬
liferation and fibrosis, and in situ thrombosis, all of
which can be explained by injury to the pulmonary
vascular endothelium.
The clinical expression of PPH will be influenced
by the underlying histologic changes so that patients
with predominant medial hypertrophy should have
more vasoreactivity than those whose predominant
lesions are thrombotic in nature. The distribution of
these lesions is likely influenced by the patient's age
at onset, gender and other genetic factors, and
4
5
6
7
So that
240S
8
9
10
11
12
13
14
National Heart, Lung, and Blood Institute Primary Pulmo¬
nary Hypertension Registry. Circulation 1989; 80:1198-1206
Wood P. Pulmonary hypertension with special reference to
the vasoconstrictive factor. Br Heart J 1958; 20:557-70
Barst RJ. Pharmacologically-induced pulmonary vasodilata¬
tion in children and young adults with primary pulmonary
hypertension. Chest 1986; 89:497-503
Sitbon O, Brenot F, Denjean A, et al Inhaled nitric oxide as
a screening vasodilator agent in primary pulmonary hyperten¬
sion: a dose-response study and comparison with prostacyclin.
Am J Respir Crit Care Med 1995; 151:384-89
Palevsky HI, Schloo BL, Pietra GG, et al. Primary pulmonary
hypertension: vascular structure, morphometry, and respon¬
siveness to vasodilator agents. Circulation 1989; 80:1207-21
Wilson DW, Segall HJ, Pan LCW, et al. Progressive inflam¬
matory and skeletal changes in the pulmonary vasculature of
monocrotaline-treated rats. Microvasc Res 1989; 38:57-80
Rosenberg HC, Rabinoviteh M. Endothelial injury and vas¬
cular reactivity in monocrotaline pulmonary hypertension.
Am J Physiol 1988; 255:H1584-91
Palmer RM, Ferrige AG, Moncada S. Nitric oxide release
accounts for the biologic activity of endothelium-derived
factor. Nature 1987; 327:524-26
relaxing
Giaid A, Saleh D. Reduced expression of endothelial nitric
oxide synthase in the lungs of patients with pulmonary
hypertension. N Engl J Med 1995; 333:214-21
Celermajer DS, Cullen S, Deanfield JE. Impairment of
endothelium dependent pulmonary artery relaxation in chil¬
dren with congenital heart disease and abnormal pulmonary
hemodynamics. Circulation 1993; 87:440-46
Reeves JT, Groves BM, Turkevich D. The case for treatment
of selected patients with primary pulmonary hypertension.
Am Rev Respir Dis 1986; 134:342-46
15 Rich S, Brundage BH. High-dose calcium channel blocking
therapy for primary pulmonary hypertension:
evidence for
Pathogenesis of Primary Pulmonary Hypertension
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21842/ on 05/02/2017
long-term reduction in pulmonary arterial pressure and re¬
gression of right ventricular hypertrophy. Circulation 1997;
76:135-41
16 Rich S, Kaufmann E, Levy PS. The effect of high doses of
calcium-channel blockers on survival in primary pulmonary
hypertension. N Engl J Med 1992; 327:76-81
17 Schrader BJ, Inbar S, Kaufmann L, et al. Comparison on the
effects of adenosine and nifedipine in pulmonary hyperten¬
sion. J Am Coll Cardiol 1992; 19:1060-64
18 Rich S, Kaufmann E. High dose titration of calcium channel
blocking agents for primary pulmonary hypertension: guide¬
lines for short-term drug testing. J Am Coll Cardiol 1991;
18:1323-27
19 Packer M, Medina N, Yushak M. Adverse hemodynamic and
clinical effects of calcium channel blockade in pulmonary
hypertension secondary to obliterative vascular disease. J Am
Coll Cardiol 1984; 4:890-96
20 Voelkel NF, Tuder RM, Weir EK. Pathophysiology of pri¬
mary pulmonary hypertension from physiology to molecular
mechanisms. In: Rubin LJ, Rich S, eds. Primary pulmonary
hypertension. New York: Marcel Dekker, 1997; 83-133
21 Filep JG. Endothelin peptides: biological actions and pathophysiological significance in the lung. Life Sci 1993; S2:
119-33
22 Yoshibayashi M, Nishioka K, Nakao K, et al. Plasma endo¬
thelin concentration in patients with pulmonary hypertension
associated with congenital heart defects: evidence for in¬
creased production of endothelin in the pulmonary circula¬
tion. Circulation
84:2280-85
1991;
23 Nootens M, Kaufmann E, Rector T, et al. Neurohormonal
activation in patients with right ventricular failure from
24
25
26
27
28
pulmonary hypertension: relation to hemodynamics and en¬
dothelin levels. J Am Coll Cardiol 1995; 26:1581-85
Giaid A, Yanagisawa M, Langleben D, et al. Expression of
endothelin-1 in the lungs of patients with pulmonary hyper¬
tension. N Engl J Med 1993; 328:1732-39
Christman BW, McPherson CD, Newman JH, et al. An
imbalance between the excretion of thromboxane and pros¬
tacyclin metabolites in pulmonary hypertension. N Engl
J Med 1992; 327:70-75
Moncada S, Korbut R, Bunting S, et al. Prostacyclin is a
hormone. Nature 1978; 273:767-68
circulating
Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary
pulmonary hypertension with continuous intravenous prosta¬
cyclin (epoprostenol). Ann Intern Med 1990; 112:485-91
Barst RJ, Rubin LJ, Long WA, et al. A comparison of
continuous intravenous prostacyclin versus conventional ther¬
apy in primary pulmonary hypertension. N Engl J Med 1996;
334:296-301
29 Shapiro SM, Oudiz RJ, Cao T, et al. Primary pulmonary
hypertension: improved long-term effects and survival with
continuous intravenous epoprostenol infusion. J Am Coll
Cardiol 1997; 30:343-49
RJ, Rubin LJ, McGoon MD,
30 Barst
et
al. Survival in primary
pulmonary hypertension with long-term continuous intrave¬
nous prostacyclin. Ann Intern Med 1994; 121:409-15
31 McLaughlin W, Genthner DE, Panella MM, et al. Reduction
in pulmonary vascular resistance with long-term prostacyclin
therapy in primary pulmonary hypertension. N Engl J Med
1998; 338:273-77
32 Leier CV, Bambach D, Nelson S, et al. Captropril in primary
pulmonary hypertension. Circulation 1983; 67:155-61
33 SOLVD Investigators. Effect of enalapril on survival in
patients with reduced left ventricular ejection fraction and
congestive heart failure. N Engl J Med 1991; 325:293-302
34 Schuster DP, Crouch EC, Parks WC, et al Angiotensin
converting enzyme expression in primary pulmonary hyper¬
tension. Am J Respir Crit Care Med 1996; 154:1087-91
35 Eisenberg PR, Lucore C, Kaufmann E, et al. Fibrinopeptide
A levels indicative of pulmonary vascular thrombosis in
patients with primary pulmonary hypertension. Circulation
1990; 82:841-47
36 Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary
hypertension: natural history and the importance of throm¬
bosis.
Circulation 1984; 70:580-87
37 Cohen M, Edwards WD, Fuster N.
Regression in thrombo¬
embolic type of primary pulmonary hypertension during 2lA
years of antithrombotic therapy. J Am Coll Cardiol 1986;
7:172-75
38 Moser KM, Fedullo PF, Finkbeiner WE, et al. Do
patients
with primary pulmonary hypertension develop extensive cen¬
tral thrombi? Circulation 1995; 91:741-45
39 Rubin LJ. ACCP Consensus Statement: primary pulmonary
hypertension. Chest 1993; 104:236-50
40 Loyd JE, Atkinson JB, Pietra GG, et al. Heterogeneity of
pathologic lesions in familial primary pulmonary hyperten¬
sion. Am Rev Respir Dis 1988; 138:952-57
41 Yamaki S, Horiuchi T, Miura M, et al. Pulmonary vascular
42
disease in secundum atrial septal defect with pulmonary
hypertension. Chest 1986; 89:694-98
Gomez-Sanchez MA, Mastre de Juan MJ, Gomez-Pajuelo C,
et al. Pulmonary hypertension due to toxic oil syndrome: a
chnicopathologic study. Chest 1989; 95:325-31
CHEST / 114 / 3 / SEPTEMBER, 1998 SUPPLEMENT
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21842/ on 05/02/2017
241S