Dr. Altay ŞahinDr. Altay ŞahinHacettepe UniversityHacettepe UniversityFaculty of MedicineFaculty of Medicine

Department of Chest DiseasesDepartment of Chest Diseases

Chronic Thromboembolic Pulmonary Chronic Thromboembolic Pulmonary Hypertension (CTEPH)Hypertension (CTEPH)

CTEPH DefinitionCTEPH Definition About 50% of CTEPH have no documented history About 50% of CTEPH have no documented history of VTE of VTE (Peacock A. Proc Am Thorac Soc 2006;3:608) (Peacock A. Proc Am Thorac Soc 2006;3:608)

Primary arteriopathy and endothelial dysfunction cause local thrombosis Primary arteriopathy and endothelial dysfunction cause local thrombosis and defects in fibrinolysis resulting impaired thrombosis resolution.and defects in fibrinolysis resulting impaired thrombosis resolution. (e.g. (e.g. Fibrinogen A(Fibrinogen A(αα) Thr312Ala increases VTE risk and resistance to thrombolysis. ) Thr312Ala increases VTE risk and resistance to thrombolysis. Suntharalingam J Eur Respir J 2008;31:736)Suntharalingam J Eur Respir J 2008;31:736)

PE usually starts the cascade of events; recurrent PE usually starts the cascade of events; recurrent PE or in situ thrombosis and endothelial PE or in situ thrombosis and endothelial dysfunction are responsible both for progression dysfunction are responsible both for progression and hemodynamic dysfunction!and hemodynamic dysfunction!

Pengo V.NEJM 2004;350:2257, Miniati M MPengo V.NEJM 2004;350:2257, Miniati M Medicine 2006;85:253, Liu P. Chin Med J 200edicine 2006;85:253, Liu P. Chin Med J 2003;116:5033;116:503

CTEPHCTEPH

France prevalence: 25/millionFrance prevalence: 25/million Scotland prevalence: 26/million,Scotland prevalence: 26/million, Following acute PE, during 94 months period: 3.8 % Following acute PE, during 94 months period: 3.8 %

(Pengo),(Pengo),

During 5 year echocardiographic follow-up: 5.1 %During 5 year echocardiographic follow-up: 5.1 %(Riberio),(Riberio),

During 1 year follow-up: % 1.3 During 1 year follow-up: % 1.3 (Miniati),(Miniati),

In patients with vascular obstruction >50%: 20.2% In patients with vascular obstruction >50%: 20.2% (Liu)(Liu)

Pengo V. NEJM 2004;350:2257, Riberio A. Pengo V. NEJM 2004;350:2257, Riberio A. Circulation 1999;99:1325Circulation 1999;99:1325

CTEPHCTEPH

Risk FactorsRisk Factors

Multiple PE,Multiple PE,

Younger age,Younger age,

Big perfusion defects,Big perfusion defects,

Idiopathic VTEIdiopathic VTE

Bonderman D. Circulation 2007;115:2153,Bonderman D. Circulation 2007;115:2153, Bonderman D. Thromb Haemost 2005;93: Bonderman D. Thromb Haemost 2005;93:512512

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Risk Factors Risk Factors

-Splenectomy, -Splenectomy,

-Ventriculo-atrial shunt for hydrocephaly,-Ventriculo-atrial shunt for hydrocephaly,

-Long term central venous catheters,-Long term central venous catheters,

-Inflammatory bowel disease,-Inflammatory bowel disease,

-Osteomyelitis -Osteomyelitis

Splenectomy 13.95 %, V-A shunt 13 %, Chr. inflammatory diseases 67.95 Splenectomy 13.95 %, V-A shunt 13 %, Chr. inflammatory diseases 67.95

%!%!

Lang I Proc Am Thorac Soc 2006;3:568Lang I Proc Am Thorac Soc 2006;3:568

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Different risks between CTEPH and PE Different risks between CTEPH and PE

-Anticardiolipin antigens -Anticardiolipin antigens

-Factor VIII, -Factor VIII,

-von Willebrand factor -von Willebrand factor

-Hyperhomosisteinemia-Hyperhomosisteinemia

-Plasma lipoprotein (a) levels -Plasma lipoprotein (a) levels -Anti-O blood group -Anti-O blood group

Auger WR. Clin Chest Med 2007;28:255Auger WR. Clin Chest Med 2007;28:255

CTEPHCTEPH

The mean PH is The mean PH is <<40 mmHg in massive PE,40 mmHg in massive PE, Difference in resolution and organization of thrombus,Difference in resolution and organization of thrombus, Vasculopathy in distal arteries,Vasculopathy in distal arteries, The degree of PH correlates with PVR which is caused by distal The degree of PH correlates with PVR which is caused by distal

vasculopathy,vasculopathy, PH continues after the removal of chronic proximal thrombus,PH continues after the removal of chronic proximal thrombus,

Hoeper MM. Circulation 2006;113:2011, PHoeper MM. Circulation 2006;113:2011, Peacock A. Proc Am Thorac Soc 2006;3:608eacock A. Proc Am Thorac Soc 2006;3:608

CTEPHCTEPH

CTEPH and IPAH (differential diagnosis may be difficult )CTEPH and IPAH (differential diagnosis may be difficult ) CTEPH and Idiopathic PulmonaryArterial Hypertension(IPAH) CTEPH and Idiopathic PulmonaryArterial Hypertension(IPAH)

similaritiessimilarities (-Plexogenic arteriopathy, -In situ trombi, -Protrombotic factors, -(-Plexogenic arteriopathy, -In situ trombi, -Protrombotic factors, -Antiphospholipid antigens, -similar response to same medical treatment)Antiphospholipid antigens, -similar response to same medical treatment)

Important differences in CTEPH Important differences in CTEPH Are CTEPH ve IPAH same disease because of the similarities?Are CTEPH ve IPAH same disease because of the similarities? In IPAH In IPAH

(-Family history (-Family history ~~ 6-10 %, -Sporadic genetic predisposition 6-10 %, -Sporadic genetic predisposition ~~ 30 % eg. BMRP II, -K/E 30 % eg. BMRP II, -K/E ~~ 1.7/1.0) 1.7/1.0)

In a prospective longitudinal study cumulative incidences after acute In a prospective longitudinal study cumulative incidences after acute PE 6 months 1.0 %, 1 year 3.1 %, 2 years 3.8PE 6 months 1.0 %, 1 year 3.1 %, 2 years 3.8 %%(Pengo V, et al.NEJM2004;350:2257) (Pengo V, et al.NEJM2004;350:2257)

There ıs no medical history for acute PE in most of CTEPH patients.There ıs no medical history for acute PE in most of CTEPH patients.

CTEPHCTEPH

No differentiation of CTEPH from IPAH only with the No differentiation of CTEPH from IPAH only with the clinical picture,clinical picture,

CXR CXR (-widening of pulmonary artery, -enlargement of right atrium and (-widening of pulmonary artery, -enlargement of right atrium and ventricle, -hypo and hyperlucent areas) ventricle, -hypo and hyperlucent areas)

EKG EKG (-right axis deviation, -Right ventricle hypertrophy -ST segment (-right axis deviation, -Right ventricle hypertrophy -ST segment depression, -inverse T wave),depression, -inverse T wave),

PFT PFT (-shows Pulm. Paranchyme and airway disease, Restrictive-Obstructive),(-shows Pulm. Paranchyme and airway disease, Restrictive-Obstructive),

Echo Echo (-Right and left ventricle dysfunction, -Agitated saline test for patent (-Right and left ventricle dysfunction, -Agitated saline test for patent foramen ovale and atrial septal defect, tricuspid regurgitation, interventricular foramen ovale and atrial septal defect, tricuspid regurgitation, interventricular septum,)septum,) After 6 weeks After 6 weeks

V/Q Scintigraphy V/Q Scintigraphy (-Subsegmental, segmental and bigger defects, usefulness?)(-Subsegmental, segmental and bigger defects, usefulness?)

CTEPHCTEPH

CTA (Multislice BT 0.5 mm - -CTA (Multislice BT 0.5 mm - -Luminal trombus, -Organized mural Luminal trombus, -Organized mural trombus, -Obstruction, -Web, -Air trapping-Small airway disease, -Veno-trombus, -Obstruction, -Web, -Air trapping-Small airway disease, -Veno-occlusive disease-ground glass nodules, interlobuler septal thickening, occlusive disease-ground glass nodules, interlobuler septal thickening, mediastinal LAP)mediastinal LAP)

MRA (No ionized radiation-During followup ! )MRA (No ionized radiation-During followup ! )–İntraluminal web, -Bands –İntraluminal web, -Bands –Organized trombus, -Subsegmental vessels not suitable for evaluation -–Organized trombus, -Subsegmental vessels not suitable for evaluation -Cardiac functions-flows, muscle mass)Cardiac functions-flows, muscle mass)

PA (Convensional angiography when CTA and MRA not sufficient)PA (Convensional angiography when CTA and MRA not sufficient) Pulmoner Angioscopy (Some complications,expensive Pulmoner Angioscopy (Some complications,expensive –shows chr. –shows chr.

Organized thrombus and intimal surface, webs, bandsOrganized thrombus and intimal surface, webs, bands Differential diagnosis Differential diagnosis

-Fibrous mediastinitis, -Pulmonary artery sarcoma-MR helpful, -Fibrous mediastinitis, -Pulmonary artery sarcoma-MR helpful, Giant cell arteritis-Takayasu’s CTA ve MRA show concentric Giant cell arteritis-Takayasu’s CTA ve MRA show concentric narrrowing)narrrowing)

Rich S. ve Macchia A. Am Heart J 2007;153Rich S. ve Macchia A. Am Heart J 2007;153;889 ve 1037;889 ve 1037

CTEPH-TreatmentCTEPH-Treatment

General therapy,General therapy, Medical treatmentMedical treatment (1-significant decrease in mortality, 2-small (1-significant decrease in mortality, 2-small

but significant increase in 6MWD-42.8m, 3-Decrease in dyspnea, 4-no significant but significant increase in 6MWD-42.8m, 3-Decrease in dyspnea, 4-no significant increase in mean survival rates.)increase in mean survival rates.)

PEA,PEA, Baloon Dilatation,Baloon Dilatation, Atrioseptosomy,Atrioseptosomy, Transplantation.Transplantation.

Mereles D. Circulation 2006;114:251Mereles D. Circulation 2006;114:251

CTEPHCTEPH

General treatment General treatment -Anticoagulation, -Anticoagulation, (to all patients with CTEPH, but more (to all patients with CTEPH, but more

beneficial in milder cases) beneficial in milder cases) -Physiotherapy-exercise and respiratory therapy* -Physiotherapy-exercise and respiratory therapy*

-Oxygen,-Oxygen,

-Diuretics, -Diuretics, -Digital, -Digital,

CTEPHCTEPH

First choice of treatment is Pulmonary First choice of treatment is Pulmonary Endarterectomy (PEA),Endarterectomy (PEA),

After PEA, some patients still may have PH After PEA, some patients still may have PH PH may recur in the later stages of PEA PH may recur in the later stages of PEA There are patients with distal arteriopathy There are patients with distal arteriopathy

having high PVR,having high PVR, There are patients with significant There are patients with significant

cardiopulmonary comorbidities,cardiopulmonary comorbidities, In some patients with WHO class I and II, In some patients with WHO class I and II,

decision is hard decision is hard

Thistlethwaite PA. J Thorac Cardiovasc SurThistlethwaite PA. J Thorac Cardiovasc Surg 2002;124:1203g 2002;124:1203

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Results of biopsy, autopsy and pulmonary endarterectomy:Results of biopsy, autopsy and pulmonary endarterectomy: -Type I (Pathology is organized thrombus in main or lobar -Type I (Pathology is organized thrombus in main or lobar

arteries) arteries) -Type II (Pathology is intimal thickening and fibrosis in -Type II (Pathology is intimal thickening and fibrosis in

proximal parts of segment arteries)proximal parts of segment arteries) -Type III (Pathology is in distal segmental and subsegmental -Type III (Pathology is in distal segmental and subsegmental

arteries) arteries) -Type IV (Pathology is distal precapillery artery vasculopathy, -Type IV (Pathology is distal precapillery artery vasculopathy,

no thromboembolic event)no thromboembolic event) Poor prognosis in distal artery vasculopathy, Poor prognosis in distal artery vasculopathy,

showing pulmonary endarterectomy is not the showing pulmonary endarterectomy is not the treatment of choice.treatment of choice.

Kim NHS. Proc Am Thorac Soc 2006;3:584Kim NHS. Proc Am Thorac Soc 2006;3:584

CTEPHCTEPH

In CTEPH diagnosed with convensional angiography or CT In CTEPH diagnosed with convensional angiography or CT angiography, V/Q scintigraphy, with Right Heart Catheterization angiography, V/Q scintigraphy, with Right Heart Catheterization

A B C D (PAH) A B C D (PAH)

PVR PVR dynes . S . Cmdynes . S . Cm-5-5 ≤ ≤1.1001.100 >>1.1001.100 >1.100 >1.100

Rup Rup > % 60 < % 60 > % 60 < % 60

PEA PEA PEA>risk PEA PEA PEA>risk Medical therapy Medical therapy

PVR=Pulmonary Vascular Resistance, Rup= Upstream Resistance, PEA= Pulmonary EndarterectomyPVR=Pulmonary Vascular Resistance, Rup= Upstream Resistance, PEA= Pulmonary Endarterectomy

CTEPH

FC I ve IIFC I ve II FC IIIFC III FC IVFC IV -Sildenafil-Sildenafil -Bosentan-Bosentan -Epoprostenol i.v.-Epoprostenol i.v. -Trepostinil s.c.-Trepostinil s.c. -Sildenafil-Sildenafil -Bosentan-Bosentan -Trepostinil i.v.-Trepostinil i.v. -Epoprostenol 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

CTEPHCTEPH

No PEA indications, symptomatic and hemodynamic or No PEA indications, symptomatic and hemodynamic or ventilation failure signs ventilation failure signs

Yes Yes No No

Medical treatment-follow-Medical treatment-follow-upup

Serious comorbidity Serious comorbidity

IImprovement mprovement Stable Stable

YesYes N Noo Serious comorbidity Serious comorbidity

Medical treatment Medical treatment YesYes No No

Baloon Dilatation Baloon Dilatation

Transplantation Transplantation

Condlifte R AJRCCM 2008; baskıdaCondlifte R AJRCCM 2008; baskıda

CTEPHCTEPH

469 patients in UK /148 patients (32%) not suitable for distal 469 patients in UK /148 patients (32%) not suitable for distal PAEPAE

survivalsurvival 1 Year(%)1 Year(%) 3 Years (%)3 Years (%) 5 Years 5 Years (%)(%)

Medical treatment 82 74 Medical treatment 82 74

PEA PEA 88 76 88 76 35 35

Ongoing pulmonary hypertension in 94% of 5-year survivors in Ongoing pulmonary hypertension in 94% of 5-year survivors in surgery groupsurgery group

Macchia A. Am Heart J 2007;153:1037, RicMacchia A. Am Heart J 2007;153:1037, Rich S. Am Heart J 2007;153:889h S. Am Heart J 2007;153:889

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Macchia A et al published a metaanalysis analyzing Macchia A et al published a metaanalysis analyzing the results of 16 studies in which Prostacyclin and the results of 16 studies in which Prostacyclin and analogs, endothelin receptor antagonists and analogs, endothelin receptor antagonists and phosphodiesterase-5 inhibitors were used for 16 phosphodiesterase-5 inhibitors were used for 16 weeks.weeks.

70% of patients WHO FC III, % 80 IV, primary 70% of patients WHO FC III, % 80 IV, primary endpoint of the study was 6MW distance. endpoint of the study was 6MW distance.

No significant decrease in mortality,No significant decrease in mortality, 6MW distance increased about 42.8 meters,6MW distance increased about 42.8 meters, Improvement in WHO FC, (in dyspnea),Improvement in WHO FC, (in dyspnea), But increase in exercise capacity does not correlate But increase in exercise capacity does not correlate

with survival. with survival.

Humbert M. AJRCCM 2008;177:574Humbert M. AJRCCM 2008;177:574

CTEPHCTEPH

Serotonin pathway is important in the Serotonin pathway is important in the pathogenesis of PAH pathogenesis of PAH (Serotonin inhibits BMP signal and (Serotonin inhibits BMP signal and stimulates BMP responsive genes. Fenfluramines are potent serotonin uptake stimulates BMP responsive genes. Fenfluramines are potent serotonin uptake inhibitors and increase circulating seratonin levels.)inhibitors and increase circulating seratonin levels.)

In the absence of Vasoactive Intestinal Peptide In the absence of Vasoactive Intestinal Peptide gene, some genes are overexpressed and some gene, some genes are overexpressed and some

are inhibitedare inhibited.. (Proliferative, proinflammatory-(Proliferative, proinflammatory-antiproliferative effects)antiproliferative effects)

Tyrosine Kinase Inhibitors Tyrosine Kinase Inhibitors (Platelet Derived Growth (Platelet Derived Growth Factor smooth muscle proliferation and migration. Tyrosine Factor smooth muscle proliferation and migration. Tyrosine kinase inhibitors block PDGF, treatment!)kinase inhibitors block PDGF, treatment!)

Soluble Guanylate Cyclase Stimulator ve Soluble Guanylate Cyclase Stimulator ve Activators Activators (Dose dependent pulmonary vasodilation and (Dose dependent pulmonary vasodilation and increase in cGMP release without causing any change in increase in cGMP release without causing any change in mean arterial pressure)mean arterial pressure)

Ito T. Current Medicinal Chemistry 2007;1Ito T. Current Medicinal Chemistry 2007;14:7194:719

CTEPHCTEPHVGEF= Vascular Endothelial Growth Factor

DN-survivin= Dominant-Negative inhibitor survivin

5-HTT=Serotonin transporter

AM= Adrenomedulin

VIP= Vasoactive Intestinal Peptide

PPAR= Peroxysome Proliferator-Activated Receptor

SOD= Superoxide Dismutase

MMF= Mycophenolate Mofetil

AT1R= Angiotensin II Type Receptor

DN-MCP-1= Dominant-Negative inhibitor of Monocyte chemoattractant Protein-1

ANP/BNP= Atrial Natriuretic Peptide Brain..

CTEPHCTEPH

CTEPH Some ControversiesCTEPH Some Controversies

-Pathogenesis of the disease unknown ? -Pathogenesis of the disease unknown ?

-The role of embolism and/or in situ thrombosis in -The role of embolism and/or in situ thrombosis in etiology and pathogenesis ? etiology and pathogenesis ?

-Autopsy and biopsy results are similar. Is it a form of -Autopsy and biopsy results are similar. Is it a form of IPAH ? IPAH ?

-About 50% no documented PE? -About 50% no documented PE? -Relapses after success pulmonary endarterectomy ? -Relapses after success pulmonary endarterectomy ? -There is no sufficient evidence based data for medical -There is no sufficient evidence based data for medical

therapy except for general treatment approach and therapy except for general treatment approach and anticoagulation.anticoagulation.

Web in CTA and convensional angiography

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Mosaic perfusion

CTEPHCTEPH

Distal vasculopathy

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CTA-early and late phases

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Obstructed artery and web in MR angiography and pulmonary angiography

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Distal vessel disease in pulmonary angiography

Before and after PAE