Morsolini Marco Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010

PULMONARY ENDARTERECTOMY:
THE PAVIA EXPERIENCE

Andrea M D’Armini, MD, FCCP
Marco Morsolini, MD, PhD

Division of Cardiac Surgery
University of Pavia School of Medicine
St. Matteo Hospital
Pavia - Italy

UNIVERSITY OF PAVIA SCHOOL OF MEDICINE - ST. MATTEO HOSPITAL - PAVIA - ITALY

PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE

INTRODUCTION

• Chronic thromboembolic pulmonary hypertension (CTEPH)
represents the only type of pulmonary hypertension surgically
treatable, in the majority of cases, without transplant

• This life-saving conservative surgery is called pulmonary
endarterectomy (PEA)



INTRODUCTION
PEA vs. LTx
• Elective surgery, non donor-dependent
• No “transplant window” to be considered
• Age is not a contraindication
• Lower post-operative complications
– early (acute graft failure, acute rejection, infections)
– late (BOS, neoplasms, infections)
• Outcome
– post-operative long term survival
– quality of life (back to normal)
– steady functional improvement


EPIDEMIOLOGY
• Epidemiologic data: in Italy ≈ 65.000 cases / year of acute
symptomatic pulmonary embolism (PE)
• Prevalence of CTEPH in pts surviving an acute PE (≈ 80 %)
is calculated between 0.5% – 3.8%
→ up to 2.000 new cases / year
• Considering asymptomatic pulmonary embolism and
misdiagnosed pulmonary embolism, the true incidence of
CTEPH may be even greater
• Jamieson SW, Kapelanski DP. Pulmonary endarterectomy. Curr Probl Surg 2000; 37:165-252
• Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001; 345:1465-72
• Pengo V, Lensing AV, Prins MH, Marchiori A, Davidson BL, Tiozzo F et al. Incidence of chronic thromboembolic pulmonary
hypertension after pulmonary embolism. N Engl J Med 2004; 350:2257-64



CURRENT SITUATION

• CTEPH is still under-diagnosed and nowadays only few
physicians are aware of the surgical procedure called PEA

• For all these reasons about 6000 PEA have been performed
worldwide so far with ≈ 40 % of all cases carried out by the
San Diego Group



NATURAL HISTORY

• Pulmonary embolism (symptomatic / asymptomatic)
• “Honeymoon” period: months / years
• Hypertensive remodeling of the patent pulmonary
vascular bed (Eisenmenger-like)
• Right ventricle hypertrophy with progressive right
heart deterioration → right failure
• Left ventricle compression with left heart functional
impairment



GENERAL CONDITIONS

• Low cardiac output with dyspnea, cough, cyanosis,
hepatomegaly, ascites, lower limb edema, syncope,
hemoptysis and interscapular olosystolic murmur

• Hypoxemia with exercise, sometimes at rest also

• Frequent positive anamnesis for deep venous
thrombosis and / or coagulative and immunologic
disorders



COAGULATIVE DISORDERS
OF LAST 185 PEAs

DISORDER % PTS MEAN ± SD RANGE
HYPERHOMOCYSTEINEMIA (µmol/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



IMMUNOLOGIC DISORDERS
OF LAST 185 PEAs

DISORDER % PTS MEAN ± SD RANGE
Anti-Nuclear Antibodies (ANA) 23.4 % – –

Lupus Anticoagulans (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 % – –



GENETIC MUTATIONS
OF LAST 185 PEAs

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 %



INDICATIONS FOR SURGERY

• The indications for the surgical treatment of these
patients are based on
CLINIC
HEMODYNAMIC

• The indications for the type of surgery are based on
ANATOMY



CLINIC

• Patients must be in NYHA functional class III or IV

• Full anticoagulation for at least 3 months

• Some Authors (we too) recently have performed PEA
even in NYHA class II patients, given the natural
history of the disease



HEMODYNAMIC

• Pulmonary hypertension (mPAP > 25 mmHg)
• Causing low cardiac output

• Resulting in calculated pulmonary vascular resistances
(PVR) > 300 dyne*sec*cm-5



ANATOMY

• The surgical treatment depends on the localization of
the lesions in the pulmonary arterial branches

• Lesions can be classified as PROXIMAL
DISTAL



PROXIMAL LESIONS



M.B. – 62 yrs M – Jul 2001 – PEA #64

Perfusion and ventilation scan

Pulmonary angiogram

Hemodynamic

mPAP 67
CI 1.6
PVR 1766



DISTAL LESIONS



S.S. – 31 yrs M – Sep 2002

Perfusion and ventilation scan

Pulmonary angiogram

Hemodynamic

mPAP 50
CI 1.8
PVR 1120



OUR PROGRAM

• National referral program

• Begin: April 1994

• To date: 266 PEAs performed



PATIENTS’ REFERRAL
OF 266 PEAs
10
2 3
79 12
Pavia
40
12 14 Pts coming from outside Italy
- Greece 1
19 2 - Uganda 1
6
4
16 1
11 10
6 1 ≤ 10 pts
11 – 20 pts
5
≥ 21 pts

11



PATIENTS’ AMOUNT

54 PEAs in 1 yr • Apr ‘94 → Jan ‘10
60

• 266 PEAs (5 redo:
50
26, 40, 56, 86 and
174 months after the
40
first PEA)
• In the majority of
Patients

30
pts (250/266) an ICF
54 PEAs in 7 yrs was placed before
20 PEA
• Lifelong
10 anticoagulation
therapy was
0 prescribed
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010



PAVIA CTEPH PROGRAM
January, 1st - December, 31st 2004 → 130 pts
EVALUATION (54 pts) FOLLOW-UP (72 pts) DLTx (4 pts)

CONFIRMED (34 pts - 63%) OTHER DIAGNOSIS (20 pts - 37%)

• PROXIMAL LESIONS (25 pts) • RECENT EMBOLIZATION (3 pts)
- 22 PEAs - 2 medical therapy
- 2 pts refused - 1 surgical embolectomy
- 1 pt died on evaluation
• TUMORS (5 pts)
- 3 pulmonary angiosarcoma
OPERABILITY RATE 74 % - 1 adenocarcinoma with pulmonary artery thrombosis
- 1 intestinal tumor with liver metastases

• DISTAL LESIONS (7 pts) • MISCELLANEOUS (12 pts)
- 5 DLTx waiting-list
- 2 medical therapy (too old for DLTx)
• ASSOCIATION WITH SEVERE EMPHYSEMA (2 pts)
- 2 DLTx waiting-list



PAVIA CTEPH PROGRAM
January, 1st - December, 31st 2009 → 121 pts
NEW EVALUATIONS (78 pts) PEAs FOLLOW-UP (43 pts)

CONFIRMED (70 pts - 90%) OTHER DIAGNOSIS (8 pts - 10%)
• MINIMAL CTE LESIONS WITHOUT PH (4 pts)
• PROXIMAL LESIONS (62 pts)
- 4 medical therapy
- 54 PEAs
• RECENT EMBOLIZATION (4 pts)
- 1 pt waiting for PEA
- 3 medical therapy
- 4 pts refused PEA
- 1 surgical embolectomy
- 2 pts with “too old” lesions (pulmonary artery
retraction)
- 1 pt general condition too compromised

OPERABILITY RATE 89 %
• DISTAL LESIONS (8 pts)
- 8 medical therapy: 5 too old for DLTx
3 too early for DLTx


CHEST STUDIES: THE PAVIA EXPERIENCE

MAIN WORLD PEA CENTERS
Cambridge, UK
≈80 PEAs / year
NATIONAL REFERRAL PROGRAM BY LAW

Bad Nauheim, Germany
≈60 PEAs / year
MORE THAN ONE PROGRAM

Pavia, Italy
≈50 PEAs / year
MORE THAN ONE PROGRAM

San Diego, California, USA
≈120 PEAs / year
NATIONAL REFERRAL PROGRAM
FOR EXCELLENCE Paris, France
≈100 PEAs / year
NATIONAL REFERRAL PROGRAM
FOR EXCELLENCE



PEA POPULATION
OF 266 PEAs

Age 56 ± 16 (11 − 84) years
Gender 134 M – 132 F

NYHA class 15 II – 122 III – 129 IV

Length III / IV 19 ± 23 months
Urgent / Emergent 64 / 266

Oxygen therapy 131 / 266



RIGHT HEART CATHETERIZATION
OF 266 PEAs

Mean ± SD Range

mPAP 47 ± 13 17 − 88 mmHg

CI 1.9 ± 0.6 1.1 − 4.1 l/min/m2

PVR 1149 ± 535 191 − 3938 dynes*sec*cm-5



ECHOCARDIOGRAPHY



CARDIAC MAGNETIC RESONANCE



ARTERIAL BLOOD GASES
OF 266 PEAs

Mean ± SD Range

Pa O2 65 ± 10 43 − 97 mmHg

Pa CO2 31 ± 7 24 − 43 mmHg

O2-sat 93 ± 3 84 − 98 %



MODIFIED BRUCE TEST
OF 266 PEAs

Steps Walking distance
No (Pa O2 < 60) 36.9% 103 ± 160 (0 – 852) meters

Step 0 - ½ 56.8%

Step 1 - 2 4.5%

Step 3 - 4 1.8%



CARDIOPULMONARY EXERCISE TESTING
OF 157 PEAs

Peak exercise

No (∆ECG, advanced NYHA IV, other) 16.3%

Watts ≤25 12.0%

Watts >25 / ≤50 50.0%

Watts >50 / ≤75 15.2%

Watts >75 6.5%



CARDIOPULMONARY EXERCISE TESTING
OF 157 PEAs

Mean ± SD Range

Peak-DP 16037 ± 4822 5600 − 30600 mmHg*FC

Peak-VO2 9.9 ± 3.6 3.0 − 29.4 ml/min/kg

Peak-Exe 50 ± 22 15 − 160 watt



PULMONARY ENDARTERECTOMY



TYPICAL SURGICAL SPECIMENS

E.L. – 38 yrs M – Dec 1999 – PEA #42
mPAP 43 → 20 (-53%)
CO 3.3 → 6.9 (+109%)
PVR 994 → 220 (-78%)

P.A. – 66 yrs M – Jun 2001 – PEA #60
mPAP 50 → 25 (-50%)
CO 2.6 → 4.4 (+69%)
PVR 1385 → 364 (-74%)



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%)

S.F. - 48 yrs F - Mar 2009 - PEA #221
mPAP 44 → 29 (-34%)
CO 2.9 → 3.5 (+21%)
PVR 1131 → 549 (-51%)


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%)



JAMIESON TYPE III

Pre-operative Pulmonary Angiogram

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%)

Pre-operative 64-HRCT



OUT OF PROPORTION PH ?


B.R.A. - 72 yrs F
mPAP 44
CO 2.9
RVEF 28
PVR 1159




JAMIESON TYPE III


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%)




OUT OF PROPORTION PH ?


G.G. - 62 yrs F
mPAP 51
CO 2.6
RVEF 19
PVR 1415




JAMIESON TYPE III


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%)




CUMULATIVE PROPORTION SURVIVING
OF 266 PEAs
100%
187 144 125 108 91 71 54 42 33 30 22 14 7 3 2
90%
89.2±1.9
80% 87.1±2.2
86.5±2.2 85.6±2.4
84.5±2.6
70% 83.1±2.9
81.6±3.2
60% 79.2±3.9 79.2±3.9
Percentage

50%

40%
Operative mortality
30% Global 24/266 (9.0%)
NYHA II 0/15 (0.0%)
NYHA III 5/122 (4.1%)
20% NYHA IV 19/129 (14.7%)

Jan 08 - Jan 10 5/92 (5.4%)
10%

0%
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180
Months after PEA



CUMULATIVE PROPORTION SURVIVING
SURGERY vs. MEDICAL THERAPY
1.0
133 113 93 54 34 14
0.9

0.8 86 .8±2.6

0.7 84.7±2.8

83.8±2.9 83.8±2.9 83.8±2.9 83.8±2.9
0.6
Percentage

0.5

0.4

0.3

0.2

0.1

0.0
0 12 24 36 48 60 72 84 96 108 120 132 144 156
Months after PEA

D’Armini A.M. Ital Heart J 2005;6(10):861-8.

Riedel M. Chest 1982;81(2):151-8.



FOLLOW-UP

• Very few data are available in the literature on mid and long
term cardiopulmonary function, particularly on exertion, and
on clinical benefits after PEA

D’Armini AM, Zanotti G, Ghio S, Magrini G, Pozzi M, Scelsi L, Meloni G, Klersy C, Viganò M. Reverse right ventricular remodeling
after pulmonary endarterectomy. J Thorac Cardiovasc Surg 2007; 133:162-8

Corsico AG, D’Armini AM, Cerveri I, Klersy C, Ansaldo E, Niniano R, Gatto E, Monterosso C, Morsolini M, Nicolardi S, Tramontin C,
Pozzi E, Viganò M. Long-term outcome after pulmonary endarterectomy. Am J Respir Crit Care Med 2008;178(4):419-24



FOLLOW-UP TIMING

• All pts underwent follow-up evaluation at:
– discharge (at this interval NYHA class, lung function, and exercise
tolerance are excluded because pts are to close to the surgical
procedure)
– 3th month
– yearly for 5 years
– 7th, 10th and 15th year (10 controls)



FOLLOW-UP DATA

• Eleven of 240 pts (4.6%) refused to participate to the study
since the beginning (2/4 pts referred from outside Italy) or at
various intervals
• For these pts we obtained only data on survival and NYHA
class on a phone-call basis
• All the other pts (95.4%) have actively participated to the
FUP study



NYHA FUNCTIONAL CLASS
NYHA Functional Class
100
90
80
70
% patients

60
I-II
50
III-IV
40
30
20
10
0
Pre-op
Pre-op 3 3m
mesi 1y
1 anno 3y
3 anni 5 5y
anni 7 7y
anni 10y
10 anni
Follow-up p < 0.01



mean PULMONARY ARTERY PRESSURE
mean Pulmonary Arterial Pressure
60

50

40
mmHg

30

20

10

0
Pre-op
Pre-op Dimiss
disch 3 mesi
3m 1 anno
1y 3 anni
3y 5 anni
5y 7 anni
7y 10 10y
anni

Follow-up p < 0.01



PULMONARY VASCULAR RESISTANCES
Pulmonary Vascular Resistances
1200

1000
dyne*sec*cm-5

800

600

400

200

0
Pre-op
Pre-op Dimiss
disch 3 mesi
3m 1 anno
1y 3 anni
3y 5 anni
5y 7 anni
7y 10 10y
anni

Follow-up p < 0.01



ECHOCARDIOGRAPHY
Before



ECHOCARDOGRAPHY
First control – POD #9



ECHOCARDIOGRAPHY
Three-month control



Before First control – POD #6



First control – POD #6 Four-year control


PULMONARY ENDARTERECTOMY: REVERSE RIGHT VENTRICULAR REMODELING

REVERSE RIGHT VENTRICULAR
REMODELING



BRAIN-TYPE NATRIURETIC PEPTIDE
BNP TIME COURSE AFTER PEA
SERUMplasmatici di BNP
Livelli BNP LEVELS

450.0

400.0

350.0

300.0

250.0
p g /m l

200.0

150.0

100.0

50.0

0.0
PRE-OP
PRE-OP DISCHARGE
DIMISSIONE 3 MONTHS
3 MESI 1 YEAR
1 ANNO 2 YEARS
2 ANNI



ARTERIAL OXYGEN PARTIAL PRESSURE
Arterial Oxygen Partial Pressure
100
90
80
70
mmHg

60
50
40
30
20
10
0
Pre-op
Pre-op 3 3m
mesi 1 anno
1y 3 3y
anni 5 anni
5y 7 anni
7y 10 anni
10y
Follow-up p < 0.01



MODIFIED BRUCE TEST

Modified Bruce Test
1000
900
800
700
meters

600
500
400
300
200
100
0
Pre-op
Pre-op 3 3m
mesi 1 anno
1y 3 anni
3y 5 anni
5y 7 7y
anni 1010y
anni
Follow-up p < 0.01


RESULTS
• In expert Centers mortality ranges between 5% and 12%
and technical failure is below 8%

• Early hemodynamic results are known to be excellent in
case of successful operation


RESULTS
• The majority of pts experienced dramatic improvement in
pulmonary hemodynamics after PEA
• After PEA the decrease in pulmonary artery pressure is
immediate (in O.R.) and associated with complete recovery of
RV morphology (at discharge)
• The functional results also show a progressive good recovery
over a longer time (about years)



REFERENCE



REFERENCE

• April 1994 – October 2008

• 204 PEAs performed

• 184 patients received a complete pre-operative
screening for thrombofilia

• Group A (HAPT – high titre > 10 U/ml) 28 pts
• Group B (LAPT – low titre > 10 U/ml) 156 pts



PATIENTS’ MANAGEMENT

• Accurate NIRS monitoring during circulatory arrests

• Attention even to minor neurological dysfunctions

• Careful anticoagulation with higher target INR

• Inferior vena cava filter positioning

• Accurate post-operative follow-up


RESULTS OF PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE

PAVIA PULMONARY ENDARTERECTOMY GROUP
• Cardiac Surgery M Viganò, AM D’Armini, C Monterosso, G Silvaggio,
S Nicolardi, M Morsolini, D Berwick, G Mattiucci
• Anestesiology M Maurelli, T Bianchi, R Veronesi, M Toscani
MA Villani, E Milanesi, B Lusona, M Gerletti
• Critical Care A Braschi, V Emmi, G Rodi, G Sala Gallini
F Capra Marzani, F Mojoli
• Cardiology L Oltrona Visconti, S Ghio, A Raisaro, L Scelsi, C Raineri
• Respiratory Disease E Pozzi, I Cerveri, A Corsico
• Radiology I R Dore
• Radiology II F Zappoli Thyrion, P Quaretti, A Azzaretti, G Rodolico
• Nuclear Medicine C Aprile
• Reumatology C Montecucco, R Caporali
• Thromboembolism F Piovella, M Barone, C Beltrametti
• Pathology U Magrini, E Arbustini, M Grasso
• General Rehabilitation E Dalla Toffola, L Petrucci
• Pulmonary Rehabilitation C Fracchia, G Callegari
• Biostatistics C Klersy


Morsolini Marco Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010

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