Dr. Altay Şahin Hacettepe University Faculty of Medicine Department of Chest Diseases

1. Dr. Altay ŞahinHacettepe UniversityFaculty of MedicineDepartment of Chest Diseases

2. Chronic Thromboembolic Pulmonary Hypertension (CTEPH) CTEPH Definition About 50% of CTEPH have no documented history of VTE (Peacock A. Proc Am Thorac Soc 2006;3:608) Primary arteriopathy and endothelial dysfunction cause local thrombosis and defects in fibrinolysis resulting impaired thrombosis resolution.(e.g. Fibrinogen A(α) Thr312Ala increases VTE risk and resistance to thrombolysis. Suntharalingam J Eur Respir J 2008;31:736) PE usually starts the cascade of events; recurrent PE or in situ thrombosis and endothelial dysfunction are responsible both for progression and hemodynamic dysfunction!

3. CTEPH • France prevalence: 25/million • Scotland prevalence: 26/million, • Following acute PE, during 94 months period: 3.8 % (Pengo), • During 5 year echocardiographic follow-up: 5.1 %(Riberio), • During 1 year follow-up: % 1.3 (Miniati), • In patients with vascular obstruction >50%: 20.2% (Liu) Pengo V.NEJM 2004;350:2257, Miniati M Medicine 2006;85:253, Liu P. Chin Med J 2003;116:503

4. CTEPH Risk Factors • Multiple PE, • Younger age, • Big perfusion defects, • Idiopathic VTE Pengo V. NEJM 2004;350:2257, Riberio A. Circulation 1999;99:1325

5. CTEPH • Risk Factors -Splenectomy, -Ventriculo-atrial shunt for hydrocephaly, -Long term central venous catheters, -Inflammatory bowel disease, -Osteomyelitis Splenectomy 13.95 %, V-A shunt 13 %, Chr. inflammatory diseases 67.95 %! Bonderman D. Circulation 2007;115:2153, Bonderman D. Thromb Haemost 2005;93:512

6. CTEPH • Different risks between CTEPH and PE -Anticardiolipin antigens -Factor VIII, -von Willebrand factor -Hyperhomosisteinemia -Plasma lipoprotein (a) levels -Anti-O blood group Lang I Proc Am Thorac Soc 2006;3:568

7. CTEPH • The mean PH is <40 mmHg in massive PE, • Difference in resolution and organization of thrombus, • Vasculopathy in distal arteries, • The degree of PH correlates with PVR which is caused by distal vasculopathy, • PH continues after the removal of chronic proximal thrombus, Auger WR. Clin Chest Med 2007;28:255

8. CTEPH • CTEPH and IPAH (differential diagnosis may be difficult ) • CTEPH and Idiopathic PulmonaryArterial Hypertension(IPAH) similarities(-Plexogenic arteriopathy, -In situ trombi, -Protrombotic factors, -Antiphospholipid antigens, -similar response to same medical treatment) • Important differences in CTEPH • Are CTEPH ve IPAH same disease because of the similarities? In IPAH (-Family history ~ 6-10 %, -Sporadic genetic predisposition ~ 30 % eg. BMRP II, -K/E ~ 1.7/1.0) • In a prospective longitudinal study cumulative incidences after acute PE 6 months 1.0 %, 1 year 3.1 %, 2 years 3.8%(Pengo V, et al.NEJM2004;350:2257) There ıs no medical history for acute PE in most of CTEPH patients. Hoeper MM. Circulation 2006;113:2011, Peacock A. Proc Am Thorac Soc 2006;3:608

9. CTEPH • No differentiation of CTEPH from IPAH only with the clinical picture, • CXR (-widening of pulmonary artery, -enlargement of right atrium and ventricle, -hypo and hyperlucent areas) • EKG (-right axis deviation, -Right ventricle hypertrophy -ST segment depression, -inverse T wave), • PFT (-shows Pulm. Paranchyme and airway disease, Restrictive-Obstructive), • Echo (-Right and left ventricle dysfunction, -Agitated saline test for patent foramen ovale and atrial septal defect, tricuspid regurgitation, interventricular septum,) After 6 weeks • V/Q Scintigraphy (-Subsegmental, segmental and bigger defects, usefulness?)

10. CTEPH • CTA (Multislice BT 0.5 mm - -Luminal trombus, -Organized mural trombus, -Obstruction, -Web, -Air trapping-Small airway disease, -Veno-occlusive disease-ground glass nodules, interlobuler septal thickening, mediastinal LAP) • MRA (No ionized radiation-During followup ! )–İntraluminal web, -Bands –Organized trombus, -Subsegmental vessels not suitable for evaluation -Cardiac functions-flows, muscle mass) • PA (Convensional angiography when CTA and MRA not sufficient) • Pulmoner Angioscopy (Some complications,expensive –shows chr. Organized thrombus and intimal surface, webs, bands • Differential diagnosis -Fibrous mediastinitis, -Pulmonary artery sarcoma-MR helpful, Giant cell arteritis-Takayasu’s CTA ve MRA show concentric narrrowing)

11. CTEPH-Treatment • General therapy, • Medical treatment(1-significant decrease in mortality, 2-small but significant increase in 6MWD-42.8m, 3-Decrease in dyspnea, 4-no significant increase in mean survival rates.) • PEA, • Baloon Dilatation, • Atrioseptosomy, • Transplantation. Rich S. ve Macchia A. Am Heart J 2007;153;889 ve 1037

12. CTEPH • General treatment -Anticoagulation,(to all patients with CTEPH, but more beneficial in milder cases) -Physiotherapy-exercise and respiratory therapy* -Oxygen, -Diuretics, -Digital, Mereles D. Circulation 2006;114:251

13. CTEPH • First choice of treatment is Pulmonary Endarterectomy (PEA), • After PEA, some patients still may have PH • PH may recur in the later stages of PEA • There are patients with distal arteriopathy having high PVR, • There are patients with significant cardiopulmonary comorbidities, • In some patients with WHO class I and II, decision is hard

14. CTEPH • Results of biopsy, autopsy and pulmonary endarterectomy: • -Type I (Pathology is organized thrombus in main or lobar arteries) • -Type II (Pathology is intimal thickening and fibrosis in proximal parts of segment arteries) • -Type III (Pathology is in distal segmental and subsegmental arteries) • -Type IV (Pathology is distal precapillery artery vasculopathy, no thromboembolic event) • Poor prognosis in distal artery vasculopathy, showing pulmonary endarterectomy is not the treatment of choice. Thistlethwaite PA. J Thorac Cardiovasc Surg 2002;124:1203

15. CTEPH • In CTEPH diagnosed with convensional angiography or CT angiography, V/Q scintigraphy, with Right Heart Catheterization A B C D (PAH) PVR dynes . S . Cm-5 ≤1.100>1.100 >1.100 Rup > % 60 < % 60 PEA PEA PEA>risk Medical therapy PVR=Pulmonary Vascular Resistance, Rup= Upstream Resistance, PEA= Pulmonary Endarterectomy Kim NHS. Proc Am Thorac Soc 2006;3:584

16. CTEPH FC I ve IIFC IIIFC IV -Sildenafil-Bosentan-Epoprostenol i.v. -Trepostinil s.c.-Sildenafil-Bosentan -Trepostinil i.v.-Epoprostenol i.v.-Iloprost -Iloprost inh -Sildenafil -Trepostinil s.c.-Trepostinil s.c. -Trepostinil i.v.-Trepostinil i.v. Combination no response+progression Therapy Atrioseptostomy and/or transplantation

17. CTEPH No PEA indications, symptomatic and hemodynamic or ventilation failure signs Yes No Medical treatment-follow-up Serious comorbidity Improvement Stable Yes No Serious comorbidity Medical treatment YesNo Baloon Dilatation Transplantation

18. CTEPH • 469 patients in UK /148 patients (32%) not suitable for distal PAE survival1 Year(%)3 Years (%)5 Years (%) Medical treatment 82 74 PEA 88 76 35 Ongoing pulmonary hypertension in 94% of 5-year survivors in surgery group Condlifte R AJRCCM 2008; baskıda

19. CTEPH • Macchia A et al published a metaanalysis analyzing the results of 16 studies in which Prostacyclin and analogs, endothelin receptor antagonists and phosphodiesterase-5 inhibitors were used for 16 weeks. • 70% of patients WHO FC III, % 80 IV, primary endpoint of the study was 6MW distance. • No significant decrease in mortality, • 6MW distance increased about 42.8 meters, • Improvement in WHO FC, (in dyspnea), • But increase in exercise capacity does not correlate with survival. Macchia A. Am Heart J 2007;153:1037, Rich S. Am Heart J 2007;153:889

20. CTEPH • Serotonin pathway is important in the pathogenesis of PAH (Serotonin inhibits BMP signal and stimulates BMP responsive genes. Fenfluramines are potent serotonin uptake inhibitors and increase circulating seratonin levels.) • In the absence of Vasoactive Intestinal Peptide gene, some genes are overexpressed and some are inhibited.(Proliferative, proinflammatory-antiproliferative effects) • Tyrosine Kinase Inhibitors (Platelet Derived Growth Factor smooth muscle proliferation and migration. Tyrosine kinase inhibitors block PDGF, treatment!) • Soluble Guanylate Cyclase Stimulator ve Activators (Dose dependent pulmonary vasodilation and increase in cGMP release without causing any change in mean arterial pressure) Humbert M. AJRCCM 2008;177:574

21. CTEPH VGEF= Vascular Endothelial Growth Factor DN-survivin= Dominant-Negative inhibitor survivin 5-HTT=Serotonin transporter AM= Adrenomedulin PPAR= Peroxysome Proliferator-Activated Receptor VIP= Vasoactive Intestinal Peptide SOD= Superoxide Dismutase MMF= Mycophenolate Mofetil AT1R= Angiotensin II Type Receptor ANP/BNP= Atrial Natriuretic Peptide Brain.. DN-MCP-1= Dominant-Negative inhibitor of Monocyte chemoattractant Protein-1 Ito T. Current Medicinal Chemistry 2007;14:719

22. CTEPH • CTEPH Some Controversies -Pathogenesis of the disease unknown ? -The role of embolism and/or in situ thrombosis in etiology and pathogenesis ? -Autopsy and biopsy results are similar. Is it a form of IPAH ? -About 50% no documented PE? -Relapses after success pulmonary endarterectomy ? -There is no sufficient evidence based data for medical therapy except for general treatment approach and anticoagulation.

23. Web in CTA and convensional angiography

24. CTEPH Mosaic perfusion

25. CTEPH Distal vasculopathy

26. CTEPH CTA-early and late phases

27. CTEPH Obstructed artery and web in MR angiography and pulmonary angiography

28. CTEPH Distal vessel disease in pulmonary angiography

29. Before and after PAE