4/18/2018 1 Pulmonary Arterial Hypertension S 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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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
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
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
– 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.