Update on Pulmonary Hypertension and

Implications for Solid Organ

Transplantation

Ivan M. Robbins, M.D.

Adult Pulmonary Hypertension Center
Vanderbilt University
 Pulmonary circulation
Low resistance, high compliance vascular
bed
Only organ to receive entire cardiac output
(CO)
Changes in CO as well as pleural/alveolar
pressure affect pulmonary blood flow
Different reactions compared to the systemic
circulation
Normally in a state of mild vasodilation
 Vascular Pressure in Systemic and
Pulmonary Circulations (mm Hg)
120/80, mean 93 25/8, mean 14
Systemic Pulmonary
Circulation Arteries Arteries Circulation
Right Left
Atrium Atrium
Mean >6 Mean 5

Body Lung

SVR= 17.6 PVR= 1.8

Right Left
Veins Ventricle Ventricle Veins
25/2-5 120/5-10
 Outline
Review classification of pulmonary hypertension
(PH)
Pulmonary arterial hypertension (PAH)
Evaluation of PH and how to differentiate PAH
from other forms of PH
PH and cardiac, renal and hepatic transplantation
Review PAH-approved therapy and treatment of
non-Group 1 PH
 Dana Point Classification of
Pulmonary Hypertension (PH)
1) Pulmonary arterial hypertension
2) Pulmonary hypertension due to left heart disease
3) Pulmonary hypertension due to lung diseases and/or
hypoxia
4) Chronic Thromboembolic pulmonary hypertension
(CTEPH)
5) Pulmonary Hypertension with unclear and/or
multifactorial mechanism
 Dana Point Classification of PAH, Group 1
Idiopathic PAH (formerly primary pulmonary
hypertension, PPH)
Heritable
Drug/toxin induced
Associated with:
Connective tissue diseases
HIV infection
Portal hypertension
Systemic to pulmonary shunts
Schistosomiasis
Chronic hemolytic anemia
 WHO Group 2 PH
Pulmonary hypertension owing to left heart
disease
Systolic dysfunction
Diastolic dysfunction
Valvular disease
Pulmonary venous obstruction
 PH with unclear or multifactorial
mechanisms: Group 5

1.Hematologic disorders
2.Systemic disorders: vasculitis
3.Metabolic disorders
4.Others: chronic renal failure on dialysis
 Definitions
Definition of PH:
mPAP > 25 mm Hg at rest

Definition of PAH:
PWP < 15
Normal LVEF
No left-sided valvular disease
PAH: A Disease of Decline & Deterioration
100 IPAH NIH Registry
Percentage Surviving

80

60

40

20

0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Years of Follow-up

Adapted from: DAlonzo GE, Ann Int Med, 1991

Outcome of Scleroderma Patients with Pulmonary
Hypertension is worse than IPAH
100
90
80
Survival, %

70 None
60
50 Lung Involvement (without
40 PHT)
30
20 PHT
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13

Years From Diagnosis of PHT

Koh et al, Br J Rheumatol, 1996
 IPAH NIH Registry
187 patients followed over 7 years
Extensive evaluation to R/O secondary
causes
mPAP-60mmHg, CI-2.3 l/min, PVRI-26 U
Mean age at Dx: 36, almost 2:1 female:male
Mean duration of symptoms before Dx: 2
years
Rich, Ann Intern Med, 1987
~Two cases per 1,000,000
 PAH is a rare disease
Incidence of IPAH: ~1-2 cases/million per year
Prevalence: 5,000 patients?
Prevalence of PAH: 30,000 patients?
~50 million Americans have systemic
hypertension
61% of American adults are overweight
27% are obese (BMI>30)
16% of Americans have diabetes
22% have hyperlipidemia
 PAH is rare in patients >65 yo
referred to our PH center
Diagnosis Number (%) (n = 248)
Pulmonary Arterial Hypertension (PAH) 37 (15%)
Idiopathic PAH 5
CTD-associated PAH 28
CHD-associated PAH 1
Portopulmonary HTN 3
PH owing to left heart disease 70 (28%)
PH owing to lung disease and/or hypoxia 35 (14%)
Chronic thromboembolic PH 19 (8%)
Other or mixed causes of PH 42 (17%)
Unknown 24 (10%)
No PH 21 (8%)
Pugh et al, submitted, 2012
 Pathogenesis of PAH 2012:
An Integrated View
Genetic
Proliferation
Predisposition

Other Risk Vascular

Thrombosis
Factors Remodeling

Altered Pathways
Vasoconstriction
and Mediators
Inflammation
 PH - History
History of smoking
ETOH/recreational drug use
Systemic hypertension
Cyanosis/murmur as a child
Joint/musculoskeletal pain
Raynauds Syndrome
FH of unexplained early cardiopulmonary disease
Previous DVT, PE or family hx of thromboembolic dz
Use of appetite suppressant drugs
 PH- Symptoms
DOE
Fatigue, weakness
Chest pain
LE or abdominal swelling
Syncope
Not typical of PAH: orthopnea
 Evaluation for PH
ECG
Chest x-ray
V/Q scan or contrasted spiral CT (+/- angiogram)
PFTs
Exercise oximetry
Echocardiogram
Right heart catheterization w/vasodilator testing
Labs: CBC, CMP, INR, ANA, HIV, TFTs
Clues to causes of PH other than PAH
Dilated LA on echo or on CT angiogram
Hx of systemic vascular disease
LVH, LAE, no evidence of RVH or RAD on
ECG
Orthopnea
Crackles, clubbing
Development of pulmonary edema with
pulmonary vasodilators
Think of disorders affecting pulmonary veins
 PH - Radiographic studies
CXR:
-large proximal PA with peripheral
tapering (pruning)
-cardiomegaly due to enlarged RA, RV
-pleural effusion is uncommon
CT:
-PA >aorta
-cardiomegaly, enlarged RV
-pericardial effusion
CXR in PAH
CXR in Eisenmenger Syndrome
Mitral Stenosis
 Enlarged main PA on CT
Standard view Coronal view

A PA
Ventilation Perfusion Lung Scan
PAH

Perf Vent
CTEPH

Perf Vent
 Evaluation for Chronic
Thromboembolic PH (CTEPH)
V/Q scan remains the best screening tool
CT angiogram is excellent for acute, proximal PE but
can miss CTEPH

PE Tanariu, N. et al,
No PE J Nucl Med, 2007

Gold standard for diagnosis is pulmonary angiogram

Safe procedure even in patients with marked PH
Mortality in 2 large studies: 0/547 and 2/202*
*Hofman LV, et al, AJR, 2004
Pitton MB, et al, AJR, 2007
CTEPH: Pulmonary Angiography

Confirms diagnosis of CTEPH in

patients with PH
Assess thrombus accessibility
Distinct angiographic patterns
Web narrowing
Poststenotic dilatation
Proximal occlusion
Pouch defects
Organized Clot Removed at Surgery
 Pulmonary Function tests
No characteristic changes

Mandatory to screen for significant restrictive

or obstructive lung disease

Diffusing capacity often significantly reduced

in patients with scleroderma (<50%)
RV, RA Enlargement on Echocardiogram

RV
LV

RA LA

Normal PH
 PH by Echo PAH
Single echo lab / Australian community of 160,000
~10% of patients had est. sPAP>40 mm Hg
Only 2.3% with PAH after full evaluation

Lung disease/ CTEPH, 0.6%

Sleep-related PAH, 2.3%
hypoventilation,
9.7% Unknown, 6.8%

Congenital heart
disease, 1.9%
Left heart
disease, 78.7%
N=483 of 4579 patients with echo PASP >40 mm Hg.
Gabby E. Am J Respir Crit Care Med. 2007;175:A713.
 Echo estimate of PAP often inaccurate in
advanced lung disease
Overestimation
Cohort: 374 lung txp pts 60 Accurate
Underestimation
Echo 2448 h prior to RHC
Prevalence of PH: 25% 40

% of studies
Echo frequently leads to
over-diagnosis of PH in 20
patients with advanced
lung disease
0
PH (-) PH (+)

Arcasoy SM et al. Am J Respir Crit Care Med. 2003;167:735-740.

 Right Heart Catheterization
Gold standard for diagnosis of PH
Crucial for determining cause of PH, i.e. pre-
vs post-capillary process
Required prior to initiating therapy for PAH
Acute vasodilator testing should be
performed at time of RHC in patients with
PAH
 Other Helpful Diagnostic Tests
(Determined by patients history)

High resolution chest CT

Cardiopulmonary exercise study
Polysomnography
Arterial blood Gas
Hepatitis serologies
Left heart catheterization, evaluation of
coronary arteries
 PH and Cardiac Transplantation
ISHLT guidelines:
no absolute cutoffs for PH that prohibits transplant1
Relative contraindication: PVR>5 or PVRI>6 or TPG
>16-20
Increased risk of RHF and death if sPAP >60 mm Hg
and one of the above
If PVR to <2.5 with vasodilator but patient becomes
hypotensive, persistent high risk (3.8% vs 27.5% 3
month mortality2
1. Mehra, M. et al, J Heart Lung Transplant, 2006
2. Costard-Jackle, et al, JACC, 1992
Causes of RV failure after cardiac
transplantation in patients with PH
Smaller mass than LV, less able to adapt to
increased afterload
Low coronary blood flow/unit mass, less
cooling, perhaps less cardioplegia
TR results from annular distortion during
implantation and from increased afterload
 PH in ESRD
Prevalence up 48% on echo reported in literature1-4
Only 10-14% had est. sPAP>45-50 mm Hg1
Largest study: 500 pts, 68 (13%) on PD
Mean sPAP: 479 mm Hg, range: 35-75 mm Hg
5.9% incidence in PD patients
Longer duration of dialysis in PH pts, 51 vs 30 months
Patients with PH had:
1. Yigla et al, Chest, 2003
Higher CO1-3 2. Nakhoul, et al Nehrol Dial Transplant, 2005
Worse survival1,3 3. Issa et al, Transplantation, 2008
4. Bozbas et al, Transplanat Proc, 2009
5. Hemnes et al, Nephrol Seminar, 2010
PH is a risk factor for decreased
survival in hemodialysis patients

Yigla, et al Kidney International, 2009

Problems with studies of PH in ESRD
No direct hemodynamic measurements
All studies are estimated pressure by echo
PH generally defined as est. sPAP>35 mm Hg
Volume status of patients not reported
RV function is reported in only one study
No measurement of PWP or PVR
Many studies involve small numbers of patients
No prospective studies
 Echocardiographic findings in ESRD
patients undergoing transplant
Patients With
Patients Without PHT
Echocardiographic Data PHT P Value
(n = 415)
(n = 85)
LV, diastole (cm) 4.9 0.5 4.7 2.0 .3
LV, systole (cm) 3.2 0.5 3.1 0.5 .8
Right ventricle (cm) 3.3 0.5 3.2 0.4 .8
Left atrium (cm) 4.0 0.7 3.5 0.6 <.0001
Right atrium (cm) 3.7 0.5 3.3 0.4 <.0001
Diastolic dysfunction (%) 18.8 21.4 .6
Systolic dysfunction (%) 22.4 13.5 .04
LV ejection fraction (%) 49.7 7.9 52.3 6.9 .002
LV hypertrophy (%) 78.8 59.8 .001
Bozbas et al, Transplantation Proceedings, 2009
PH is a associated with decreased survival
after renal transplant
Retrospective analysis of 215/472 renal txp pts who
had echo and est. RVSP obtainable1
48% on no HD prior to txp, only 10 on PD
Mean RVSP 3410 mm Hg, range 21-71
RVSP <35 mm Hg in 68%, 35-50 mm Hg in 22%,
>50 mm Hg in 10% (22 pts)
Time on HD significantly related to development of
PH independent of other risk factors
1.Issa et al, Transplantation, 2008
 Summary
Pulmonary hypertension being recognized more
frequently in patients with ESRD
LV dysfunction and fluid overload are the
primary factors contributing to clinically
significant PH in patients on HD
Although PH is associated with worse outcome,
patients are not dying of rh failure
PH, as with other disorders, is associated with
worse outcome
PH in patients with portal hypertension

All patients must be

screened for PH
Portopulmonary HTN:
mPAP> 25 mm Hg
PVR> 3 units
PWP <15 mm Hg

Krowka, MJ Semin Respir Crit Care Med, 2012

 Portopulmonary hypertension
~5% of pts in a large epidmiological study of PAH
Occurs in 5.3-8.5% of liver transplant candidates
Outcome is poor untreated: 14% and 4% in 2
uncontrolled studies
Death can occur due to RH failure or liver dz
Treated, survival is improved: 40-68% 5 yr
survival
Can obtain MELD exception if hemodynamic
improvement with PAH therapy
Implications for liver transplantation
Higher risk with mPAP>35 mm Hg
Up to 36% post-tx in-hospital mortality due to:
Acute RH failure during reperfusion of liver
Frequent need for enormous amount of blood
products
Mild PH with normal PVR generally resolves
after transplant
Effect of Tx in pts with mPAP>35 mm Hg with
increased PVR is unpredictable
Treatment of Pulmonary
Hypertension
 Treatment of non PAH-pulmonary
hypertension
Pulmonary Venous Hypertension:
Treat heart failure with afterload reduction
Systolic or diastolic
MV or AV disease
Replace the valve
Pulmonary vein stenosis
Pulmonary vein stenting
 Treatment of non PAH-pulmonary
hypertension
PH associated with disorders of the respiratory
system and/or hypoxemia:
Rx of hypoxemia is often the main therapy

PH due to chronic thromboembolic disease:

Thromboendarterectomy for proximal disease
Can consider PAH therapy for distal disease
 Adjunctive treatments of PAH

Anticoagulation
Diuretics
Digoxin
Oxygen
Calcium channel blockers
Exercise
Salt restriction
Targets for current PAH-specific therapy
Prostacyclin Pathway Endothelin Pathway Nitric Oxide Pathway

Arachidonic Acid Big Endothelin Arginine

Prostacyclin Endothelin- Nitric Oxide

Synthase converting Synthase
Enzyme

Prostacyclin Endothelin-1 Nitric Oxide

cAMP cGMP Exogenous

Endothelin Nitric Oxide
Prostacyclin
Prostacyclin Receptor
Derivatives
Derivatives Antagonists Phosphodiesterase Type-5

Endothelin Endothelin
Receptor A Receptor B Phosphodiesterase
Type-5 Inhibitors

Vasodilatation Vasoconstriction Vasodilatation

and and and
Antiproliferation Proliferation Antiproliferation

Humbert M et al. N Engl J Med. 2004

 Specific PAH Treatment
Epoprostenol (generic and Flolan)
Treprostinil (Remodulin) Prostaglandins
Iloprost (Ventavis)
Bosentan (Tracleer) Endothelin receptor
antagonists (ERAs)
Ambrisentan (Letairis)
Tadalifil (Adcirca) Phosphodiesterase 5
inhibitors (PDE5 inhibitors)
Sildenafil (Revatio)
 Comparison of Medical Treatments
for PAH
Cost $ Route Frequency Ease Side Long-term
(annual) of Use effects Randomized
data
Epoprostenol ~100,000 IV Continuous + +++ No

Treprostinil >175,000 SQ, IV, Continuous ++ +++ No

Inhaled
Iloprost ~175,000 Inhaled 6-9x per day ++ ++ No

Sildenafil ~15,000 Oral TID +++ + No

Tadalafil ~12,000 Oral Daily +++ + No

Bosentan ~75,000 Oral BID ++++ + No

Ambrisentan ~75,000 Oral Once a day ++++ + No

 PAH Determinants of Risk
Lower Risk Determinants of Risk Higher Risk
Clinical evidence of
No Yes
RV failure

Gradual Progression Rapid

II, III WHO class IV

Longer (>400 m) 6MWD Shorter (<300 m)

Minimally elevated BNP Very elevated

Pericardial effusion,
Minimal RV dysfunction Echocardiographic findings
significant RV dysfunction

Normal/near normal
Hemodynamics High RAP, low CI
RAP and CI

McLaughlin VV, McGoon MD. Circulation. 2006;114:1417-1431.

 LUNG TRANSPLANTATION
The only cure for PAH
100

IPAH in UNOS database

75
Survival (%)

50

N=13
25 Single Lung (N =247)

Double Lung (N=444) N=18

P = 0.3
0
0 1 2 3 4 5 6 7 8 9 10
Years
 Take Home Points
PH can not be diagnosed by Echo alone, need a
thorough evaluation for all patients
Right heart catheterization is necessary in ALL patients
to accurately diagnose PH
PAH is a progressive disease, even with Rx
Make sure the patient has PAH before treating
Despite multiple therapies, lung transplantation is the
only curative treatment for PAH
PH negatively impacts outcome of all solid organ
transplants