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

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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

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PHT

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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

CXR in PAH

CXR in Eisenmenger Syndrome

Mitral Stenosis

PAA

Enlarged main PA on CT Standard view Coronal view

Ventilation Perfusion Lung Scan

Perf Vent

Perf Vent

CTEPHCTEPH

PAHPAH

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

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

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 (-)

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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 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

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

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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