Chronic thromboembolic pulmonary hypertension (CTEPH) results from obstruction of the major pulmonary arteries by unresolved or organized pulmonary emboli that have become incorporated into the vessel wall, ultimately causing increased pulmonary vascular resistances. Without intervention, CTEPH is a progressive, fatal disease for which there is no proven effective medical therapy. Pulmonary endarterectomy (PE) is the treatment of choice. Lung transplantation is indicated only in few cases when PE is not feasible.
Pulmonary hypertension (PH) accounts for substantial morbidity and mortality. Except when lung or heart–lung transplantation is considered, chronic thromboembolic PH (CTEPH) is the only form of potentially surgically curable PH, making its recognition crucial. Chronic thromboembolic obstruction of the major pulmonary arteries occurs as a result of diagnosed or unrecognised acute pulmonary embolism (PE) and may lead to PH and cor pulmonale. CTEPH should be considered in patients with unexplained dyspnoea even when no definitive history of acute PE is evident.1
Epidemiology and Pathophysiology
A recent prospective, long-term follow-up study assessed the incidence of symptomatic CTEPH in consecutive patients after a single acute episode of PE.2 The cumulative incidence of symptomatic CTEPH was 1% at six months, 3.1% at one year and 3.8% at two years – much higher than previously suspected. The most likely factor to increase the risk of CTEPH was previous PE (odds ratio 19.0), although younger age, a larger perfusion defect and idiopathic PE at presentation also increased the risk. Acute PE is likely the initiating event even when there is no documented history of acute venous thromboembolism.
Although serial angiographic studies are limited to small numbers of patients, incomplete resolution is visible in many patients as late as three weeks after an acute pulmonary embolic event.3 When serial perfusion scans have been performed, up to 66% of patients show persistence of abnormal perfusion on scans performed several months after the primary event,4 although perfusion scanning often underestimates the extent of angiographic obstruction in chronic PE.5 It is unclear why some patients do not resolve the acute embolism and then develop PH.
A thrombophilic disorder is found in only a minority of patients.8 A lupus anticoagulant is present in 10–20% of patients with CTEPH.6,7 Abnormal fibrinolysis or pulmonary endothelial pathology could be responsible for incomplete thrombus resolution, but this remains unclear.9,10 Many patients are asymptomatic for months to years after the initial thromboembolic event. A pulmonary hypertensive arteriopathy, similar to that seen in patients with other forms of PH, has been documented in CTEPH, and these small-vessel changes may contribute substantially to the haemodynamic deterioration seen in many patients.11,12
Main or lobar occlusion is by no means required for the evolution of CTEPH. Prognosis without surgery correlates with the severity of the PH at the time of diagnosis. Five-year survival in patients with a mean pulmonary artery pressure greater than 40mmHg at the time of diagnosis has been shown to be 30%.13 A mean pulmonary artery pressure as low as 30mmHg may be a threshold for poor prognosis.14
Clinical Manifestations and Diagnostic Approach
The initial symptom in patients with CTEPH is usually progressive exertional dyspnoea. With progression, particularly as right ventricular failure develops, oedema, chest pain, lightheadedness and syncope may develop.Patients with CTEPH may have subtle physical findings such as an accentuated P2. Subsequently, physical findings compatible with the presence of PH and right ventricular failure develop. High-pitched systolic bruits, particularly audible at end inspiration, caused by turbulent flow through partially obstructed vessels may be auscultated over the lung fields. These are not specific, as they may also be present in large-vessel arteritis, tumours of the pulmonary artery and peripheral pulmonic stenosis.15
There is often a delay of two to three years from the onset of symptoms to securing the diagnosis,16,17 particularly in patients without a history of acute PE. Symptoms may be mistakenly attributed to deconditioning, advanced age, anxiety or other cardiopulmonary diseases such as asthma, and a lack of awareness of the disease plays a role in this delay. Cardiomegaly by chest radiograph with right-sided chamber enlargement and dilation of the central pulmonary arteries is eventually seen. The lung fields are generally clear in the absence of concomitant lung disease, but there may be peripheral opacities, suggesting previous infarction. Areas of hypoperfusion or hyperperfusion with a prominent interstitial pattern may be evident.
While there are no classic spirometric changes diagnostic of CTEPH, approximately 20% of patients will have a mild to moderate restrictive defect probably caused by parenchymal scarring.18 The single-breath-diffusing capacity for carbon monoxide may be normal or mildly or moderately reduced.
Hepatic congestion may elevate liver function tests. Elevation of blood urea nitrogen, creatinine and uric acid may occur with a reduction in renal blood flow. Prolonged hypoxaemia may lead to secondary polycythemia. An elevated activated partial thromboplastin time may suggest the possibility of a lupus anticoagulant. While arterial blood oxygen levels can be normal even in the setting of significant PH, many patients will experience a decline in PO2 with exercise. Hypoxaemia in the setting of CTEPH is due to ventilation–perfusion (VQ) inequalities, a reduction in cardiac output causing a decline in mixed venous oxygen saturation and right-to-left shunting of blood through a patent foramen ovale.19
Transthoracic echocardiography nearly always reveals some objective evidence of PH. Echocardiographic estimation of the right ventricular systolic pressure, evaluation of right-sided chamber size and leftward displacement of the intraventricular septum offer evidence of PH and serve to estimate the severity of the disease.20
After the chest radiograph, spiral computed tomography (CT) is probably the most common initial imaging test. CT features suggesting CTEPH include evidence of organised thrombus lining the pulmonary vessels, enlargement of the right ventricle and central pulmonary arteries, variation in size of segmental arteries, bronchial artery collaterals, a mosaic parenchymal perfusion pattern and changes compatible with infarcts.21 The absence of these findings does not rule out surgically correctable disease. Chronic thromboembolic disease is usually bilateral, and unilateral disease should raise suspicion for alternative diagnoses, such as tumour, lymphadenopathy and fibrosing mediastinitis. CT is also useful in characterising co-existent parenchymal lung disease.
VQ lung scanning plays a pivotal role in determining whether PH is due to thromboembolism. One or more mismatched segmental or larger defects are generally present in CTEPH, while in other causes of PH such findings are much less common. Grey zones of relative hypoperfusion may be present on the perfusion scan, indicating areas of recanalisation that may underestimate the extent of obstruction.5 A single mismatched segmental defect in a patient with PH could indicate CTEPH; thus, the VQ scan is a vital part of the evaluation even when the CT is unimpressive. CT and VQ scanning are often complementary.
Right heart catheterisation is important in quantitating the severity of the PH as echocardiography is not reliable in this regard. Measurement of oxygen saturations in the vena cava, the right heart chambers and the pulmonary artery may document shunting. Coronary angiography and left heart catheterisation may be useful, depending on the pateint’s history and echocardiographic evaluation. These data are important in assessing pre-operative risk when pulmonary thromboendarterectomy (PTE) is considered.
Pulmonary angiography remains the gold standard test for characterising the pulmonary vasculature and is performed to ascertain the presence and exact location of thromboembolic disease, as well as to determine surgical accessibility. In experienced hands, angiography can be performed safely even in severe PH. CTEPH results in retraction and partial recanalisation of vessels, resulting in pouch defects, pulmonary artery webs, areas of focal narrowing (bands), intimal irregularities, abrupt narrowing of major pulmonary arteries and obstruction of main, lobar or segmental pulmonary arteries.22 Focal vessel narrowing can be seen in congenital pulmonic stenosis and also in medium- or large-vessel arteritis. Complete obstruction or abrupt narrowing of the central pulmonary arteries can occur from pulmonary vascular tumours or extravascular compression. Pulmonary angioscopy is used in a significant minority of patients for pre-operative evaluation.23 Angioscopy allows visualisation of the intima of central pulmonary arteries. Its most useful role appears to be in identifying operative candidates whose angiographic findings suggest limited disease.
Surgical Therapy – Pulmonary Thromboendarterectomy
PTE can substantially improve symptoms, haemodynamics and survival. The majority of patients are World Health Organization (WHO) functional class III or IV prior to PTE and become class I or II with resumption of normal activities after surgery.
While there have been many reports of the surgical treatment of CTEPH,6,16,17,24,25 much of the surgical experience in PTE has been reported from the University of California at San Diego Medical Center in the US. Other centres worldwide have increasing experience, but few have extensive experience with hundreds of operations performed.
PTE is considered in patients who are symptomatic and have impairment of haemodynamics or oxygenation at rest or with exercise. Pre-operative pulmonary vascular resistance in surgical candidates is usually >300dyn/sec/cm-5, and most often in the range of 800–1,000dyn/sec/cm-5.26 Thromboendarterectomy may be considered in patients with normal or nearly normal haemodynamics if vigorous athletic activity is a significant part of their lifestyle. The sometimes seemingly disproportionate dyspnoea in these individuals is a function of elevated dead space and minute ventilation requirements as well as inadequate cardiac output with exercise.
Candidacy for PTE is determined by the location and extent of proximal thromboembolism. Thrombi must involve the main, lobar or proximal segmental arteries; disease originating more distally is not accessible with current techniques. It is important to determine whether the amount of surgically accessible thrombus correlates with the degree of haemodynamic impairment. Failure to significantly reduce the pulmonary vascular resistance with PTE is usually because of secondary small-vessel arteriopathy. This scenario increases the peri-operative mortality rate and worsens the long-term outcome.27 It is important to realise that thrombus may line the central pulmonary arteries in other forms of PH; the presence of centrally located thrombus on spiral CT scanning does not uniformly confirm the diagnosis of CTEPH. In these conditions the clot may be of in situ origin and surgery may not be appropriate.28,29
Severe left ventricular dysfunction is an absolute contraindication to PTE. Morbid obesity, advanced age, severe right ventricular dysfunction and other significant co-morbid diseases increase the peri-operative morbidly and mortality, but are not prohibitive. Concomitant coronary artery bypass surgery or valve replacement can be performed at the time of PTE, so pre-operative evaluation is important.
The surgical technique has been outlined in detail elsewhere.30 Briefly, PTE is a true endarterectomy of the obstructed major pulmonary arteries. The organised thromboembolic lesions are removed, markedly improving perfusion. A median sternotomy incision with cardiopulmonary bypass and deep hypothermia with periods of circulatory arrest is utilised. During the immediate post-operative period, the principal concerns are adequate mechanical ventilation, proper inotropic drug management, aggressive diuresis and early initiation of anticoagulation.
Whether or not PTE can be performed, supportive therapy with oxygen and diuretics is utilised to treat hypoxaemia and right ventricular failure. Data are accumulating with drugs used for pulmonary arterial hypertension. Long-term treatment with epoprostenol may be of benefit in selected patients,31,32 and experience with other agents is increasing.33 A prospective, randomised, blinded, placebo-controlled study has been conducted in inoperative CTEPH patients and those with persistent PH after PTE using the oral endothelin antagonist bosentan. Results are pending.
More than 2,000 PTE procedures have been performed worldwide with about 1,500 of them performed at one centre. In a review of surgical series published since 1996, peri-operative mortality rates ranged from 5 to 24%, with significant variation in haemodynamic improvement reported.1 In view of the high risk of PTE, patients should be referred to centres with experience that provide a multidisciplinary approach to the evaluation and treatment of CTEPH. Owing to the fact that surgical and perioperative morbidity and mortality are substantially influenced by the degree of right ventricular dysfunction and the presence of secondary small-vessel vasculopathy, surgical intervention is best considered earlier in the disease process rather than waiting until there is severe clinical deterioration with advanced right ventricular failure. Individuals who are inoperable, or who continue with significant residual PH after surgery, should be considered for lung transplantation, and potentially for medical therapy.