Presentation Outline

1. Pulmonary Arterial Hypertension: Disease State and Treatment OptionsDr. William HarveyDirector Pulmonary Artery Hypertension ClinicIU Health North Hospital

2. Presentation Outline • Definition of PAH • Pathophysiology • Epidemiology • Clinical classification • Natural history • Signs and symptoms • Diagnosis • Treatment of PAH

4. Pulmonary Arterial Hypertension: Definition and Histological Characteristics • Mean PA pressure >25 mm Hg or 30 mm Hg with exercise (PCWP ≤15 mm Hg) • PVR >3 Wood units • Increased pressure load on RV • Eventual right-sided heart failure and death adventitia lumen intima Plexiform lesion media Normal pulmonary arteriole Pulmonary arteriole in PAH Barst et al. J Am Coll Cardiol. 2004;43:40S-47S.

5. PathophysiologyPulmonary Artery Hypertension

6. Pathogenesis of PAH: Vasoconstriction Vasodilation Vasoconstriction Decreased NO synthase Prostacyclin NO Increased Endothelin Serotonin Thromboxane

7. Mechanisms of Pathology for PAH Endothelinpathway Prostacyclinpathway Nitricoxidepathway Endothelial cells L-arginine Preproendothelin Proendothelin Arachidonicacid Prostaglandin I2 NOS Nitric oxide Prostaglandin I2 Endothelin-1 Endothelin-receptor A Endothelin-receptor B Exogenous nitric oxide Prostacyclinderivates cGMP Endothelin-receptor antagonists cAMP Phosphodiesterase type 5 Vasodilatation and antiproliferation Vasodilatation and antiproliferation Vasoconstriction and proliferation Phosphodiesterase type 5 inhibitor Humbert, et al. N Engl J Med. 2004;351:1425-1436.

8. Pathophysiology

10. Epidemiology/ClassificationPulmonary Artery Hypertension

12. Epidemiology of PAH (WHO Group I)1 • Idiopathic PAH2 • Incidence is approximately 2 to 5 per million per year • 2 to 3 times more prevalent in women • Mean age of 37 years at diagnosis3 • Familial PAH • Observed in about 6% to 10% of PAH cases3 • Associated PAH • Approximately 27% of patients with CTD (scleroderma or mixed CTD) have PAH4 • Equally high prevalence in limited and diffuse disease5 • Each year, 0.5% of patients with HIV develop PAH6 • Prevalence of portopulmonary hypertension is 4% to 15% among patients undergoing evaluation for liver transplantation7-8 • 15% to 30% of all patients with congenital heart disease have PAH9 1. Simonneau et al. J Am Coll Cardiol. 2004;43(12 suppl):5S-12S. 2. Gaine and Rubin. Lancet. 1998;352:719-725. 3. Rich et al. Ann Intern Med. 1987;107:216-223. 4. Wigley et al. Arthritis Rheum. 2005;52:2125-2132. 5. Launay et al. J Rheumatol. 2007;34:1005-1011. 6. Limsukon et al. Mt Sinai J Med. 2006;73:1037-1044. 7. Colle et al. Hepatology. 2003;37:401-409. 8. Kuo et al. Chest. 1997;112:980-986. 9. Landzberg. Clin Chest Med. 2007;28:243-253.

16. Epidemiology of PAH • Rare disease (orphan designation) of the pulmonary microvasculature affecting 50,000 to 100,000 people in the United States1 • Affects all ages and races • Most prevalent in 4th and 5th decades of life • Higher prevalence in females • True incidence and prevalence may be underestimated • Due to under diagnosis (e.g., in patients with HIV) and misdiagnosis (e.g., asthma)2 • Prevalence of PAH may increase because of demographic trends in associated conditions 1. Rubin. Chest. 1993;104:236-250. 2. Ghamra and Dweik. Cleve Clin J Med. 2003;70:S2-S8.

17. 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 1 Idiopathic (IPAH) Heritable (PAH) BMPR2 ALK1 Endoglin (with or without hereditary hemorrhagic telangiectasia) Unknown Drugs and Toxins induced Associated with Connective Tissue Diseases HIV Infection Portal Hypertension Congenital Heart Diseases Schistosomiasis Chronic hemolytic anemia Persistent pulmonary hypertension of the newborn Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.

18. 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 2 Pulmonary hypertension owing to left heart disease Systolic dysfunction Diastolic dysfunction Valvular disease Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.

19. 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 3 Pulmonary hypertension owing to lung diseases and/or hypoxia Chronic obstructive pulmonary disease Interstitial lung disease Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.

20. 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 4 Chronic thromboembolic pulmonary hypertension (CTEPH) Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.

21. 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 5 Pulmonary hypertension with unclear multifactorial mechanisms Hematologic disorders: myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.

22. NYHA Functional Classification Rich, ed. Executive summary from the World Symposium on Primary Pulmonary Hypertension, Evian, France, 1998:6-10.

23. WHO Functional Classification Rubin. Chest. 2004;126(suppl 1):7S-10S.

24. Natural HistoryPulmonary Artery Hypertension

25. 69% 56% 46% 38% Natural History of PAH: NIH Registry1,2 Predicted survival* Percent survival Predicted survival Years NIH = National Institutes of Health.Predicted survival according to the NIH equation. Predicted survival rates were 69%, 56%, 46%, and 38% at 1, 2, 3, and 4 years, respectively. The numbers of patients at risk were 231, 149, 82, and 10 at 1, 2, 3, and 4 years, respectively. *Patients with primary pulmonary hypertension, now referred to as idiopathic pulmonary hypertension. 1. Rich et al. Ann Intern Med. 1987;107:216-223. 2. D’Alonzo et al. Ann Intern Med. 1991;115:343-349.

26. Survival by PAH Etiology Prognosis in Mixed Treated/Untreated Cohorts Percent survival Years CHD = congenital heart disease; CVD = collagen vascular disease; HIV = human immunodeficiency virus; PAH = pulmonary arterial hypertension; PPH = primary pulmonary hypertension; PoPH = portopulmonary hypertension.McLaughlin et al. Chest. 2004;126:78S-92S.

27. PAH/SSc Progresses Even More Rapidly 100 90 80 No Lung involvement 70 60 Percent Survival 50 Lung Involvement without PAH 40 30 PAH 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years from Diagnosis of Pulmonary Hypertension Koh, et al. Br J Rheumatol 1996

28. Signs/Symptoms Pulmonary Artery Hypertension

29. Symptoms of PAH McLaughlin et al. J Am Coll Cardiol. 2009;53:1573-1619. Dizziness and/or fainting (syncope) Shortness of breath (dyspnea) Chest pain (angina) Feeling tired or worn out (fatigue) Swollen ankles and legs (edema) See slides 33-39 for Important Safety Information about Remodulin and refer to the Full Prescribing Information provided.

32. REVEAL Database: Most Frequent Symptoms at Diagnosis Abstract Dyspnea at rest Cough Dizzy/lightheaded Presyncope/syncope Edema Chest pain/discomfort Other Fatigue Dyspnea on exertion IPAH APAH 0 25 50 75 100 N=1479. Incidence (%) Elliott EG, et al. Chest. 2007;132(suppl 4):631S.

33. Implications of Syncope in Patients with PAH Abstract 100 80 P<0.01 60 Survival, % 40 Syncopal at diagnosis Non-syncopal at diagnosis 20 0 0 1 2 3 4 5 Follow-up, years N=475 adults with Group 1 PAH completing standardized symptom assessment at time of diagnosis. P<0.01. Hazard ratio 2.56 [95% CI, 1.26, 4.84]. Le RJ, et al. Chest. 2010;138:927A.

34. Diagnosis of PAH

35. Diagnosis of PAH* ANA = antinuclear antibody; CHD = congenital heart disease; LVEDP = left ventricular end-diastolic pressure; PFT = pulmonary function test; RA = right atrial; RV = right ventricular; RVSP = right ventricular systolic pressure; TR = tricuspid regurgitation; VQ = ventilation-perfusion. *Additional tests may be ordered to rule out possible causes of PAH (pulmonary arteriography, blood tests [HIV, hepatic disease, scleroderma], polysomnography [sleep-disordered breathing]). †Required for referral.

38. Chest X-Ray Consistent With PH Image courtesy of Vallerie McLaughlin, MD

39. 39

40. IVS RV LV RA LA Signs of PAH on Echocardiogram with Doppler Apical Four Chamber • Increased sPAP or TR jet • Right atrial and ventricular hypertrophy • Flattening of intraventricular septum • Small LV dimension • Dilated PA McGoon, et al. Chest 2004

41. Echocardiogram:Parasternal Short Axis Image courtesy of Vallerie McLaughlin, MD

42. Echocardiogram: Apical Four Chamber Image courtesy of Vallerie McLaughlin, MD

43. Echocardiogram: Tricuspid Regurgitation Modified Bernoulli’s Equation: 4 x (V)² + RAP = RVSP (PASP) V=tricuspid jet velocity (m/s); RAP= right atrial pressure; RVSP=right ventricular systolic pressure; PASP=pulmonary artery systolic pressure. Image courtesy of Vallerie McLaughlin, MD

47. Accuracy of PH Diagnosis by Echocardiography in Advanced Lung Disease Cohort study of lung transplant patients (n=374) All patients Doppler echo 24 to 48 hours prior to RHC Prevalence of PH: 25% Echo frequently inaccurate leading to over diagnosis of pulmonary hypertension in patients with advanced lung disease Diagnosis of PH Overestimation Accurate Underestimation Studies (%) No Pulmonary Hypertension Pulmonary Hypertension Arcasoy SM, et al. Am J Respir Crit Care Med. 2003;167(5):735-740.

49. Actual Diagnoses of Patients Referred to PH Specialty Clinic Abstract Interstitial Lung Disease Venous Thromboembolism Other Structural Heart Disease Obstructive Sleep Apnea LV Dysfunction Obstructive Lung Disease All Alternative Diagnoses Moghbelli MH, et al. Am J Respir Crit Care Med. 2008;177:A923.