Pulmonary Arterial Hypertension

1. Pulmonary Arterial Hypertension Xiaosong Zhao, MD, PhD Presbyterian Hospital of Dallas January 3, 2006

2. Significance of Pulmonary arterial hypertension Pulmonary arterial hypertension is the third cause of CHF The median survival was 2.8 years with an estimated 5-year survival of 34%. ---NIH Registry. Ann Intern Med 1991; 115: 343-349

3. Annual number of hospitalizations among persons with pulmonary hypertension, United States, 1980–2002 CDC, National Hospital Discharge Survey.

4. Definitions Pulmonary hypertension is an elevation in pulmonary vascular pressure caused by an isolated increase in pulmonary arterial pressure or by increase in both pulmonary arterial and pulmonary venous pressure. Pulmonary arterial hypertension refers to a sustained elevation of mean pulmonary arterial pressure to greater than 25 mmHg at rest or more than 30 mmHg during exercise, with normal pulmonary capillary wedge pressure and left ventricular end-diastolic pressure (<15 mm Hg) .

5. WHO Classification of pulmonary hypertension (Venice 2003; revised from Evian 1998)

6. Histopathology • Main vascular changes of PAH • Vasoconstriction • SMC and endothelial-cell proliferation • fibrosis • thrombosis intima media • Severe concentric laminar intimal fibrosis • Medial hypertrophy • in situ thrombosis of the small residual lumen

7. Stimuli: shear stress, Po2, Viruses (HIV, HHV-8) Autoimmunity (CREST,SLE), Drugs Intrinsic susceptibility (PPH-1,BMPR2,Kv) Pulmonary endothelial-cell dysfunction or injury (Endothelin-1,Nitric Oxide and prostacyclin pathway) Imbalance of vascular effectors Perturbations in the normal relationships between vasodilators and vasoconstrictors, growth inhibitors and mitogenic factors, antithrombotic and prothrombotic determinants. Main vascular changes of PAH Vasoconstriction SMC and endothelial-cell proliferation fibrosis thrombosis Pathophysiology

8. Regulation of pulmonary arterial tone

9. Clinical presentation of PAH A 33 yo F presented to her PCP w/ a 6M h/o gradually progressive exertional dyspnea. She had lightheadedness and near-syncope while climbing steps. She was mildly obese but had otherwise previously been in good health. Her vital signs were normal, her lungs were clear, and cardiac examination showed a slightly prominent second heart sound, a systolic murmur, a heave over the left parasternal border. A initial dx of exercise-induced asthma was made, and use of an inhaled bronchodilator was prescribed. The pt’s symptoms did not diminish. A CXR showed mild cardiomegaly and a slightly prominent main pulmonary artery. PFTs showed only mild reduction in DLCO, an EKG showed right-axis deviation and possible RVH. Then, echocardiogram was done, which showed RVH, RAE, flattening of the interventricular septum, and moderate TR with an calculated (estimated) pulmonary artery systolic pressure of 60 mmHg.

10. Clinical Assessment H & P 6MWT

11. History • Exertional dyspnea • Fatique or weakness • Peripheral edema and/or ascites • Angina • Near syncope or syncope “An impressive feature … was the contrast between the appearance of good health when at rest and the striking discomfort evoked by even mild exertion.” ------ original clinical description by Dr. David Dresdale, 1951

12. Physical Examination • Cardiovascular findings: Large a wave in the jugular venous pulse; Prominent v waves in the jugular venous pulse Low-volume carotid arterial pulse with a normal upstroke; Left parasternal (right ventricular) heave; Systolic pulsation in the second left intercostal space; Ejection click and flow murmur in the second left intercostal space; Closely split second heart sound with a loud pulmonic component; Fourth heart sound of right ventricular origin Third heart sound of right ventricular origin High-pitched early diastolic murmur of pulmonic regurgitation, Holosystolic murmur of tricuspid regurgitation Signs of right ventricular failure (hepatomegaly, peripheral edema, and ascites) Cyanosis • Patients whose PAH is associated with another illness often have clinical features of that disease.

13. CXR-PA view Enlargement of the main pulmonary artery and its major branches, with marked tapering of peripheral arteries .

14. CXR-lateral view Encroachment of the retrosternal air space -- right ventricular enlargement/hypertrophy

15. CXR-PA view The right ventricle and atrium may also be enlarged.

16. ECG • Highly specific but not very sensitive. • Right axis deviation • Right atrial and right ventricular enlargement. • Right bundle branch block • ST and T wave changes in the anterior precordial leads.

17. Echocardiography • Enlargement of the right atrium and ventricle with normal or small left ventricular dimensions. • Abnormal septal motion as a result of the right ventricular volume and pressure overload. • Delayed opening of the pulmonic valve, midsystolic closure, and an increase in the ratio of right ventricular pre-ejection time to total ejection time. • Doppler echocardiographic quantitation of right ventricular systolic pressure may be obtained by measuring the velocity of the tricuspid regurgitant jet and using the Bernoulli formula. PAP = 4 x velocity2 + RAP

18. Echocardiogram Right atrial and ventricular enlargement and flattening of the intraventricular septum -- parasternal short axis view (a) and four chamber view (b).

19. Doppler Echocardiogram

20. Representation of Echocardiographic findings

21. Pulmonary Function Tests • Usually completely normal for PPH • Vital capacity may be reduced to approximately 80% • Hyper-reactivity of the bronchial tree is common, which can lead to a misdiagnosis of asthma • Diffusing capacity for carbon monoxide (DLCO) is mildly reduced to approximately 60 to 80% • Presence of arterial hypoxemia is due to V/Q mismatch and/or reduced mixed venous oxygen saturations resulting from low cardiac output

22. Right heart Catheterization • The diagnosis of PAH cannot be confirmed without right heart catheterization (gold standard) • patients with PAH should have a low or normal pulmonary capillary wedge pressure

23. Exercise Test – 6MWT • The 6-minute walk test (6MWT) is recommended as a standard exercise test by American Thoracic Society • Healthy subjects’ 6MWDs: 400 to 700 m and it varies. • It is commonly used for • Before-and-after treatment comparisons • Measuring functional status • Predicting hospitalization and death

24. Treatment • General measures Physical activity; Diuretics; Supplemental oxygen Digoxin; Anticoagulation • Specific treatment 1. Calcium channel blockers: nifedipine and diltiazem 2. Prostacylin analogues: Epoprostenol; Treprostinil; Iloprost; 3.Endothelin receptor antagonists: Dual endothelin receptor antagonist: Bosentan Selective ETA receptor antagonist: sitaxsentan, Ambrisentan 4. Phosphodiesterase-5 inhibitors: sildenafil • Interventional and surgical therapy: atrial septostomy,Lung or heart-lung transplantation

25. Treatment -- General measures • Physical activity and lifestyle changes • Counseling • Cardiopulmonary rehabilitation program • Graded exercise activities: bike riding and swimming -- safe • Isometric activities: lifting weights or stairclimbing – presyncope or syncope • Young women: birth control

26. Potentially Hazardous Activities for Patients with Pulmonary Arterial Hypertension Rubin, L. J. et. al. Ann Intern Med 2005;143:282-292

27. Treatment -- General measures Diuretics: to achieve symptom relief Loop diuretics and/or potassium-sparing aldosterone inhibitors: cautious vs. courage Low salt diet

28. Treatment -- General measures • Supplemental oxygen To keep O2Sat > 90% Nocturnal desaturation may occur in patients with pulmonary hypertension, even in the absence of daytime hypoxemia or sleep-disordered breathing. Some experts suggest an assessment of noctural oximetry in patients with pulmonary hypertension in order to determine whether nocturnal supplemental oxygen therapy is indicated to maintain satisfactory oxygen saturation during sleep. --- Lewis J. Rubin, 2004

29. Treatment -- General measures • Digoxin Increase in resting cardiac output of approximately 10% Long-term benefit of digoxin administration is not clear

30. Treatment -- General measures • Anticoagulation– oral warfarin to achieve INR 1.5 to 2.5 • Pts with PAH are likely at higher risk for thromboembolic complications: • in situ thrombosis • Decreased activity level • Slower blood flow • Dilated right-sided heart chambers • Especially, the presence of an implanted central catheter for administering PAH medications • The fragile hamodynamic state and limited cardiopulmonary reserve – high risk for death even from a small thromboembolism

31. Treatment • General measures Physical activity; Diuretics; Supplemental oxygen Digoxin; Anticoagulation • Specific treatment of PAH 1. Calcium channel blockers: nifedipine and diltiazem 2. Prostacyclin analogues: Epoprostenol; Treprostinil; Iloprost; 3.Endothelin receptor antagonists: Dual endothelin receptor antagonist: Bosentan Selective ETA receptor antagonist: sitaxsentan, Ambrisentan 4. Phosphodiesterase-5 inhibitors: sildenafil • Interventional and surgical therapy: atrial septostomy, lung or heart-lung transplantation

32. Five-year survival of PPH patients who responded to calcium channel blockers (95%) versus those that did not respond from the same series and historical controls from the NIH registry. Rich S, Kaufmann E, Levy PS. N Engl J Med 1992;327:76–81.

33. Kaplan-Meier survival estimates in 178 patients with PPH from the initiation of epoprostenol therapy

34. Survival of 162 patients with PPH treated with epoprostenol compared to expected survival based on the NIH registry equation

35. Mean ({+/-}SE) Change in Six-Minute Walking Distance from Base Line to Week 16 in the Placebo and Bosentan Groups Rubin, L. J. et al. N Engl J Med 2002;346:896-903

36. Mean Changes from Baseline, with 95 Percent Confidence Intervals, in the Six-Minute Walking Distance at Week 12 in the Placebo and Sildenafil Groups Galie, N. et al. N Engl J Med 2005;353:2148-2157

37. Treatment • General measures Physical activity; Diuretics; Supplemental oxygen Cardiac glycosides; Anticoagulation • Specific treatment of PAH 1. Calcium channel blockers: nifedipine and diltiazem 2. Prostacylin analogues: Epoprostenol; Treprostinil; Iloprost; 3.Endothelin receptor antagonists: Dual endothelin receptor antagonist: Bosentan Selective ETA receptor antagonist: sitaxsentan, Ambrisentan 4. Phosphodiesterase-5 inhibitors: sildenafil • Interventional and surgical therapy: atrial septostomy, lung or heart-lung transplantation

38. WHO classification of functional status of patients with pulmonary hypertension

39. Acute Vasoreactivity Test • The test: using right-heart catheterization to measure pulmonary arterial pressure when challenged with vasodilators ( adenosine IV, or Epoprostenol IV, or NO inhale) • A positive response is considered when there is a greater than 10 mmHg reduction in mean pulmonary artery pressure, to a mean pulmonary artery pressure of less than 40 mmHg.

40. Treatment algorithm for pulmonary arterial hypertension

41. Back to the case – pretreatment evaluation Initial evaluation at the referral center included a 6MWT of 305 m. Right-heart catheterization showed a pulmonary arterial pressure of 65/30 mmHg (mean 42 mmHg), RAP of 12 mmHg, pulmonary capillary wedge pressure of 6 mmHg, and cardiac output of 3.2 L/min. The pt was thought to have idiopathic PAH, falling into WHO pulmonary hypertension class III on the basis of her symptoms. Treatment options were discussed with the pt, including medical therapy, diet, exercise, travel, altitude exposure, and pregnancy. Little change was seen in hemodynamic measurements with the inhalation of NO.

42. Back to the case -- treatment The pt began receiving bosentan, 62.5 mg PO Bid, and the dosage was titrated to 125 mg BID after 1 mo. 3 mo later, echo showed an estimated PASP 55 mmHg And results of the 6MWT had increased by 35 m. the pt reported less dyspnea and greater activity tolerance. She saw her specialist every 3 mo and F/U with her PCP regularly. Two years later, pt reported gradually worsening fatigue, dyspnea on exertion, ankle edema, and an episode of near-syncope. The 6MWT results were slightly worse compared with baseline, and right-heart catheterization showed PAP 75/36 mmHg (mean 48 mmHg). RAP was 13 mmHg, PCWP was 7 mmHg, and cardiac output was 2.7 L/min. An indwelling central venous catheter was placed, and long-term intravenous epoprostenol therapy was initiated. Although relatively little evidence supports combined use of bosentan and epoprostenol, bosentan treatment was continued during the initiation of epoprostenol therapy. The pt also began receiving diuretic therapy and was referred for evaluation for lung transplantation. 18 mo later, fatigue had lessened, ankle edema had resolved, and the 6-min walking distance was 330 m. The pt decided not to pursue lung transplantation at this time.

43. Rubin, L. J. et. al. Ann Intern Med 2005;143:282-292

44. Rubin, L. J. et. al. Ann Intern Med 2005;143:282-292

45. Stimuli: shear stress, Po2, Viruses (HIV, HHV-8) Autoimmunity (CREST,SLE), Drugs Intrinsic susceptibility (PPH-1,BMPR2,Kv) Pulmonary endothelial-cell dysfunction or injury (Endothelin-1,Nitric Oxide and prostacyclin pathway) Imbalance of vascular effectors Perturbations in the normal relationships between vasodilators and vasoconstrictors, growth inhibitors and mitogenic factors, antithrombotic and prothrombotic determinants. Main vascular changes of PAH Vasoconstriction SMC and endothelial-cell proliferation fibrosis thrombosis Future prospective ? VEGF PDGF inhibitor

46. References • Rubin LJ, Rich S. Primary Pulmonary hypertension. Marcel Dekker, Inc.,1997 • Vallerie V. McLaughlin and Stuart Rich, Pulmonary Hypertension. Curr Probl Cardiol 2004;29:575-634. • S. H. LEE & L. J. RUBIN, Current treatment strategies for pulmonary arterial hypertension . Journal of Internal Medicine 2005; 258: 199–215 • Robyn J. Barst, Michael McGoon, Adam Torbicki, Olivier Sitbon, Michael J. Krowka, Horst Olschewski and Sean Gaine, Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:40S–47S • Michael McGoon, David Gutterman, Virginia Steen,Robin Barst, Douglas C. McCrory, Terry A. Fortin,and James E. Loyd, Screening, Early Detection, and Diagnosis of Pulmonary Arterial Hypertension. CHEST 2004; 126:14S–34S • Lewis J. Rubin,and David B. Badesch, Evaluation and Management of the Patient with Pulmonary Arterial Hypertension. Ann Intern Med. 2005;143:282-292.

47. Thank you

48. WT 8 months KO 8 months

49. Diagram of Pulmonary and Systemic Circulation

50. Physiology of pulmonary arterial pressure PR*V, R =8l/r4 1/Rtotal = 1/Ra + 1/Rb + … 1/Rn (parallel resistance) PE, in situ thrombosis, vascular bed damage Rtotal = Rartery + Rarterioles + Rcapillaries (series resistance)