Chronic thromboembolic pulmonary hypertension

Relationship between obstruction and pulmonary vascular resistance

The extent of vascular obstruction is a major determinant of the severity of pulmonary hypertension in patients with CTEPH. In most cases, >40% of the pulmonary vascular bed is obstructed. Worsening of pulmonary hypertension may involve recurrent thromboembolism or in situ thrombosis, and remodelling of small distal pulmonary arteries in the nonoccluded areas, similar to that encountered in primary pulmonary hypertension. Several lines of evidence support this hypothesis: 1) a low correlation between the extent of central obstruction and the degree of pulmonary hypertension 9; 2) documented progression of pulmonary hypertension in the absence of recurrence of thromboembolism 9; 3) evidence of redistribution of the pulmonary blood flow after thromboendarterectomy from the nonoccluded to the newly endarterectomised areas as a result of the greater vascular resistance in the nonobstructed vascular bed 10; 4) histopathological evidence of pulmonary vasculopathy with medial hypertrophy, intimal thickening and plexiform lesions 11; and 5) persistent pulmonary hypertension despite satisfactory central thromboendarterectomy in ∼10% of patients. This latter group of patients may represent an overlap syndrome with primary pulmonary arterial hypertension and CTEPH. Interestingly, the current authors recently observed two cases of pulmonary hypertension in two families. The first one was related to CTEPH, and was cured by surgical thromboendarterectomy, whereas the other was due to primary pulmonary arterial hypertension and was successfully treated with prostacyclin infusion (data not shown).

A substantial component of the persistent postoperative pulmonary hypertension may also arise from a distal pulmonary vasculopathy that develops in the occluded pulmonary vascular bed. These alterations have been reproduced in the postobstructive pulmonary vascular bed of animal models by ligation of one pulmonary artery 12. This postobstructive pulmonary vasculopathy includes development of precapillary bronchial-to-pulmonary vascular anastomoses, pulmonary arterial remodelling and abnormal pulmonary artery vascular reactivity with dysfunction of the pulmonary endothelium 13. In these animal models the contralateral lung remains normal. Similarly, recent histopathological studies have suggested that, in the advanced form of CTEPH, the distal vasculopathy affected the obstructed pulmonary vessels more than the nonobstructed vessels 14.

In a piglet model of chronic left pulmonary artery obstruction, the present authors have recently shown progressive improvement of pulmonary vascular resistance after reimplantation of the left pulmonary artery, reflecting the slow regression of the structural and functional alterations that had developed in the pulmonary vascular bed during lung ischaemia (data not shown). Similar progressive long-term improvement in pulmonary vascular resistance has been observed in humans with CTEPH after thromboendarterectomy 15. Thus, long-term improvement in pulmonary vascular resistance after pulmonary thromboendarterectomy may reflect the regression of arteriopathical changes in resistance vessels in both the formerly obstructed and nonobstructed parts of the lung. Lastly, a recent study of patients with the most severe form of CTEPH suggested that chronic prostacyclin administration prior to thromboendarterectomy decreases pulmonary vascular resistance and improves postoperative course 16. The authors speculate that prostacyclin therapy may not only provide benefit by dilating pulmonary vessels but also by inhibiting vascular growth and small vessel remodelling.

Cause of thrombi formations

Pulmonary thromboembolism or in situ thrombosis in CTEPH may be initiated or aggravated by abnormalities in either the clotting cascade, endothelial cells or platelets, all of which interact in the coagulation process. Platelet abnormalities and biochemical features of a procoagulant environment within the pulmonary vasculature support a potential role for thrombosis in initiation of the disease in some patients. In most cases, however, it remains unclear whether thrombosis and platelet dysfunction are a cause or consequence of the disease. Therefore, it is interesting to compare the abnormalities of coagulation seen in patients with primary pulmonary arterial hypertension and CTEPH, to differentiate whether they are causes or consequences of the pulmonary hypertensive process.

Coagulation takes place on the surface of platelets and endothelial cells. The intrinsic and extrinsic coagulation pathways converge with the binding of activated factors X and V to the cell surface endothelium or platelet to form the prothrombinase complex. This enzyme converts circulating prothrombin into thrombin. Thrombin is responsible for the conversion of fibrinogen into fibrin and releasing fibrinopeptide A. Under normal conditions the procoagulant functions of the endothelial cells appear to be expressed to a minimal degree, while their anticoagulant and profibrinolytic properties predominate. Resting endothelium produces a variety of clotting factors, such as von Willebrand factor, tissue factor and factor V, but in inactive form and in small quantities. These cells also possess potential binding sites for additional clotting factors, including factor IX/IXa, factor X, thrombin and possibly fibrinogen, but the system is down-regulated in such a way that intravascular clotting is normally avoided. The prominent anticoagulant mechanisms include inactivation of factors IIa, IXa and Xa by the heparin-antithrombin III system, inactivation of factors Va and VIIa by the thrombomodulin-thrombin-protein C‐protein S system, and inhibition of platelet aggregation by prostacyclin and nitric oxide. The baseline profibrinolytic component includes the elaboration and surface-binding of tissue-plasminogen activator and of plasminogen activator inhibitor type 1. Activation of endothelial cells results in surface expression of tissue factor, down-regulation of the thrombomodulin-thrombin-protein C‐protein S system, down-regulation of the profibrinolytic system and a reduction in the release of nitric oxide and prostacyclin. These events favour the participation of endothelium in procoagulant and antifibrinolytic reactions.

There is biological evidence that intravascular coagulation is a continuous process in patients with all forms of pulmonary arterial hypertension. Indeed, the blood level of fibrinopeptide A, which reflects thrombin activity, is markedly elevated in all patients with pulmonary arterial hypertension 17. Whether these changes are a result of genetic deficiencies of antithrombotic pathways, or dysfunction of endothelial cells and/or platelets secondary to the pulmonary vascular injury, can be questioned.

Echocardiography

Trans-thoracic echocardiography allows diagnosis of pulmonary hypertension and demonstrates the degree of right ventricular distension as well as the compression of the left ventricle. In addition, the pressures in the right atrium and the degree of tricuspid regurgitation are shown, and other cardiac anomalies are excluded. A right to left shunt through a reopening of the foramen ovale is sought during the echocardiogram by intravenous injection of microbubbles in saline (fig. 1⇓).

Pulmonary perfusion scan

A pulmonary perfusion scan is shown in figure 2⇓. Lung perfusion scans reveal segmental, large and usually bilateral defects, whereas the ventilation scan is mostly homogenous. It is essential to differentiate between primary pulmonary hypertension and CTEPH. In primary pulmonary hypertension, the lung perfusion scan is usually near normal or shows patchy nonsegmental defects. However, there is a major and rare exception, veno-occlusive disease, which can be confused with CTEPH 24. A lung perfusion scan does not, however, reveal the severity of the disease, the prognosis or predict the response to various types of therapy 25.

Right heart catheterisation

Right heart catheterisation is performed during pulmonary angiography. It is essential as it provides unbiased data for the quantification of severity of the disease and postoperative prognosis.

Pulmonary angiography

Pulmonary angiography confirms the diagnosis of chronic pulmonary thromboembolic disease 26–28 and determines the chance of success of endarterectomy according to the location of disease, proximal versus distal. Ideal angiographical techniques are required, showing the entire arterial tree of each lung captured in the same frame. Angiography must include serial pictures, from the injection of dye into the pulmonary artery to the venous return in the pulmonary veins, including parenchymography to show the nonperfused areas.

The right pulmonary arterial tree is studied in anterior and lateral views. The mediastinal arteries are well seen on anterior views. Lateral views are required in order to visualise the intermediary arterial trunk and its branches (dorsal to the right upper lobe, middle lobe, superior segment, as well as the four segmental branches of the basilar segments).

The left pulmonary arterial tree is studied in an anterior and left anterior oblique or lateral view in order to differentiate the lingular territory from the basilar segments.

Interpretation of angiography in cases of CTEPH is more difficult than in acute pulmonary emboli, which appears as a discrete intraluminal defect. There are five angiographic features that are characteristic of chronic thromboembolic disease (fig. 3⇓) these are as follows: 1) a sacciform stop from obstruction of the pulmonary artery which when located at the origin of the right or left pulmonary artery, can be mistaken for pulmonary agenesis; 2) transverse bands resembling chordae tethering the arterial lumen; 3) irregularities of the arterial wall; and 4) abrupt change in the calibre of the artery; and 5) absence of segmental or lobar arterial branches with parenchymal defects in these territories.

Helical computed tomography

High-resolution helical CT can show obstruction or a reduction in the diameter of the arterial lumen when compared to the external diameter of the pulmonary artery. Very proximal lesions on the right or left pulmonary arterial trunks are well characterised, whereas the distal lesions downstream from the first branches are rarely visible. Hence, a normal CT scan does not exclude the diagnosis of chronic pulmonary thromboembolic disease and does not preclude the possibility of pulmonary endarterectomy.

CT scanning is essential to exclude rare conditions that may present with similar symptoms, such as chronic pulmonary thromboembolic disease. This differential diagnosis includes fibrous mediastinitis, mediastinal carcinoma and sarcoma of the pulmonary artery. CT scans also delineate artheromatous calcifications of the pulmonary artery in long-standing disease, which increase the technical difficulty of the endarterectomy 29. In the current authors' view, third generation CT scanners are much better at delineating obstruction of segmental branches and showing the development of the bronchial circulation, which is indicative of the obstructive aetiology seen in pulmonary hypertension (fig. 4⇓).

Angiosarcoma of the pulmonary artery

This primary malignancy of the pulmonary artery usually has its origin in the pulmonary artery trunk. It surrounds the pulmonary valve and progressively extends towards branches of the pulmonary artery, most often bilaterally. The diagnosis is suggested by slowly progressive symptoms without acute episodes or previous thromboembolic disease, the presence of a large quantity of endoluminal material proximally (particularly in the main pulmonary artery), extraluminal extension of the tumour and by the detection of pulmonary regurgitation on echocardiography secondary to diseased leaflets. One of the series of eight patients recently operated on by the present authors presented with a positron emission tomography (PET) scan positive for activity along the pulmonary artery. While the diagnosis may be suspected based on these findings, it must be confirmed at the time of surgery, on pathological analysis of a frozen section. Surgical treatment of rare cases of unilateral angiosarcoma requires a pneumonectomy extending into the bifurcation of the pulmonary artery. Treatment of bilateral diseases requires an endarterectomy of each of the pulmonary arteries with a resection of the pulmonary arterial trunk and of the pulmonary valve, followed by the placement of a vascular interposition graft between the right ventricular outflow tract and the pulmonary artery with a valvular homograft or a prosthetic valve (fig. 5⇓).

Tumour emboli into the pulmonary artery

Renal cancer, thyroid cancer, testicular cancer and uterine cancer among others may release emboli to the pulmonary arteries, which become obstructed either by embolisation or by direct extension of the tumour through the vena cava and right heart chambers. Uterine leiomyomatosis deserves a special mention; a benign tumour with vascular tropism that can lead to invasion of the inferior vena cava and obstruction of the pulmonary arteries. Similarly, testicular tumours may continue to grow as a teratoma into the inferior vena cava and the pulmonary arteries after response to chemotherapy and normalisation of tumoral markers (fig. 6⇓).

Hydatic emboli

Hydatic cysts of the liver can migrate spontaneously or during hepatic surgery into the inferior vena cava and the pulmonary arteries, causing downstream thrombosis and obstruction of a large part of the pulmonary vascular bed. The diagnosis of this form of pulmonary hypertension is aided by the clinical context and positive serology (fig. 7⇓).

Pulmonary arteritis

Pulmonary hypertension secondary to Takayashu's or Behcet's arteritis presents typical lesions on angiography with false aneurysm of the pulmonary artery associated with in situ thrombosis. These lesions are associated, respectively, with arteritis in the supra-aortic trunks or with cutaneomucosal lesions. They may be improved by dilatation if there is a principal lesion with a gradient.

Fibrous mediastinitis

Fibrous mediastinitis can closely resemble chronic thromboembolic disease on angiography and on CT scan, and can cause severe pulmonary hypertension. The essential difference is that fibrous mediastinitis encases other structures, such as the superior vena cava, oesophagus, phrenic and recurrent nerves, pulmonary veins possibly with postcapillary hypertension, and the bronchi. Bronchoscopy plays an important role in the diagnosis by detecting widening of the carinal bifurcations and obstruction of the bronchial ostia. Attempted resection of the perivascular gangue has been unsuccessful and the only currently available treatment of fibrous mediastinitis are angioplasty or placement of a vascular shunt between the pulmonary arterial trunk and the distal pulmonary artery beyond the obstruction, within the lung fissure if the distal vascular bed remains patent (fig. 8⇓).

Technique of pulmonary endarterectomy

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% 2, 5, 30–36. The intraluminal material is, at this stage, composed of fibrous tissue inseparable from the intima and, therefore, inaccessible to thrombectomy or dilatation. Therefore, a true endarterectomy is required, starting at the level of right and left pulmonary arteries inside the pericardium and progressively extended distally into each of the branches of the pulmonary arterial tree (fig. 9⇓).

Patients suffering from this disease quickly develop a systemic hypervascular neovascularisation from bronchial and intercostal arteries through residual adhesions between the chest wall and the visceral pleura due to previous emboli. The development of a systemic-to-pulmonary artery circulation at the precapillary level results in significant back bleeding from the pulmonary artery at the time of endarterectomy. The only way to stop this bleeding, which continuously fills the pulmonary artery and obstructs the surgical field, is to arrest the systemic circulation under conditions of deep hypothermia, between 18–20°C. In order to limit the time of circulatory arrest, the cardiopulmonary bypass is stopped only after identification of the correct plane for endarterectomy. After completion of endarterectomy on the first side, the extra-corporeal circulation is resumed for ∼15 min before the contralateral endarterectomy is performed. This sequential technique with intermediate reperfusion limits the cumulated period of circulatory arrest to <55 min.

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. This approach avoids the dissection of highly vascular tissue surrounding blood vessels and pleural adhesions.

Pulmonary endarterectomy is truly an endovascular procedure 29 that can benefit from video technology. The angioscope illuminates the lumen of the pulmonary artery and the videocamera allows the distal arterial divisions to be viewed better, displayed on screen for the surgeon and surgical assistants. The operation is divided into four parts.

Recipient selection criteria

Recipient selection criteria at the Marie-Lannelongue Hospital currently includes: age <55 yrs; the absence of mechanical respiratory insufficiency due to scoliosis; absence of phrenic paralysis; and absence of recent neoplastic disease or other potentially life-threatening diseases.

Transplantation for pulmonary arterial hypertension is indicated for patients with a life expectancy of <1 yr, consistent with a functional status of NYHA stage III or IV. 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 UI are indications for transplant.

Types of pulmonary transplantation

Single lung, bilateral lung or heart-lung transplantations have been performed in patients suffering from end-stage pulmonary hypertension. The latter is the current authors' preferred approach, because it gives greater pulmonary reserve to the patients who may suffer bronchiolitis obliterans and infection. The transplanted heart is adapted to the pulmonary circulation, which helps to avoid left ventricular dysfunction or right ventricular outflow tract obstruction secondary to hypertrophic cardiomyopathy, both of which may be seen after bilateral lung transplantation performed for pulmonary hypertension.

An advantage of bilateral lung transplantation is that the donor heart can be transplanted into another recipient awaiting heart transplantation alone. Compared to heart-lung transplantation, however, bilateral lung transplantation patients can potentially develop bronchial ischaemia extending into the distal bronchial tree and leading to anastomotic dehiscence or stenosis. Lung and heart-lung transplantation for CTEPH is often associated with severe bleeding due to the multiple neovascularised pleural adhesions and to the development of significant bronchial arterial circulation from the intercostal and bronchial arteries 38.

Regardless of the operation, pulmonary transplantation is always associated with: 1) low donor rate that will never match the number of patients awaiting transplantation; 2) postoperative mortality rate of ∼20%; 3) life-long immunosuppression; 4) succeptibility to bacterial, viral and fungal infections, and post-transplant lymphoproliferative disease associated with prolonged immunosuppression; and 5) episodes of acute and, even more worrisome, chronic rejection leading to bronchiolitis obliterans and respiratory failure.

Results of pulmonary transplantation

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 ∼20% and was not significantly different between the operation performed (table 6⇓).

A total of 35 patients developed bronchiolitis obliterans of whom 18 died. Seven patients developed a malignancy, five of which were lymphomas. Two patients underwent re-transplantation: one patient had a single lung transplant 10 yrs after heart-lung transplantation; and the other underwent heart-lung transplant 14 yrs after single left lung transplantation. The actuarial 5‐yr survival is 52% and 12 patients are currently alive >10 yrs after transplantation (fig. 12⇓).