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Update in Pulmonary Vascular Diseases 2012
Martin R. Wilkins
1
, John Wharton
1
, and Mark T. Gladwin
2
1
Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College London, United Kingdom; and
2
Department
of Medicine and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
Pulmonary vascular disease presents a considerable therapeu-
tic challenge. A look at the past year shows that it is a highly
active field of research. About 2,500 publications from many
countries appeared on PubMed in 2012. Here we focus on
some major emerging themes and follow an established
tradition (1), reviewing primarily articles published in
AJRCCM.
Some of the results of these studies have been previously re-
ported in the form of an abstract (2–4).
PULMONARY ARTERIAL HYPERTENSION IN THE
MODERN ERA: PATHOLOGY, DEMOGRAPHICS,
AND ASSOCIATIONS
Textbook descriptions of the vascular pathology of pulmonary
arterial hypertension (PAH) precede the era of modern therapeu-
tics. Stacher and colleagues, using a large collection of explanted
lung tissue (62 patients with PAH), courtesy of the Pulmonary Hy-
pertension Breakthrough Initiative, have applied systematic sam-
pling and analysis to provide an important update (5). Significant
observations include heterogeneity in structural remodeling
within the same lung and between lungs from different patients;
that the primary differences between PAH and healthy lung
reside in intima fractional thickness; that medial fractional
thickness overlapped with measurements made in healthy
tissue; and the presence of marked perivascular inflamma-
tion. The study supports the concept of pathologically dis-
tinct subphenotypes, even in idiopathic PAH (IPAH), and
poses the challenge to identify these at an earlier stage of the
disease (6).
This report should be understood in the context of the changing
demographics of PAH. Ling and colleagues published the largest
cohort of incident PAH, with 482 newly diagnosed patients pre-
senting between 2001 and 2009 (7). The mean age was 50 years,
compared with 36 years in the landmark National Institutes of
Health registry from 1987. Patients older than 50 years were
more obese, had more comorbidities, and worse survival pros-
pects than younger patients. The shift in demographics likely
reflects increased awareness of PAH and a change in referral to
specialist centers. The diagnosis of PAH in older patients, who
are more likely to suffer from coincident systemic hypertension
and ischemic heart disease, demands an obsessional approach
to measuring pulmonary capillary wedge pressure to distin-
guish PAH from pulmonary venous hypertension associated
with left ventricular (LV) dysfunction (8). The high prevalence
of diabetes in older patients with PAH may be simply
contemporaneous, but there is increasing awareness of an asso-
ciation between PAH and insulin resistance and metabolic dis-
turbance may have an intimate role in the development of
PAH (9).
In common with other registries (10), the U.K. and Ire-
land cohort shows improved patient outcomes in the last 10
years. Survival at 1, 2, 3, and 5 years was 92.7, 84, 73.3, and
61.1%, respectively. Although tempting to attribute this im-
provement to new treatments, changing demographics and
a general improvement in patient follow-up and manage-
ment are also factors. Higher mortality and increased risk
of clinical worsening are associated with lower socioeco-
nomic class, independent of clinical features and baseline
hemodynamics (11).
Pulmonary hypertension (PH) is a significant cause of mor-
bidity and mortality in children, and the Tracking Outcomes
and Practice in Pediatric Pulmonary Hypertension Registry
has been established as a global prospective study to explore
the demographics, treatment, and outcomes in pediatric PH
(12). Of the 362 patients recruited with confirmed PH 87%
had PAH and several age-specific characteristics were iden-
tified that emphasize the need for further pediatric-based
studies. These include the type and distribution of associated
disorders (notably congenital heart disease), the high preva-
lence of comorbidities such as trisomy 21, the frequent oc-
currence of syncope, and apparent preservation of right-heart
function despite severe PH (12).
FRESH INSIGHTS INTO MECHANISMS
The ENCODE (Encyclopedia of DNA Elements) Project showed
that less than 2% of the human genome encodes protein whereas
about 60% is transcribed into RNA sequences, many of which
may be concerned with gene regulation (13). Short RNA tran-
scripts, microRNAs (miRs), have emerged as critical posttran-
scriptional regulators of gene expression. More than 1,400 miRs
have been identified and the levels of several are affected by or
predicted to change in experimental PH (14, 15). Pullamsetti and
colleagues have provided proof-of-concept that miR inhibitors,
antagomirs, may offer a novel therapeutic strategy in PAH; inhi-
bition of miR-17 attenuated the PH phenotype in both hypoxia-
and monocrotaline-induced PH (16). Further investigations are
required to establish which miR(s) might be targeted and taken
to clinical trials in patients with PAH. Other RNA molecules are
also being developed as therapeutic agents, including Spiegelmers.
These are stable mirror isomers of RNA that bind specific
chemokines with high (subnanomolar) affinity. Spiegelmer
NOX-A12 blocks stromal cell–derived factor-1 (CXCL12)
and, given to monocrotaline-treated rats with established
PH, inhibits the accumulation of pulmonary inflammatory
cells, reduces cardiovascular remodeling, and improves he-
modynamics (17).
Epigenetic differences (i.e., variation in gene expression and
phenotype that do not result from alteration in DNA sequence)
are now thought to have a role in PAH. In addition to the suppres-
sion of gene expression by miRNAs, the principal mechanisms of
(Received in original form March 11, 2013; accepted in final form May 6, 2013)
Correspondence and requests for reprints should be addressed to Martin Wilkins,
M.D., NIHR–Wellcome Trust Imperial CRF, Imperial Centre for Translational
and Experimental Medicine, Imperial College London W12 0NN, UK. E-mail:
m.wilkins@imperial.ac.uk
Am J Respir Crit Care Med Vol 188, Iss. 1, pp 23–28, Jul 1, 2013
Copyright ª2013 by the American Thoracic Society
DOI: 10.1164/rccm.201303-0470UP
Internet address: www.atsjournals.org
epigenetic regulation include DNA methylation and the modifica-
tion of histone proteins associated with DNA in chromatin. Acet-
ylation is one the most frequent posttranslational modifications
of histones and is a dynamic process regulated by histone acetyl-
transferases and histone deacetylases. Studies in cells and animal
models have demonstrated antiinflammatory and antiremodeling
properties of histone deacetylase inhibitors that could be benefi-
cial in patients (18, 19). But these compounds target multiple cell
types and selectivity is the key to identifying an inhibitor to take
forward for PAH. Concerns about myocardial toxicity also dictate
that we should proceed with caution.
Stacher and colleagues observed a correlation between peri-
vascular infiltration and remodeling of the intima and media
in lungs of patients with PAH (5). Savai and colleagues quan-
tified the cellular infiltration in explanted lungs from patients
with IPAH and found that, except for FoxP3
1
regulatory T
(Treg) cells, the number of mast cells, macrophages, dendritic
cells, and subsets of T cells and B cells in the adventitia was
increased throughout small (diameter, 20–50 mm) to large (di-
ameter, .150 mm) remodeled pulmonary arteries (17). Large
accumulations of lymphocytes have also been localized to ter-
tiary (ectopic) lymphoid follicles adjacent to remodeled vessels,
with chemokines (e.g., CXCL13), lymphotoxin-a/-b, and immu-
noregulatory cytokines (IL-7 and IL-21) implicated in their for-
mation and function (20). Interestingly, lymphoid neogenesis
was not observed in patients with flow-induced PAH (Eisenmenger
syndrome). Together with the accumulation of CD138
1
plasma
cells and deposition of immunoglobulins, this suggests that local
generation of antibodies and autoimmunity are important in
IPAH (20). In-depth studies of the perturbation of specific cell
subtypes (e.g., Treg cells [21] and natural killer cells [22]) in the
circulation as well as lung tissues are now critical to our under-
standing the role of inflammatory mechanisms and altered im-
munity in the progression of PAH (1).
Infection with HIV and intravenous drug use are known to be
independent risk factors for the development of PAH. The con-
comitant use of opioids and amphetamines represents a potential
“second hit” in the pathogenesis of HIV-PAH (23). Spikes and
colleagues treated macaques with morphine before and after
simian immunodeficiency virus inoculation and observed pul-
monary vascular remodeling, including intimal and medial
thickening and plexiform-like lesions, and more severe perivas-
cular inflammation than animals receiving morphine or simian
immunodeficiency virus inoculation alone (24). The combined
insult was also associated with Pneumocystis infection, raised
circulating IL-8 and monocyte chemotactic protein-1 (CCL2)
levels, and evidence of enhanced pulmonary endothelial apo-
ptosis and proliferation. Morphine potentiated the apoptotic
and proliferative effects of HIV viral proteins (Tat, Nef, and
gp-120
CM
), promoted oxidative stress, and affected vascular en-
dothelial growth factor expression/activation in human pulmo-
nary microvascular endothelial cells (24). It remains to be seen
whether other forms of drug abuse have a similar effect, but
these novel findings support a multiple hit hypothesis in the
pathogenesis of HIV-PAH and provide a new model for lon-
gitudinal investigations of pulmonary hemodynamics as well as
vascular remodeling in PAH (25).
Growth factors and the altered expression/activity of receptor
tyrosine kinases (RTKs) are implicated in PAH. Investigation of
RTK transduction pathways identified a common adaptor pro-
tein, p130
Cas
, for major growth factors involved in PAH, includ-
ing platelet-derived growth factor, fibroblast growth factor-2,
and epidermal growth factor (26). Importantly, patients with
IPAH exhibited increased circulating levels and expression/
activity of p130
Cas
in distal pulmonary arteries, modulating
the proliferative and migratory effects of the growth factors
in cultured pulmonary artery smooth muscle cells (PASMCs) and
endothelial cells. Adaptor p130
Cas
protein expression/activity
was also increased in the lungs of rodents with hypoxia- and
monocrotaline-induced PH, and treatment with RTK inhibitors
(gefitinib, dovitinib, and imatinib) reduced both p130
Cas
levels
and inhibited the progression of PH and cardiovascular remod-
eling (26). These observations need to be confirmed and, while
selective inhibitors are not currently available, p130
Cas
may rep-
resent a circulating biomarker reflecting the progression of pul-
monary vascular disease and response to therapy.
The elevation of intracellular Ca
21
levels in PASMCs is con-
sidered to be an important step in pulmonary contraction and
vascular remodeling (27). The entry of Ca
21
into the cytoplasm
occurs via receptor-operated and store-operated Ca
21
channels,
and their initial opening is caused by the activation of a G
protein–coupled receptor known as the extracellular Ca
21
-sensing
receptor (CaSR or GPRC2A). Data have implicated enhanced
CaSR expression and function in the proliferation of PASMCs
from patients with IPAH, as well as the development of PH in
experimental animal models, and suggest that pharmacological
blockade of the receptor or inhibition of expression may be
a potential therapeutic strategy in the future (27).
Increasing evidence indicates that mineralocorticoid recep-
tor signaling has a role in cardiovascular disease, modulating
macrophage and immune cell function and promoting inflamma-
tion and oxidative stress in the heart and vascular tissues (28),
and the renin–angiotensin–aldosterone system is activated in
patients with IPAH (29). de Man and colleagues showed that
circulating levels of renin, angiotensin I, and angiotensin II
(AngII) are raised in IPAH and associated with disease progres-
sion and outcome (30). Local angiotensin-converting enzyme
activity, AngII type I receptor expression, and downstream sig-
naling were increased in pulmonary arteries and endothelial
cells from patients with IPAH. Furthermore, AngII selectively
induced the proliferation of PASMCs from patients with IPAH
and this was blocked by the AngII type I receptor antagonist,
losartan. The potential therapeutic significance of these obser-
vations was underlined by the finding that chronic losartan treat-
ment delayed the progression of pulmonary vascular remodeling
and right ventricular (RV) dysfunction in the monocrotaline rat
model (30). Other agents are also available that target the renin–
angiotensin–aldosterone system. Preclinical studies have shown the
therapeutic potential of aldosterone inhibitors in PAH (31), and
the effect of spironolactone on collagen metabolism in PAH is
now undergoing clinical investigation (ClinicalTrials.gov identi-
fier NCT01468571).
THE ROLE OF ESTROGENS
The role of female sex, and specifically estrogenic hormones, in the
penetrance, severity, and even treatment of PAH is the subject of
active research. However, the findings are not congruent and in
fact paradoxical. For example, there is a female predominance
in IPAH and increased penetrance of PAH in female members
of families with mutations in the bone morphogenetic protein
receptor type 2 (BMPR2) gene (32). But 2-methoxyestradiol ther-
apy is protective in monocrotaline-induced PH and female ro-
dents often develop less severe hypoxia-induced PH and RV
failure (33). These findings have been referred to as the “estrogen
paradox” and the potential mechanisms comprehensively re-
viewed (32, 34).
Lahm and colleagues investigated the role of direct estrogen
receptor activation by 17b-estradiol versus the downstream
effects of its metabolites in the setting of hypoxia-induced PH
in mice (35). 17b-Estradiol therapy was protective, inhibiting
cell proliferation and activating autophagy to limit PH and
24 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 188 2013
RV hypertrophy. Using selective estrogen receptor, catechol
O-methyltransferase, and CYP450 inhibitors, 17b-estradiol
appeared to directly activate estrogen receptor-a, indepen-
dent of the estrogen receptor-band downstream metabolites,
reduce extracellular signal–regulated kinase-1/2 (ERK1/2)
activation, increase p27
Kip1
expression, and increase auto-
phagy, leading to improvement in pulmonary pressures and
RV function (35). It is somewhat surprising that the effects
of 17b-estradiol were mediated predominantly by activation of es-
trogen receptor-a, as the estrogen receptor-bknockout mouse
develops hypertension and vascular dysfunction and activation of
this receptor has antiproliferative effects. Further studies are re-
quired to fully reconcile these observations if nonhormonal selec-
tive estrogen receptor ligands are to be developed for PAH.
SIX-MINUTE WALK, HEART RATE, AND RV
FUNCTION IN PAH
Right heart function is the most important determinant of sur-
vival in patients with PAH. A number of studies have refined
specific parameters of right heart function, such as 6-minute walk
distance, heart rate recovery (HRR), and novel measures of RV
glycolytic activity, to assess clinical risk. Although the 6-minute
walk test (6MWT) is the “workhorse” efficacy end point in
clinical trials, the magnitude of improvement in walk distance
with therapy that is clinically meaningful remains unknown. In
a retrospective analysis of data from the Pulmonary Hyperten-
sion Response to Tadalafil (PHIRST) trial, Mathai and col-
leagues used distributional and anchor-based methodologies
to conclude that a distance of greater than 33 m is associated
with improvement in quality-of-life measures (36). These results
are consistent with a more extensive analysis of 10 randomized
clinical trials of PAH-targeted therapy, which found that an
increase greater than 42 m best predicted a reduction in the
time to clinical worsening (37). It has been appreciated for some
time, however, that the threshold level (e.g., achieving .380 m)
is more important than a small improvement over baseline and
is likely to assume a greater role in the assessment of new
therapies in the future (38).
Information obtained after completion of the 6MWT also ap-
pears to have value. Minai and colleagues assessed the associa-
tion between HRR (defined as the difference in heart rate at the
end of 6MWT and 1 min after completion of the 6MWT) and
clinical worsening in 75 consecutive patients with PAH (39).
The best predictors of clinical worsening were an HRR less than
16 (hazard ratio, 5.2), which occurred in 40% of patients eval-
uated, and the mean pulmonary arterial pressure (hazard ratio,
1.04). HRR was also a better predictor of clinical worsening
than 6MWT. The accompanying editorial emphasized the im-
portance of heart rate control in cardiovascular risk assessment
and noted two caveats: the relatively high number of subjects
who were receiving b-blocker therapy (25%) in the group with
an HRR less than 16 and lack of information about whether the
HRR profile can be improved with therapy (40). Future studies
in larger cohorts evaluated before and after therapy will help to
address these questions and further support the proposed use-
fulness of measuring HRR in patients with PAH (39, 41).
Whereas PAH is characterized by right heart failure, progres-
sive diastolic RV pressure overload can adversely affect LV di-
astolic filling and output. Displacement of the interventricular
septum during the diastolic phase with right heart failure can
compromise LV filling and volume (referred to as diastolic ven-
tricular interaction or interdependence). Kasner and colleagues
explored this mechanism in patients with nonsevere PAH
(mean pulmonary artery pressure, 29 mm Hg), using invasive
pressure–volume loop analysis during simultaneous atrial
pacing to a heart rate of 120 beats/minute (42). Remarkably,
even in these mildly affected patients their stroke volumes
dropped by about 25% during pacing. They then occluded
the inferior vena cava to transiently reduce RV filling. With
this maneuver, the LV end-diastolic volume increased 7% and
end-diastolic pressures dropped, resulting in an 11% increase
in cardiac output. This elegant study provides proof that the
heart rate–dependent increase in RV pressure/volume over-
load adversely impacts LV cardiac filling and output, even in
the setting of normal LV systolic function. This has clear impli-
cations for diseases such as sickle cell anemia and portopulmo-
nary hypertension, which are characterized by high baseline
cardiac output states and mild-to-moderate elevations in pulmo-
nary pressures, yet poor prospective survival rates (43, 44).
Cardiac magnetic resonance imaging provides a noninvasive
means of assessing pulmonary hemodynamics and cardiac struc-
ture and function, and studies have explored the use of modern
techniques that may help indentify local abnormalities in RV
function and predict survival in patients with PAH (45, 46).
Another approach that could be useful in evaluating the sever-
ity of PAH and response to therapy is the measurement of
a shift from oxidative phosphorylation to glycolytic metabolism,
using positron emission tomographic imaging of
18
F-labeled
deoxyglucose (FDG) uptake. FDG uptake, via glucose transporter-
1, is increased in the RV of patients with IPAH and in IPAH
pulmonary vascular cells in culture (47). Marsboom and col-
leagues evaluated the relationship between FDG uptake, cellu-
lar glycolytic activity, and PH severity in monocrotaline and
Sugen/hypoxia rat models (48). FDG uptake increased in the
pulmonary vasculature as well as the RV, and the signal in the
vasculature was related to increased cellular glycolytic activity
in proliferating smooth muscle and endothelial cells. This was
characterized by increased glucose transporter-1 expression,
inhibition of pyruvate dehydrogenase activity by pyruvate de-
hydrogenase kinase, and reductions in mitochondrial oxidative
phosphorylation. The increase in glycolytic activity correlated
closely with disease progression and response to two therapies:
inhibition of pyruvate dehydrogenase kinase by dichloroacetate
and inhibition of tyrosine kinase by imatinib. Hypoxia-inducible
factor-1awas also implicated in the development of the glycolytic
phenotype. The clinical usefulness of measurements of FDG up-
take in IPAH remains to be determined.
SICKLE CELL DISEASE–ASSOCIATED PH
Mehari and colleagues summarized the hemodynamic param-
eters of 84 patients with sickle cell disease and clinical suspicion
of PH from a cohort of 529 monitored up to 9 years, the largest
prospectively screened sickle cell cohort to date (44). Fifty-five
patients (10% of the total cohort) had PH and of these 31 (6%
of the cohort) had PAH. PH was the major independent risk
factor for death and risk was determined primarily by the
severity of precapillary pulmonary artery pressures, specifi-
cally pulmonary vascular resistance and transpulmonary pres-
sure gradients, but not pulmonary artery occlusion pressure
values. These findings are consistent with those of a Brazilian
cohort, in which the 10% of patients with PH had the highest
risk of death (49). In both studies, the risk of PH was associated
with the severity of hemolytic anemia, suggesting that patients
with all forms of chronic hemolytic anemia should be evaluated
for possible PH.
GENETICS OF PAH
Familial PAH is inherited as an autosomal dominant condition
and may show anticipation, with younger age of onset and death
Pulmonary, Sleep, and Critical Care Updates 25
in subsequent generations, as well as reduced penetrance (only
z20% of individuals carrying the mutant gene develop the dis-
ease). Having allowed sufficient time to elapse to capture all
affected cases in the analysis of age at diagnosis and death,
Larkin and colleagues reanalyzed 355 individuals with BMPR2
mutations from 53 PAH families in the Vanderbilt University
PH registry (50). Their results suggest that genetic anticipation
is an artifact, reflecting an ascertainment bias where only the
early-onset cases are apparent in recent generations. Nonethe-
less, additional genetic and environmental factors are likely to
be important in determining which genetically susceptible indi-
viduals develop the disease (51) and studies provide evidence
that the phenomenon of reduced penetrance in BMPR2 mutant
carriers is due in part to alterations in alternative splicing (52).
Analysis of lymphocytes from patients and unaffected carriers
with BMPR2 mutations showed that patients produced more of
the alternatively spliced BMPR2 isoform B (missing exon 12)
compared with the full-length isoform A, the ratio between the
two being controlled by an exonic splice enhancer in exon 12
and its associated splicing factor, SRSF2. The study represents
a significant step toward understanding which BMPR2 mutant
carriers may eventually manifest the disease and could facilitate
the development of novel therapies (53).
Flynn and colleagues developed an original approach to
explore the molecular pathways that may influence disease
penetrance in PAH, using gene expression profiling of cultured
lymphocytes to compare patients with heritable disease and
asymptomatic familial control subjects who carry nonsense-
mediated decay-positive (NMD
1
)BMPR2 mutations (54).
The NMD pathway is responsible for degrading mRNA tran-
scripts that contain premature termination codons, thereby pre-
venting translation of unnecessary or harmful transcripts.
Patients with NMD
1
BMPR2 mutations are thought to develop
PAH because of haploinsufficiency and exhibited a “PAH pen-
etrance signature,” comprising 23 up-regulated and 12 down-
regulated genes. This was subjected to in silico and Connectivity
Map (cMap) analysis, revealing differences in the production of
reactive oxygen species between patients and unaffected rela-
tives. More importantly, the combination of gene expression pro-
files and bioinformatic analysis may identify novel pathways in
the pathogenesis of pulmonary vascular disease that are respon-
sive to U.S. Food and Drug Administration (FDA)–approved
drugs, the actions of which are already included in the cMap
database (54).
THERAPY AND CLINICAL TRIALS
The high mortality of PAH documented in registry studies
underlines the need for new treatments. The study by Stacher
and colleagues indicates that current treatments have little di-
rect impact on vascular remodeling (5). For example, plexi-
form lesions were more common in patients who had received
a prostanoid than in patients who had not. Nonetheless, drugs
based on current pathways remain the most likely to enter clinical
practice in 2013. In addition to the oral prostanoid selexipag (55),
a new dual endothelin antagonist (macitentan) (2) and a soluble
guanylate cyclase stimulator (riociguat) (3, 4) were both reported
to have positive clinical results in 2012.
The nitric oxide (NO)–cyclic guanylate cyclase signaling path-
way remains an attractive treatment target for PAH, at least in
adults. Baliga and colleagues have reported that dietary nitrate,
via conversion to nitrite by oral bacteria with nitrate reductase
capacity, and dietary nitrite reduced RV pressure and hypertrophy,
and pulmonary vascular remodeling in experimental PH (56). The
proposed mechanism is dependent on reduction of nitrite to form
NO by both endothelial NO synthase and xanthine oxidoreductase.
The authors suggest that exploitation of this mechanism (i.e., dietary
nitrate/nitrite supplementation) represents a viable, orally ac-
tive therapy for PH. Along these lines, inhaled nitrite is also
being examined as a potential therapy for PAH (ClinicalTrials.
gov identifier NCT01431313).
In contrast, the FDA has issued a warning about the use of
sildenafil in children with PAH, due to an apparent increase
in long-term mortality. The phosphodiesterase type 5 inhibitor
sildenafil is approved for use in the treatment of PAH in children
in Europe but not the United States. The FDA concerns are
based on a single-center, placebo-controlled trial that evalu-
ated the effects of sildenafil at low, medium, or high doses in
treatment-naive children who were diagnosed with IPAH or
PAH associated with congenital heart disease (57). Increased
mortality was reported in patients randomized to high-dose sil-
denafil monotherapy at 3 years when compared with lower dose
groups. There was no untreated control group. The FDA warn-
ing raised objections from the expert community and readers
are referred to their advice with respect to the continued use of
sildenafil in children and the future use of this drug (58).
The strategy of moving from vasorelaxing agents to drugs that
target directly the vascular remodeling in PAH has raised safety
concerns in humans. A striking example of this is the differential
effect of dasatinib in rodent models of PH and humans. Like
other RTK inhibitors, dasatinib is effective in attenuating PH
in monocrotaline and hypoxic rat models (59), but Montani
and colleagues detected an increase in PAH in patients taking
dasatinib for chronic myeloid leukemia (60). RTK inhibitors are
a large drug class and dasatinib is comparatively unselective.
Elucidating the mechanism of the association of PAH with
dasatinib would not only help steer the development of other
RTK inhibitors but also may provide important insight into the
pathophysiology of PAH.
CONCLUSIONS
The studies published over the last year have advanced but also
tested our understanding of the pathology and management of
pulmonary vascular disease. Considering all the data, including
the apparent anomalies (i.e., letting all the data speak), is the
secret to building on this foundation in the year to come.
Author disclosures are available with the text of this article at www.atsjournals.org.
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