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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)
PulmonaryCirculation
Systemic Circulation Arteries Arteries
Veins Veins
120/80, mean 93 25/8, mean 14
LeftAtriumMean 5
RightAtrium
Mean >6
RightVentricle25/2-5
LeftVentricle120/5-10
LungBody
SVR= 17.6 PVR= 1.8
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)
• HeritableDrug/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
0
20
40
60
80
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0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Years of Follow-up
Per
cent
age
Sur
vivi
ng
Adapted from: D’Alonzo GE, Ann Int Med, 1991
IPAH NIH Registry
Koh et al, Br J Rheumatol, 1996
Outcome of Scleroderma Patients with Pulmonary Hypertension is worse than IPAH
0
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0 1 2 3 4 5 6 7 8 9 10 11 12 13
Years From Diagnosis of PHT
PHT
Lung Involvement (without PHT)
None
Sur
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l, %
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
VascularRemodeling
Other Risk Factors
Altered Pathways and Mediators
GeneticPredisposition
Pathogenesis of PAH 2012:An Integrated View
Proliferation
Vasoconstriction
Thrombosis
Inflammation
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
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
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*
Tanariu, N. et al, J Nucl Med, 2007
*Hofman LV, et al, AJR, 2004 Pitton MB, et al, AJR, 2007
PENo PE
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
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%)
N=483 of 4579 patients with echo PASP >40 mm Hg.Gabby E. Am J Respir Crit Care Med. 2007;175:A713.
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%
Arcasoy SM et al. Am J Respir Crit Care Med. 2003;167:735-740.
Echo estimate of PAP often inaccurate in advanced lung disease
• 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
PH (-)
% o
f stu
dies
0
20
40
60
PH (+)
OverestimationAccurateUnderestimation
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 patient’s 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, 20062. 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: 47±9 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:– Higher CO1-3
– Worse survival1,3
1. Yigla et al, Chest, 20032. Nakhoul, et al Nehrol Dial Transplant, 20053. Issa et al, Transplantation, 20084. Bozbas et al, Transplanat Proc, 20095. 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 DataPatients 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 .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
Echocardiographic findings in ESRD patients undergoing transplant
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%, 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 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
Humbert M et al. N Engl J Med. 2004
Targets for current PAH-specific therapy
Big Endothelin
Endothelin-converting
Enzyme
EndothelinReceptor A
EndothelinReceptor B
Vasoconstrictionand
Proliferation
EndothelinReceptor
Antagonists
Endothelin-1
Endothelin Pathway
Arginine
Nitric OxideSynthase
Vasodilatationand
Antiproliferation
Nitric Oxide
cGMP ExogenousNitric Oxide
Phosphodiesterase Type-5
PhosphodiesteraseType-5 Inhibitors
Nitric Oxide Pathway
Arachidonic Acid
ProstacyclinSynthase
Vasodilatationand
Antiproliferation
Prostacyclin
cAMP
ProstacyclinProstacyclinDerivativesDerivatives
ProstacyclinDerivatives
Prostacyclin Pathway
Specific PAH Treatment
• Epoprostenol (generic and Flolan®)
• Treprostinil (Remodulin®)
• Iloprost (Ventavis®)
• Bosentan (Tracleer®)
• Ambrisentan (Letairis®)
• Tadalifil (Adcirca®)
• Sildenafil (Revatio®)
Endothelin receptor antagonists (ERAs)
Phosphodiesterase 5 inhibitors (PDE5 inhibitors)
Prostaglandins
Comparison of Medical Treatments for PAH
Cost $(annual)
Route Frequency Ease of Use
Side effects
Long-termRandomized data
Epoprostenol ~100,000 IV Continuous + +++ No
Treprostinil >175,000 SQ, IV, Inhaled
Continuous ++ +++ No
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 RiskLower RiskLower Risk Determinants of Risk Higher RiskHigher Risk
NoClinical evidence of
RV failureYes
Gradual Progression Rapid
II, III WHO class IV
Longer (>400 m) 6MWD Shorter (<300 m)
Minimally elevated BNP Very elevated
Minimal RV dysfunction Echocardiographic findingsPericardial effusion,
significant RV dysfunction
Normal/near normalRAP and CI
Hemodynamics High RAP, low CI
McLaughlin VV, McGoon MD. Circulation. 2006;114:1417-1431.
LUNG TRANSPLANTATION
The only cure for PAH
0
25
50
75
100
0 1 2 3 4 5 6 7 8 9 10
Years
Su
rviv
al
(%)
Single Lung (N =247)
Double Lung (N=444) N=18
N=13
P = 0.3
IPAH in UNOS database
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