This document summarizes the experience of pulmonary endarterectomy (PEA) at a hospital in Pavia, Italy. It describes that PEA is the primary treatment for chronic thromboembolic pulmonary hypertension (CTEPH), and has better long-term outcomes than lung transplantation. The Pavia center has performed over 357 PEAs since 1994 and has developed expertise in evaluating, diagnosing, and performing the surgery on CTEPH patients.

1. Andrea M D’Armini, MD, FCCP PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE “CTEPH” Cardiac Surgery University of Pavia School of Medicine Foundation I.R.C.C.S. “San Matteo” Hospital Pavia, Italy

2. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE BACKGROUND Chronic Thromboembolic Pulmonary Hypertension CTEPH Acute Pulmonary Embolism

9. U. G. PRE DLTx U. G. 1° POST DLTx DLTx for FAMILIAL PULMONARY HYPERTENSION PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE THORACIC TRANSPLANTATION 1357 TRANSPLANTS (17/11/1985 – 09/06/2011)

10. DLTx for FAMILIAL PULMONARY HYPERTENSION RIGHT HEART CATHETERIZATION PRE-DLTx 1° POST-DLTx Right Atrium 13 9 Right Ventricle 118/0 25/0 Pulmonary Arterial Pressure 118/82/60 38/25/16 ( -70% ) Systemic Arterial Pressure 96/76/61 113/73/53 Pulmonary Capillary Wedge Pressure 5 10 Cardiac Output 2.9 6.2 ( +114% ) Cardiac index 1.6 4.0 Pulmonary Vascular Resistance 2134 155 ( -91% ) PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE THORACIC TRANSPLANTATION 1357 TRANSPLANTS (17/11/1985 – 09/06/2011)

11. HLTx for EISENMENGER’S SYNDROME M. P. PRE HLTx M. P. 1° POST HLTx PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE THORACIC TRANSPLANTATION 1357 TRANSPLANTS (17/11/1985 – 09/06/2011)

12. HLTx for EISENMENGER’S SYNDROME PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE THORACIC TRANSPLANTATION 1357 TRANSPLANTS (17/11/1985 – 09/06/2011) Systolic Pulmonary Arterial Pressure 105 mmHg Right Ventricular End-Diastolic Diameter 110 mm Inferior Vena Cava 34 mm PRE-OPERATIVE ECHOCARDIOGRAPHY Right Atrium 6 mmHg Right Ventricle 23/0 mmHg Pulmonary Arterial Pressure 23/11/6 mmHg Pulmonary Capillary Wedge Pressure 6 mmHg Cardiac Output 7.1 L/min Cardiac Index 4.3 L/min/m 2 Pulmonary Vascular Resistance 45 dyne*sec*cm -5 POST-OPERATIVE RIGHT HEART CATHETERIZATION

19. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE COAGULATIVE DISORDERS DISORDER % PTS MEAN ± SD RANGE HYPERHOMOCYSTEINEMIA ( μ mol/L) 72.6 % 21.7 ± 8.3 14.1 – 63.2 EXCESS FACTOR VIII ANTIGEN (%) 78.2 % 206.7 ± 33.9 161.1 – 392.9 EXCESS FACTOR VIII RISTOCETIN (%) 47.6 % 182.1 ± 46.6 150.0 – 334.0 EXCESS FACTOR VIII (%) 27.4 % 179.3 ± 25.8 153.4 – 220.0 PAI EXCESS (U/ml) 53.2 % 5.1 ± 1.2 3.6 – 7.9 FACTOR V LEIDEN 15.3 % 1.34 ± 0.55 0.50 – 1.99

20. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE IMMUNOLOGIC DISORDERS DISORDER % PTS MEAN ± SD RANGE Anti-Nuclear Antibodies (ANA) 23.4 % – – Lupus Anticoagulant (LAC) 19.4 % – – Anti-Cardiolipin Antibodies (ACA) IgG 20.2 % 56.3 ± 40.3 10.3 – 121.0 Anti-Cardiolipin Antibodies (ACA) IgM 13.7 % 30.8 ± 30.5 7.3 – 101.0 Anti-Phospholipid Antibodies (APA) IgG 14.5 % 63.2 ± 36.5 8.4 – 121.0 Anti-Phospholipid Antibodies (APA) IgM 12.9 % 28.0 ± 23.5 10.1 – 91.3 Positive Direct Coombs’ Test 8.9 % – –

21. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE GENETIC MUTATIONS MUTATION % PTS C677T MTHFR (HOMOCYSTEINEMIA) HETEROZYGOSIS 50.8 % HOMOZYGOSIS 19.4 % TOTAL 70.2 % A1298C MTHFR (HOMOCYSTEINEMIA) HETEROZYGOSIS 44.4 % HOMOZYGOSIS 9.7 % TOTAL 54.1 % G20210A PROTHROMBIN (FACTOR II) 8.1 % G1691A FACTOR V (FACTOR V LEIDEN) 5.6 %

23. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE REFERENCE

24. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE REFERENCE

25. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE REFERENCE

26. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE REFERENCE

28. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE CLINIC The clinical indication changes substantially according to the different surgical treatment of CTEPH

32. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE PROXIMAL LESIONS

33. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE M.B. – 62 yrs M – Jul 2001 – PEA #64 Perfusion and ventilation scan Pulmonary angiogram Hemodynamic mPAP 67 CI 1.6 PVR 1766

34. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE DISTAL LESIONS

35. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE S.S. – 31 yrs M – Sep 2002 Perfusion and ventilation scan Pulmonary angiogram Hemodynamic mPAP 50 CI 1.8 PVR 1120

37. Concomitant severe parenchymal lung disease is the real absolute contraindication to PEA Such patients are not suitable for PEA and must be listed for DLTx (if indicated) PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE CONTRAINDICATION TO PEA

38. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE P.B. – 60 yrs M – Jun 2002 Perfusion and ventilation scintigraphy Pulmonary angiography CT scan Hemodynamic mPAP 28 CI 1.9 PVR 645

40. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE REFERENCE

43. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE AMOUNT OF PATIENTS 65 PEAs in almost 8 yrs 65 PEAs in 1 yr

44. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE AMOUNT OF PATIENTS NEW EVALUATIONS + 100%

45. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE AMOUNT OF PATIENTS DIAGNOSTIC ACCURACY 63% 76% + 13%

46. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE AMOUNT OF PATIENTS OPERABILITY RATE 74% 89% + 15%

47. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE AMOUNT OF PATIENTS PEAs PERFORMED + 195 %

51. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE MAIN WORLD PEA CENTERS Paris, France ≈ 100 PEAs / year NATIONAL REFERRAL PROGRAM FOR EXCELLENCE Cambridge, UK ≈ 80 PEAs / year NATIONAL REFERRAL PROGRAM BY LAW Pavia, Italy ≈ 60 PEAs / year MORE THAN ONE PROGRAM Bad Nauheim, Germany ≈ 50 PEAs / year MORE THAN ONE PROGRAM San Diego, California, USA ≈ 130 PEAs / year NATIONAL REFERRAL PROGRAM FOR EXCELLENCE

52. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE SURGICAL TREATMENT OF CTEPH 08-MAR-1991 First HLTx for CTEPH 11-APR-1994 First PEA 28-JUL-2003 First PEA in patient listed for DLTx 25-DEC-1995 First DLTx for CTEPH

53. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE TRANSPLANT FOR CTEPH 18 / 79 MORE DIAGNOSIS MORE DISTAL PEAs

54. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE PEA POPULATION OF 357 PEAs

55. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE RIGHT HEART CATHETERIZATION OF 357 PEAs

56. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE ECHOCARDIOGRAPHY OF 357 PEAs

58. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE ECHOCARDIOGRAPHY OF 357 PEAs

59. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE ECHOCARDIOGRAPHY

60. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE CARDIAC MAGNETIC RESONANCE OF 244 PEA

61. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE CARDIAC MAGNETIC RESONANCE OF 244 PEA

62. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE CARDIAC MAGNETIC RESONANCE

63. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE LUNG FUNCTION OF 357 PEAs

64. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE ARTERIAL BLOOD GASES OF 357 PEAs

65. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE MODIFIED BRUCE TEST OF 357 PEAs

66. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE CARDIOPULMONARY EXERCISE TESTING OF 200 PEAs

67. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE CARDIOPULMONARY EXERCISE TESTING OF 200 PEAs

70. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE SURGICAL INSTRUMENT

71. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE PULMONARY ENDARTERECTOMY

72. E.L. – 38 yrs M – Dec 1999 – PEA #42 mPAP 43  20 (-53%) CO 3.3  6.9 (+109%) PVR 994  220 (-78%) PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE TYPICAL SURGICAL SPECIMENS P.A. – 66 yrs M – Jun 2001 – PEA #60 mPAP 50  25 (-50%) CO 2.6  4.4 (+69%) PVR 1385  364 (-74%)

73. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE DISTAL LESIONS JAMIESON TYPE III LEARNING CURVE

74. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE JAMIESON TYPE I vs. TYPE II vs. TYPE III L.M.E.L. - 65 yrs M - Oct 2004 - PEA #119 mPAP 39  19 (-51%) CO 4.4  5.4 (+23%) PVR 665  222 (-66%) G.A.C. - 52 yrs F - Jul 2003 - PEA #96 mPAP 48  27 (-44%) CO 2.1  4.2 (+100%) PVR 1638  381 (-77%) B.A. - 43 yrs F - May 2009 - PEA #233 mPAP 49  19 (-61%) CO 3.3  5.0 (+52%) PVR 1067  224 (-79%)

75. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE JAMIESON TYPE III B.A. - 43 yrs F - May 2009 - PEA #233 mPAP 49  19 (-61%) CO 3.3  5.0 (+52%) RVEF 16  35 (+119%) PVR 1067  224 (-79%)

76. Pre-operative Pulmonary Angiogram Pre-operative 64-HRCT F.C. - 33 yrs F - Apr 2009 - PEA #225 mPAP 52  20 (-62%) CO 4.6  4.7 (+2%) RVEF 32  41 (+28%) PVR 870  255 (-71%) PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE JAMIESON TYPE III

77. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE OUT OF PROPORTION PH ? Pre-operative Pulmonary Angiogram Pre-operative 64-HRCT B.R.A. - 72 yrs F mPAP 44 CO 2.9 RVEF 28 PVR 1159

78. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE JAMIESON TYPE III Pre-operative Pulmonary Angiogram Pre-operative 64-HRCT B.R.A. - 72 yrs F - Mar 2009 - PEA #222 mPAP 44  33 (-25%) CO 2.9  4.9 (+69%) RVEF 28  34 (+21%) PVR 1159  457 (-61%) B.R.A. - 72 yrs F mPAP 44 CO 2.9 RVEF 28 PVR 1159

79. Pre-operative Pulmonary Angiogram Pre-operative 64-HRCT G.G. - 62 yrs F mPAP 51 CO 2.6 RVEF 19 PVR 1415 PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE OUT OF PROPORTION PH ?

80. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE JAMIESON TYPE III Pre-operative Pulmonary Angiogram Pre-operative 64-HRCT G.G. - 62 yrs F - Sep 2009 - PEA #240 mPAP 51  27 (-47%) CO 2.6  4.0 (+54%) RVEF 19  24 (+26%) PVR 1415  460 (-68%) G.G. - 62 yrs F mPAP 51 CO 2.6 RVEF 19 PVR 1415

81. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE CUMULATIVE PROPORTION SURVIVING OF 357 PEAs Operative mortality Global 32/357 (9.0%) NYHA II 0/33 (0.0%) NYHA III 8/165 (4.8%) NYHA IV 24/159 (15.1%) Jan 08 – May 11 13/183 (7.1%) 89.2  1.9 87.1  2.2 86.5  2.2 85.6  2.4 84.5  2.6 83.1  2.9 81.6  3.2 79.2  3.9 79.2  3.9

82. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE CUMULATIVE PROPORTION SURVIVING SURGERY vs. MEDICAL THERAPY Riedel M. Chest 1982;81(2):151-8. D ’ Armini A.M. Ital Heart J 2005;6(10):861-8.

83. SURGICAL TREATMENT OF CTEPH: FROM TRANSPLANT TO CONSERVATIVE SURGERY CUMULATIVE PROPORTION SURVIVING 45 PTS ON WAITING LIST FOR TRANSPLANT IN CTEPH

84. SURGICAL TREATMENT OF CTEPH: FROM TRANSPLANT TO CONSERVATIVE SURGERY CUMULATIVE PROPORTION SURVIVING 18 TRANSPLANTS IN CTEPH

85. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE FOLLOW-UP In literature few data are reported on mid- and long- term cardiopulmonary function, particularly on exertion, and on clinical outcomes after PEA

88. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE NYHA FUNCTIONAL CLASS Pre-op 3m 1y 3y 5y 7y 10y p < 0.01

89. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE mean PULMONARY ARTERY PRESSURE p < 0.01 Pre-op disch 3m 1y 3y 5y 7y 10y

90. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE PULMONARY VASCULAR RESISTANCES p < 0.01 Pre-op disch 3m 1y 3y 5y 7y 10y

91. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE ECHOCARDIOGRAPHY Before PEA

92. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE ECHOCARDOGRAPHY First echo after PEA – POD #9

93. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE ECHOCARDIOGRAPHY 3-months FUP after PEA

94. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE CARDIAC MAGNETIC RESONANCE Before PEA First CMR after PEA – POD #6

95. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE CARDIAC MAGNETIC RESONANCE 4-years FUP after PEA First CMR after PEA – POD #6

96. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE REVERSE RIGHT VENTRICULAR REMODELING

97. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE ARTERIAL OXYGEN PARTIAL PRESSURE p < 0.01 Pre-op 3m 1y 3y 5y 7y 10y

98. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE MODIFIED BRUCE TEST p < 0.01 Pre-op 3m 1y 3y 5y 7y 10y

103. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE PULMONARY ENDARTERECTOMY IN THE ELDERLY EXTENSION OF SURGICAL CRITERIA

105. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE AGE

106. PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE CUMULATIVE PROPORTION SURVIVING OF 261 vs. 96 PEAs 90.9  2.2 86.9  3.0 88.5  2.6 89.3  2.5 85.0  3.5 85.0  3.5 81.2  5.7 78.0  6.3 78.0  6.3