Pulmonary Arterial Hypertension

Transcription

1 Learning Objectives 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 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 1

2 Pathogenesis 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 Early Vasoconstriction Overexpression of Vasoconstrictors Endothelin (ET-1)- plexiform lesions Thromboxane (TX) A₂ Excessive Vasoconstriction Impaired production of vasodilators ino Prostacyclin Abnormal function Endothelial dysfunction World Health Organization (WHO) Group Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH BMPR ALK-1, ENG, SMAD9, CAV1, KCNK Unknown 1.3 Drug and toxin induced 1.4 Associated with: Connective tissue disease HIV infection Portal hypertension Congenital heart diseases Schistosomiasis 1 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1 Persistent pulmonary hypertension of the newborn (PPHN) 2

3 WHO Group 2013 WHO Group Pulmonary hypertension due to left heart disease 2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 3. Pulmonary hypertension due to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4. Chronic thromboembolic pulmonary hypertension (CTEPH) 5. Pulmonary hypertension with unclear multifactorial mechanisms 5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH WHO group 2013 functional class vs Panama functional class 3

4 Epidemiology 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 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. Data prospective prospective International, prospective, retrospective observational Centers in country Years Patients patients 362 (3 months to 18 years, 3263 pediatric PH patients 58.4% Caucasian 46% IPAH/HPAH PAH diagnosed by RHC) 2845 with PAH (group 1) age of 36 ± 15 years 54% acquired PAH 88% with PAH 8% lung disease 57 % IPAH or HPAH 5 % left heart disease 36% acquired PAH <1% thromboembolic with CDH Trisomy 21 frequent 3 with chronic chromosomal disorder at thromboembolic or 12% miscellaneous Transient PH included 13% with 58% PPHN chromosomal 42% APAH-CHD anomalies Sex 1.7:1 female 4.8:1 female 1.4:1 female predominance Onset of 2 years months, with 20% > symptoms to 2 years diagnosis Survival 2.8 years 1 yr-96 ± 4%, 1 yr-87%, 1 yr -68%, 3 yr- 84 ± 5% 3 yr- 78% 3 yr- 48% 5 yr -74 ± 6% 5 yr- 57% 5yr -34% 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 4

5 o o ACVRL1, BMPR2 CAV1, ENG With Add-on Preliminary-evidence Genes of BMPR1B,GDF2,KCNA5, KCNK3, SMAD9 Genetics of PAH 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: o ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, FOXF1, KCNK3, SMAD9 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 History Suspicion 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 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. 5

6 Echocardiogram 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 Echocardiogram 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 6

7 PFT Lung perfusion Polysomnography (Sleep study) CT scan CXR Cardiac 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 7

8 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 Rp = Cardiac Index 55mmHg 7mmHg Rp = 2.2 l/min/m 2 (Measured by thermo-dilution) Rp = 21.8 Wood Units x meters 2 Normal Rp 3 Wood Units x meters 2 Laboratory 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 8

9 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) Pharmacology Options Endothelin 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 Most frequent first line oral / enteral therapy 9

10 Pharmacology Options Prostanoid 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 Current Surgical / Interventional Options 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 Lung Transplant Survival Survival (%) All Ped LTx Median=5.5 yrs N=19 Median=5.8 yrs Time after transplant (years) Ped HrtTx, 1-10yrs Median=16.4 yrs 10

11 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: Austin, E. and Loyd, J. The Genetics of Pulmonary Hypertension. Circulation Research Jun 20;115(1): 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: Barst RJ, Ertel SI, Beghetti M, Ivy DD. Pulmonary arterial hypertension: a comparison between children and adults. Eur Respir J 2011;37: Berger, Rolf M F et al. Clinical Features of Paediatric Pulmonary Hypertension: A Registry Study. Lancet (2012): PMC. Web. 13 Apr Clabby et al. Journal of American Colloge of Cardiology Vol. 30, No. 2 August 1997: D'Alto, Michele & Merola, Assunta & Dimopoulos, Konstantinos. (2015). Pulmonary hypertension related to congenital heart disease: A comprehensive review. Global Cardiology Science and Practice /gcsp 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 Pulmonary Circulation 1.2 (2011): PMC. Web. 13 Apr 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 Suppl S):13. Lammers AE, Adatia I, Cerro MJ, et al. Functional classification of pulmonary hypertension in children report from the PVRI PediatricTaskforce, Panama Pulm Circ 2011;1: Prins, Kurt W., and Thenappan. WHO Group I Pulmonary Hypertension: Epidemiology and Pathophysiology. Cardiology clinics 34.3 (2016): PMC. Web. 13 Apr Schulze-Neick, I., and Beghetti, M. Issues related to the management and therapy of paediatric pulmonary hypertension. Europe Respiratory Review 2010;19:118, van Loon RL, Roofthooft MT, Hillege HL, et al. Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to Circulation 2011;124: