1. Chronic Thromboembolic Pulmonary
Artery Hypertension(CTEPH)
By-
Dr Awadhesh Kr Sharma

2. The Truth about Chronic Thrombo-embolic Pulmonary
Arterial Hypertension (CTEPH)
CTEPH is a deadly disease
Insidious in onset
Once symptomatic, progresses rapidly without
treatment
Medical therapies exist, but most tested in
patients with advanced disease
(NEJM Jan 27,2011 Page351-360)

4. CTEPH
Chronic thromboembolic pulmonary hypertension
(CTEPH) is an important cause of pulmonary
hypertension that is commonly considered to be the
consequence of acute pulmonary embolic disease.
Following an acute event, unresolved residual
thrombus becomes organised and fibrosed, leading to
ongoing obstruction to pulmonary blood flow.
Untreated, this leads to progressive pulmonary
hypertension, right ventricular dysfunction and death
(Suntharalingam J. et al. Thorax 2007)

5. “Not a disease, but a
syndrome in which the
pressure in the pulmonary
circulation is raised.”
Peacock, Pulmo Circ 2nd ed

6. Definition
Chronic thromboembolic pulmonary hypertension is
defined as-
 mean pulmonary-artery pressure greater than 25 mm
Hg that persists 6 months after pulmonary embolism
is diagnosed
(J Am Coll Cardiol 2009;54:Suppl:S43-S54.)
Occurs in 2 to 4% of patients after acute pulmonary
embolism.
(Chest 2006;130:172-5)

7. Natural History of CTEPH
Honeymoon period after acute PE
Usually present in their 40s
Later presents with dyspnea, hypoxemia &
RV dysfunction
Death usually due to RV failure
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.

9. mPAP>50 mean survival 6.8 yrs
Fibrinolysis in acute PE shown to reduce
the frequency of CTEPH.
Most of CTEPH pts. even on
anticoagulants will progress to Rt heart
failure and death untreated
(Kline J et al,Chest 2009;136:1202-10)

10. Incidence
 0.5% to 3.8% of pts after an acute PE & in upto 10% of those with a
history of recurrent PE will develop CTEPH.
 A prospective follow-up study of 78 survivors of acute pulmonary
embolism, Four patients (5.1%) developed definite CTEPH, and 3 of
these subsequently underwent successful PEA.
(Ribeiro A, Lindmarker P, Johnsson H, Juhlin-Dannfelt A, Jorfeldt L. Pulmonary embolism: one-year
follow-up with echocardiography Doppler and five-year survival analysis. Circulation. 1999;99:1325–
1330.)
 The only identifiable risk factors for persistent pulmonary
hypertension were an age 70 years and a systolic pulmonary artery
pressure 50 mm Hg at the initial presentation.
 In another prospective follow-up study of 223 patients who presented
with acute pulmonary embolism, the incidence of symptomatic
CTEPH was 3.1% at 1 year and 3.8% at 2 years (Pengo V, Lensing AW, Prins MH, Marchiori
A, Davidson BL, Tiozzo F,Albanese P, Biasiolo A, Pegoraro C, Iliceto S, Prandoni P. Incidence of chronic thromboembolic
pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350:2257–2264. )

11. Risk factors for CTEPH

12. VTE Risk factors
Hypercoagulability
Malignancy
Nonmalignant thrombophilia
Pregnancy
Postpartum status (<4wk)
Estrogen/ OCP’s
Genetic mutations (Factor V Leiden, Protein C & S deficiency, Factor
VIII, Prothrombin mutations, anti-thrombin III
deficiency)
Venous Statis
Bedrest > 24 hr
Recent cast or external fixator
Long-distance travel or prolong automobile travel
Venous Injury
Recent surgery requiring endotracheal intubation
Recent trauma (especially the lower extremities and pelvis)

13. VTE Risk factors
Specific to women:
 Obesity BMI ≥ 29
 Pregnancy
 Hypertension
 Heavy smoking (> 25cigs/day)
 Hormone replacement therapy
 OCP’s 10-30/100,000 users vs. 4-8/100,000 non-users.

14. While the hypercoagulable state has been clearly
associated with the development of CTEPH, not all of
the aforementioned factors have been clearly linked
with CTEPH.
Plasma VIII elevated in 41% of pts of CTEPH.
Lupus anticoagulant 10% of CTEPH
Anticardiolipin antibody in 20% CTEPH
Protein C,S & antithrombin deficiencies <1% of pts
with CTEPH.

15. Factors specific to pulmonary embolism
Recurrent or unprovoked pulmonary embolism
Large perfusion defects when pulmonary embolism
detected
Young or old age when pulmonary embolism
detected
Pulmonary-artery systolic pressure >50 mm Hg at
initial manifestation of pulmonary embolism

16. Chronic medical conditions
Infected surgical cardiac shunts or pacemaker or
defibrillator leads
Post-splenectomy
Chronic inflammatory disorders
Cancer

17. Thrombotic factors
Lupus anticoagulant or antiphospholipid antibodies
Increased levels of factor VIII
Dysfibrinogenemia

18. Genetic factors
ABO blood groups other than O
HLA polymorphisms
Abnormal endogenous fibrinolysis

19. CTEPH: ASSOCIATIONS
 Non O blood type
CTEPH vs PAH ( 88% vs. 56%)
 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.

20. SPLENECTOMY AS A RISK FACTOR FOR CTEPH
Prevalence of Splenectomy in CTEPH is significantly
higher than in IPAP and control.
Mean interval from S/p Splenecotmy  CTEPH onset: 16
+_ 9 yrs
Retrospective Chart Review of 257 pt referred for CTEPH
over 10 yrs vs. IPAH vs. other pulm diseases. in CTEPH –
8.6% ( CI 95%, [5.2-12.0%]) had splenectomy vs. 2.5% ( CI
95%, [ 0.7-4.4%]) IPAP and 0.56% ( CI 95%,[0-1.6%]) in
other pulm diseases †
Again most Splenectomy – distal CTEPH, not PEA
candidates.
Jais X, et al Splenectomy and chronic thromboembolic pulmonary hypertension. Thorax
2005;60:1031–1034

21. Pathophysiology
Small vessel arteriopathy-
- medial hypertrophy
- intimal proliferation
- microvascular thrombosis
- plexiform lesion formation
 Persistent macrovascular obstruction
 Vasoconstriction
 Neurohumoral factors
-endothelin 1- potent vasoconstrictiors/triggers of
microvascular changes.
(Reesink HJ et al,Circ J 2005;70:1058-63)

24. Progression of CTEPH
Acute or recurrent PTE in pulmonary arteries
Organisation these thrombi
Occurence in situ thrombus due to slow blood flow in obstructed pulmonary arteries
Occurence of arteritis in non obstructed small distal pulmonary
arteries(remodelling)
Increased PVR, pulmonary hypertension
CTEPH

25. Histopathological paradox
Tissues/vessels distal to occluded segment- normal
Distal vessel distal to patent pulmonary arterial
segments- small vessel abnormalities
Arrows – not perfused due obstruction
by clots. ( normal vessels downstream)
RUL get all the flow of R lung –
remodeling on Bx
Moser,Braunwald et al,Chest 1973;64:29-
35

26. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Clinical presentation -
 The diagnosis of CTEPH is usually not made until the degree of
pulmonary hypertension is advanced
 A patient may carry on relatively normal activities following a
pulmonary embolic event, whether clinically apparent or occult,
even when extensive pulmonary vascular occlusion has occurred
(asymptomatic –honeymoon – period)
Fedullo PF et al.N Engl J Med 2001

27. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Clinical presentation -
 Patients who have CTEPH typically complain of exertional
dyspnea and a gradual decrease in exercise tolerance over
months to years
 Diagnostic delay :
 Nonspesific nature of symptoms
 Absence of a history of prior acute symptomatic venous
thromboembolism (DVT / PE)
 The average delay from the onset of cardiopulmonary symptoms
to establisment of the correct diagnosis can range from 2 to 3
years
Fedullo PF et al.Semin Resp Crit Care Med 2003
Auger WR et al. Clin Chest Med 2007

28. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Clinical presentation -
Progressive dyspnea and exercise intolerance due to CTEPH are often
erroneously attributed to ;
 coronary artery disease
 cardiomyopathy
 congestive heart failure
 interstitial lung disease
 COPD (mild)
 asthma
 physical deconditioning
 psychogenic dyspnea
Prior to consideration of a pulmonary vascular problem as a basis for
their complaints, many patients with CTEPH have undergone ;
 left-sided cardiac catheterizations (one or more )
 coronary angiograms
 lung biopsy.
 enrolling in an exercise program
 seeking psychiatric help.
Fedullo PF et al.N Engl J Med 2001
Auger WR et al. Clin Chest Med 2007

29. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Clinical presentation
Symptoms
 Progressive dyspnea
 Nonproductive cough (especially with exertion)
 Hemoptysis
 Palpitations
 A change voice quality or hoarseness
 Exertional chest pain
 Near-syncope or syncope
 Lower extremity edema
Fedullo PF et al.Semin Resp Crit Care Med 2003
Auger WR et al. Clin Chest Med 2007

30. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Clinical presentation
Physical examination -
May be subtle early in the course of the illness.
In time obvious findings develop, which may include :
 Right ventricular lift
 Jugular venous distension
 Prominent A and V wave venous pulsations
 Fixed splitting of S2 with an accentuated pulmonic component
 A right ventricular S4 gallop
 A tricuspid regurgitation murmur
 Hepatomegaly
 Ascites
 Peripheral edema, which may be a result of either chronic lower
extremity venous outflow obstruction or right ventricular failure.
Fedullo PF et al.N Engl J Med 2001
Auger WR et al. Clin Chest Med 2007

31. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Clinical presentation
Physical examination -
The presence of flow murmurs over the lung fields(30 percent of
patients).
 turbulent flow through partially obstructed or recanalized pulmonary
arteries
 high pitched and blowing in quality
 heard over the lung fields rather than the precordium, accentuated during
inspiration
 frequently heard only during periods of breath-holding
 they have not been described in primary pulmonary hypertension, which
represents the most common competing diagnostic possibility
Fedullo PF et al.N Engl J Med 2001
Auger WR et al. Clin Chest Med 2007

32. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Diagnosis
Pulmonary function tests
 Useful for excluding coexisting parenchymal lung disease or airflow
obstruction
 Often within normal limits
 The majority of patients with CTEPH have a reduction in the single breath
diffusing capacity for carbon monoxide (DLCO); a normal value, however, does
not exclude the diagnosis
 Approximately 20 percent of patients demonstrate a mild to moderate
restrictive defect
 A mild obstructive defect may be present as a result of mucosal hyperemia,
which is related to development of a large bronchial arterial collateral
circulation
Steenhuis KS. Et al. Eur Respir J 2000
Auger WR et al. Clin Chest Med 2007

33. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Diagnosis
Blood gas analysis
 Resting arterial PO2 may be within normal limits
 Hypoxemia at rest implies very severe right ventricular disfunction or the
presence of a right -to- left shunt, as through a patent foramen ovale
 Majority of patients have a decline in the arterial PO2 with exercise
 The alveolar-arterial oxygen gradient is typically widened
 Dead space ventilation (VD/VT) is often increased at rest and worsens with
exercise
 Minute ventilation is typically elevated as a result of the increased dead space
ventilation.
Fedullo PF et al. N Engl J Med 2001
Auger WR et al. Clin Chest Med 2007

34. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Diagnosis
Chest radiography
 Often normal
 Enlargement of both main
pulmonary arteries or asymmetry
in the size of the central
pulmonary arteries
 Areas of hypoperfusion or
hyperperfusion
 Evidence of old pleural disease,
unilaterally or bilaterally
 Right atrial or right ventricular
enlargement, based on the outline
of the right cardiac border
( especially on the lateral film by
encroachment on the normally
empty retrosternal space)
 Cardiomegaly
Eur Radiol 2007;17:11-21

35. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Diagnosis
Electrocardiography (ECG)
 Right axis deviation
 Right ventricular hypertrophy
 Right atrial enlargement
 Right bundle – branch block
 ST segment displacement
 T- wave inversions in anterior precordial and inferior limb leads
Auger WR et al. Clin Chest Med 2007

36. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Diagnosis
Echocardiography
 Enlargement and reduced systolic
function of the right ventricle are
usually apparent,
 Leftward septal displacement can
impair left ventricular filling and
performance
 ECHO is useful for the excluding;
 Left ventricular dysfunction
 Valvular disease
 Cardiac malformations
 Sensitive but not specific
Menzel T et al. Chest 2000
Auger WR et al. Clin Chest Med 2007

37. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Diagnosis
Radioisotopic V / Q scanning –
 In chronic thromboembolic disease, at least one (and more
commonly, several) segmental or larger mismatched ventilation-
perfusion defects are present but not spesific for this condition
 In idiopathic pulmonary arterial hypertension (IPAH) , perfusion
scans are either normal or exhibit a "mottled" appearance
characterized by subsegmental defects
 V- scannig of the lungs is almost always normal
J Nuclear Med 2007;48:680-4

38. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Diagnosis
Radioisotopic V / Q scanning –
 Conditions indistinguishable from CTEPH in V/Q appearance :
 Extrinsic vascular compression from mediastinal adenopathy or fibrosis
 Primary pulmonary vascular tumors ( ie. Angiosarcoma )
 Pulmonary veno-occlusive disease
 Large-vessel pulmonary arteritis
 Additional imaging studies are needed to define the vascular abnormality
and establish the diagnosis
 Cannot localize the extent of the disease
 Cannot determine surgical accessibility
Hasegawa I et al. AJR 2004
Fedullo PF et al. N Engl J Med 2001

39. (CTEPH)
Diagnosis
Computed tomogaphy (CT)
CT findings in CTEPH :
 Right atrial and ventricular enlargement
 Chronic thromboembolic material within
dilated central pulmonary arteries
 Central pulmonary artery enlargement
 Variations in the size of lobar and
segmental- level vessels
 Mosaic perfusion of the lung parenchyma
 Peripheral, scar- like densities in hypo-
attenued lung regions
 Presence of mediastinal collateral vessels
arising from the systemic arterial
circulation
(Eur J Radiol 2009;71:49-54)

41. Diagnosis
Computed tomogaphy (CT) -
CT imaging is also valuable in :
 Assesment of the lung parenchyma in patients who have
coexisting emphysematous or restrictive lung disease
 Detection mediastinal pathology that might account for
occlusion of the central pulmonary arteries

42. CTA
CT angiography efficacy graeter in the main & lobar
pulmonary arteries
CTA efficacy decreases in the segmental &
subsegmental vessels.
(Eur Radiol 2009;71:49-54)

43. M R Angiography
Limited sensitivity
No extra advantage over CTA
(Ann Med Intern2010;1 52:434-43)

44. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Diagnosis
Pulmonary angiography
 Pouch defects
 Pulmonary artery webs or
bands
 Intimal irregularities
 Abrupt narrowing of the major
pulmonary arteries
 Obstruction of lobar or
segmental vessels at their
point of origin, with complete
absence of blood flow to
pulmonary segments normally
perfused by those vessels
Fedullo PF et al. N Engl J Med 2001

45. Chronic thromboembolic pulmonary hypertension
(CTEPH)
Diagnosis
Cardiac catheterization
 Defines the severity of the pulmonary hypertension and degree of
cardiac dysfunction
 Biplane imaging provides optimal anatomical detail
 When dilated and overlapping vessels are present, the lateral view
provides more detailed images of lobar and segmental anatomy than
those obtained with an anterior–posterior view alone
Fedullo PF et al. N Engl J Med 2001
Auger WR et al. Clin Chest Med 2007

46. (CTEPH)
Diagnosis
Pulmonary angioscopy
A diagnostic fiberoptic device, was developed specifically for preoperative
evaluation.
The angioscopic features of organized, chronic emboli :
 Roughening or pitting of the intimal surface,
 Bands and webs traversing the vascular lumen,
 Pitted masses of chronic embolic material within the lumen,
 Partial recanalization.
 Intimal plaques are a nonspecific finding in pulmonary hypertension
of any cause.
 Angioscopy is performed in approximately 30 percent of patients undergoing
evaluation for thromboendarterectomy
Fedullo PF et al. N Engl J Med 2001

47. (NEJM Jan 27,2011 Page351-360)

48. Proposed algorithm for the diagnostic approach to patients with CTEPH. Ventilation-perfusion
scanning is the recommended screening procedure because a normal perfusion scan virtually rules
out CTEPH. When perfusion scans show indeterminate results...
Hoeper M M et al. Circulation 2006;113:2011-2020
Copyright © American Heart Association

49. Treatment of CTEPH

50. Proposed Treatment approach
Hoeper M et al, Chronic Thromboembolic Pulmonary
Hypertension, Circulation 2006; 113; 2011 - 2020

51. Pulmonary thromboendarterectomy
 The most effective therapy –
- Pulmonary thromboendarterectomy.
(J Am Coll Cardiol 2009;54:Suppl:S67-S77.)
 Improvement in hemodynamics after pulmonary thrombo-endarterectomy
causes
- Reverse right ventricular remodeling
 The beneficial effect usually persists, unless small-vessel arteriopathy or
recurrent pulmonary embolism develops.
(Long-term outcome after pulmonary endarterectomy. Am
J Respir Crit Care Med 2008;178:419-24.)

52. Pulmonary thromboendarterectomy is considered
in symptomatic patients who have hemodynamic
or ventilatory impairment at rest or with exercise.
The mean pulmonary vascular resistance in
patients undergoing surgery is 800 to 1000
dyn·sec·cm.
Thromboendarterectomy is also considered in
patients who have normal or nearly normal
pulmonary hemodynamics at rest but in whom
marked pulmonary hypertension develops during
exercise.

53. Pulmonary endarterectomy is performed during
circulatory arrest, removing obstructive material from
each pulmonary artery, and its lobar and segmental
branches, (20–30 branches in total), and is the only
way to reduce pulmonary vascular resistance by at
least 50%.
The operation is performed entirely through a
median sternotomy and through the pericardium
without having to open the pleura or to dissect the
pulmonary artery outside the pericardium.
Circulation. 2006;113:2011-2020

54. It is interesting to note that the mortality rate from this
operation is closely related to the haemodynamic severity.
For pulmonary resistance 900 dynes/s/cm-5, the mortality
rate was 4%, and increased to 10% in patients with
resistance between 900–1,200 dynes/s/cm-5, and to 20%
for higher resistance.
For the last 40 patients of the series,the authors excluded
operating on patients with the very distal form of
thomboembolism associated with severe haemodynamic
alterations, and the mortality rate dropped to 5%.
Circulation. 2006;113:2011-2020

55. Obstructed lumen
Patent lumen
Aspirating>
dissector
Thromboembolic
material being removed
with forceps Circulation. 2006;113:2011-2020

58. The only absolute contraindication to
thromboendarterectomy is the presence of severe
underlying lung disease, either obstructive or
restrictive
Advanced age, severe right ventricular failure,
and the presence of collateral disease influence
the risk assessment but are not absolute
contraindications.
Placement of a filter in the inferior vena cava is
recommended before surgery in all pts except
those with a clearly defined source of emboli
other than the deep veins in the legs.

59.  Preoperative predictors of favorable outcomes include
1- A pulmonary vascular resistance of less than 1200 dyn • sec •
cm−5
2- The absence of major coexisting conditions.
 Patients in whom the postoperative pulmonary vascular resistance
decreases by at least 50%, to a value of less than 500 dyn • sec • cm−5,
have a more favorable.
(Circulation 2007;115:2153-8.)

60. Pulmonary Endarterectomy
Chance of cure in proximal obstruction driven Pulmonary
Hypertension only
Surgical classification
Group1: 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 ds.
Group 1 & 2 - most favorable outcome.
(J Thorac Cardiovasc Surg 2007;133:58-
64.)

61. Early diagnosis and PEA early can decrease
small vessel contribution to PVR i.e and
make a patient better PEA candidate
Medical bridge to PEA with vasodilators in
pts. with high Pre –Op PVR who otherwise
are good PEA candidate .

62. Proposed way to determine if PEA will lower PVR
Rt heart cath with Pulm. Artery Occlusion
technique:
- based on assumption of decay PAOP
waveform.
- PVR may be partitioned to large arterial
( upstream) and small arterial + venous
( downstream).

63. 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)

64. N Eng J Med,2011, V ol 345, No 20

65. The 30-day mortality ranges from less than 5% in the
most experienced centers to 10% in general.
The two most common anticipated postoperative
sequelae are –
1-The pulmonary-artery steal syndrome
2-Reperfusion pulmonary edema
(J Thorac Cardiovasc Surg 2007;133:58-64.)

66. EXPERIENCE AND RESULTS WITH PULMONARY THROMBOENDARTERECTOMY-A SINGLE INSTITUTION
EXPERIENCE IN
THE INDIAN SUBCONTINENT
Chattuparambil B, Shetty D P, Cherian G, Murali Mohan BV, Karthik GA, Punnen J
Narayana Hrudayalaya Institute of Cardiac Sciences, No. 258/A, Bommasandra Industrial
Area, Anekal Taluk, Bangalore, India .PIN-560099
Between June 2004 and December 2010 209 patients
referred to our institute with CTEPH underwent
Pulmonary Thrombo Endarterectomy. The diagnosis
was based on 64-slice CT Pulmonary Angiography.
The data was analysed retrospectively.

67. RESULTS
209 patients in the 15-69 year age group underwent PTE between June 2004 and
December 2010. The male: female ratio was 1.5:1.2 ,5 patients had CTEPH, 4 had acute
pulmonary embolism with unstable hemodynamics and failure of thrombolysis. Two
patients underwent redo PTE. 154 cases were isolated PTE while 55 were combined
procedures. 47.8% (100/209) had proven deep venous thrombosis .The overall mortality
for the procedure was 12.9% (27/209). The causes of mortality were persistent pulmonary
arterial hypertension in 66.6% (18/27), reperfusion edema in 22.2 % (6/27) and
mechanical injury in 11.1%(3/27).The pulmonary arterial pressure regressed to <40 mm
Hg in 71.7% (150/209) .The mean duration of ICU stay was 6 days (3-50).The mean
duration of ventilatory support was 3.3 days (1-19).15 patients required Extracorporeal
Membrane Oxygenation (ECMO) support for varied reasons. Of these, there were two
survivors. The mean duration of hospital stay was 13 days (9-60). Two patients died out
of hospital, one of recurrent pulmonary embolism following discontinuation of
anticoagulation and one of persistent pulmonary arterial hypertension.180 patients are
still on regular follow up, and 30 of them have persistent pulmonary hypertension with
NYHA class I-III symptoms. The rest are doing extremely well with good quality of life.

68. Balloon Pulmonary-Artery Angioplasty
 Balloon pulmonary-artery angioplasty is an alternative therapy in
selected patients who have inoperable disease due to distal surgically
inaccessible disease or persistent or recurrent pulmonary
hypertension after thromboendarterectomy.
 Successful balloon pulmonary angioplasty may reduce pulmonary-
artery pressure in patients with chronic thromboembolic pulmonary
hypertension
 However, experience with this procedure is very limited, and it is
rarely performed
Masaharu Kataoka, MD
CIRCINTERVENTIONS.112.971390 Published online before print November 6, 2012

69. Balloon Pulmonary Angioplasty for Treatment of Chronic Thromboembolic Pulmonary Hypertension
Jeffrey A. Feinstein, MD, MPH; Samuel Z. Goldhaber, MD; James E. Lock, MD;Susan M. Ferndandes, PA-C; Michael
JLandzberg, MD
Background—Although pulmonary thromboendarterectomy is increasingly successful for the definitive
treatment of chronic thromboembolic pulmonary hypertension (CTEPH), not all patients have surgically accessible
disease. Others are poor surgical candidates because of comorbid illness. Therefore, for selected patients, we defined
and implemented an alternative interventional strategy of balloon pulmonary angioplasty (BPA).
Methods and Results—Eighteen patients (mean age, 51.8 years; range, 14 to 75 years) with CTEPH underwent
BPA; they averaged 2.6 procedures (range, 1 to 5) and 6 dilations (range, 1 to 12). Selection of pulmonary artery
segments for
dilation required (1) complete occlusion, (2) filling defects, or (3) signs of intravascular webs. After an average of 36
months of follow-up (range, 0.5 to 66 months), the average New York Heart Association class improved from 3.3 to
1.8 (P,0.001), and 6-minute walking distances increased from 209 to 497 yards (P,0.0001). Pulmonary artery mean
pressures decreased from 43.0612.1 to 33.7610.2 mm Hg (P50.007). Eleven patients developed reperfusion
pulmonary edema; 3 required mechanical ventilation.
Conclusions—BPA reduces pulmonary artery hypertension in patients with CTEPH and is associated with long-
term improvement in New York Heart Association class and 6-minute walking distances. BPA is a promising
interventional technique that warrants randomized comparison with medical therapy in CTEPH patients who are not
surgical candidates. (Circulation. 2001;103:10-13.)
Key Words: balloon n angioplasty n embolism n thrombus n pulmonary heart disease

70. Pulmonary transplantation
 The lungs, in contrast to other transplantable organs, are in contact
with the external milieu through the tracheobronchial tree and are at
risk of pneumonia during donor resuscitation.
 Recipient selection criteria
1. age <55 yrs;
2. absence of mechanical respiratory insufficiency due to scoliosis;
3. absence of phrenic paralysis
4. absence of recent neoplastic disease or other potentially life-
threatening diseases.

71. Indications for transplant
 Patients with a life expectancy of <1 yr,consistent with a functional
status of NYHA stage III orIV.
 Recent worsening of dyspnoea and haemodynamic parameters, such
as a right atrial pressure of >12 mmHg, pulmonary arterial pressure
>60 mmHg, a cardiac index <2.2 L/min-1/m-2 or indexed pulmonary
resistance >30 U

72. Lung transplant for CTEPH
Heart and lung, b/l lungs, single lung
Heart lung best  less bronchial ischemia, heart
already adapted to pulm. Circulation
An advantage of bilateral lung transplantation is
that the donor heart can be transplanted into
another recipient awaiting heart transplantation
alone
True to all: life long immune supression,
rejections ( acute, chronic), susceptibility to viral,
fungal infections) Eur Respir J 2004; 23: 637–648.

73. In the series of 101 pulmonary transplants performed
for pulmonary hypertension at the Marie-
Lannelongue Hospital between 1986–2002, 18 were for
CTEPH. There were 70 heart-lung, 28 bilateral and
only three single lung transplants. The perioperative
mortality was y20% and was not significantly different
between the operation performed
Eur Respir J 2004; 23: 637–648.

74. Eur Respir J 2004; 23: 637–648.

75. Medical Therapy
Anticoagulation is prescribed in most patients with
chronic thromboembolic pulmonary hypertension.
Among patients with unprovoked or idiopathic
pulmonary embolism, an indefinite duration of
anticoagulation has reduced the risk of recurrent
venous thromboembolism & CTEPH.
(Comparison of low-intensity warfarin therapy with conventional-intensity
warfarin therapy for long-term prevention of recurrent venous
thromboembolism. N Engl J Med 2003;349:631-9.)

76. About 50% CTEPH rejected for PEA
Pt. w/ high PVR mainly d/t small vessels – poor surgical candidates.
 Traditional therapies:
 Anticoagulants, diuretics, digitalis, oxygen
Agreement on Anticoagulation to in situ thrombosis ( goal INR 2-3)
 Diuretics for volume overload in R CHF.
 Novel Therapies
 Prostacyclin analogues,
 Endothelin receptor blocker
 PDE 5 inhibitor

77.  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.
 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

78. Prostacyclin agonist
Powerfull systemic & pulmonary vasodilator
Platelet aggregation inhibitor
Antiproliferative
Cytoprotective
Fibrinolytic

79. Epoprostenol-
- short half life of 3 min
- continuous iv infusion through tunnelized catheter
- started at 1ng/kg/min & gradually increased toby 1 ng/kg/min every
12 hr upto 10 ng/kg/min
- side effects are jaw pain,headache,diarrheas,flushes,lower limb
pain,nausea,vomitting
(Robbins et al 1998,chest 114:1269-1275)

80.  Treprostinil
- S/C administration
- 22.5 ng/kg/min
(Results based on TRIUMPH study)
ILLOPROST
- By inhalation
- six to nine inhalation a day for at least 30 min
- Iloprost is given by 2.5- or 5.0-µg ampules via a dedicated
nebulizer (Olschewski et al ,2002)
Beraprost
- oral
- significant improvement on the 6 MWD in IPAH in double
blind study conducted by Galie et al .2002,NEJM 353:2148-2157.

81. Epoprostenol
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:
595 - 600

82. Endothelin receptors antagonist
 Powerful vasoconstrictor(ET-A receptors)
 Promoter of smooth muscle cell proliferation(ET-B receptors)
 Dual ET-1 receptors antagonist
Bosentan-(2008 International PHA Conference and Scientific Sessions)
- side effects systemic vasodilation and hepatic dysfunction
- The approved dosage of bosentan is 125 mg twice daily
Selective ET-A receptor antagonists-
Sitaxsentan – 100mg daily dose
- 65 m increase in 6MWD (Barst et al.2002)
- once daily at a 100 mg dose
Ambrisentan- once daily at a 5-mg dose
Eur Respir J 2012; 20: 203 - 400

83. PDE 5 inhibitiors
Sildenafil (The recommended dosage is 20 mg three times daily, but
dosages as high as 80 mg three times daily have been used safely )
Tadalafil (The effective dose was 40 mg once daily.)
Vardenafil
Stabilizes c GMP and NO; potent pulmonary
vasodilator.
J Heart Lung Transplant. 2010 Jun;29(6):610-5
(Chronic thromboembolic and pulmonary arterial hypertension share acute
vasoreactivity properties. Chest 2006;130:841-6.)

84. 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: 1139 - 1141

85. Calcium channel blockers
- vasodilator
- Nifedipine 90-240 mg/day or dilitiazem 360-900
mg/day
- effective in pts having positive response to acute
testing with vasodilators
- only 12.6% of pts could be treated by CCB
(Based on studies by Rich et al & Sitbon et al study on 557
pts in 1998 published in Eur Respir J 2:265-270)

86. Role of IVC filters 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.*
 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 : 1770 - 1776

87. Potential future therapies
Tyrosine kinase inhibitors
- PDGF inhibitors
- causes regression of pulmonary vascular remodelling
Rho Kinase inhibitors
- causes vasodilation & prevents vascular remodeling
- Fasudil
( Fagan et al 2010,Am J Physiol Lung Cell Mol Physiol 287:L 656-664)
Statins-
- enhances bone morphogenetic receptor II ( BMPR-II)
( Hu et al 2006,Biochem Biophys Res Commun 339:59-64)
Vasoactive Intestinal Peptide-
- potent bronchodilator
- systemic & pulmonary vasodilator
- via inhalation
(Said et al 2007,circulation 115:1260-1268)

88. SSRI
- Protective effects on occurrence of PAH in
animal model
Adrenomedullin-
- vasodilator peptide
- smooth muscle cell proliferator inhibitor
- iv/inhalation
( Nagaya et al 2004,circulation 109:351-356)

89. Guanylate cyclase (sGC) stimulator
Data from the Phase 3 CHEST-1 trial (Chronic
Thromboembolic Pulmonary Hypertension sGC-
Stimulator Trial)
261 patients were randomized and treated with either
riociguat or placebo
Riociguat also showed statistically significant
improvements in select secondary endpoints, including
pulmonary vascular resistance (PVR) (P<0.0001), N-
terminal prohormone brain natriuretic peptide (NT-
proBNP) (P<0.0001) and WHO functional class (FC)
(P=0.0026).

90. Recommendations for chronic
thromboembolic pulmonary hypertension
Statement Class Level
The diagnosis of CTEPH is based on the presence I C
of pre-capillary PH (mean PAP 25 mmHg,
PWP 15 mmHg, PVR .2 Wood units) in
patients with multiple chronic/organized
occlusive thrombi/emboli in the elastic
pulmonary arteries (main, lobar, segmental,
subsegmental)
In patients with CTEPH lifelong anticoagulation is I C
indicated
Surgical pulmonary endarterectomy is the I C
recommended treatment for patients with
CTEPH
European Heart Journal (2009) 30, 2493–
2537

91. Statement Class Level
Once perfusion scanning and/or CT angiography IIa C
show signs compatible with CTEPH, the patient
should be referred to a centre with expertise in
surgical pulmonary endarterectomy
The selection of patients for surgery should be IIa C
based on the extent and location of the
organized thrombi, on the degree of PH, and on
the presence of co-morbidities
PAH-specific drug therapy may be indicated in IIb C
selected CTEPH patients such as patients not
candidates for surgery or patients with residual
PH after pulmonary endarterectomy
European Heart Journal (2009) 30, 2493–
2537

92. In patients with operable CTEPH, PTE is the
treatment of choice for improved hemodynamics
functional status, and survival. Level of evidence:
low; benefit: substantial; grade of recommendation: B.
In patients with CTEPH deemed inoperable or
with significant residual postoperative PH,
balloon dilation, PAH medical therapy, or LT may
be considered. Level of evidence: low; benefit:
small/weak; grade of recommendation: C.
Pulmonary Arterial Hypertension: ACCP
Guidelines 2007

93. Indian perspective
First heart-lung transplant in India in 1999 in Madras
medical mission
 2 more patients underwent transplant after
that
initial experience is encouraging

94. Apixaban for Extended Treatment of Venous
Thromboembolism
Background
Apixaban, an oral factor Xa inhibitor that can be
administered in a simple, fixed-dose regimen, may be an
option for the extended treatment of venous
thromboembolism.
Methods
Patients with venous thromboembolism who had
completed 6-12 months of anticoagulation therapy were
randomized to apixaban 2.5 mg twice daily (n = 840),
apixaban 5 mg twice daily (n = 813), versus placebo twice
daily (n = 829). Study drugs were administered for 12
months.
N Engl J Med 2012;Dec 8

95. Interpretation:
Among patients with venous thromboembolism who
had completed 6-12 months of anticoagulation
therapy, extended therapy with apixaban (2.5 mg or 5
mg twice daily) reduced symptomatic recurrent
venous thromboembolism or death. Clinical benefit
was accomplished without an increase in major
bleeding; however, clinically relevant nonmajor
bleeding was increased with apixaban 5 mg compared
with placebo
N Engl J Med 2012;Dec 8

96. ASPIRE
Trial design: Patients who had a first episode of unprovoked venous thromboembolism
and completed initial anticoagulation therapy were randomized to aspirin 100 mg daily (n =
411) vs. placebo daily (n = 411).
Results
(p = 0.09)  Recurrent venous thromboembolism at 37
months: 14% with aspirin vs. 18% with placebo
18 (p = 0.09)
 The following events are reported per year for
% 14 aspirin vs. placebo:
 Major vascular event: 5.2% vs. 8.0% (p = 0.01)
 Major bleeding and clinically relevant
nonmajor bleeding: 1.1% vs. 0.6% (p = 0.22)
 Major vascular event, major bleeding, or all-
cause mortality: 6.0% vs. 9.0% (p = 0.01)
Conclusions
• Among patients with unprovoked first venous
thromboembolism who completed initial
anticoagulation therapy, the use of aspirin failed
Aspirin Placebo to reduce the primary outcome of recurrent
venous thromboembolism
Brighton TA, et al. N Engl J Med 2012;Nov
4:[Epub]

97. Conclusions
 Chronic thromboembolic pulmonary hypertension (CTEPH) is
an important complication of acute VTE
 The average delay from the onset of symptoms to establisment
of the correct diagnosis can range from 2 to 3 years
 2D ECHO is an early & important laboratory method to
determine the severity of the disease
 V/Q sscannig gives considerable clues in the diagnosing of
CTEPH
 Right- heart catheterization should be considered in any patient
with unexplained dyspnea and segmental or larger defects on
V/Q perfusion scanning, especially if there is echocardiographic
evidence of right atrial or right ventricular dysfunction