Pulminary hypertension

Slide 1 : Pulmonary Arterial Hypertension:Bench to Bedside DHMC Core Curriculum

Slide 2 : Disclosures Speakers Bureau Merck, Pfizer, Actelion, Encysive Consultant Actelion Encysive

Slide 3 : Cardiac Hemodynamics 0-5 20/ 0-5 6-10 22/ 6-10 120/10 120/80

Slide 5 : WHO World Symposium, Venice 2003 PAH Classification I. Pulmonary arterial hypertension Familial Idiopathic (formerly called primary) Related to: Collagen-vascular disease Congenital heart disease, shunts Portal hypertension HIV infection Drugs / toxins/other Hemoglobinopathies (Sickle cell, thalassemia) Other II. PH related to pulmonary venous hypertension (left heart disease) III. PH related to disorders of respiratory system IV. PH caused by thromboemboli PE Non-thrombotic pulmonary embolism: tumor, parasites V. Miscellaneous: Sarcoid, extrinsic compression

Slide 6 : Helpful Studies ECG, CXR, ECHO Routine labs: LFTs, ANA, HIV serology, CBC Pulmonary thromboemboli: Perfusion lung scan, CT scan, pulmonary angio OSA: sleep study

Slide 7 : Right Heart CatheterizationDiagnostic Gold Standard RA and RV pressures Pulmonary artery pressure PAOP (capillary wedge pressure) Cardiac output Calculated pulmonary vascular resistance Prognostic (RAP, CI, mPAP) Response to vasodilator challenge

Slide 8 : 82/32 (50)

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Slide 10 : Hemodynamics

Slide 11 : WHO 2003 Classification I. PULMONARY ARTERIAL HYPERTENSION (PAH) II. PULMONARY HYPERTENSION WITH LEFT HEART DISEASE III. PULMONARY HYPERTENSION ASSOCIATED WITH LUNG DISEASE AND/OR HYPOXEMIA IV. PULMONARY HYPERTENSION RESULTING FROM CHRONIC THROMBOTIC AND/OR EMBOLIC DISEASE V. MISCELLANEOUS

Slide 12 : Pulmonary Venous Hypertension Mitral valve disease Aortic valve disease Systemic hypertension Left ventricular dysfunction Systolic Diastolic Constrictive pericarditis Restrictive cardiomyopathies Diabetic cardiomyopathy

Slide 13 : Is It Left Heart Disease? Paroxsymal nocturnal dyspnea Orthopnea Atrial fibrillation Absence of right axis deviation Left atrial enlargement History of systemic hypertension, diabetes, coronary artery disease Obesity

Slide 14 : Case Presentation 70 yo man with tissue MVR in 2000 Noted to have a mitral stenosis murmur on exam in 2005 without symptoms. Echo 2005: Mild to moderate valve stenosis, PASP 45mmHg Acute pulmonary edema in summer 2006.

Slide 15 : Transesophageal ECHO

Slide 16 : Hemodynamics

Slide 17 : Case Presentation 57 yo woman, treated for recurrent right heart failure PMH: Morbid obesity, hypertension, diabetes Physical exam showed Wt 298 lbs, JVD, S4, accentuated P2, peripheral edema ECHO: PASP 82, RV dilated, LVEF 60%, normal mitral valve

Slide 18 : Hemodynamics

Slide 19 : WHO Classification I. PULMONARY ARTERIAL HYPERTENSION (PAH) II. PULMONARY HYPERTENSION WITH LEFT HEART DISEASE III. PULMONARY HYPERTENSION ASSOCIATED WITH LUNG DISEASE AND/OR HYPOXEMIA IV. PULMONARY HYPERTENSION RESULTING FROM CHRONIC THROMBOTIC AND/OR EMBOLIC DISEASE V. MISCELLANEOUS

Slide 20 : Lung/Respiratory Diseases Associated with PH COPD* Asthma Cystic fibrosis Bronchiectasis Bronchiolitis obliterans Central alveolar hypoventilation Obesity-hypoventilation syndrome* Obstructive sleep apnea* Neuromuscular diseases Kyphoscoliosis* Thoracoplasty Sequelae of pulmonary tuberculosis Sarcoidosis Pneumoconiosis Drug-related lung diseases Extrinsic allergic alveolitis Connective tissue diseases Idiopathic interstitial pulmonary fibrosis* Interstitial pulmonary fibrosis of known origin Respiratory Insufficiency of “Central” Origin Obstructive Lung Diseases Restrictive Lung Diseases

Slide 21 : Emphysema Fibrosis Lung/Respiratory Diseases Associated with PH

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Slide 23 : WHO Classification I. PULMONARY ARTERIAL HYPERTENSION (PAH) II. PULMONARY HYPERTENSION WITH LEFT HEART DISEASE III. PULMONARY HYPERTENSION ASSOCIATED WITH LUNG DISEASE AND/OR HYPOXEMIA IV. PULMONARY HYPERTENSION RESULTING FROM CHRONIC THROMBOTIC AND/OR EMBOLIC DISEASE V. MISCELLANEOUS

Slide 24 : Case Presentation 24 yo man with a history of seizures, recent frontal lobe neurosurgery Developed sudden dyspnea and weakness two days before and again on the day of admission CT of chest showed a large pulmonary embolism in main PA

Slide 25 : Cath Lab

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Slide 28 : Idiopathic (formerly primary PAH) Familial (FPAH) Related to: Connective tissue disease – HIV infection Congenital heart disease – Drugs and toxins Portal hypertension – Other PAH with significant venule and/or capillary involvement Pulmonary veno-occlusive disease Pulmonary capillary hemangiomatosis Proceedings of the 3rd World Symposium on Pulmonary Arterial Hypertension. J Am Coll Cardiol. 2004;43:1S-90S. Group I WHO: PAH

Slide 29 : Vascular Remodeling Pathophysiology of PAH:An Integrated View

Slide 30 : Schematic Progression of PAH Time PAP PVR CO Pre-symptomatic/ Compensated Symptomatic/ Decompensating Symptom Threshold Right Heart Dysfunction Declining/ Decompensated

Slide 31 : Prostacyclin Prostacyclin synthase Nitric oxide Nitric oxide synthase VIP Kv channel Fibrinolysis Endothelin-1 Serotonin Thromboxane A2 Clotting Factors Angiopoietin-1 PAI-1 Growth factors Oxidant stress Inflammation Reduced Activity Increased Activity PAI=plasminogen activator inhibitor; VIP=vasoactive intestinal peptide. Mediators and Pathways in PAH

Slide 32 : Humbert M, et al. NEJM. 2004.

Slide 33 : History of NR 63yo woman notes increasing dyspnea, particularly past 6 months, now O2 dependent Moderate COPD by PFTs, smoker RA, on immunosuppressives ECHO demonstrates RA/RV dilatation, 3+ TR, PASP 80 mmHg, septal flattening, normal LV

Slide 34 : Physical Exam WD, small frame, 63 yo woman, BP 120/70 P 90 R 16, Wt. 119 lbs, O2 sat 99% on 2L nasal HEENT: Moderate JVD Lungs: Clear Cardiac exam: Loud P2, TR murmur, RV lift. ABD: unremarkable Ext: 1-2+ edema bilat

Slide 35 : Hemodynamics

Slide 36 : Humbert M et al. N Engl J Med. 2004;351:1425-1436. Targets for Current or Emerging Therapies in PAH

Slide 37 : FDA-Approved Therapies

Slide 38 : Epoprostenol Synthetic salt of prostacyclin Rapid efficacy; short,3- to 5-min half-life Approved for Class III and IV Invasive: requirescontinuous IV infusion Individualized dosingregimen required Two RCTs showing efficacy

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Slide 40 : Epoprostenol: Side Effects Flushing Headache Diarrhea, nausea, vomiting Jaw pain Myalgia Hypotension Anxiety, nervousness, agitation Chest pain Dizziness Bradycardia Abdominal pain Dyspnea Back pain Sweating Dyspepsia Paresthesia Tachycardia Delivery site complications

Slide 41 : Treprostinil Longer-acting prostacyclin analogue (~4-h half-life) Subcutaneous infusion; recently approved for IV use Approved for Class II-IV Efficacy slower thanepoprostenol, requireshigher doses Site pain problematicwith subcutaneousinfusion

Slide 42 : Site Reaction to Treprostinil

Slide 43 : Iloprost Longer-acting prostacyclin analogue(20- to 30-min half-life) Aerosolized delivery system Approved forClass III and IV Requires frequentinhalations (6-9x/d)

Slide 44 : Humbert M et al. N Engl J Med. 2004;351:1425-1436. Endothelin Receptor Antagonists: Arginine Nitric OxideSynthase VasodilatationandAntiproliferation Nitric Oxide cGMP ExogenousNitric Oxide Phosphodiesterase Type-5 PhosphodiesteraseType-5 Inhibitors Nitric Oxide Pathway Arachidonic Acid ProstacyclinSynthase VasodilatationandAntiproliferation Prostacyclin cAMP ProstacyclinDerivatives ProstacyclinDerivatives Prostacyclin Pathway

Slide 45 : Bosentan Oral, dual (ETA and ETB) endothelin receptor antagonist Two RCTs showing efficacy Approved doses: 62.5 mg bid starting dose for 4 weeks increased to 125 mg bid maintenance dose Approved for Class III and IV

Slide 46 : Bosentan Prevented Significant Hemodynamic Decline -1.6mm Hg +5.1mm Hg -223dyn-sec-cm-5 +191 dyn-sec-cm-5 0.52L/min/m2 +0.5L/min/m2 Bosentan therapy significantly improved hemodynamics over 12 weeks Conventional therapy led to worsening hemodynamics over 12 weeks ‡ significant change vs baseline ‡ ‡ Adapted from Channick, et al. Lancet 2001. Treatment Effect: 6.7 mm Hg - 415 dyn-sec cm-5 1.02 L/min/m2 ‡ ‡

Slide 47 : Bosentan Safety Mild anemia may be induced LFT surveillance monthly Teratogencity: may be an ERA class effect Ensure negative Pregnancy test before Rx Monthly thereafter Headaches, peripheral edema

Slide 48 : Humbert M et al. N Engl J Med. 2004;351:1425-1436. Phosphodiesterase Type-5 Inhibitors: Mechanism

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Slide 50 : Sildenafil Side Effects Nose bleed Headache Dyspepsia Flushing Insomnia Erythema Dyspnea exacerbated Rhinitis Diarrhea Myalgia Pyrexia Gastritis Sinusitis Paresthesia

Slide 51 : PAH Determinants of Risk McLaughlin VV, McGoon MD. Circulation. 2006;114:1417-143