Chronic thromboembolic pulmonary hypertension (CTEPH)

Chronic thromboembolic
pulmonary hypertension
Presenter: Praveen Gupta
Moderator: Dr Joseph
JIPMER
Pondicherry
India

Introduction
 CTEPH caused by chronic obstruction of major pulmonary arteries
 Amenable to cure by pulmonary endarterectomy (PEA)
 ≈5 individuals per million per year (Orphan disease)
 Cumulative incidence, 0.1% and 9.1% after symptomatic PE
 Routine screening after acute PE not recommended
 Most common subsets of precapillary PH
 Underdiagnosis
 common delay or lack of referral to expert centers for surgery
Hoeper MM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Circulation. 2006 Apr 25.

Definition
 Precapillary PH by invasive right heart catheterization (mean pulmonary artery pressure
≥25 mm Hg, mean pulmonary arterial wedge pressure ≤15 mm Hg)
 Presence of chronic/organized flow-limiting thrombi in the elastic pulmonary arteries
(main, lobar, segmental, subsegmental)
 After at least 3 months of effective anticoagulation.

Thrombophilia and CTEPH
 Antithrombin deficiency
 Protein C deficiency
 Protein S deficiency
 Factor V Leiden
 Plasminogen deficiency
 Anticardiolipin antibodies
 Blood group types A, B, and AB
 Non-O blood group carriers also have higher levels of von Willebrand factor and factor VIII
 Elevated plasma levels of lipoprotein(a)

Dartevelle P, Fadel E, Mussot S, Chapelier A, Herve P, De Perrot M, Cerrina J, Ladurie FL, Lehouerou D, Humbert M, Sitbon O. Chronic
thromboembolic pulmonary hypertension. European Respiratory Journal. 2004 Apr 1;23(4):637-48.

Suntharalingam J, Morrell NW. Pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH).
InAdvances in Vascular Medicine 2009 (pp. 225-231). Springer, London.

Vascular obstructive lesions in acute pulmonary embolism (A) and chronic thromboembolic pulmonary hypertension (CTEPH; B). The CTEPH
patient underwent bilateral pulmonary endarterectomy; however, only the right-side specimen is shown. Images courtesy of Dr. Joyce Johnson (A)
and Tarek Absi (B)
Matthews DT, Hemnes AR. Current concepts in the pathogenesis of chronic thromboembolic pulmonary hypertension.
Pulmonary circulation. 2016 Jun;6(2):145-54.

Microvasculopathy in chronic thromboembolic pulmonary hypertension involving pulmonary arterioles, venules and capillaries. Schematic representation of
anastomosis between systemic and pulmonary circulation through hypertrophic bronchial arteries and vasa vasorum. PA: pulmonary artery; PVOD: pulmonary
veno-occlusive disease; PAH: pulmonary arterial hypertension. Reproduced and modified from [67] with permission.
Simonneau G, Torbicki A, Dorfmüller P, Kim N. The pathophysiology of chronic thromboembolic pulmonary hypertension. European
Respiratory Review. 2017 Mar 31;26(143):160112.

Pulmonary endarterectomy specimens stained with hematoxylin and eosin. A, Neointimal thickening, 18×; B, region of fibrotic chronic
thromboembolic pulmonary hypertension clot containing extracellular matrix and spindle-shaped cells, 290×; C, fresh red clot within an area of
organized clot, 100×; D, obstructing lesion with areas of recanalization, 170×.
Matthews DT, Hemnes AR. Current concepts in the pathogenesis of chronic thromboembolic pulmonary hypertension.
Pulmonary circulation. 2016 Jun;6(2):145-54.

Jamieson classification system of pulmonary endarterectomy specimens
Shenoy V, Anton JM, Collard CD, Youngblood SC. Pulmonary thromboendarterectomy for chronic thromboembolic pulmonary
hypertension. Anesthesiology: The Journal of the American Society of Anesthesiologists. 2014 May 1;120(5):1255-61.

Clinical Characteristics
 Median age is 63 years, and surgical cases are younger (57 years)
 Rare in children
 In Europe, both sexes are equally affected, whereas women in Japan
 Nonspecific or absent in early stage
 Right heart failure in advanced disease stages
 Early diagnosis is difficult
 Median time of 14 months between symptom onset and diagnosis

Clinical Characteristics
 Episodic disease course in CTEPH
 Symptomatic thromboembolic event, followed by honeymoon period
 Hemoptysis more frequently with idiopathic PAH
 Differentiate CTEPH from PAH
 Comparative survival in CTEPH has been reported to be twice that of PAH

Diagnostic Procedures
 Unexplained PH should be subjected to a CTEPH evaluation
 Suspicion should be high with history of previous VTE
 PE survivors with persistent dyspnea

ECG
 P-pulmonale
 Right bundle branch block
 T-wave abnormalities
 RAD

Echocardiography
 Recommend first diagnostic step
 Estimating peak velocity of tricuspid valve regurgitation
 Atrioventricular pressure gradients
 Right atrial dilatation
 Right ventricular dilatation
 Reduced right ventricular contractility
 Doppler flow abnormalities in the right ventricular outflow tract
 Can miss pulmonary hypertension in as many as 10–31% of cases

Cardiopulmonary exercise testing
 Hyperventilation

Ventilation/perfusion scintigraphy
 Imaging modality of choice for exclusion of CTEPH
 Ventilation/perfusion scan planar images on at least 6 views combined with single-photon
emission CT remain the preferred initial diagnostic test for CTEPH
 Normal V/Q scan excludes CTEPH with sensitivity of 90–100% and specificity of 94–100%

Tanabe N, Sugiura T, Tatsumi K. Recent progress in the diagnosis and management of chronic thromboembolic pulmonary
hypertension. Respiratory investigation. 2013 Sep 1;51(3):134-46.

Diagnosis of CTEPH
 Subsequent investigations aim to define the nature and extent of thromboembolic disease
 To assess surgical suitability.
 Pulmonary angiography, MRI angiography and CTPA

CT pulmonary angiography
 Sensitivity of 51% compared with >96% sensitivity of V/Q scan
 Absence or sudden loss of contrast filled vessels,
 Best appreciated by following individual vessels while scrolling sequential slices.
 Filling defects are not commonly seen.
 If filling defects are present, they occur eccentrically within the vessel lumen
 In acute pulmonary embolism CTPA typically shows central filling defects

CT pulmonary angiography
 Diagnosis missed unless the radiologist is specifically asked to look
 Pulmonary artery webs and bands, wall irregularities, stenoses, and, as well as
bronchial collaterals
 Identify LMCA compression
 Identifies emphysema, bronchial disease, and mediastinal or interstitial lung
disease, as well as infarcts, vascular and pericardial malformations, and thoracic
wall deformities
 Perfusion inequalities manifest as a mosaic parenchymal pattern with dark areas
corresponding to relatively decreased perfusion.

 MRI is inferior to CT
 Intravascular imaging, with ultrasound and optical coherence tomography providing
new insights into the vascular obstructions of CTEPH

Pulmonary angiography
 Definitive for the diagnosis and assessment of surgically correctable CTEPH
 Safe, even with severe pulmonary hypertension.
 Findings include vascular webs ,abrupt vascular cut‐offs
 Filling defects per se are less common
 Anteroposterior and lateral views taken to define the extent of disease

Pulmonary endarterectomy cast and corresponding pulmonary angiogram
McNeil K, Dunning J. Chronic thromboembolic pulmonary hypertension (CTEPH). Heart. 2007 Sep 1;93(9):1152-8.

Patient with inoperable chronic thromboembolic pulmonary hypertension showing a typical aspect of subpleural hypoperfusion at the capillary phase of pulmonary
angiography. Image kindly provided by P. Dartevelle, French National Reference Centre of Pulmonary Hypertension, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
Simonneau G, Torbicki A, Dorfmüller P, Kim N. The pathophysiology of chronic thromboembolic pulmonary hypertension. European Respiratory Review. 2017 Mar 31;26(143):160112.

Right heart catheterisation
 Mandatory
 Measurement of PAOP to exclude post-capillary PH
 LVEDP by left ventricular catheterisation
 Measure cardiac output , because PVR assess prognosis and the risks associated with PEA
 Early stages patients to have a near‐normal resting mPAP, with significant pulmonary
hypertension manifesting only with exercise

 DSA remains the gold standard for assessment of pulmonary revascularization
 Combination of imaging with the indispensable hemodynamic assessment
 Ring-like stenosis, pouches, webs, occlusions, and distal lesions
 Distribution of disease (ie, subpleural perfusion) have been associated with
postoperative outcome

Completed diagnostic pathways of chronic thromboembolic pulmonary hypertension imaging and their therapeutic consequences, according to the algorithm shown in Figure
3, illustrating an operable and a nonoperable patient case. Examples of technetium-99 m–labeled aerosol ventilation (A) and perfusion (B) images are shown, labeled as high
probability under Prospective Investigation of Pulmonary Embolism Diagnosis criteria. High-resolution computed tomographies (C) and spiral computed tomographic
angiographies (D), as well as side-selective pulmonary angiographies in the anteroposterior right (E), left (G), and lateral projections (F and H), are shown. Patient 1
in A1 through I1 is a 69-year-old man with past medical history of deep vein thrombosis and acute pulmonary embolism. He underwent pulmonary endarterectomy (specimen
in I1) in addition to coronary artery bypass grafting in the rewarming period. At the time of surgery, type II disease was encountered, with a larger amount of thromboembolic
material than was expected on the basis of the imaging studies, which is commonly the case. He was discharged home 1 week postoperatively with normal right ventricular
function and pulmonary vascular resistance of 70 dyne·s/cm5 compared with 450 dyne·s/cm5 preoperatively. Patient 2 in A2through I2 is 49-year-old woman with history of
progressive shortness of breath on exertion for many years. After initiation of pulmonary arterial hypertension therapy, right heart catheterization revealed only moderate
pulmonary hypertension and a few distal segmental and subsegmental obstructions. Surgery was not believed to be beneficial for this patient. In contrast to A, there is no
pulmonary endarterectomy specimen in B.

Treatment Algorithm
 PEA is the only curative treatment
 Periprocedural mortality <2% to 5%
 A center adequate expertise :20 PEAs per year with a mortality rate <10%
 Decision should be made by a CTEPH team
 Should not be considered nonoperable if not reviewed by at least 2 independent
experienced PEA surgeons

Principle of PEA
 Endarterectomy must be bilateral
 Approach median sternotomy.
 Identification of the correct dissection
plane
 Perfect visualization is essential by use
of circulatory arrest that is usually
limited to 20 minutes at a time and
supported by cooling to 18°C.
 A complete endarterectomy is essential

PEA
 Tricuspid repair is not performed
 Long term outcomes excellent
 significant improvements in haemodynamics and functional capacity
 Reverse pulmonary vascular remodelling can occur for up to a year post‐PEA
 . Recurrent CTEPH after successful PEA is extremely rare
 Redo PEA is commonly not as successful

Factors determining the outcome of PEA
 Increasing severity of right ventricular dysfunction preoperatively, poorer outcome
 Immediate postoperative PVR <590 dyne·s/cm5 had better long-term outcomes
than PVR ≥590 dyne·s/cm5
 Higher downstream and lower upstream resistance increased risk for persistent PH
and poor outcome after PEA.
 upstream resistance <60% are at highest risk for adverse outcomes after PEA

PEA
 Occurrence of reperfusion lung injury due to loss of endothelial integrity
 Mild (non‐cardiogenic) pulmonary odema to a severe diffuse alveolar damage
 Up to a third of patients will require prolonged (>2 days) ventilatory support
 Responsible for approximately half of the mortality associated with the procedure
 Minimal use of catecholamines
 utilizing low tidal volumes and low peak inspiratory pressures

PEA
 Cerebral injury associated with cardiopulmonary bypass and circulatory arrest.
 Minimal circulatory arrest times
 Reduced morbidity are achieved with increased surgical experience

Lung Transplantation
 Rare intervention
 Transplantation may be considered for young patients who are not candidates for
other treatments

Balloon Pulmonary Angioplasty
 18 nonoperable CTEPH ,subjected to balloon dilatation
 11 patients developed reperfusion pulmonary edema, and 3 mechanical ventilation
 only applicable in cases where discrete stenoses are present in the main or
segmental pulmonary arteries, and is ineffective if significant distal or small vessel
disease existed

Balloon Pulmonary Angioplasty
 Japanese investigators refined BPA by using smaller balloons, balloon inflations per session
to 1 or 2 pulmonary vascular segments, and by use of intravascular imaging
 Pulmonary Edema Predictive Scoring Index reduced the incidence of reperfusion pulmonary
edema to 2%
 BPA gaining attention in elderly and frail, for low-risk palliation

Medical Treatments
 Life-long anticoagulation (INR 2 to 3 )
 IVC filter placement is not mandatory because origin of clot may be other sites
 Riociguat, met the primary end point for nonoperable CTEPH or
persistent/recurrent PH after PEA
 In the CTREPH trial , subcutaneous treprostinil has confirmed improvement in
exercise capacity, hemodynamics, and quality of life at 6 months

Ghofrani HA, D'armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A,
Neuser D. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. New England Journal of Medicine.
2013 Jul 25;369(4):319-29.

Contemporary diagnostic and therapeutic algorithm.

Take home message
 More research to understand the mechanisms of fibrotic vascular remodeling
 Methods to prevent and predict microvascular disease
 Riociguat for nonoperable CTEPH and persistent/recurrent PH after PEA
 BPA has been refined in Japan ,
 A complete bilateral PEA remains the best treatment option

Chronic thromboembolic pulmonary hypertension (CTEPH)

Chronic thromboembolic pulmonary hypertension (CTEPH)

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