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Chronic Thromboembolic Pulmonary Hypertension Ilya Lantsberg, MD May 7 th, 2008.

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1 Chronic Thromboembolic Pulmonary Hypertension Ilya Lantsberg, MD May 7 th, 2008

2 Case of Mr. G HPI : HPI : 52 y.o AA M w/ PMHx of DVT x 2 on Coumadin and LE Edema on Lasix, known Hx of Pulm. HTN ( NYHA class IV) 52 y.o AA M w/ PMHx of DVT x 2 on Coumadin and LE Edema on Lasix, known Hx of Pulm. HTN ( NYHA class IV) DOE over past 2 yrs ; syncope during coughing to his cardiologist’s office. Pt. was told that his syncope is “cough related”. DOE over past 2 yrs ; syncope during coughing to his cardiologist’s office. Pt. was told that his syncope is “cough related”. 4 days PTA – had hemoptysis  called PMD  admitted via ER. 4 days PTA – had hemoptysis  called PMD  admitted via ER.

3 ROS: DOE(+), no CP, melena, recent bronchitis, PNA, prior hemoptysis, prior syncope, wt. changes., No hx splenectomy, no Hx chr. Inflamm. d/o ROS: DOE(+), no CP, melena, recent bronchitis, PNA, prior hemoptysis, prior syncope, wt. changes., No hx splenectomy, no Hx chr. Inflamm. d/o FHx: no hx of bleeding or clotting d/o FHx: no hx of bleeding or clotting d/o SHx: exsmoker 35 ppd, no ETOH, no drugs, works as pharmacist SHx: exsmoker 35 ppd, no ETOH, no drugs, works as pharmacist VSS. Sat 98%; HR 87 VSS. Sat 98%; HR 87 PE significant for JVD(+), clear lungs, accentuated S2, systolic murmur, distended abdomen and 3+ pedal edema. PE significant for JVD(+), clear lungs, accentuated S2, systolic murmur, distended abdomen and 3+ pedal edema. Lab: CBC nl, INR-2.5 ( on Coumadin), SMA remarkable for cr 1.5 ( on Lasix); bicarb 28; BNP – 1214, CE(-) x 3 Lab: CBC nl, INR-2.5 ( on Coumadin), SMA remarkable for cr 1.5 ( on Lasix); bicarb 28; BNP – 1214, CE(-) x 3

4 TTE: EF=65%, PASP = 101 mm Hg, septal flattening, severe RAE, severe RV dysfxn, decr. RV fxn TTE: EF=65%, PASP = 101 mm Hg, septal flattening, severe RAE, severe RV dysfxn, decr. RV fxn CTA: multiple eccentric b/l PE, markedly enlarged PA, ascites, anasarca CTA: multiple eccentric b/l PE, markedly enlarged PA, ascites, anasarca

5 V/Q: multiple large mismatched perfusion defects in LLL, RUL. V/Q: multiple large mismatched perfusion defects in LLL, RUL.

6 Hospital Course. Coumadin held; Heparin gtt started Coumadin held; Heparin gtt started Cath R and L Cath R and L L heart cath – normal coronaries, EF=55%. R heart Cath - unable to obtain PCWP;PASP/D/M- 104/35/67 –after Nitr.OX  93/40/59 TPVR – 1134 dsc. CT consult for PEA CT consult for PEA IVC Filter placed IVC Filter placed Revatio started Revatio started Surgery and Flolan are refused by the patient Surgery and Flolan are refused by the patient Discharged home on Revatio Discharged home on Revatio On Tracleer doing well 3 weeks later On Tracleer doing well 3 weeks later

7 PE spectrum Massive PE + HD collapse Submassive PE With RV dilation PE with nl BP and no RVF

8 Pengo et al.; Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257–2264. Design Prospective study Prospective study Objective To determine incidence of CTEPH after acute PE To determine incidence of CTEPH after acute PE Subjects 223 acute first PE no prior DVT and/or PE Duration of follow up Follow up every 6 month first 2 years up to 10 years Follow up every 6 month first 2 years up to 10 years How cohort is screened Any dyspnea screened by TTE, if high PAP  V/Q and pulm A- graphy and RHC. CTEPH Dx if s/mPAP > 40/25 mm Hg and PCWP nl if s/mPAP > 40/25 mm Hg and PCWP nl and on a –graphy with pouching, webs, or bands with or without poststenotic dilatation, intimal irregularities, abrupt narrowing, or total occlusion. Confirmed by experts Epidemiology of CTEPH

9 The Cumulative Incidence of CTPH after a First Episode of Pulmonary Embolism without Prior Deep-Vein Thrombosis Pengo et al.; Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257–2264.

10 Which acute PE pts at risk? Normal lungs TPA > PAI  favors clot resolution Normal lungs TPA > PAI  favors clot resolution Prior episodes of PEs, Larger Q defects, Younger from another study.‡ Prior episodes of PEs, Larger Q defects, Younger from another study.‡ Get Echo 6 wks after acute PE - to see if PAP still high. If nl PAP – clot resolved. Get Echo 6 wks after acute PE - to see if PAP still high. If nl PAP – clot resolved. Impossible to get CTEPH in animal models by repeated embolizations Impossible to get CTEPH in animal models by repeated embolizations ‡ ‡ Ribeiro A, et a Pulmonary embolism: one-year follow-up with echocardiography Doppler and five-year survival analysis. Circulation 1999;99:1325–1330.)

11 Design Systematic analysis of studies of PE resolution by CT and VQ Methods Only 4 of 25 potential studies included InclusionCriteria prospective and involve consecutive patients; prospective and involve consecutive patients; symptomatic PE diagnosed by angiography or helical CT, high- probability V/Q or intermediate-probability V/Q scan with Doppler(+) symptomatic PE diagnosed by angiography or helical CT, high- probability V/Q or intermediate-probability V/Q scan with Doppler(+) imaging tests at follow-up; imaging tests at follow-up; duration and type of treatment of PE with a minimum administration of anticoagulant therapy of 6 weeks and no allowance of vena cava ligation, femoral ligation, or pulmonary embolectomy duration and type of treatment of PE with a minimum administration of anticoagulant therapy of 6 weeks and no allowance of vena cava ligation, femoral ligation, or pulmonary embolectomy prior history of DVT prior history of DVT clear follow-up clear follow-up Results PE resolution is not achieved in > 50% of patients 6 months after diagnosis of PE, after 6 month resolution stays at plateau phase Conclusion Since large interpatient variation reimaging is suggested prior to discontinuation of anticoagulation. Nijkeuter, M. et al. Chest 2006;129:

12 Included studies: {diamondsuit}, Wartski and Collignon33; *, van Rossum et al35; {blacksquare}, Hvid-Jacobsen et al32; and {blacktriangleup}, Remy-Jardin et al

13 Proposed Risk factors for CTEPH Prior PE thrombosis LA, Factor VIII, APL LA, Factor VIII, APL Splenectomy, inflammation ( OM, IBD) Splenectomy, inflammation ( OM, IBD) AT, Factor V Leiden, plasminogen deficiency, Protein S, Anticardiolipin AB?? AT, Factor V Leiden, plasminogen deficiency, Protein S, Anticardiolipin AB?? associated statistically Blood type Lp (a) thrombolysis Abnormal fibrinogen Prior staph infection 2/3 of all cases no prior PE 4% in 2 years Unresolved thromboemboli

14 Is it increased thrombosis? Result: Out of prothrombotic factors studies only APA ( antiphospholipid) and associated with LA ( Lupus anticoagulant ) more frequent in CTEPH. ( 20%) vs 10(%) in PPH Factor VIII - level above 230IU/ dL in 41% CTEPH, level persisted after PE. Conclusion: CTEPH does not result from thrombophilia, although APA, LA and F VIII are elevated Wolf M, et. al Thrombotic risk factors in pulmonary hypertension. Eur Respir J 2000;15:395–399.CTEPH147ptPPH99pt Contrl100pt Quest. Is there increased prevalence of prothrombotic conditions in CTEPH? Design Functional assays, PCR to detect conditions in CTEPH and PPH pts.

15 non O blood type non O blood type CTEPH vs PAH ( 88% vs. 56%) † Lp (a) Lp (a) CTEPH vs. PAH vs. Control ( 26.6 mg/dl, 9.6 mg/dl, 7.2 mg/dl) ‡. † † Bonderman D, et al. High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension. Thromb Haemost 2003;90:372–376. ‡ ‡ Ignatescu M, et al. Plasma Lp(a) levels are increased in patients with chronic thromboembolic pulmonary hypertension. Thromb Haemost 1998;80:231–232. CTEPH: ASSOCIATIONS

16 SPLENECTOMY AS A RISK FACTOR FOR CTEPH Case control study: 109 CTEPH vs. 187 did not develop CTEPH after PE  having prior splenectomy: independent Risk factor ( Odds ratio (OR)- 13, 95% CI, 2.7 – 127.0)* Retrospective Chart Review of 257 pt referred for CTEPH over 10 yrs vs. IPAH vs. other pulm diseases. in CTEPH – 8.6% ( CI 95%, [ %]) had splenectomy vs. 2.5% ( CI 95%, [ %]) IPAP and 0.56% ( CI 95%,[0-1.6%]) in other pulm diseases † Result: Mean interval from S/p Splenecotmy  CTEPH onset: 16 +_ 9 yrs most with distal disease. Prevalence of Splenectomy in CTEPH is significantly higher than in IPAP and control. most with distal disease. Prevalence of Splenectomy in CTEPH is significantly higher than in IPAP and control. * * Bonderman Det al. Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension. Thromb Haemost 2005;93:512–516. † †Jais X, et al Splenectomy and chronic thromboembolic pulmonary hypertension. Thorax 2005;60:1031–1034.

17 Jais X, et al Splenectomy and chronic thromboembolic pulmonary hypertension. Thorax 2005;60:1031–1034.

18 SPLENECTOMY AND THROMBOSIS Prothrombotic state post Splenectomy Prothrombotic state post Splenectomy ( higher incidence of MI, CVA, priapism, SMA thrombosis) Possible mechanism: Possible mechanism: loss of RBC filtering loss of RBC filtering abnormal RBC persist in circulation abnormal RBC persist in circulation abnormal exposure of phosphatidylserine on outer RBC membrane  coagulation cascade activation. abnormal exposure of phosphatidylserine on outer RBC membrane  coagulation cascade activation. Number of RBC with abnormal modified phosphatidylserine expression multiplied by 20 s/p splenectomy Number of RBC with abnormal modified phosphatidylserine expression multiplied by 20 s/p splenectomy Again most s/p Splenectomy – distal CTEPH, not PEA candidates. Again most s/p Splenectomy – distal CTEPH, not PEA candidates. Jais X, M. Splenectomy and chronicthromboembolic pulmonary hypertension. Thorax 2005;60:1031–1034

19 Ventriculo - atrial shunts ( OR 13, 95% CI, 2.5 – 129) Ventriculo - atrial shunts ( OR 13, 95% CI, 2.5 – 129) Chronic inflammatory Disorders ( IBD and OM) (OR 6.7, 95% CI 7.9 – ) Chronic inflammatory Disorders ( IBD and OM) (OR 6.7, 95% CI 7.9 – ) Bonderman D, et al. Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension. Thromb Haemost 2005;93:512–516. CTEPH: ASSOCIATIONS WITH INCREASED THROMBOSIS

20 Is it altered thrombus resolution? 1. Abnormal fibrinogen Timopthy A Morris, et al, Fibrin derived from patients with Chronic Thromboembolic Pulmonary Hypertension is resistant to Lysis Am J Resp Crit Care Med Vol 173 pp , 2006 Objective: is fibrin from CTEPH patients more resistant to plasmin- mediated lysis than control? Methods 1. Fibrinogen from ( CTEPH and control)  fibrin clots in vitro, 2. Fibrin digested with plasmin for upto 6 hrs 3. Digestion Products compared in both groups by polyacrylamide gel electrophoresis and Western blotting. Results release of N-terminal fragments from the beta-chain of fibrin ( cell signaling, cell migration, and angiogenesis) was delayed in CTEPH compared with control subjects (p < 0.01).

21 Timopthy A Morris, et al, Fibrin derived from patients with Chronic Thromboembolic Pulmonary Hypertension is resistant to Lysis Am J Resp Crit Care Med Vol 173 pp , 2006 Note: persistance of intact fibrin in CTEPH group. B chain persists and digested fragments delayed in CTEPH

22 Possible mechanism of scar formation Timopthy A. Morris, et al Fibrin derived fro patients with Chronic Thromboembolic Pulmonary Hypertension is resistant to Lysis Am J Resp Crit Care Med Vol 173 pp , 2006 persistance of Fibrin stimulus for proliferation of neighboring cells remodeling of the fibrin network into organized tissue.

23 ALTERED FIBRINOLYSIS II: ROLE OF STAPH ALTERED FIBRINOLYSIS II: ROLE OF STAPH Association between tissue infection and fibrosis described in Liver, Lung * Association between tissue infection and fibrosis described in Liver, Lung * Bacterial infection induces upregulation TGF ß – a profibrotic cytokine** Bacterial infection induces upregulation TGF ß – a profibrotic cytokine** VA Shunt patients with prior shunt infection are associated with CTEPH** VA Shunt patients with prior shunt infection are associated with CTEPH** * *Rockey DC. Hepatic fibrogenesis and hepatitis C. Semin Gastrointest Dis. 2000;11:69–83.; Vassallo R. Viral-induced inflammation in interstitial lung diseases Semin Respir Infect. 2003;18:55– 60. Li Z, Li J. Local expressions of TGF-1, TGF-1RI, CTGF, and Smad-7 in; Helicobacter pylori-associated gastritis. Scand J Gastroenterol. 2006;41: 1007–1012 Jais X, M. Splenectomy and chronicthromboembolic pulmonary hypertension. Thorax 2005;60:1031–1034 Bannerman DD, Paape MJ, Chockalingam A. Staphylococcus aureus intramammary infection elicits increased production of transforming growth factor-, 1, and 2. Vet Immunol Immunopathol. 2006;112: 309–315

24 Evidence from mouse model: delayed clot resolution of Staph infected clots. thrombi vs noninfected emboli from IVC. thrombi vs noninfected emboli from IVC. Result: staph infected thrombi are larger, have more collagen and have more Vimentin (+) cells on day 14 and 28 Control  staph  Control  D. Bonderman et. Role of staphylococci in Misguided thrombus resolution of Chronic Thromboembolic Pulmonary Hyperension Arteriosclerosis, Thrombosis and Vascular Biology 2008; 28; staph 

25 Question Is persistance of thrombus a consequence of infection? How they did it

26 Analysis of thromboemboli (s/p PEA in 19 CTEPH pt.) vs. thromboemboli (s/p thrombectomy in acute PE.) Result: significantly more fibrosis in CTEPH (chronic clots) vs in fresh clots in PE. D. Bonderman et. Role of staphylococci in Misguided thrombus resolution of Chronic Thromboembolic Pulmonary Hypertension Arteriosclerosis, Thrombosis and Vascular Biology 2008; 28; A,C- from PE ; BD from CTEPH

27 CTEPH staph (+) vs CTEPH staph (-) thrombi: association with fibrosis Control ( n=28) 0/28 vs CTEPH ( n=26) 7/28 staph DNA (+) in thrombus [6 of 7 VA shunts, PPM carriers. Control ( n=28) 0/28 vs CTEPH ( n=26) 7/28 staph DNA (+) in thrombus [6 of 7 VA shunts, PPM carriers. DNA sequencing  S Aureus 5 cases and S epidermis 1 case DNA sequencing  S Aureus 5 cases and S epidermis 1 case DNA(+) CTEPH vs. DNA (-) CTEPH sample collagen content ( / vs 5.23+/- 3.68%. DNA(+) CTEPH vs. DNA (-) CTEPH sample collagen content ( / vs 5.23+/- 3.68%. Conclusion: among CTEPH group: more Bacterial DNA content  more fibrosis. Conclusion: among CTEPH group: more Bacterial DNA content  more fibrosis. D. Bonderman et. Role of staphylococci in Misguided thrombus resolution of Chronic Thromboembolic Pulmonary Hypertension Arteriosclerosis, Thrombosis and Vascular Biology 2008; 28;

28 Role of Staph in CTEPH: a proposed mechanism AV shunt and PPM carriers with Staph (+) CTEPH clots had prior staph infection, but not actively infected (no active bacterial metabolism on Cx etc.) AV shunt and PPM carriers with Staph (+) CTEPH clots had prior staph infection, but not actively infected (no active bacterial metabolism on Cx etc.) S Aureus protein A mimicking TNF- αlfa to activate its receptor  proinflammatory and profibrotic signaling and S Aureus protein A mimicking TNF- αlfa to activate its receptor  proinflammatory and profibrotic signaling and Peptidoglycan from S Aureus causes rapid release of TNF alfa resulting in TGF ß induction resulting in misguided thrombus resolution with disproportionate fibrosis. Peptidoglycan from S Aureus causes rapid release of TNF alfa resulting in TGF ß induction resulting in misguided thrombus resolution with disproportionate fibrosis. D. Bonderman et. Role of staphylococci in Misguided thrombus resolution of Chronic Thromboembolic Pulmonary Hypertension Arteriosclerosis, Thrombosis and Vascular Biology 2008; 28;

29 Natural History of CTEPH Most present late Most present late Diagnosed and Untreated - only from Historical Data pre 1982 ( pre PEA): Diagnosed and Untreated - only from Historical Data pre 1982 ( pre PEA): 49 pts. on A/C only; If mPAP>30 mmHg  3 yr survival 10%. 49 pts. on A/C only; If mPAP>30 mmHg  3 yr survival 10%. But, another study in 48 pts. mPAP>50  mean survival 6.8 yrs. But, another study in 48 pts. mPAP>50  mean survival 6.8 yrs. Conclusion : Most of CTEPH pts. even on A/C will progress to R heart failure and death untreated. Riedel M, Stanek V, Widimsky J, et al. Longterm follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982;81:151–8.

30

31 Pathophysiology of CTEPH “ two compartment pulmonary vascular bed”: “ two compartment pulmonary vascular bed”: 1)  organized, incorporated into intimal layer  PVR initially  PAP 2) flow to normal open parts of pulm. Vasculature  exposure to shear forces in small-vessels  remodeling of small arteries  predisposition to thrombosis  in PAP 3) High PAP is sum of proximal PEs + distal secondary small vessel arteriopathy. 4) Arteries distal to unresolved PE, unexposed to high PAP, are protected from high PAP and normal histologically. 5) In situ thrombosis progresses disease but not initiates it Unresolved thromboemboli

32 Current understanding “ two compartment pulmonary vascular bed”: Peacock et al, Controversies, Uncertainties and Future Research on the Treatment of Chronic Thromboembolic Pulmonary Hypertension; Proc Am Thor Soc Vol 3. Pp , 2006

33 Arrows – not perfused due obstruction by clots. ( normal vessels downstream) RUL get all the flow of R lung – remodeling on Bx. Angiography and Biopsy in CTEPH Hoeper M et al, Chronic Thromboembolic Pulmonary Hypertension, Circulation 2006; 113;

34 An alternate view of CTEPH: reversal of events 1° arteriopathy  2° in situ thrombosis  failure of thrombus resolution. 1° arteriopathy  2° in situ thrombosis  failure of thrombus resolution. Hx DVT < 50% Hx DVT < 50% Class IV CTEPH ( distal arteriopathy withsubsegmental thrombosis) vs. PPH with associated thrombosis? Class IV CTEPH ( distal arteriopathy withsubsegmental thrombosis) vs. PPH with associated thrombosis?

35 Making a Diagnosis: History and Physical. History: History: Prior Hx PE/ DVT in < 50 %. Prior Hx PE/ DVT in < 50 %. If had PE  “ honeymoon” no symptoms x month to yrs. If had PE  “ honeymoon” no symptoms x month to yrs.Symptoms- 1. progressive DOE and rest, hemoptysis +/- 2. later in disease  R CHF: fatigue, palpitations, syncope, LE edema. Physical Exam: Physical Exam: Left parasternal heave, pulm. S2, tricuspid regurge murmur ( syst. Murmur), Later in disease - Sx of R CHF: JVD, HJR, HSM, LE edema, ascities Bruit over peripheral lung fields in 10% CTEPH – pathognomonic ( from turbulent flow to partially occluded areas )

36 Labs and Imaging in CTEPH LABS LABSnonspecific BNP is of value – as marker of RV dysfunction, Cardiac enzymes rule out other causes. d dimer ? LE doppler + in 35 – 45 % of CTEPH pt* LE doppler + in 35 – 45 % of CTEPH pt* EKG – later: RV strain, RV hypertrophy EKG – later: RV strain, RV hypertrophy CXR – may show dilated size of PA, paucity of arteries in some areas, may be normal. CXR – may show dilated size of PA, paucity of arteries in some areas, may be normal. ECHO - initially picks up high PASP; ( routine rpt 6 wks after acute PE with high PAP recommended); r/o other causes for dyspnea ( valves, LV fxn); Test of choice for screening. ECHO - initially picks up high PASP; ( routine rpt 6 wks after acute PE with high PAP recommended); r/o other causes for dyspnea ( valves, LV fxn); Test of choice for screening. Fedullo et al. The natural History of acute and chronic thromboembolic disease: the search for missing link. Eur Respir J 2000 ; 15: 4359

37 Imaging 2 V/Q and CT may underestimate clot burden. V/Q 1. Normal V/Q  r/o CTEPH. 2. In CTEPH - multiple, b/l Q defects with normal V. DDx - pulmonary venooclusive dz, pulm. Capillary angiomatosis, fibrosing mediastinatis, pulmonary vasculitis, sarcoma of pulmonary artery. DDx - pulmonary venooclusive dz, pulm. Capillary angiomatosis, fibrosing mediastinatis, pulmonary vasculitis, sarcoma of pulmonary artery. A – C : ventilation D – F : perfusion Dartevelle P, et al, Chronic Thromboembolic Pulmonary Hypertension; Eur Respir J 2004; 23:

38 CTEPH vs IPAH testsCTEPHIPAH V/Q Multiple segm perf defects Normal or nonhomogeneity of perfusion nonhomogeneity of perfusion Pulm Angio gram Vascular lesions Vascular obliteration

39 CTA in CTEPH – CTA in CTEPH – eccentric thrombus, eccentric thrombus, subpleural densities, subpleural densities, mosaic attenuation mosaic attenuation ( black – hypo perfused blocked normal arteries) white – perfused under high pressure, plexiform). useful to r/o other causes on DDx. useful to r/o other causes on DDx. Hoeper M et al, Chronic Thromboembolic Pulmonary Hypertension, Circulation 2006; 113;

40 Useful points about CT. IPAH may thrombose PA secondarily. Would look like CTEPH on CTA IPAH may thrombose PA secondarily. Would look like CTEPH on CTA Specific for CTEPH – large bronchial artery collaterals – very specific for CTEPH (except in rare congenital causes of high PAP). Specific for CTEPH – large bronchial artery collaterals – very specific for CTEPH (except in rare congenital causes of high PAP). Absence of visible central clots does not r/o CTEPH. Absence of visible central clots does not r/o CTEPH.

41 Helical CT in CTEPH development of bronchial arteries arising from the aorta (a), the communication between intercostal arteries and pulmonary arteries through pleural adhesions created after pulmonary embolism (b). Dartevelle P, et al, Chronic Thromboembolic Pulmonary Hypertension; Eur Respir J 2004; 23:

42 DDx of DDx of obstructive pulmonary hypertension Other causes of pulmonary arterial obstruction, be it extrinsic, endoluminal or parietal must be excluded. Angiosarcoma of the pulmonary artery Dartevelle P, et al, Chronic Thromboembolic Pulmonary Hypertension; Eur Respir J 2004; 23:

43 DDx of obstructive PA hypertension 2 Hydatic emboli Hydatic cysts of the liver  migrate spontaneously or during hepatic surgery to IVC  to PA  downstream thrombosis obstruction of a large part of the pulmonary vascular bed. (occlusion of the left pulmonary artery by hydatic cysts which have migrated from the liver) Dartevelle P, et al, Chronic Thromboembolic Pulmonary Hypertension; Eur Respir J 2004; 23:

44 DDx of obstructive PA hypertension 3 DDx of obstructive PA hypertension 3 Tumor emboli into the pulmonary artery teratoma from a testis. The tumor arises from retroperitoneal nodes (a) and goes up to both pulmonary arteries throughout the right chambers of the heart (b). Dartevelle P, et al, Chronic Thromboembolic Pulmonary Hypertension; Eur Respir J 2004; 23:

45 DDx of obstructive PA hypertension 4 fibrosing mediastinitis involving and obstructing the right pulmonary artery and stenosing the left pulmonary artery. Dartevelle P, et al, Chronic Thromboembolic Pulmonary Hypertension; Eur Respir J 2004; 23:

46 Pulmonary Angiography in CTEPH Pulmonary angio and R heart cath Pulmonary angio and R heart cath most important to decide on operability. Does the degree of proximal clot burden explain degree of PVR/ PAP? –R heart cath + Pulm A –graphy Does the degree of proximal clot burden explain degree of PVR/ PAP? –R heart cath + Pulm A –graphy Defects in main, lobar, proximal segment – proximal dz. Defects in main, lobar, proximal segment – proximal dz.

47 Distal vs Proximal CTEPH – relative contribution of small vessels to PAP. (A) extensive central pulmonary clots + PVR= 900 (below 1000) dyne · s · cm5 that is fully attributable to the visible lesions,  PEA the treatment of choice. (B), CTEPH with a more distal distribution + PVR=2000 ( above 1000 ) dyne · s · cm5. high PVR likely due to small vessels  at risk for post PEA persistent high PAP; the risk of surgery is markedly elevated, Hoeper M et al, Chronic Thromboembolic Pulmonary Hypertension, Circulation 2006; 113;

48 Proposed diagnostic approach to CTEPH Hoeper M et al, Chronic Thromboembolic Pulmonary Hypertension, Circulation 2006; 113;

49 Proposed Treatment approach Hoeper M et al, Chronic Thromboembolic Pulmonary Hypertension, Circulation 2006; 113;

50

51

52 Pulmonary Endarterectomy Chance of cure in proximal obstruction driven Pulmonary Hypertension only Chance of cure in proximal obstruction driven Pulmonary Hypertension only Pre op ( A); PVR -768 dyne · s · cm5. Three days postop (B) PVR dyne · s · cm5. Hoeper M et al, Chronic Thromboembolic Pulmonary Hypertension, Circulation 2006; 113;

53 Mean reduction of PVR is 65 % in PEA, NYHA III, IV  I, II, exercise capacity, and gas exchange improved* Fedullo et al, Chronic Thromboembolic Pulmonary Hypertension, N Eng J Med, V ol 345, No 20

54 Determining successful outcome of PEA Upto 50% pt. referred to PEA  rejected. Patient factors: will pt handle PEA? Patient factors: will pt handle PEA? Contraindications to PEA: - Severe Chronic Lung Disease ( FEV1/ FVC or TLC); reperfusion lung injury (Mech-m: localized high permeability, PMN mediated. Within 24 hrs postop; on CXR: infiltrates in areas where PEA done. Rx supportive) - RV failure, CRI – not absolute contraindications Surgical factors: Are clots accessible? Surgical factors: Are clots accessible? Experience of surgeon Experience of surgeon proximity on a-graphy proximity on a-graphy Other factors: pt. can take PEA + clots accessible but if at the same time significant small vessel disease  won’t benefit PAP. Other factors: pt. can take PEA + clots accessible but if at the same time significant small vessel disease  won’t benefit PAP.

55 Important points on PEA pre op From R cath  PVR + from PA A- graphy  prox.vs distal PVR is a sum of chronic emboli and small vessel arteriopathy. Ex 1: PVR high + see nothing on A- graphy  PVR due to small inoperable arteriopathy  no PEA Ex 2: PVR high + see some clots (proximal) on A graphy  ?? Is PVR totally attributed to proximal? ( If cant answer – may do PEA and remove proximal clots only to realize PVR due to small arteriopathy) High Pre op PVR = increased post PEA mortality High Pre op PVR = increased post PEA mortality Hartz et al: PVR>1100 dsc  PEA mortality 41% vs PVR 1100 dsc  PEA mortality 41% vs PVR < 1100  6% Dartvelle et al: preop PVR 900 – 1200 – preop mortality – 10%; Preop PVR >1200 dsc  20% Persistent PAH Post PEA = missed concomitant small vessel dz  increased post op PEA mortality Persistent PAH Post PEA = missed concomitant small vessel dz  increased post op PEA mortality 500 CTEPH s/p PEA w/ postop PVR> 500 dsc  mortality 30% vs. postop PVR 500 dsc  mortality 30% vs. postop PVR < 500  mortality 0.9%

56 Surgical classification based on Postop PAPm and PVR POSTOP OUTCOME IN PEA PATIENTS BY OPERATIVE CLASSIFICATION GROUP Classification Group Variable (n 76) (n 81) (n 38) (n 7 ) Mean decr in PASP mm Hg Mean decr in PVR, dynes · s · cm Group 1: fresh thrombus in main lobar Group 2: intimal thickening prox. to segmental arteries Group 3: within distal segmental arteries Group 4: distal vasculopathy w/o visible thromboembolic dz. Group 1 & 2 - most favorable outcome.

57 Some questions on PEA? What can decrease small vessel contribution to PVR i.e and make a patient better PEA candidate? What can decrease small vessel contribution to PVR i.e and make a patient better PEA candidate? Early diagnosis and PEA early. ( however, recall alternate view a-pathy first  thrombosis secondary) What to do with Pt. with High Pre –Op PVR in otherwise good PEA candidate ( high PVR totally due to prox lesions)? What to do with Pt. with High Pre –Op PVR in otherwise good PEA candidate ( high PVR totally due to prox lesions)? Medical bridge to PEA with Vasodilators. ( 1 of 3 proposed indications, see below)

58 Proposed way to determine if PEA will lower PVR R heart cath with Pulm. Artery Occlusion technique: based on assumption that decay PAOP waveform, PVR may be partitioned to large arterial ( upstream) and small arterial + venous ( upstream) and small arterial + venous ( downstream). R up – resistance upstream.

59 Copyright ©2004 American Heart Association Kim, N. H.S. et al. Circulation 2004;109:18-22 Sample pulmonary artery pressure occlusion waveforms from 2 patients with (A) primarily upstream resistance (note the relatively rapid drop in pressure to Ppao) and (B) significant downstream resistance (longer time is needed for the pressure to reach Ppao)

60 Proposal for Pre PEA classification PROPOSAL FOR PRE-PEA CLASSIFICATION Class A B C PAH Pulm a graphy R cath, dynes · s · cm5 PVR 1,100 >1,100 +PH Rup >60% <60% CT Treatment PEA PEA medical medical Vasodilate prior to PEA

61 Lung transplant for CTEPH Indicated with Life expectancy 12, PAP>60, CI 12, PAP>60, CI < 2.2 Heart and lung, b/l lungs, single lung Heart and lung, b/l lungs, single lung Heart lung best  less bronchial ischemia, heart already adapted to pulm. Circulation Heart lung best  less bronchial ischemia, heart already adapted to pulm. Circulation True to all: life long immune supression, rejections ( acute, chronic), susceptibility to viral, fungal infections) True to all: life long immune supression, rejections ( acute, chronic), susceptibility to viral, fungal infections)

62 Medical Therapy About 50% CTEPH rejected for PEA Pt. w/ high PVR mainly 2/2 small vessels – poor surgical candidates. Traditional therapies: Traditional therapies: anticoagulants, diuretics, digitalis, oxygen anticoagulants, diuretics, digitalis, oxygen Agreement on Anticoagulation to in situ thrombosis ( goal INR 2-3) Lasix for volume overload in R CHF. Lasix for volume overload in R CHF. Novel Therapies Novel Therapies prostacyclin analogues, prostacyclin analogues, endothelin receptor blocker endothelin receptor blocker PDE 5 inhibitor PDE 5 inhibitor

63 Evidence for novel Rx CTEPH and IPAH are similar and maybe even overlap and these work in IPAH. CTEPH and IPAH are similar and maybe even overlap and these work in IPAH. Situations for medical RX in CTEPH Situations for medical RX in CTEPH 1) can’t do PEA ( too much distal or small vessel dz) or not a candidate for other reasons. 1) can’t do PEA ( too much distal or small vessel dz) or not a candidate for other reasons. 2) can do PEA, but PVR too risky high or PEA is far away  bridge to PEA. 2) can do PEA, but PVR too risky high or PEA is far away  bridge to PEA. 3) post PEA still w/ symptoms and PVR high 3) post PEA still w/ symptoms and PVR high ( group 4)

64 Epoprostenol Bressler P. et al evaluated bridging x 6 wks pre PEA ( n=6) w severe CTEPH ( PVR>1200). Bressler P. et al evaluated bridging x 6 wks pre PEA ( n=6) w severe CTEPH ( PVR>1200). Result: mean reduction in PVR of 28% ( median 33%). Post PEA  improved CI, mPAP and TPR P. Bresser et al Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension Eur Respir J 2004; 23:

65 Bosentan Endothelin – potent vasoconstrictor. High plasma amount of Endothelin and upregulator of type B receptors in CTEPH Bonderman et al evaluated Bosentan in inoperable CTEPH Bonderman et al evaluated Bosentan in inoperable CTEPH ( n=16) x 6 month. Result: better functional NYHA class, 6MWD improved, BNP reduced Bonderman et. Al. Bosentan Therapy for Inoperable Chronic Thromboembolic Pulmonary Hypertension Chest 2005; 128;

66 PDE 5 inhibitiors Sildenafil – stabilizes c GMP and NO; potent pulmonary vasodilator. Nonoperable distal progressive CTEPH ( mPAP= 52, PVRI 1,935) On cath pt. had vasodilator reactivity to inhaled nitric oxide. Nonoperable distal progressive CTEPH ( mPAP= 52, PVRI 1,935) On cath pt. had vasodilator reactivity to inhaled nitric oxide. Results: after 6 month 6MWD and PVR improved. Ghofrani et. al; Sildenafil for long –term treatment of non – operable chronic thromboembolic pulmonary hypertension. Am J Resp Crit Care Med 2003; 167:

67 Role of IVC filters in CTEPH sparse evidence in CTEPH sparse evidence in CTEPH F/u study (n=18) IVC Filter to prevent recurrence PE long term as well as high risk periop period.* F/u study (n=18) IVC Filter to prevent recurrence PE long term as well as high risk periop period.* IVC Filters + A/C  reoperation in post PEA** IVC Filters + A/C  reoperation in post PEA** Experts disagree on utility of IVC, slightly more agreement on periop IVC Filter placement for PEA. * * Hajduk et al, implantation of LGM inferior vena Cava Filters in patients with Chronic Pulmonary Hypertension during a course of major vessel Thromboembolism: observation of 18 patient ( in polish). Pneumonol Alergol Pol 1996; 64:154 – 160 **Mo M et al, Reoperative pulmonary Thromboendarterectomy. Ann Thorac Surg 1999; 68 :

68 Outcome of CTEPH patient and predictors of mortality Background Splenectomy, ventriculoatrial shunt, permanent central intravenous lines, IBD and OM associated with CTEPH. ( AMC) Splenectomy, ventriculoatrial shunt, permanent central intravenous lines, IBD and OM associated with CTEPH. ( AMC) Objective to define the impact of these novel risk factors on survival. Objective to define the impact of these novel risk factors on survival. Design 181 CTEPH pt. retrospectively analyzed survival and presence associated medical conditions, age, sex, hemodynamic parameters, modified New York Heart Association functional class at diagnosis, CTEPH type, PEA, and anti-cardiolipin antibodies/ Lupus anticoagulant. Duration median observation time months (range, 0.03 to 152) Results 1. PEA (hazard ratio, 0.14; 95% CI, 0.05 to 0.41; P=0.0003), 2. AMC (associated medical conditions )(hazard ratio, 3.17; 95% CI, 1.70 to 5.92; P=0.0003) were predictors of survival. Thirty-day postoperative mortality (24% versus 9%) and the incidence of postoperative pulmonary hypertension (92% versus 20%) were substantially higher in patients with associated medical conditions Conclusion splenectomy, permanent central intravenous lines, and certain inflammatory disorders, predict poor survival in CTEPH Bonderman D, et al. Predictors of outcome in chronic thromboembolic pulmonary hypertension. Circulation 2007;115:2153–2158

69 Copyright ©2007 American Heart Association Bonderman, D. et al. Circulation 2007;115: A, Overall patient cohort; B, unoperated patients

70 CTEPH CONCLUSIONS Suspect in patients with Acute PE and PASP > 40 without hemodynamic failure. Suspect in patients with Acute PE and PASP > 40 without hemodynamic failure. Progressive dyspnea in known PE patient should be screened by 2 D echo. Progressive dyspnea in known PE patient should be screened by 2 D echo. Splenectomy, Chronic Inflammatory conditions, prior PE, hx of VentriculoAtrial shunt, Hx of Staph bacteremia are some of the risks for CTEPH Splenectomy, Chronic Inflammatory conditions, prior PE, hx of VentriculoAtrial shunt, Hx of Staph bacteremia are some of the risks for CTEPH Only 4% post acute PE develop CTEPH within 2 years Only 4% post acute PE develop CTEPH within 2 years 2D TTE is good screening test if pt. c/o persistent dyspnea post PE. If PAP is high  refer for R H C to get accurate pressures. 2D TTE is good screening test if pt. c/o persistent dyspnea post PE. If PAP is high  refer for R H C to get accurate pressures.

71 Normal VQ test rules out CTEPH. Normal VQ test rules out CTEPH. CTA may not reveal clots in CTEPH. Alternately, if obstructing densities are seen within PA branches r/o Obstructing Pulmonary Artery conditions CTA may not reveal clots in CTEPH. Alternately, if obstructing densities are seen within PA branches r/o Obstructing Pulmonary Artery conditions Once diagnosis of CTEPH is made based on R H C, V/Q and CTA consider starting medical therapy for high PAP, A/C and refer for PEA. Once diagnosis of CTEPH is made based on R H C, V/Q and CTA consider starting medical therapy for high PAP, A/C and refer for PEA. Perioperative IVC Filter is recommended. Perioperative IVC Filter is recommended. Regardless of whether or not pt is accepted for PEA Revatio, Tracleer, Flolan may improve outcome. Regardless of whether or not pt is accepted for PEA Revatio, Tracleer, Flolan may improve outcome. CTEPH CONCLUSIONS


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