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Pulmonary Arterial HypertensionS Melissa Magness, MSN, APRN, CNP-AC

Overview of pulmonary arterial hypertension basics • Defining the disease process (pathogenesis),

epidemiology, genetics, diagnostic testing of pulmonary hypertension and management including both pharmacologic and surgical management of the disease

Disclosures

• I have no financial relationship with a commercial interest to disclose.

• Nitric oxide and bosentan are the only FDA approved therapy for pediatric PH

Learning Objectives

Search “pulmonary hypertension pediatrics” on google images….

Diagnosis

• Hemodynamic based definition of PAH:• Mean PAP ≥ 25 mmHG

• Pulmonary capillary wedge pressure (PCWP) < 15 mmHG

• Pulmonary vascular resistance (PVR) ≥ 3 woods units

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Pathogenesis

• Pulmonary system is low pressure/high flow with thin (low transmural pressure) pulmonary arteries (PA)

• PAH is a disease of the small PA’s with vascular narrowing leading to progressive increase in pulmonary vascular resistance

• Multifactorial– Pulmonary vascular dysfunction– Pulmonary vascular proliferation– Extracellular matrix remodeling – Inflammation

Pathogenesis

Early Vasoconstriction

Excessive Vasoconstriction Abnormal function

Endothelial dysfunction

Impaired production of vasodilators • iNO• Prostacyclin

Overexpression of Vasoconstrictors • Endothelin (ET-1)-

plexiform lesions• Thromboxane (TX) A₂

World Health Organization (WHO) Group 2013

1. Pulmonary arterial hypertension1.1 Idiopathic PAH1.2 Heritable PAH

1.2.1 BMPR21.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown

1.3 Drug and toxin induced1.4 Associated with:

1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases1.4.5 Schistosomiasis

1′ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis

1′′ Persistent pulmonary hypertension of the newborn (PPHN)

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WHO Group 2013

2. Pulmonary hypertension due to left heart disease2.1 Left ventricular systolic dysfunction2.2 Left ventricular diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract obstruction and

congenital cardiomyopathies

3. Pulmonary hypertension due to lung diseases and/or hypoxia3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive and obstructive

pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases

WHO Group 2013

4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Pulmonary hypertension with unclear multifactorial mechanisms5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative

disorders, splenectomy5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis,

lymphangioleiomyomatosis5.3 Metabolic disorders: glycogen storage disease, Gaucher disease,

thyroid disorders5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal

failure, segmental PH

WHO group 2013 functional class vs Panama functional class

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Epidemiology

• With an estimated prevalence of 15 to 50 cases per 1 million adults, PAH is a rare disease.

• PAH is even less common in children, with an estimated prevalence of 10 cases per 1 million children.

Registry National Institute of Health

Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (Reveal)

Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP)

Netherlands PH Service

Data prospective prospective International, prospective, observational

retrospective

Centers 32 54 19 8 in country

Years 1981-1985 2006-2009 2008-2010 1991-2006

Patients 187• 58.4% Caucasian• age of 36 ± 15 years

3515 patients• 46% IPAH/HPAH • 54% acquired PAH

362 (3 months to 18 years, PAH diagnosed by RHC) • 88% with PAH

• 57 % IPAH or HPAH • 36% acquired PAH

with CDH• 3 with chronic

thromboembolic or miscellaneous

• 13% with chromosomal anomalies

3263 pediatric PH patients• 2845 with PAH (group 1)• 8% lung disease• 5 % left heart disease • <1% thromboembolic • Trisomy 21 frequent

chromosomal disorder at 12%

• Transient PH included • 58% PPHN • 42% APAH-CHD

Sex predominance

1.7:1 female 4.8:1 female 1.4:1 female

Onset of symptoms to diagnosis

2 years 18-32 months, with 20% > 2 years

Survival 2.8 years 1 yr -68%,3 yr- 48% 5yr -34%

1 yr-96 ± 4%, 3 yr- 84 ± 5% 5 yr -74 ± 6%

1 yr-87%, 3 yr- 78% 5 yr- 57%

Current/Ongoing Registries

TOPP-2 registry • International, non-interventional, prospective registry including

children and adolescents newly diagnosed with pulmonary hypertension (PH) to gain further insights in the disease course and long-term outcome of PH in childhood

Pulmonary Hypertension Association Registry (PHAR)

• Collecting data from WHO Group 1 PH (PAH) and WHO Group 4 PH (chronic thromboembolic pulmonary hypertension [CTEPH]) who are starting evaluation and/or treatment at a PHCC

Genetics of PAH

• Idiopathic PAH (IPAH) 15 times more prevalent than Heritable PAH (HPAH)– Hemodynamics are similar

• Patients with BMPR2 (Bone morphogenic protein receptor type 2) overall are sicker, diagnosed about 10 years earlier with earlier mortality– Unlikely to responds to acute vasodilator testing

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Genetics of PAH

o ACVRL1, BMPR2 CAV1, ENG

o With Add-on Preliminary-evidence Genes of BMPR1B,GDF2,KCNA5, KCNK3, SMAD9

o ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, FOXF1, KCNK3, SMAD9

• Known mutations of PAH associated dominant genes• BMPR2 (75% of HPAP cases) • ACVRL1• ENG• CAV1• SMAD9• BMPR1B• GDF2• KCNA5• KCNK3

• Current recommendations include testing for BMPR2 due to higher prevalence

• Lab panels exist from at least 2 companies:

Genetics of PAH

• Specific considerations:– Involvement of genetics counselor to support

families in implications of testing– Testing for evaluation of patient or familial based

risk assessment?• 50 % chance of inheritance of BMPR2 gene mutation

from parent to offspring• 20-30% lifetime risk for asymptomatic relatives with the

same gene mutation

– Recommendations in screening follow up?

Clinical Presentation & Exam

Clinical HistorySuspicion for PH - dyspnea, chest pain, dizziness, syncope, arrhythmia, hemoptysis, peripheral edema, ascites, and other secondary disease associated with PH (CHD, CLD, Liver Disease, etc.)

Physical Examination• right ventricular lift• palpable P2• prominent auscultation of P2 • pulmonary or tricuspid

insufficiency murmur• ascites • hepatosplenomegaly • peripheral edema

Diagnostics

• Echocardiogram: at diagnosis and average of 4-6 months follow up

• EKG • 6 minute walk

– No data to support predictability of survival in pediatrics• Exercise cardiopulmonary testing

– Not much data, but bike or treadmill• MRI

– Gold standard for RV evaluation. Including size, mass and function.

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DiagnosticsEchocardiogram

• Estimate of PAP and PVR– Velocity of tricuspid regurgitation (TR)– Position of interventricular septum (IVS)

• Quantified by eccentricity index (EI)

– Estimate of PVR (have not been validated)• PA notching

– Shortening of the PA acceleration time and midsystolic notching of the PA Doppler signal

• RV pre-ejection period– Time between QRS onset and pulmonary flow onset

Normal RVH

DiagnosticsEchocardiogram

• Assessment of Ventricular function

– Right Ventricular (RV) function and dimension

– Right atrial (RA) size

– Intracardiac shunts and direction

– LV function: helpful in prognosis

• Tricuspid annular planar excursion (TAPSE): evaluated in adults for PAH

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Diagnostics

• PFT

• Lung perfusion

• Polysomnography (Sleep study)

• CT scan

• CXR

DiagnosticsCardiac catheterization

• Cardiac catheterization goals– Confirm diagnosis/assess severity

– Acute vasodilator testing

– Assess OR readiness of systemic to pulmonary artery shunts

– Evaluate treatment response

– Pre transplant assessment

PAH and Anesthesia

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One more time…

• Hemodynamic based definition of PAH:• Mean PAP ≥ 25 mmHG

• Pulmonary capillary wedge pressure (PCWP) < 15 mmHG

• Pulmonary vascular resistance (PVR) ≥ 3 woods units

Mean PA Pressure – Mean Wedge Pressure

Cardiac IndexRp =

Rp =55mmHg 7mmHg–

2.2 l/min/m2

(Measured by thermo-dilution)

Rp = 21.8 Wood Units x meters2

Normal Rp ≤ 3 Wood Units x meters2

DiagnosticsLaboratory testing

• Basic: – CBC, urinalysis, renal, biomarkers (BNP or NT-proBNP), blood gas

• Coagulation:– Factor VIII, factors II, V, VII, factor V Leiden, lupus anticoagulant,

Protein C and S, Igm, IgG, antithrombin III mutation, platelet function assay

• Portal Hypertension: – LFT, hepatitis screen, abdominal/liver ultrasound

• Thyroid• Connective tissue disease:

– ESR/CRP, ANA, anti DNA, C3, C4 complement, ANCA, rheumatoid factor

• HIV testing, toxins, drugs

Risk assessment

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Treatment

Pharmacology Options

Phosphodiesterase 5 (PDE-5) inhibitors

– Short acting (sildenafil/Revatio®) enteral and IV formulations

– Long acting (tadalafil/Adcirca®)

• Mode of action

– Delays degradation of cGMP

– Promotes nitric oxide production

– Cause vasodilatation in the pulmonary vasculature (and the systemic circulation…i.e. side effects)

• Most frequent first line oral / enteral therapy

Pharmacology OptionsEndothelin receptor antagonists (ERA)

(no available suspensions)

– Short acting – (bosentan/Tracleer®)

– Long acting – (ambrisentan/Letairis ®)– (macitentan/Opsumit ®)

• Mode of action

– Endothelin released by endothelial cells

– Potent smooth muscle constrictor

– Receptor binding results increased intra-cellular calcium, smooth muscle contraction and vascular cell proliferation

Non selective for ERAa and ERAb receptors

50 fold increase in ERAa blockade

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Pharmacology OptionsProstanoid Therapy

– Short acting - (epoprostenol/Flolan®/Veletri®) IV formulations

– Long acting - (treprostinil/ IV & SQ Remodulin ®, inhaled Tyvaso® & enteral Orenitram®)

• Mode of action

– Binds to endothelial prostacyclin receptors, signaling adenyl cyclase to produce cAMP

– cAMP activates protein kinase A, in turn dephosphorylates myosin light chain and inhibits myosin light-chain kinase

– Results in smooth muscle relaxation and vasodilation

Prostacyclin receptor agonist: (selexipag, Uptravi ®)− active metabolite selective to IP receptor versus other prostanoid

receptor

Balloon atrial Septostomy - Intra atrial right to left shunt

1. Decompress right atrium

a. Decrease in saturations compensated

by increase in cardiac output

2. Reserved for experienced centers / bridge

to lung transplantation

Current Surgical / Interventional Options

Potts shunt

• The left pulmonary artery is anastomosed to the descending aorta, allowing the desaturated blood to go from the left pulmonary artery to the lower part of the body (arrow)

• RV pressures should be suprasystemic

• Allows for decompression of the RV, improving function

• Differential upper to lower saturations of greater than 10

Current Surgical / Interventional Options

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10

Su

rviv

al (

%)

Time after transplant (years)

N=19Median=5.8 yrs

All Ped LTxMedian=5.5

yrs

Ped HrtTx, 1-10yrsMedian=16.4 yrs

Lung Transplant Survival1991-2009

Current Surgical / Interventional Options

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Survival References• Abman SH, Hansmann G, Archer S, et al. American Heart Association and American Thoracic Society

joint guidelines for pediatric pulmonary hypertension. Circulation 2015; 132:2037–2099.

• Austin, E. and Loyd, J. “The Genetics of Pulmonary Hypertension”. Circulation Research. 2014 Jun 20;115(1):189-202.

• Barst RJ, McGoon MD, Elliott CG, Foreman AJ, Miller DP, Ivy DD. Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Circulation 2012;125:113–22.

• Barst RJ, Ertel SI, Beghetti M, Ivy DD. Pulmonary arterial hypertension: a comparison between children and adults. Eur Respir J 2011;37:665–77.

• Berger, Rolf M F et al. “Clinical Features of Paediatric Pulmonary Hypertension: A Registry Study.” Lancet 379.9815 (2012): 537–546. PMC. Web. 13 Apr. 2018.

• Clabby et al. Journal of American Colloge of Cardiology Vol. 30, No. 2 August 1997:554–60

• D'Alto, Michele & Merola, Assunta & Dimopoulos, Konstantinos. (2015). Pulmonary hypertension related to congenital heart disease: A comprehensive review. Global Cardiology Science and Practice. 2015. 42. 10.5339/gcsp.2015.42.

References • Del Cerro, Maria Jesus et al. “A Consensus Approach to the Classification of Pediatric Pulmonary Hypertensive

Vascular Disease: Report from the PVRI Pediatric Taskforce, Panama 2011.” Pulmonary Circulation 1.2 (2011): 286–298. PMC. Web. 13 Apr. 2018.

• Ivy DD, Abman SH, Barst RJ, et al. Pediatric pulmonary hypertension. J Am Coll Cardiol 2013; 62:D117–D126.

• Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. Journal of the American College of Cardiology 2004;43(12 SupplS):13.

• Lammers AE, Adatia I, Cerro MJ, et al. Functional classification of pulmonary hypertension in children report from the PVRI PediatricTaskforce, Panama 2011. Pulm Circ 2011;1:280–5.

• Prins, Kurt W., and Thenappan. “WHO Group I Pulmonary Hypertension: Epidemiology and Pathophysiology.” Cardiology clinics 34.3 (2016): 363–374. PMC. Web. 13 Apr. 2018.

• Schulze-Neick, I., and Beghetti, M. Issues related to the management and therapy of paediatric pulmonary hypertension. Europe Respiratory Review 2010;19:118, 331-339.

• van Loon RL, Roofthooft MT, Hillege HL, et al. Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005. Circulation 2011;124:1755–64.