Chronic thromboembolic pulmonary hypertension (CTEPH) results from an obstruction of the pulmonary vessels with organized blood clots. It is estimated that 3.8% of patients suffering an acute pulmonary embolus will develop CTEPH.25 However, a significant proportion of CTEPH cases may originate from asymptomatic venous thromboembolism.26.
Patients at greatest risk include those with previous episodes of venous thromboembolism, massive and submassive pulmonary embolism, an elevated PASP on admission, or elevated pressure 2 months after initial presentation. Additional risk factors for CTEPH include the presence of ventriculoatrial shunts for the treatment of hydrocephalus, low-grade malignancy, splenectomy, chronic osteomyelitis, inflammatory bowel disease, and thyroid replacement therapy.27,28
The pathophysiology of CTEPH is related to increased resistance to flow through the pulmonary arteries, initially from obstruction of pulmonary arteries (usually main to subsegmental levels) by organized thromboembolic material and subsequently from vascular remodeling in smaller unobstructed vessels.29 The vascular remodeling arises in response to increased flow and consequent shear stress in the distal unobstructed pulmonary arterial vascular bed.
The most common symptoms of CTEPH are exertional dyspnea and fatigue, although chest pain, syncope, hemoptysis, and vertigo are also observed. The clinical course is initially episodic, with long "honeymoon periods" of only mild or no symptoms. If CTEPH is left untreated, there is a progressive increase in PVR, RV dysfunction, and death.
The diagnosis of CTEPH is made based on radiologic investigations performed during the assessment of pulmonary hypertension.
The characteristic findings on chest radiograph in CTEPH are enlargement of the RV and prominence of the central pulmonary arteries. If thrombosis or embolism occurs in the central pulmonary arteries, then asymmetrical and/or bulging vessels may be present. Another feature of CTEPH is decreased vascularity termed mosaic oligemia.30 These areas of decreased vascularity on plain radiographs can be confirmed on pulmonary angiography to be associated with chronic emboli (Fig. 24–16). "Peripheral pruning" or discordance in caliber between central and peripheral pulmonary arteries is a distinct feature of PAH regardless of the underlying etiology and thus will often be visible in CTEPH.
Plain chest radiograph in chronic thromboembolic pulmonary hypertension demonstrating prominent pulmonary arteries and peripheral pruning.
The role of ventilation/perfusion scintigraphy is to distinguish IPAH from CTEPH. With CTEPH, the ventilation/perfusion scan is usually high probability, showing multiple mismatch segmental or larger perfusion defects (Fig. 24–17). A normal or low probability scan effectively excludes CTEPH.31,32 In patients who have intermediate- or high-probability scans, the diagnosis of CTEPH can usually be confirmed by CT pulmonary angiography (CTPA).
Ventilation/perfusion scan in patient with chronic thromboembolic pulmonary hypertension showing multiple mismatched perfusion defects. Kr81m, krypton-18m; MAA, macroaggregated albumin; Tc99m, technetium-99m.
Although ventilation/perfusion scintigraphy is a safe and highly sensitive test for suspected CTEPH, large mismatch perfusion defects may arise in other processes that result in obliteration of the central arteries and veins. These "CTEPH mimics" include large-vessel vasculitis, pulmonary artery sarcoma, extrinsic compression due to cancer, lymphadenopathy, fibrosing mediastinitis, and pulmonary veno-occlusive disease.33
The hallmark of CTEPH on CTPA is the absence or sudden loss of contrast-filled vessels. Abnormalities in the main pulmonary artery may be highly suggestive of CTEPH, with the most common finding being the eccentric location of thrombus, resulting in a crescentic filling defect adjacent to the vessel wall34 (Fig. 24–18). Other vascular signs of CTEPH that are visible on CT are recanalization within intraluminal fillings and arterial webs (Fig. 24–19) and stenoses.
Computed tomography pulmonary angiogram demonstrating bilateral filling defects due to laminated thrombus in the right and left pulmonary arteries (arrows).
Computed tomography pulmonary angiogram demonstrating an arterial web in the right middle lobe pulmonary artery (arrow).
Bronchial artery hypertrophy occurs in approximately half of patients with CTEPH and only rarely in IPAH.35 It occurs most commonly in chronic inflammatory diseases of the airways and when there is chronic pulmonary hypoperfusion, when the bronchial arteries act as a collateral blood supply to the pulmonary parenchyma. Bronchial artery hypertrophy is defined as curvilinear mediastinal vessels >1.5 mm in diameter, seen along the course of the proximal bronchial tree and is best identified on coronal reformatted projections (Fig. 24–20). In CTEPH, the distal circulation may be morphologically normal and therefore able to accommodate this increased collateral supply, whereas in IPAH, the plexogenic arteriopathy is centered at arteriolar level.
Computed tomography pulmonary angiogram with coronal reformatted projection showing bronchial artery hypertrophy (arrow) in a patient with chronic thromboembolic pulmonary hypertension.
In CTEPH, there is mosaic oligemia visible on high-resolution scanning, caused by obliteration of parts of the vascular bed (Fig. 24–21). This results in hypoperfusion with arteries of diminished size in some areas and with normal or increased perfusion and enlarged arteries in other areas.
High-resolution computed tomography scan of chest showing subtle areas of mosaic oligemia (arrows) in a patient with chronic thromboembolic pulmonary hypertension.
Peripheral lung parenchymal opacities are another common finding in CTEPH36,37 (Fig. 24–22). They represent pulmonary infarcts due to occlusion of segmental and smaller pulmonary arteries and therefore occur more commonly in "peripheral-type" CTEPH than "central-type."
High-resolution computed tomography showing multiple peripheral lung opacities (arrows) in a patient with distal chronic thromboembolic pulmonary hypertension.
At present, pulmonary angiography remains the definitive investigation for the diagnosis and assessment of surgically correctable CTEPH. The typical findings include vascular cut-offs representing complete occlusion of the vessel (Fig. 24–23) and vascular webs that result from organization of thromboembolic material in the vessel lumen with subsequent scar formation. Smaller pulmonary arteries can appear tortuous and taper rapidly, particularly in patients with distal inoperable CTEPH (Fig. 24–24).
Conventional pulmonary angiogram in a patient with chronic thromboembolic pulmonary hypertension demonstrating abrupt cut-off of the right middle lobe pulmonary artery (arrow) and a paucity of vessels in the right mid zone.
Pulmonary angiogram demonstrating tortuous, rapidly tapering pulmonary arteries and a generalized paucity of vessels in the right lower zone of a patient with distal inoperable chronic thromboembolic pulmonary hypertension.
The ECG and echocardiographic abnormalities observed in CTEPH are similar to those seen in IPAH, which have been discussed earlier in this chapter.
Magnetic resonance angiography (MRA) does not require exposure to radiation or nephrotoxic contrast agents and is becoming increasingly important in the diagnosis, assessment, and long-term follow-up of patients with CTEPH. In experienced centers, images produced with MRA are comparable to those acquired using conventional pulmonary angiography.
All patients with suspected CTEPH should undergo right heart catheterization to confirm the presence of pulmonary hypertension (mean PAP >25 mm Hg), to measure cardiac output (usually by thermodilution technique), and to calculate PVR. Right heart catheterization and pulmonary angiography are often performed as a single procedure.
It is widely recognized that the definitive treatment for CTEPH is pulmonary endarterectomy (PEA). It is the only proven treatment to give prognostic and symptomatic benefit. PEA is performed on cardiopulmonary bypass via a median sternotomy and involves the removal of organized and incorporated fibrous obstructive tissues from the pulmonary arteries. Completion of the endarterectomy procedure is usually possible within a 20-minute period of circulatory arrest for each lung.
PEA is a major undertaking, often performed in patients with significant RV dysfunction, and should only be carried out at a specialized center by a PEA-experienced surgeon. The decision as to whether PEA is feasible will depend on the abnormalities seen on CT and conventional angiography, on the hemodynamics observed at right heart catheterization, and on whether the patient has other significant comorbidities. Patients with proximal disease have a much better risk-to-benefit ratio from surgery than patients with more distal disease. Patients with a PVR >1200 dyne/s/cm have a higher risk of mortality with attempted PEA.38,39 In patients with a PVR disproportionately higher than the segmental obstruction visible by imaging, there is less benefit from PEA and a much higher risk of mortality. There are very few absolute contraindications to surgery, and good results have even been achieved in patients over age 80 years.
Despite the complexity of the procedure, PEA is associated with mortality rates of only 5% to 10%.37 Severe preoperative RV dysfunction and residual postoperative pulmonary hypertension are both associated with poor outcome after PEA. In many cases, RV and pulmonary hemodynamics will return to normal within hours of the procedure. Following a successful PEA, the occurrence of reperfusion lung injury is common, with up to a third of patients requiring prolonged ventilatory support, and is a key factor in determining perioperative morbidity and mortality.40 Shorter cardiac arrest periods, the use of cooling jackets to the head, and antegrade cerebral perfusion techniques have reduced the occurrence of cerebral injury associated with PEA.
All patients with CTEPH should receive lifelong anticoagulation with warfarin in the therapeutic international normalized ratio range between 2 and 3. It is common practice to insert an inferior vena cava filter in patients with CTEPH undergoing PEA surgery to reduce the risk of thromboembolism in the early postoperative period until full anticoagulation is reestablished.
The natural history of untreated CTEPH is dismal; <20% of patients survive for 2 years if the mean PAP is >50 mm Hg at the time of presentation.41 Although PEA is a realistic option for cure, unfortunately, up to 50% of patients are judged inoperable.42
In recent years, there has been increasing use of PAH-specific medical therapies in CTEPH. They have been used in a number of settings, including to provide hemodynamic stability prior to surgery, in patients with persisting or recurrent pulmonary hypertension despite PEA, and in patients who have distal inoperable disease.43-45 Use of the endothelin receptor antagonist bosentan in patients with inoperable CTEPH was associated with improvements in pulmonary hemodynamics, although not all studies report improvements in exercise capacity.46,47 There are currently ongoing studies examining the potential use of endothelin receptor antagonists, PDE-5 inhibitors, prostanoids, and other novel agents in CTEPH.
An overweight 38-year-old woman, with a background of inhaler-controlled asthma, was referred with 18 months of worsening breathlessness. She had no past history of deep vein thrombosis or pulmonary embolism and no significant family history. On examination, she was cyanosed, with resting oxygen saturation of 90%, and had bilateral pitting ankle edema.
Her ECG showed right axis deviation and RV hypertrophy. Chest radiograph demonstrated prominent pulmonary arteries and some peripheral pruning (Fig. 24–25). On echocardiogram, she had a severely dilated RV with poor systolic function, dyskinetic septal motion, and elevated estimated PASP. The bubble contrast study was negative.
Enlarged pulmonary arteries and peripheral pruning on chest x-ray.
The patient had a high-probability ventilation/perfusion scan, with bilateral mismatched perfusion defects (Fig. 24–26). CTPA demonstrated a dilated main pulmonary artery (Fig. 24–27), dilated right-sided cardiac chambers (Fig. 24–28), multiple filling defects, cut-off of the right interlobar artery, and a paucity of vessels in the right lower lobe. There was also evidence of a left interlobar artery web (Fig. 24–29). CT also showed multiple peripheral lung parenchymal opacities (Fig. 24–30) and mosaic oligemia (Fig. 24–31).
High probability ventilation/perfusion scan.
Dilated main pulmonary artery on computed tomography pulmonary angiogram.
Dilated right ventricle and right atrium on computed tomography pulmonary angiogram.
Right-sided filling defect and left pulmonary artery web (arrow).
High-resolution computed tomography of chest showing multiple peripheral pulmonary opacities (arrows).
High-resolution computed tomography of chest demonstrating a subtle area of mosaic oligemia (arrow).
She proceeded to right heart catheterization, which confirmed severe pulmonary hypertension (mean PAP, 58 mm Hg; cardiac index, 1.9 L/min/m2; PVR, 8.7 Wood units). Conventional pulmonary angiography was performed and confirmed the abnormalities identified at CTPA, namely the right-sided cut-off and a paucity of vessels in the lower lobes, particularly on the right (Fig. 24–32). The diagnosis of CTEPH was confirmed.
Right interlobar artery cut-off on conventional pulmonary angiogram (arrow).
The patient was then anticoagulated, commenced on the PDE-5 inhibitor sildenafil as disease-targeted therapy to improve pulmonary hemodynamics, and referred to the national PEA center for consideration of PEA.