1. Update on Pulmonary Hypertension and Implications for Solid Organ Transplantation
Ivan M. Robbins, M.D.
Adult Pulmonary Hypertension Center
Vanderbilt University

2. 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

3. Vascular Pressure in Systemic and Pulmonary Circulations (mm Hg)
120/80, mean 93
25/8, mean 14
Systemic
Circulation
Pulmonary
Circulation
Arteries
Arteries
Right
Atrium
Mean >6
Left
Atrium
Mean 5
Body
Lung
SVR= PVR= 1.8
Right
Ventricle
25/2-5
Left
Ventricle
120/5-10
Veins
Veins

4. 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

5. 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

6. 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

7. WHO Group 2 PH Pulmonary hypertension owing to left heart disease
Systolic dysfunction
Diastolic dysfunction
Valvular disease
Pulmonary venous obstruction

8. 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

9. Definitions Definition of PH: Definition of PAH:
mPAP > 25 mm Hg at rest
Definition of PAH:
PWP < 15
Normal LVEF
No left-sided valvular disease

10. PAH: A Disease of Decline & Deterioration20 40 60 80
100
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
Years of Follow-up
Percentage Surviving
IPAH NIH Registry
Adapted from: D’Alonzo GE, Ann Int Med, 1991

11. Years From Diagnosis of PHT
Outcome of Scleroderma Patients with Pulmonary Hypertension is worse than IPAH 10 20 30 40 50 60 70 80 90
100 1 2 3 4 5 6 7 8 9 11 12 13
Years From Diagnosis of PHT
PHT
Lung Involvement (without PHT)
None
Survival, %
Koh et al, Br J Rheumatol, 1996

12. 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

13. 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

14. 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%)
Patients aged 65 years or older referred to VUMC Pulmonary Vascular Disease Center for known or suspected PH between XXX (time that PH panel was made) and 9/2011.
Patients with previously established PAH who presented for transfer of care were excluded.
Patients were classified by pulmonary vascular disease specialist according to standard guidelines.
Pugh et al, submitted, 2012

15. Pathogenesis of PAH 2012: An Integrated View
Other Risk
Factors
Altered Pathways and Mediators
Genetic
Predisposition
Proliferation
Vasoconstriction
Thrombosis
Vascular
Remodeling
Inflammation

16. PH - History History of smoking ETOH/recreational drug use
Systemic hypertension
Cyanosis/murmur as a child
Joint/musculoskeletal pain
Raynaud’s Syndrome
FH of unexplained early cardiopulmonary disease
Previous DVT, PE or family hx of thromboembolic dz
Use of appetite suppressant drugs

17. PH- Symptoms DOE Fatigue, weakness Chest pain LE or abdominal swelling
Syncope
Not typical of PAH: orthopnea

18. 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

19. 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

21. 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

22. CXR in PAH

23. CXR in Eisenmenger Syndrome

24. Mitral Stenosis

25. Enlarged main PA on CT Standard view Coronal view

28. Ventilation Perfusion Lung Scan
CTEPH
PAH

29. 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
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* PE
No PE
Tanariu, N. et al,
J Nucl Med, 2007
*Hofman LV, et al, AJR, 2004
Pitton MB, et al, AJR, 2007

30. 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

31. Organized Clot Removed at Surgery

32. 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%)

33. RV, RA Enlargement on EchocardiogramLV RA LA
Normal PH

34. 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
Left heart
disease, 78.7%
PAH, 2.3%
Congenital heart
disease, 1.9%
Lung disease/
Sleep-related
hypoventilation,
9.7%
CTEPH, 0.6%
Unknown, 6.8%
It is important to recognize that while echo is an excellent screening tool when there is suspicion of PH, the echo and cath are complementary, and one cannot substitute for the other.
This slide depicts data from a single echo lab on the ultimate diagnosis reached in 483 patients found to have PH on echo.
Not unexpectedly, the majority had left heart disease and, importantly, only a small number (2%) had PAH.
While these data are subject to referral bias and we cannot be certain of the diagnostic criteria used, the point remains:
The echo and cath are each essential.
We cannot be certain of PAH on the basis of the echo alone.
N=483 of 4579 patients with echo PASP >40 mm Hg.
Gabby E. Am J Respir Crit Care Med. 2007;175:A713.

35. Echo estimate of PAP often inaccurate in advanced lung disease
Overestimation
Accurate
Underestimation
Cohort: 374 lung txp pts
Echo 24–48 h prior to RHC
Prevalence of PH: 25%
Echo frequently leads to over-diagnosis of PH in patients with advanced lung disease 20 40 60
% of studies
Although the echo is often remarkably accurate in its estimate of pulmonary pressures, in certain situations (as depicted here in patients with advanced lung disease undergoing evaluation for transplant) it can be less reliable.
The point is NOT that echo is less valuable.
Echo provides important structural, valvular, functional data that are complementary to the cath.
Rather, the point is that both tests are essential to be certain of the right diagnosis.
PH (-)
PH (+)
Arcasoy SM et al. Am J Respir Crit Care Med. 2003;167:

36. 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

37. PH: The Importance of Hemodynamics
Pulmonary venous hypertension
Mixed etiology
PCWP >15 mm Hg VC RA RV PA PV LA LV Ao PC
Right heart catheterization (RHC) is the diagnostic gold standard for PH.
RHC is required to confirm the diagnosis of PH and assess its severity (for prognosis), exclude left heart disease, and perform vasoreactivity testing.
This slide represents the cardiovascular connections in series: [VC=vena cava, RA=right atrium, RV=right ventricle, PA=pulmonary artery, PC=pulmonary capillary bed, PV=pulmonary venous bed, LA=left atrium, LV=left ventricle, Ao=aorta].
Patients with PH in WHO group I (PAH), III, or IV have “pre-capillary” PH, where the left-sided filling pressure (PWCP and/or LVEDP) is normal and the pulmonary vascular resistance (PVR) is elevated.
In the case of pulmonary venous hypertension (“passive” or “post-capillary” PH), which is related to diseases of the left heart, PA mean pressure and PCWP are elevated, whereas PVR is normal.
For some patients the picture is mixed: left-sided filling pressure and PVR are both elevated.
Clinically, this situation is seen most commonly with advanced systolic LV failure or restrictive cardiomyopathy (typically associated with “reactive” pulmonary vasoconstriction).
Patients with a high CO state (“hyperkinetic” PH) have elevated mean PAP and CO, yet normal LV filling pressure and PVR.
PAH
PH with respiratory disease
CTEPH
Other:
High CO
PCWP ≤15 mm Hg
PVR ≤3 Wood units
PCWP ≤15 mm Hg
PVR >3 Wood units 37

38. Other Helpful Diagnostic Tests (Determined by patient’s history)
High resolution chest CT
Cardiopulmonary exercise study
Polysomnography
Arterial blood Gas
Hepatitis serologies
Left heart catheterization, evaluation of coronary arteries

39. 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

40. 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

41. 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: 47±9 mm Hg, range: mm Hg
5.9% incidence in PD patients
Longer duration of dialysis in PH pts, 51 vs 30 months
Patients with PH had:
Higher CO1-3
Worse survival1,3
1. Yigla et al, Chest, 2003
2. Nakhoul, et al Nehrol Dial Transplant, 2005
3. Issa et al, Transplantation, 2008
4. Bozbas et al, Transplanat Proc, 2009
5. Hemnes et al, Nephrol Seminar, 2010

42. PH is a risk factor for decreased survival in hemodialysis patients
Yigla, et al Kidney International, 2009

43. 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

44. Echocardiographic findings in ESRD patients undergoing transplant
Echocardiographic Data
Patients With PHT
(n = 85)
Patients Without PHT
(n = 415)
P Value
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
Left atrium (cm)
4.0 ± 0.7
3.5 ± 0.6
<.0001
Right atrium (cm)
3.7 ± 0.5
3.3 ± 0.4
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

45. 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 34±10 mm Hg, range 21-71
RVSP <35 mm Hg in 68%, 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

46. 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

47. 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

48. Portopulmonary hypertension
~5% of pts in a large epidmiological study of PAH
Occurs in % 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

49. 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

50. Treatment of Pulmonary Hypertension

51. 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

52. 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

53. Adjunctive treatments of PAH
Anticoagulation
Diuretics
Digoxin
Oxygen
Calcium channel blockers
Exercise
Salt restriction

54. Targets for current PAH-specific therapy
Arachidonic Acid
Prostacyclin Synthase
Vasodilatation and Antiproliferation
Prostacyclin
cAMP
Prostacyclin Derivatives
Prostacyclin Pathway
Big Endothelin
Endothelin- converting Enzyme
Endothelin Receptor A
Endothelin Receptor B
Vasoconstriction and Proliferation
Endothelin Receptor Antagonists
Endothelin-1
Endothelin Pathway
Arginine
Nitric Oxide Synthase
Vasodilatation and Antiproliferation
Nitric Oxide
cGMP
Exogenous Nitric Oxide
Phosphodiesterase Type-5
Phosphodiesterase Type-5 Inhibitors
Nitric Oxide Pathway
Humbert M et al. N Engl J Med. 2004

55. Specific PAH Treatment
Epoprostenol (generic and Flolan®)
Treprostinil (Remodulin®)
Iloprost (Ventavis®)
Bosentan (Tracleer®)
Ambrisentan (Letairis®)
Tadalifil (Adcirca®)
Sildenafil (Revatio®)
Prostaglandins
Endothelin receptor
antagonists (ERAs)
Phosphodiesterase 5
inhibitors (PDE5 inhibitors)

56. Comparison of Medical Treatments for PAH
Cost $
(annual)
Route
Frequency
Ease
of Use
Side
effects
Long-term
Randomized data
Epoprostenol
~100,000 IV
Continuous +
+++ No
Treprostinil
>175,000
SQ, IV, Inhaled ++
Iloprost
~175,000
Inhaled
6-9x per day
Sildenafil
~15,000
Oral
TID
Tadalafil
~12,000
Daily
Bosentan
~75,000
BID
++++
Ambrisentan
Once a day

57. PAH Determinants of Risk
Lower Risk
Determinants of Risk
Higher Risk No
Clinical evidence of RV failure
Yes
Gradual
Progression
Rapid
II, III
WHO class IV
Longer (>400 m)
6MWD
Shorter (<300 m)
Minimally elevated
BNP
Very elevated
Minimal RV dysfunction
Echocardiographic findings
Pericardial effusion, significant RV dysfunction
Normal/near normal RAP and CI
Hemodynamics
High RAP, low CI
McLaughlin VV, McGoon MD. Circulation. 2006;114:

58. LUNG TRANSPLANTATION The only cure for PAH
IPAH in UNOS database
Survival was calculated using the Kaplan-Meier method, which incorporates information from all transplants for whom any follow-up has been provided. Since many patients are still alive and some patients have been lost to follow-up, the survival rates are estimates rather than exact rates because the time of death is not know for all patients. Survival rates were compared using the log-rank test statistic.
P = 0.3

59. 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