Refining Views of Co-morbidities and
Vascular Responsiveness in
Pulmonary Arterial Hypertension
Roham T. Zamanian, MD, FCCP
Assistant Professor of Medicine
Director, Adult Pulmonary Hypertension Clinical Service
Division of Pulmonary & Critical Care Medicine
Stanford University School of Medicine
Disclosures:
Personal Financial Relationships with Commercial interests
relevant to medicine, within the past 3 years:
Consultant: Gilead, United Therapeutics, Ikaria, Bayer, Actelion
Industry-Sponsor Research: United Therapeutics, Gilead, Actelion
Personal Financial Relationships with Non-Commercial interests
relevant to medicine, within the past 3 years:
Research Grants:
- Vera Moulton Wall Center for Pulmonary Vascular Disease
- NIH/NHLBI
- NIH/NIAID
Personal relationships with tobacco industry entities within the
past 3 years:
No relationships to disclose
No “off-label” discussions in this presentation.
Pulmonary Hypertension - Diagnostic Definition:
Diagnostic gold standard = hemodynamics
Rest:
• Mean PAP >25 mmHg (normal 10-15 mmHg)
Exercise:
• Mean PAP > 30 mmHg
PAH = above + PCWP or LVEDP <15 mmHg
(normal 8-10 mmHg)
Associated with adverse changes
• In the pulmonary vasculature (arteriopathy)
• At the level of the right ventricle (hypertrophy)
Courtesy Marlene Rabinovitch
Dana Point Classification of Pulmonary Hypertension
1. Pulmonary Arterial Hypertension
3. Pulmonary hypertension due to lung diseases and/or
1.1 Idiopathic PAH
hypoxia
1.2 Heritable
3.1 Chronic obstructive pulmonary disease
1.2.1. BMPR2
3.2 Interstitial lung disease
1.2.2. ALK1, endoglin (with or without hereditary hemorrhagic
3.3 Other pulmonary diseases with mixed restrictive and
telangiectasia )
obstructive pattern
1.2.3 Unknown.
1.3 Drug- and toxin-induced
3.4 Sleep-disordered breathing
1.4 Associated with
3.5 Alveolar hypoventilation disorders
1.4.1. Connective tissue diseases
3.6 Chronic exposure to high altitude
1.4.2 HIV infection
3.7 Developmental abnormalities
1.4.3 Portal hypertension
1.4.4 Congenital heart diseases
1.4.5 Schistosomiasis
4. Chronic thromboembolic pulmonary hypertension
1.4.6 Chronic hemolytic anemia
(CTEPH)
1.5 Persistent pulmonary hypertension of the newborn
1’. Pulmonary veno-occlusive disease (PVO) and/or pulmonary
5. PH with unclear multifactorial mechanisms
capillary hemangiomatosis (PCH)
2. Pulmonary hypertension due to left heart disease
2.1
Systolic dysfunction
2.2 Diastolic dysfunction
2.3 Valvular disease
5.1 Hematologic disorders: myeloproliferative disorders
splenectomy.
5.2 Systemic disorders, sarcoidosis, pulmonary
Langerhans cell histiocytosis, lymphangioleiomyomatosis,
neurofibromatosis, vasculitis
5.3 Metabolic disorders: glycogen storage disease,
Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis,
chronic renal failure on dialysis.
Simonneau et al, JACC 2009
Outcomes in the Current Era:
Stanford Adult & Pediatric Experience
Zamanian et al 2011
REVEAL: Parameters Independently Associated With Survival
(Cox Proportional Hazard Estimates)
HR p-value
APAH-CTD
APAH-PoPH
FPAH
1.59 <0.001
3.60 <0.001
2.17 0.012
Renal insufficiency
Males age ≥60 yrs
1.90 <0.001
2.18 <0.001
I
III
IV
0.42 0.039
1.41 0.008
3.13 <0.001
Heart rate >92 bpm
Systolic BP <110 mm Hg
1.39 0.005
1.67 <0.001
≥440 m
<165 m
0.58 0.008
1.68 <0.001
<50 pg/mL
>180 pg/mL
0.50 0.003
1.97 <0.001
WHO Group I
PAH Subgroups
Demographics and
Comorbidities
NYHA/WHO
Functional Class
Vitals
6MWD
BNP
ECHO
Pericardial effusion: any
1.35
0.014
DLCO
% predicted DLCO ≥80
% predicted DLCO ≤32
0.59
1.46
0.031
0.018
RHC
mRAP >20 mm Hg
PVR >32 Wood Units
1.79 0.043
4.08 <0.001
1/8
1/4
1/2
1
2
4
Reduced risk
Increased risk
Hazard ratios and 95% CI
Benza RL et al. Circulation. 2010; 122:164-172.
8
REVEAL: Observed 1-year Survival From Time of
Enrollment According to Predicted Risk Strata
100
80
Survival
(%)
Risk strata
Low
Average
Moderately high
High
Very high
60
40
0
No. at risk:
Low
Average
Mod. high
High
Very high
0
1
2
3
1374
665
280
295
102
1368
659
277
293
100
1364
657
274
291
96
1359
653
269
284
89
4
5
6
7
8
Months from enrollment
1356
648
264
277
81
Benza RL et al. Circulation. 2010;122:164-172.
1352
647
263
270
74
1351
640
260
263
72
1346
628
259
255
69
1341
625
255
247
61
9
10
11
12
1336
618
254
241
59
1311
604
249
238
55
1304
602
244
233
52
1303
596
243
225
49
What Is the Optimal Treatment Strategy?
Anticoagulate ± Diuretics ±
Oxygen ± Digoxin
Acute Vasoreactivity Testing
Positive
Negative
Oral CCB
No
Sustained
Response
Yes
Continue
CCB
LOWER RISK
DETERMINANTS OF RISK
HIGHER RISK
No
Clinical evidence of RV failure
Yes
Gradual
Progression of symptoms
Rapid
II, III
WHO class
IV
Longer (>400 m)
6MWD
Shorter (<300 m)
Peak VO2 >10.4 mL/kg/min
CPET
Peak VO2 <10.4 mL/kg/min
Minimal RV dysfunction
Echocardiography
Pericardial effusion,
significant RV
enlargement/dysfunction;
RA enlargement
RAP <10 mm Hg;
CI >2.5 L/min/m2
Hemodynamics
RAP >20 mm Hg;
CI <2.0 L/min/m2
Minimally elevated
BNP
Significantly elevated
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Therapeutic Options in USA for PAH – September 2012
Traditional Tx
•
•
•
Supplemental O2
Diuretics
Oral vasodilators
•
•
•
•
warfarin
•
•
•
Digitalis
•
•
Epoprostenol
Treprostinil
(IV/SQ/Inhaled)
Inhaled Iloprost
ERA’s
•
Inotropic agents
•
Prostanoids
•
(CCB)
Anticoagulants
•
FDA Approved for PAH
Bosentan
Ambrisentan
Investigational Tx
•
•
•
•
•
•
•
Sildenafil
Tadalafil
•
•
•
•
•
•
Oral Treprostinil
ERA’s
•
PDE-5 Inhibitors
•
Prostanoids
Actelion-1
Tyrosine Kinase Inhib’s
Rho-Kinase Inhib’s
Elastase Inhib’s
Dicholoroacetate (DCA)
TetrahydroBiopterin
S. Guanylate Cyclase Act’s
FK-506
LTA4 Hydrolase Inhib’s
Stem Cell Tx
A Paradigm Shift in PAH Clinical Research
• Although we realize that WHO Group I PAH has numerous etiologies, we
have assumed to be “homogeneous” in its biology/physiology.
• Over the last decade there has been an explosion of clinical research in
PAH / PH focused on therapeutics.
• A call for clinical-translational research
• It is time for a Paradigm Shift: New Tools and Topics
• Identification of Novel (modifiable?) Risk Factors / Co-morbidities
• Refining our understanding of acute and chronic vascular responsiveness
• Recognition of potentially novel therapeutics
Overview
Insulin Resistance in PAH:
• Pulmonary Arterial Hypertension (PAH) is a vascular disease
characterized by inflammation, proliferation, and
vasoconstriction.
• Multi-factorial & Complex
• Unlikely that a single factor, pathway, mutation in etiology
• Obesity, hyperlipidemia, and insulin resistance (IR) are known
risk factors for systemic cardiovascular diseases (CVD).
• Impact of obesity or IR in PAH instigation or progression have
not been validated.
• Several lines of evidence though, suggest a link between insulin
resistance and PAH…..
IR in PAH: Suggestive Links
• Obesity is associated with Insulin resistance
• Obesity + Inactivity  IR
• Obesity is common in PAH and maybe an overlooked risk factor.
• Exercise intolerance is a feature of severe PAH
• Insulin resistance has been linked to congestive heart failure and
idiopathic cardiomyopathies
• Elevation of “factors” and inflammatory cytokines which have
been implicated in PAH are also involved in pathogenesis of IR
• IL-6, ET-1, ADMA, MCP-1
Humbert el al. AJRCCM 1995
Ikeda et al. Am J Physiol Heart Circ Physiol 2002
Stuhlinger et al. JAMA 2002
Yudkin el al. Lancet 2005
Abenhaim et al. NEJM 1996
Rich et al. Chest 2000
Taraseviciute et al. Eur J Med Res 2006
PPARg Activation Reverses PAH in Insulin Resistant
ApoE Deficient Mice
IR
5
4
6
6
Hansmann et al Circulation 2007
Hypothesis
• Insulin resistance:
• May be more prevalent in the PAH population
• May be associated with disease severity
• Modulation of insulin resistance may lead to improved
outcomes in PAH
Design & Methods
• Prospective screening of patients with pulmonary arterial
hypertension at SUMC PH Clinic between 2004-2006.
• The National Health and Nutrition Examination Survey
(NHANES) as control population.
• Identification of TG/HDL-C ratio as a surrogate marker for insulin
resistance.
• Excluded: Overt Diabetics, Secondary PH forms including those
with pulmonary parenchymal disease and left heart failure
• Data Collection (PAH): detailed demographic, functional,
hemodynamics, and event-free survival.
Receiver-operating Characteristic Curves for
Metabolic Markers of Insulin Resistance
McLaughlin & Reaven et al. Ann Int Med. 2003
Higher Prevalence of IR in PAH
Zamanian et al, ERJ 2009
Unlike Healthy Controls Insulin Resistance in PAH is
NOT Associated with Age or BMI
Zamanian et al, ERJ 2009
Zamanian et al, ERJ 2009
IR is a Predictor of Short-term Worse Outcomes
79%
58%
Log-rank p = 0.043
Zamanian et al, ERJ 2009
Age & BMI Adjusted Univariate Analysis
Zamanian et al, ERJ 2009
Right Ventricular Glucose Metabolism is Altered in IR PAH
RV
LV
Healthy
RV
LV
IR PAH
RV
LV
IS PAH
FIGURE 1: Representative FDG
PET/CT images in (A) a healthy
control and (B and C) 2 patients
with PAH. (A) Fasting images in
a healthy subject reveal nearly
absent uptake in the right
ventricle (RV) and minimal
patchy FDG activity in the lateral
wall of the left ventricle (LV)
which is considered normal. (B)
By
comparison,
abnormally
intense FDG activity can be
identified throughout the right
ventricular myocardium in an
insulin resistant (IR) patient with
PAH.
The activity appears
significantly greater throughout
the RV than in the LV. (C)
Interestingly, even non-fasting,
glucose challenged images in an
insulin sensitive (IS) PAH patient
demonstrate relatively normal
RV FDG uptake highlighting the
potential differences in RV
myocardial metabolism between
IS and IR PAH.
Impact of IR on RV Structure & Function:
MESA-RV Study
• The Multi-Ethnic Study of Atherosclerosis (MESA) performed
interpretable cardiac MRIs on 5,004 participants without clinical
cardiovascular disease at six field centers.
• 4168 non-diabetic healthy controls were evaluated categorized
as IR or IS and Cardiac MRI data analyzed.
• IR in healthy cohort is associated with higher BMI, systolic and
diastolic blood pressure, and higher CRP.
Parameter
RVEDM, g
RVEDV, mL
RVESV, mL
RVEF, %
RVSV, mL/min
Insulin
Sensitive
21.48±0.11
125.01±0.55
37.69±0.33
70.66±0.19
90.02±0.55
Insulin
Resistant
20.86±0.11
123.19±0.55
36.74±0.33
70.61±0.19
85.67±0.55
p
<0.0001
0.0077
0.0269
0.9728
<0.0001
Zamanian et al ATS 2012 A3453
Impact of IR on RV Function in PAH
Hemodynamic Data
mRAP (mmHg)
mPAP (mmHg)
RVEDP (mmHg)
PCWP (mmHg)
CO (L/min)
SV (mL)
PVR (WU)
IS (n=59)
8+/-3.9
51+/-13.5
12.5+/-4.5
10.8+/-3.5
3.9+/-1.2
53+/- 20.5
11.7+/-6
IR (n=25)
8.2+/-4.3
51.5+/-15
12.5+/-6
10.5+/-3.3
4.1+/-1.6
55.5 +/- 25
12.7+/-7.9
p
>0.05
>0.05
>0.05
>0.05
>0.05
>0.05
>0.05
Echocardiography
MV E (cm/sec)
MV A (cm/sec)
Lat E‘ (cm/sec)
E/A
E/E'
TAPSE (cm)
IS n=19
81.5+/-17
72.5+/-23.5
13.9+/-3.5
1.18+/-0.4
6.1+/-1.6
2+/-0.4
IR n=11
64.5+/-19
78.5+/-18
10.4+/-2.2
0.8+/-0.2
6.3+/-1.9
2.1+/-0.3
p
<0.05
>0.05
<0.01
<0.01
>0.05
>0.05
LA maximum volume index (cm2/m2)
19.5+/-7
17+/-4.5
>0.05
RA maximum volume index (cm2/m2)
45+/-25
40+/-18
>0.05
RV-MPI
0.6+/-0.18
0.65+/-0.18
>0.05
TR max PG (mmHg)
RV FAC (%)
IVC (cm)
TR max PG (mmHg)
RV FAC (%)
IVC (cm)
82.4+/-16
26+/-10
1.7+/-0.5
82.4+/-16
26+/-10
1.7+/-0.5
75.8+/-15
24+/-11
1.6+/-0.6
75.8+/-15
24+/-11
1.6+/-0.6
>0.05
>0.05
>0.05
>0.05
>0.05
>0.05
Skhiri et al ATS 2012 A3463
Early Experience with Pioglitazone in PAH
Bosentan
Pioglitazone
Interim Summary
• Insulin resistance is more prevalent in women with PAH than the
general female population.
• Although obesity may be a link between IR and PAH, our results
do not support the idea that obesity alone is the cause of insulin
resistance in pulmonary arterial hypertension.
• Though IR confers a poorer prognosis, Insulin resistance in PAH
does not appear to correlate with functional class or disease
severity.
• IR may be linked to subtle changes in diastolic ventricular
function and right ventricular metabolism.
Clinical Case Scenario
• 35 yo French female (mother of 2)
• Historically very active  3-5 sets of tennis daily
• Over last year with profound dyspnea
• Can’t garden
• 1 episode of LOC picking up child
RPAP
RPCWP
RPAP after 5 minutes NO @ 20 ppm
Vasoreactivity Traditionally Defined
• Right Heart Catheterization:
• Reduction in mPAP by at least 10 mmHg
• Must reduce to a mPAP of <40 mmHg.
• Cardiac output must be maintained or improved as a result.
• Agents used:
• Nitric Oxide
• Adenosine
• Epoprostenol
• Standard of Care in 1st time RHC for iPAH.
French Registry:
Response to Acute Vasodilator Challenge
Response (%)
10.3%
6.8%
2.6%
3.3%
1.6%
0%
Idiopathic
Portal Anorexigens
Familial Connective Congenital
Tissue
Heart Hypertension
0%
0%
HIV
>2 Factors
N=649.
Challenge with vasodilator at time of right heart catheterization.
Humbert M, et al. Am J Respir Crit Care Med. 2006;173(9):1023-1030.
Survival in IPAH on Oral Calcium Channel Blocker
Therapy
(Long-term Calcium Channel Blocker Therapy)
Cumulative Survival
1.0
Responders
0.8
0.6
Failures
0.4
0.2
0
Subjects
at Risk (n)
0
2
4
6
8
38
19
33
12
30
7
22
4
13
0
10
Years
8
12
3
14
3
16
2
18
1
Responders
Failures
Survival endpoint included those who received transplants or were lost to follow-up. Acute response
defined as defined by a fall in both mean pulmonary artery pressure (PAP) and pulmonary vascular
resistance (PVR) >20%.
Sitbon O, et al. Circulation. 2005;111(23):3105-3111.
Thinking of the Right Ventricle – PA Compliance
• Pulmonary arterial compliance (SV/Ps-Pd) is being recognized as an
important contributor to right ventricular afterload and has been shown
to be a strong predictor of survival.
• Vasoreactivity or milder degrees of vascular responsiveness have not
yet been correlated with pulmonary vascular compliance.
Lankhaar J-W et al. European Heart Journal (2008)29,1688-1695
Hypotheses
1. Vasoreactivity is found not only in IPAH but also other forms of
PAH and can change over time.
2. Even a mild degree of vasoresponsiveness is of
prognostic value.
3. Correlating changes in PVR, mPAP and PAC during
vasoreactivity testing could help identify additional patients with a
reactive vascular bed.
Methods
• Retrospective study (220 patients PAH Group 1) presented to
Stanford Medical Center between 2000 - 2010.
• Diagnosed at the time of RHC with vasodilator testing with 20ppm NO
• Demographics, functional status, medication as well as hemodynamic
parameters were evaluated.
•
A positive vasoreactivity was defined by a reduction in pulmonary
artery mean pressure (PAPm)  10 mmHg to reach an absolute value
of PAPm ≤ 40mmHg with an increased or unchanged cardiac output
after challenge with NO (20 PPM)
•
Previous definitions of actue vasoreactivity (as defined by changes in
pulmonary vascular resistance (PVR) or PAPm by > 20%) was also
evaluated
Spiekerkoetter et al, ATS 2011
Overall Demographics and Clinical Characteristics
Female:Male
168:59 (74%,26%)
44.8 ± 0.9
Age:
Therapies
None
96 (42%)
Prostanoids
PAH etiology:
Epoprostenol
20 (9%)
Iloprost
9 (4%)
Treprostinil
7 (3%)
IPAH
38 (17 %)
Drugs and toxins
54 (24 %)
CTD
45 (20 %)
ERA
38 (17%)
Portal hypertension
12 (5 %)
PDE-I
54 (24%)
Congenital heart disease
41 (18 %)
multifactorial
37 (16 %)
NYHA
Baseline
hemodynamics
NO
challenge
p
mRA
9.3 ± 0.3
-
N/A
mPAP
56.1 ± 1.0
51.8 ± 1.1
< 0.001
9.7 ± 0.3
-
N/A
I
4%
PCWP
II
29%
CI
2.13 ± 0.04
2.18 ± 0.05
< 0.005
III
45%
SV
48.5 ± 1.3
52.8 ± 1.5
< 0.001
IV
22%
PVRI
23.8 ± 0.8
20.0 ± 0.8
< 0.0001
HR
81.6 ± 1.2
78.2 ± 1.2
< 0.0001
MAP
83.3 ± 1.4
83.8 ± 1.1
NS
PAC
0.96 ± 0.04
1.16 ± 0.05
< 0.001
6-min walk (m) (n=204)
NT-pro BNP pg/mL (n=110)
381 ± 10
1276 ± 168
* 27% on CCB held for VR testing, 28 (12%) on multiple therapies
Spiekerkoetter et al, ATS 2011
Clinical Characteristics Based on VR Status
Non-Vasoreactive
n=203
New Definition
Vasoreactivity
n=17
Old definition
Vasoreactivity
n=54
IPAH
31 (15%)
7 (39%)
16 (30%)
D&T
49 (23%)
5 (28%)
5 (9%)
CTD
43 (21%)
2 (11%)
10 (19%)
Portal hypertension
12 (6%)
0
1 (2%)
Congenital
40 (19%)
1 (6%)
7 (13%)
Multifactorial
34 (16%)
3 (16%)
15 (27%)
I
8 (4%)
0
1 (2%)
II
55 (24%)
9 (50%)
21 (39%)
III
91 (44%)
7 (39%)
25 (46%)
IV
46 (22%)
2 (11%)
7 (13%)
49 (22%)
1 (5%)
7 (13%)
9 (4%)
0
2 (4%)
PAH etiology
NYHA class
events
death
transplant
Spiekerkoetter et al, ATS 2011
Spiekerkoetter et al, ATS 2011
Acute Vasoreactivity isn’t “the” determinant to outcomes in PAH
Spiekerkoetter et al, ATS 2011
2007
2009
Arterial
Phase
CHRONIC VASCULAR REACTIVITY
VASCULAR REMODELING?
Capillary
Blush
Diffusing Capacity for Carbon Monoxide as a Surrogate
of Chronic Vaso-reactivity (remodeling?)
• Diffusing capacity of the lung for carbon monoxide (DLCO) is a
relatively simple, standardized, inexpensive, and widely available
pulmonary function test.
• DLCO is recognized as a measure of pulmonary gas exchange
efficiency across the alveolar capillary interface. Decreased DLCO is
associated with conditions such as parenchymal (e.g. interstitial lung
diseases, emphysema) and pulmonary vascular diseases.
• The decrease in DLCO in pulmonary hypertension has been thought
to be due to pulmonary arterial remodeling and subsequent reduction
in perfused pulmonary capillary bed.
• Furthermore, reduction in DLCO has been related to the degree of
functional capillary surface area loss in scleroderma associated
pulmonary arterial hypertension (PAH), suggesting that DLCO is also a
marker of endothelial cell function.
DLCO Cont
• Numerous recent studies have demonstrated the clinical utility of DLCO
in PAH. Baseline DLCO can predict long-term survival in PAH.
• Decreasing DLCO over time can also predict the development of
pulmonary hypertension in patients at risk, such as ones with limited
scleroderma.
• While changes in DLCO over time have been demonstrated to be more
powerful in predicting prognosis in idiopathic pulmonary fibrosis than
single-point DLCO measurement, there are currently no studies
evaluating the extent and utility of delta DLCO in pulmonary
hypertension.
Aims
1) to validate previous findings that decreased baseline DLCO is a
predictor of poor prognosis
2) to describe changes in DLCO over time (DLCOdelta)
3) to investigate the prognostic utility of DLCOdelta in patients with PH.
We hypothesized that decrease in DLCO over time is a predictor of
poor prognosis.
Saito et al, ATS 2011
PAH or CTEPH
(n=313)
Figure 1
No DLCO (n=18)
Subjects with DLCO
(n=295)
TLC > = 60%
(n=250)
TLC
TLC < 60% (n=16)
TLC unavailable
(n=29)
FVC > = 60%
(n=250)
DLCO available
(n=268)
FVC
FVC < 60% (n=11)
DLCOadj
DLCOadj unavailable
(n=22)
“Total Cohort”
DLCOadj available
(n=246)
Legend:
Included
Excluded
“Follow-up Cohort”
DLCOadj available @ 1yr
(n=34)
DLCOadj @ follow up
unavailable
(n=22)
Figure 2
100
Survival (%)
75
50
DLCOadj >80%
DLCOadj 40-80%
25
DLCOadj <40%
Log-rank p = 0.0035
0
0
365
730
1095
1460
Days
1825
2190
2555
2920
Figure 3
Figure 4
100
Survival (%)
75
50
25
Absolute increase in DLCO>=10%
Absolute increase in DLCO<10% or loss
Log-rank p=0.029
0
0
365
730
1095
1460
Days
1825
2190
2555
2920
External Validation Cohort
DLCOdec *
DLCOstab
DLCOinc **
Figure 1: Change in DLCO & Survival – Kaplan Meier analysis demonstrates best survival for patients who had improvement
of DLCO over time.
* DLCOdec vs DLCOstab Log rank p=0.041.
** DLCOinc vs DLCOstab Log rank p=0.007.
Conclusions
• Advancement in understanding of co-morbidities in a rare disorder
such as PAH may have profound clinical and therapeutic
implications.
• Insulin resistance is modifiable (pharmacologic versus non-pharm)
• Improvement in clinical phenotyping of the acute vasoreactive
pulmonary hypertension patient is needed.
• Gain of Vaso-responsiveness maybe suggestive of “reverse
•
remodelling”
Potentially informative of novel clinical endpoints and mechanisms of
action.
Acknowledgements:
Juliana Liu
Sherrie Jones
Angela Herrera
Darlene Frie
Yuwen Liao
Val Scott
Andrew Hsi
Patricia Del Rosario
Allyson Rupp
Nathan Brunner
Krithika Ramachandran
Mark Nicolls
Mark Krasnow
Marlene Rabinovitch
Jeffery Feinstein
Francois Haddad
Vinicio De Jesus Perez
Edda Spiekerkoetter
Kristina Kudelko
Lorinda Chung
Ramona Doyle
Steven Kawut
Work Supported by:
NIH/NHLBI NHLBI-HV-10-05, 1U01HL107393-01, PAR-09-185, N01-HV-00242
Vera Moulton Wall Center for Pulmonary Vascular Disease