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Imaging in Chronic Thromboembolic Pulmonary Hypertension

Renapurkar, Rahul D. MD; Shrikanthan, Sankaran MD; Heresi, Gustavo A. MD; Lau, Charles T. MD, MBA; Gopalan, Deepa MRCP, FRCR

doi: 10.1097/RTI.0000000000000256
Review Articles

Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the potentially curable causes of pulmonary hypertension and is definitively treated with pulmonary thromboendartectomy. CTEPH can be overlooked, as its symptoms are nonspecific and can be mimicked by a wide range of diseases that can cause pulmonary hypertension. Early diagnosis of CTEPH and prompt evaluation for surgical candidacy are paramount factors in determining future outcomes. Imaging plays a central role in the diagnosis of CTEPH and patient selection for pulmonary thromboendartectomy and balloon pulmonary angioplasty. Currently, various imaging tools are used in concert, with techniques such as computed tomography (CT) and conventional pulmonary angiography providing detailed structural information, tests such as ventilation-perfusion (V/Q) scanning providing functional data, and magnetic resonance imaging providing a combination of morphologic and functional information. Emerging techniques such as dual-energy CT and single photon emission computed tomography-CT V/Q scanning promise to provide both anatomic and functional information in a single test and may change the way we image these patients in the near future. In this review, we discuss the roles of various imaging techniques and discuss their merits, limitations, and relative strengths in depicting the structural and functional changes of CTEPH. We also explore newer imaging techniques and the potential value they may offer.

*Section of Thoracic Imaging

Cardiovascular Imaging Laboratory

Section of Nuclear Medicine, Imaging Institute

§Section of Pulmonary and Critical Care Medicine, Cleveland Clinic, Cleveland, OH

Department of Radiology, VA Palo Alto Health Care System, Palo Alto, CA

Department of Radiology, Imperial College Hospitals, London, UK

Gustavo Heresi: Bayer Healthcare: speaker's bureau, advisory board and consultant. The remaining authors declare no conflicts of interest.

Correspondence to: Rahul D. Renapurkar, MD, Section of Thoracic Imaging, L10, Imaging Institute, Cleveland Clinic, Cleveland, OH 44195 (e-mail:

Pulmonary hypertension (PH) is a common medical problem characterized by elevated pulmonary arterial pressures, which can lead to right ventricular (RV) failure (cor pulmonale). Defined by mean pulmonary artery pressure (mPAP)≥25 mm Hg at rest on right heart catheterization (RHC), the natural history of this disease is variable and depends on its underlying cause.1

Chronic thromboembolic pulmonary hypertension (CTEPH), one of the increasingly recognized causes of PH, follows a single or recurrent event of acute pulmonary embolism (PE). The exact incidence of this disease is uncertain, although various studies have suggested that it may occur after approximately 0.57% to 3.8% of acute pulmonary embolic events and in up to 10% of patients with recurrent PE.2–5 Often, patients present with nonspecific symptoms such as exertional dyspnea secondary to dead space ventilation and increased cardiac demand.6 With improved understanding of the disease, there is increasing recognition of a subset of patients with “chronic thromboembolic disease (CTED)” who have signs of vascular obstruction and functional impairment but with normal resting mPAP.7 The survival rate without intervention in CTEPH is poor and fairly similar to rates seen with other forms of PH.7 Early diagnosis and treatment are critical in preventing secondary distal arteriolar vasculopathy. As the clinical presentation is fairly nonspecific, the diagnosis of CTEPH requires a high degree of clinical suspicion, particularly early in its course. The greatest difficulty lies in distinguishing CTEPH from idiopathic pulmonary arterial hypertension (IPAH). Although IPAH is predominantly a small vessel disease, it can be complicated by in situ thrombosis resulting in larger central thrombi. In such cases, the concomitant presence of large vessel and microvascular disease in both entities poses a diagnostic challenge.8

Medical options for patients with CTEPH include anticoagulants, vasodilators, and remodeling agents targeted to decrease the pulmonary vascular resistance (PVR). Surgery, however, remains the definitive treatment in these patients; pulmonary thromboendarterectomy (PTE) is the procedure of choice, with favorable short-term and long-term outcomes.9–12 Also, there is increasing evidence to support PTE for patients with symptomatic CTED.13 Two of the critical factors in identifying good candidates for surgical intervention are accessibility of the thrombi and severity of hemodynamic and ventilatory impairment. Recently, minimally invasive techniques such as balloon pulmonary angioplasty (BPA) have been tried with increasing success in patients with inoperable CTEPH.14

Imaging plays 2 critical roles in patients with CTEPH: (1) diagnosis and (2) appropriate patient selection for interventional or surgical therapies. In this review, we evaluate the role of various imaging modalities in the diagnosis and preoperative evaluation of CTEPH and also analyze their strengths and limitations.

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The current classification presented during the Fifth World Symposium held in 2013 in Nice, France, divides PH into 5 groups on the basis of the cause (Table 1).15 CTEPH is classified as group 4 disorder. Group 1 disorders include PH caused by insult at the precapillary level, denoted as pulmonary arterial hypertension (PAH). Although pulmonary venoocclusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are postcapillary diseases, these are included in group 1, as the histologic changes and clinical presentation of these conditions are similar to those of other group 1 conditions. Conditions related to left heart disease are the most common cause of PH and are included in group 2.

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The natural history of an acute pulmonary embolic event is near-total resolution with no or minimal residual hemodynamic consequences. It is still unclear why certain patients develop CTEPH after acute PE.16 Several hypotheses have been proposed, including the presence of an underlying hypercoagulable state in patients who develop CTEPH.17 The antiphospholipid antibody syndrome is the most commonly encountered hypercoagulable state, occurring in up to 20% of patients with CTEPH.18 Additional factors such as thrombophilia and disturbed vascular remodeling also contribute to the disease (Fig. 1). Several factors such as infection, immune phenomena, inflammation, circulating and vascular-resident progenitor cells, thyroid hormone replacement, or malignancy19 may lead to disturbed vascular remodeling. Endothelial dysfunction and endothelial-mesenchymal transition may also play a part.19 The end result is disturbed resolution of the thrombus, with partial recanalization or formation of cords or webs in the vessel lumen, which may partially restore the flow20 (Fig. 1). The organized clot can contract, causing shrinkage, obstruction, and atrophy of the vessel itself. The mechanisms resulting in subsequent development of PH are multifactorial. In some studies, the finding of increased baseline PAP at the time of index PE event was associated with higher risk for subsequent development of PH, suggesting that the severity of the acute PE event might be a predictor of subsequent CTEPH.21 The development of small vessel disease (pulmonary arteriopathy) also contributes to the evolution of PH. It is unclear whether the degree of pulmonary arteriopathy is related to the duration of PH before the diagnosis of CTEPH. Several medical conditions have been associated with the development of small vessel disease, such as ventriculo-atrial shunts for the treatment of hydrocephalus, splenectomy, inflammatory bowel disease, low-grade malignancy, and thyroid replacement therapy.19

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Understanding the Concept of Small Vessel Versus Large Vessel Disease

The exact definition of small vessels in pulmonary vasculature is poorly understood. Histologically, there is a gradual transition from elastic to muscular arteries to arterioles. The point on computed tomography (CT) imaging at which a vessel becomes categorized as “a small vessel” is partly limited by the spatial resolution of CT; a pulmonary arteriole measures approximately 100 μm and is not directly visualized on standard thin-section CT images.20 For clinically classifying the disorders of PH into small vessel and large vessel group disorders with PH with relatively normal perfusion on imaging tests such as ventilation-perfusion (V/Q) scanning or pulmonary angiogram are grouped into small vessel diseases (such as IPAH), whereas patients with PH and at least ≥1 segmental perfusion defects are classified as having large vessel disorders (such as CTEPH). This is undoubtedly an oversimplification, and often patients show a component of both small vessel and large vessel changes.

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The initial goal of diagnostic evaluation is confirmation of the presence of PH. Doppler echocardiography is the best initial screening test, but RHC is absolutely necessary to confirm the presence of PH. Transthoracic echocardiography allows calculation of right ventricular systolic pressure by measuring the peak tricuspid regurgitation velocity and using the modified Bernoulli equation21 (Fig. 2, Cine clip 1, Supplemental Digital Content 1, However, the pulmonary artery systolic pressure (PASP) measured by transthoracic echocardiography may differ from RHC measurements.22

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Chest Radiography

Chest radiography is often performed as a part of baseline evaluation and may be normal in the early course of the disease. In advanced cases, chest radiography can depict findings related to PH with dilated right and left pulmonary arteries (PAs) (Fig. 3). RV enlargement in response to chronic PVR elevation may manifest radiographically as enlargement of the cardiac silhouette and obliteration of the retrosternal clear space on lateral chest radiography.23 Right atrial enlargement leading to prominence of the right heart border on frontal chest radiography may also be observed.23 Focal areas of lung parenchymal oligemia or avascularity can be seen in regions of compromised blood flow secondary to thromboembolic disease.23 Unilateral or bilateral pleural thickening and parenchymal scarring, which are likely a sequelae of previous acute embolic episodes, may also be observed (Fig. 3). In a study on 36 patients, characteristic findings of focal areas of avascularity or enlarged right descending PA (diameter>20 mm) together with pleuritic abnormalities were found to be helpful in differentiating CTEPH from IPAH.24

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Once the diagnosis of PH has been established, the next crucial step is to determine the cause of the PH. CTEPH should always be considered even in patients without a history of venous thromboembolism or risk factors for thromboembolism, as their clinical presentation can be clinically indistinguishable from those with PAH.25

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V/Q Scintigraphy

Although CT imaging has increasingly supplanted V/Q scintigraphy for the diagnosis of acute pulmonary thromboembolism, a V/Q scan is used at many centers as the initial imaging test for establishing the diagnosis of CTEPH. In a retrospective survey comparing V/Q scintigraphy with CT angiography (CTA), the V/Q scan was found to be superior to CTA with a sensitivity of 97.4% and a specificity of 90% to 95% (vs. a sensitivity of 51% and a specificity of 99% with CTA).26 However, a more recent study found comparable sensitivities for V/Q and CTA in the diagnosis of CTEPH.27 Nevertheless, V/Q scanning offers a reliable and convenient way to exclude CTEPH from consideration, as a low-probability V/Q scan virtually excludes this diagnosis, and thus it remains the preferred initial screening imaging test.

A typical V/Q abnormality in CTEPH includes ≥1 segmental or larger mismatched perfusion defects (Fig. 4). This is in contrast to disorders of small vessels such as IPAH or PVOD, in which perfusion may be normal or may demonstrate a mottled appearance characterized by subsegmental defects.28,29 It should be noted that mismatched segmental defects have also been described with PVOD, although they are a rare occurrence.30

Although V/Q scanning offers a quick and easy way to exclude CTED as a cause of PH, this imaging technique has important limitations. Several other nonembolic conditions can cause large mismatched segmental perfusion defects, such as the following:

* Intrinsic PA tumors such as sarcoma (Fig. 5),

* Fibrosing mediastinitis,

* Fibrosis caused by radiation therapy to the mediastinal and hilar regions,

* Vasculitis.

Consequently, it is imperative to obtain additional cross-sectional imaging such as CT to evaluate the lung parenchyma and mediastinal structures and to exclude other pathologies. Second, with CTED, it is not uncommon to find areas of matched V/Q defects, which can somewhat negate the benefits of this study. In our experience, areas of matched V/Q defects likely reflect the compensatory response of the lung to chronic hypoperfusion leading to eventual reduction in ventilation in those areas. Third, the degree of vascular obstruction and hemodynamic compromise is often underquantified by V/Q scintigraphy when compared with conventional angiography or at surgery.31 A possible explanation for this drawback may be the development of channels through the centrally obstructing lesions or partial recanalization or organization of thrombi after an acute event, which permits the radiotracer to reach the periphery of the lungs.

The planar nature of conventional V/Q scans unmasks limitations inherent to 2-dimensional (2D) techniques. Lung segment overlap and shine-through may result in errors in the localization and quantification of perfusion defects. As a result, 3D techniques, such as single photon emission (SPECT) V/Q, have been advocated as a way to improve the accuracy of perfusion defect localization and quantification. SPECT V/Q affords a significant advantage over conventional V/Q scans, offering improved sensitivity and specificity and a lower incidence of nondiagnostic scans.32–34

With the availability of SPECT-CT scanners, SPECT-CT V/Q imaging is now possible as well (Fig. 6). A noncontrast CT is used primarily for attenuation correction, although the anatomic information obtained by CT can be used to exclude obvious nonembolic causes of perfusion defects, such as neoplasm, thereby improving the specificity of the study. Several studies have shown improved specificity and overall accuracy with SPECT-CT V/Q scanning compared with conventional and SPECT V/Q scanning.35,36 Another benefit of this technique is its accurate mapping of the perfusion defect to the respective segments of the lung using cross-sectional imaging data (Fig. 7).37 However, the inclusion of CT does increase the radiation dose delivered to a patient relative to SPECT V/Q and V/Q imaging.

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CT is a frontline technique for the assessment of suspected acute thromboembolic disease. Excellent spatial and contrast resolution, rapid scan times, and detailed evaluation of the lung parenchyma are some of the advantages that CTA offers. For routine clinical purposes, a standard non–electrocardiogram (ECG)-gated CTA is usually sufficient, although some studies have shown the added value of ECG gating and of newer protocols such as high pitch imaging.38

CT findings in patients with CTEPH may vary according to the severity of the disease, the amount of vascular obstruction, and the degree of PH.39 These imaging findings can be divided into those related to CTED and those related to PH, each of which can be subdivided into vascular signs and lung parenchymal signs.

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CT Findings Related to CTED—Vascular Signs

Because of its superior spatial and contrast resolution, CTA can directly depict the extent and burden of thrombotic disease as peripherally as the subsegmental PA branches. As thrombi of different ages may exhibit different features on CT40 (Table 2), CTA may also distinguish acute thromboembolic events superimposed on a background of chronic disease.

In PAs, complete thrombotic occlusion may manifest on CTA as abrupt luminal narrowing and cutoff with no distal opacification. This has been classically described as the “pouch sign” on conventional angiography, with contrast forming a convex appearance at the distal occluded vessel.41 Partially occlusive filling defects may be seen on CTA as webs or bands lying in the periphery of the vessel,41–43 reflecting partially resolved thrombi (Fig. 8A). In advanced cases, the thrombi may manifest as eccentric irregular thickening of the vessel wall with reduced luminal caliber (Figs. 8B, C). Organizing thrombi can contract, resulting in small and focal stenotic segments, followed by areas of poststenotic dilation41–43 (Fig. 8D). In CTED, residual thrombus may occasionally calcify.

CTA also allows the differentiation of CTED from other etiologies and helps establish the diagnosis of CTEPH. With CTA, acute and chronic thrombotic occlusion can be differentiated by the size of the occluded vessel; typically, the vessel with acute thrombus is expanded, whereas in CTE the affected vessel is attenuated (Table 2). Occasionally, patients with massively enlarged PAs as in Eisenmenger syndrome can develop in situ thrombosis. Typical in situ thrombi adhere to the walls of the central enlarged PAs and do not float inside the lumen.44 Unlike CTEPH, the signs of clot retraction, reduction in the caliber of affected vessels, and secondary lung parenchymal findings of oligemia and infarcts are not seen with in situ thrombosis.44 Differentiation of in situ thrombosis from CTEPH has clinical implications as anticoagulation would increase the risk of bleeding in patients with in situ thrombosis.

Enlargement of the bronchial arteries is a nonspecific response to chronically occluded PAs.45,46 The degree of systemic collaterization including the pleural and intercostal arteries is related to the degree of obstruction and is more common with centrally located thromboembolic disease. In severe cases of CTEPH, enlarged bronchial arteries may contribute to up to 30% of the pulmonary blood flow.47 Interestingly, 1 study found a higher incidence of bronchial artery hypervascularization in patients with CTEPH (73%) compared with that in patients with IPAH (14%).46 Identification of the collaterals, particularly the bronchial arteries, is important, as these patients have an increased incidence of hemoptysis.48 Presence of dilated bronchial arteries has prognostic significance and is associated with lower mortality after PEA, possibly related to distal pulmonary microvasculature sparing.49 Thin-section maximum-intensity projection coronal images are fairly effective in depicting bronchial arteries. However, bronchial hypervascularization is not specific to CTEPH; these can be encountered in other conditions leading to chronic hypoxia, such as interstitial fibrotic lung disease, bronchiectasis, and chronic infection.

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CT Findings Related to CTED—Lung Parenchymal Signs

Mosaic attenuation is a term used to describe a multilobular patchwork of varying lung parenchymal attenuation50 that is often observed in patients with CTEPH. The imaging pattern of mosaic attenuation is by and large nonspecific and can be seen in several pathologies, such as small airway disease, small vessel disease, and primary lung parenchymal disease such as hypersensitivity pneumonitis. In the setting of CTEPH, the regions of lower lung parenchyma attenuation usually represent hypoperfused lung tissue and are associated with attenuated vascular markings51 (Fig. 9). In some situations, air trapping may also contribute to lower lung parenchymal attenuation in patients with CTEPH, most likely because of secondary impairment of the small airways.52 Regions of higher lung parenchymal attenuation in CTEPH usually represent hyperperfused lung tissue resulting from redistribution of pulmonary blood flow. Augmented perfusion from collateral vessels may also contribute to focal areas of hyperattenuation. Differentiation from small airway disorders can be aided by assessing the size of vessels within the low attenuation zones (attenuated with small vessel and normal with small airway disorders) and by expiratory imaging, which can highlight air trapping in areas of low attenuation with small airway disorders. Minimum-intensity projection CT technique improves the detection of the mosaic attenuation pattern, whereas maximum-intensity projection images highlight variations in vessel caliber.

Cylindrical bronchiectasis is occasionally observed within segmental and subsegmental bronchi in the setting of CTED, adjacent to severely stenosed or thrombosed PAs.53 Although the exact cause is unknown, hypoxic bronchodilation has been suggested as a possible mechanism.54

Patients with CTE typically show changes related to old infarcts, although acute infarcts secondary to superimposed acute thromboembolic disease are not uncommon. On CT, in its most acute form, the infarct appears as an area of consolidation and/or ground-glass opacity, in keeping with an area of pulmonary hemorrhage. As the infarction evolves, it acquires the typical appearance of an infarct, seen as a peripheral wedge-shaped, pleura-based density. Other characteristic findings include internal air lucencies, truncated apex (cutoff tip), and a thickened vessel leading to the apex of the infarct, the vascular sign.55 Over time, the infarct contracts and resolves, leaving residual scars or bands. There may be an associated pleural reaction, manifested as pleural thickening or fluid.56 Nodules and cavitary opacities are not uncommon.

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CT Findings Related to PH—Vascular Signs

Increasing PVR can act in concert with other factors and lead to the development of PH, which is reflected on CT as enlargement of central PAs. PA diameters over 29 mm are often used as a threshold for PH. The measurement is performed at the plane of the pulmonary bifurcation orthogonal to the vessel course57,58 (Fig. 10). In a recent study, right and left PAs over 18 mm in size were found to be best predictors of mortality in patients with bronchiectasis.59 A ratio of distal main PA to aortic diameter of over 1 is also suggestive of PH, particularly in younger patients.58 ECG-gated examinations have been shown to improve the evaluation of functional parameters such as PA distensibility and RV function in these patients.60,61

In long-standing PH, mural calcifications can develop. Chronically elevated PAP can lead to secondary morphologic changes in the pulmonary vascular tree, such as vessel tortuosity and arterial pruning. In a pilot study on 24 patients, automated extraction of lung vessels from the CT data set and calculation of tortuosity of the segmented lung vessels were found to be helpful in noninvasive assessment of severity of PH.62 Another study showed good correlation of fractional dimension with elevated PAP.63 A similar study on 18 patients showed that patients with CTEPH exhibited greater pruning of the distal vasculature, greater dilation of proximal arteries, and increased tortuosity in the pulmonary arterial tree.64 These measurements correlated with invasive metrics of pulmonary hemodynamics, suggesting that these may be used to assess disease severity. It is still unclear whether these morphologic changes can help distinguish CTEPH from other groups of PH. One finding that may help is that CTEPH was not associated with dilation of proximal veins or increased tortuosity in the venous system. Also, the location of the pruned vasculature might provide clues; upper lobe–predominant pruning would be expected in smoking-related PH.65

Development of right heart dysfunction is a natural endpoint of PH and is a main cause of death in these patients. Chronically elevated pulmonary pressures increase the workload on the heart, resulting in RV hypertrophy and enlargement (Fig. 10). Assessment of RV is suboptimal on non–ECG-gated examinations but is improved on ECG-gated studies.60 RV hypertrophy can be reliably diagnosed when the free wall of the RV measures over 4 mm66 (Fig. 10). RV enlargement can be reliably predicted when the ratio of the diameter of the RV to that of the left ventricle (LV) is over 1 (Fig. 9). Increased septal angle on ECG-gated studies is seen with elevated PAP and correlates with PVR in patients with CTEPH67 (Fig. 10). Mild pericardial reaction in the form of effusion or thickening may also be noted.68

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CT Findings Related to PH—Lung Parenchymal Signs

Analysis of lung parenchyma allows identification of disorders of groups 3 and 5 PH, such as emphysema, interstitial lung disease (ILD), sarcoidosis, or Langerhans cell histiocytosis.69,70 Recognition of the CT findings related to these diseases allows exclusion of CTEPH as the cause of PH. As described above, mosaic attenuation of the lung parenchyma can be seen with any cause of PH and can be related to chronic thrombotic disease or distal vasculopathy. However, it is more frequently seen in CTEPH compared with other etiologies of PH.51 Centrilobular lung nodules may also be observed in patients with PH, which are believed to be related to repeated episodes of pulmonary hemorrhage leading to macrophage ingestion of red blood cells and formation of cholesterol granulomas71 (Fig. 11). Although characteristically seen with IPAH,72 these can also be seen with long-standing left to right heart shunts as well as ILDs, including subacute hypersensitivity pneumonitis and smoking-related respiratory bronchiolitis.70 In PVOD, ground-glass opacities can be seen in diffuse, geographic, mosaic, perihilar, patchy, or centrilobular patterns.73 The nodules seen with PCH are larger than the true centrilobular nodules, and these ground-glass nodules are larger than those seen with PVOD.74 In PVOD, additional discrimators over PCH and idiopathic PAH are the presence of interlobular septal thickening and pleural effusions.70,75 A rare cause of centrilobular nodules in the setting of PH includes intravenous injection of filler substances such as talc, which induces a foreign body reaction around the arterioles.76

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Dual-Energy CT (DECT)

DECT uses attenuation differences at various energy levels to differentiate between tissue materials. X-ray attenuation is dependent on Compton scatter and photoelectric absorption, which vary with photon energies and material compositions. The probability of photoelectric effect increases with increasing atomic number and decreases with increasing photon energy.77 For materials with higher atomic numbers, such as iodine, the photoelectric effect markedly decreases with increasing photon energy, resulting in a rapid decrease in Hounsfield unit value. Thus, by using low and high voltages, relative differences in the absorption characteristics of materials such as iodine and xenon can be exploited to characterize their content within the tissue. The iodine within a voxel is quantified, and iodine perfusion maps are generated. It should be noted that these are not true perfusion images, as they measure iodine content at a single time point. However, these images do serve as an effective surrogate for the assessment of perfusion.78 Automated quantification of perfused blood volume (PBV) images can be done, which allows objective comparison of perfusion abnormalities in different lung segments.

Hemodynamic impairment is a critical factor in determining whether a patient is eligible for surgical intervention, and DECT offers the potential for “one-stop” assessment of this factor. As on V/Q and magnetic resonance imaging (MRI) scans, acute perfusion defects on DECT are seen as wedge-shaped areas of decreased attenuation and corresponding decreased iodine content (Fig. 12). Some studies have shown excellent correlation between the perfusion maps obtained using DECT and those obtained using V/Q scans and SPECT-CT examinations.79,80 Limited but encouraging data correlating regional perfusion maps with hemodynamic parameters and lung parenchymal findings have been reported. In 1 study, DECT allowed the identification of areas of mismatching, using a partition value of 20 Hounsfield unit to differentiate areas of residual perfusion distal to proximally occluded segments.81 These areas were postulated to be perfused by collaterals (such as bronchial arteries); the presence of such segments could be predictive of greater postoperative success than matched defects. In the same study, no significant correlation was found between PBV maps and RHC-derived mPAP and PVR.81 However, in another study in 25 patients with CTEPH, automated PBV values inversely correlated with PASP and mPAP.82 There was also a trend of PBV values to correlate inversely with PVR.82 Similarly, a recent study showed that automated lung PBV scoring can serve as a noninvasive estimator of clinical CTEPH severity, especially in comparison with the mPAP and PVR.83 Another study on 391 patients demonstrated that PH patients demonstrate increased main PA enhancement with a reciprocal reduction and greater variation in parenchymal enhancement; a DECT ratio of central to parenchymal enhancement correlated with PVR.84

Another novel application of DECT is the ability to differentiate between acute and CTED and assess the amount of bronchial artery collaterization (Fig. 13). As noted earlier, some studies have shown that the presence of bronchial artery collaterization is associated with better postoperative success.42,66 Using a 2-phase scanning protocol, in a study on 114 patients, it was shown that chronic PE segments showed more enhancement on delayed phases than did acute PE segments, suggesting more collateral supply to these regions.85

DECT can also help in the assessment of the various causes of mosaic attenuation and provide results that point to a specific vascular pathology.86 For example, in areas of ground-glass opacities, by demonstrating increased or no perfusion, it can aid in differentiating a vascular process from primary lung infiltration. DECT also aids in the differential diagnosis of various groups of PH.87 Typically, group 1 diseases such as IPAH demonstrate mottled perfusion as compared with the segmental defects with CTEPH. Perfusion abnormalities may also be caused by parenchymal destruction as in ILD, diffuse small airway disease, or pulmonary emphysema. Correlating the PBV maps with lung reconstructions can show that these defects match the areas of parenchymal destruction and thus help differentiate group 3 PH disorders. Finally, DECT can be used to assess V/Q. Use of inert agents such as xenon has been applied to map distribution in the lung parenchyma and thereby generate information on ventilation.88 Initial study results have been encouraging, suggesting that a true DECT V/Q study may be possible.89

Although DECT offers considerable promise in CTEPH, PBV maps require careful interpretation. Pseudodefects can be seen because of artifacts such as beam-hardening artifacts or motion artifacts near the heart or the diaphragm. These artifacts need to be avoided or recognized before a diagnosis is reached.87 Typical beam-hardening defects affect the medial right lung (predominantly in the right upper lobe) due to contrast in SVC. As noted above, PBV maps always require interpretation in relation to morphologic pulmonary reconstructions in order to exclude underlying lung process such as emphysema.

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MRI and MR Angiography (MRA)

MRI and MRA play a growing role in the evaluation of pulmonary thrombotic disease. Some tools, such as cine imaging and phase-contrast velocity-encoded MRI (PC-MRI), provide valuable functional information and have a definite role in the follow-up of patients.90 However, technical demands and suboptimal evaluation of lung parenchyma currently limit the use of MRI as a single imaging test in CTEPH.

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MR Findings Related to Pulmonary Thromboembolic Disease—Anatomy

Imaging features of pulmonary thromboembolic disease on contrast-enhanced MRA are similar to those seen on CTA, including irregular eccentric filling defects within the PAs, intraluminal webs and bands, and areas of stenoses and occlusion91 (Fig. 14, Cine clip 2, Supplemental Digital Content 2, A lack of signal intensity in the normal lung limits evaluation of the peripheral vasculature, as the low signal intensity of the occluded vessel is indistinguishable from that of the surrounding lung.92 Typically, branches down to the segmental levels can be reliably assessed with MRI.93 Because of its higher spatial resolution, better contrast-noise ratio, and faster imaging times (enabling better breath-holding), CT is better suited for subsegmental vasculature assessment than MRI and remains the diagnostic test of choice for the evaluation of morphologic abnormalities.94 However, as most surgically accessible thrombi are limited to the central and segmental branches, the ultimate significance of subsegmental disease characterization is unknown.

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MR Findings Related to Pulmonary Thromboembolic Disease—Function

Cine steady state free precession imaging is an accepted reference standard for the evaluation of LV and RV function, with excellent accuracy and reproducibility.95 PC-MRI allows for estimation of cardiac output with low interobserver and intraobserver variability.96 PC-MRI and cine steady state free precession imaging can also be combined to quantify shunt fraction (Qp/Qs), which indirectly reflects the degree of bronchopulmonary shunting in these patients.42

Recent research has shown good correlation between MRI-derived mPAP and PVR measurements and angiographic measurements.97,98 MRI can highlight indirect signs of elevated PAP, including delayed enhancement at the septal insertion points of the myocardium and systolic bowing of the interventricular septum toward the LV, which is explained by the mechanical dyssynchrony resulting from RV overload and elongation and LV underfilling.99,100 Functional indices such as PVR, mPAP, and RV function have important prognostic implications and can be used to assess functional improvement after pulmonary thromobendarterectomy.91,101,102 Emerging techniques such as 4D velocity flow mapping may provide additional insights into flow patterns in pulmonary circulation.103

In theory, MRI seems to be a good option for perfusion imaging, which could make this modality a true “one-stop” test for assessing PH and CTEPH. Limited data evaluating the assessment of lung perfusion with MRI have shown good correlation with perfusion scintigraphy.93,104 One of the constraints involved in assessing lung perfusion is the dynamic nature of pulmonary microcirculation. Quantitative perfusion parameters, including mean transit time, time to peak, and blood volume, can be estimated on the basis of the indicator dilution theory, but this estimation involves several assumptions and limitations.105 One of the main limiting factors is that indicator dilution theory is applicable to intravascular agents, whereas most gadolinium agents are extracellular agents; the effect of the agent diffusing into the extracellular space is not fully clear. The nonlinear function of gadolinium agents and lack of correction for patient hematocrit are additional limitations of this method.106 In addition, some of the published studies involved time-resolved MRA with view sharing, which involves incorporation of data from previous time points. Although this technique can provide qualitative assessment of perfusion (and defects) (Cine clip 3, Supplemental Digital Content 3,, quantitative perfusion imaging is not truly achieved, as this technique requires evaluation of the blood flow in a region over multiple time points. The use of noncontrast Fourier decomposition has also been explored as a method for assessing V/Q, as this technique requires no intravenous or inhaled contrast.107,108

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RHC and Conventional Angiography

RHC remains the gold standard for defining the severity of PH and for assessing the severity of cardiac dysfunction. Hemodynamic assessment during RHC is typically performed at rest, although some patients may benefit from exercise-induced measurements.109 In such patients, exercise is postulated to uncover compensatory mechanisms and may unmask a clinically relevant stage of CTEPH with coexisting small vessel hypertensive changes.110 Using waveform analysis, this technique may help to identify a subset of patients with small vessel disease who may not benefit from surgery.111

Although considered the gold standard for the diagnosis of CTEPH, conventional angiography has steadily decreased in utliziation with the increasing use of cross-sectional imaging such as CT.112 The success of BPA might change this status in the near future and mark a resurgence of catheter angiography. The risks associated with angiography should be considered carefully, particularly in patients with PH, as contrast agents can potentially precipitate vasodilation and hypotension. Nonetheless, conventional angiography is generally safe and can be performed as part of RHC, when appropriate precautions are taken.113

RHC and conventional angiography are used to define the surgical accessibility of the thrombotic lesions, to quantify PVR, and to determine whether PVR is secondary to surgically treatable disease or distal arteriopathy.42,114 Biplane angiography is preferred, as concurrent orthogonal acquisitions improve interpretation of the pulmonary vessels, particularly lobar and segmental branches. Direct endovascular visualization (angioscopy) may be performed; however, its use has declined as newer noninvasive techniques provide satisfactory means to assess surgical accessibility of thrombotic disease.115

Five angiographic patterns have been described in the literature, including “pouching” defects, webs or bands, intimal irregularities, abrupt vascular narrowing, and complete vascular obstruction41 (Fig. 12C). As the thrombus can retract and assimilate in the vessel lumen and cause varying degrees of retraction and occlusion, interpretation of angiographic patterns can be challenging. Consequently, CT probably provides more reliable evaluation of pulmonary thromboembolic disease—particularly in subsegmental branches.94 Conventional angiography allows for excellent qualitative assessment of the pulmonary blood flow and in mapping perfusion defects (Cine clip 4, Supplemental Digital Content 4,

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PTE is a complex surgical procedure and a true endarterectomy in which surgically accessible thrombotic material is removed. Typically, thromboembolic burden in main, lobar, and segmental branches is deemed operable, whereas distal (subsegmental/microvascular) disease is usually considered inoperable. However, assessment of surgical candidacy can often be influenced by several other factors such as age, conditioning, degree of hemodynamic impairment, and preoperative PVR.116 Often, a multidisciplinary discussion among surgeons, pulmonologists, and radiologists is necessary in clinical decision making. For radiologists, one of the key points to note is that if the extent of anatomic disease correlates with the degree of increased PVR, the disease is usually deemed operable. However, if the disease burden appears mild or relatively normal in the context of disporoportionately elevated PVR, the possibility of small vessel arteriopathy is likely.116

The roles of various imaging modalities in the evaluation of common causes of PH are summarized in Table 3. The roles of various imaging techniques in assessing the morphologic and functional changes of CTEPH are summarized in Table 4.

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Imaging is often used to monitor patients on medical therapy and for assessment of response to therapy following PEA and BPA. Successful PTE is associated with immediate improvement in hemodynamics, with reduction in PVR and PASP.117 Several noninvasive tools can be used in conjunction with clinical tools such as 6-minute walk test to assess functional recovery. Echocardiography is the easiest and readily available test and can be used to assess posttherapy LV and RV remodeling. Newer techniques such as 2D speckle tracking may allow better assessment of cardiac function after therapy.118 One of the disadvantages of echocardiography, however, is that direct visualization of the disease burden is not possible. CTA and MRI are well suited for depiction of improvement of thrombus burden, although they are not routinely used. MRI, although slightly inferior to CTA in the assessment of pulmonary vascular thrombotic disease, can be extremely helpful in the evaluation of functional recovery. Several MRI-based noninvasive biomarkers such as PA maximum flow velocity, acceleration time/ejection time, and distensibility can be evaluated using MRI.119 RV remodeling and adaptation is also better evaluated with MRI than with any other imaging technique.120

A major role of imaging is in the assessment of complications. After PTE, some of the early complications include reperfusion pulmonary edema and PA steal syndrome. PA steal syndrome, seen in approximately 70% of patients after PTE, is characterized by new areas of V/Q mismatching and reflects the redistribution of blood flow from normally perfused lung to the newly endarterectomized segments.121 One of the intermediate to long-term complications of PTE is residual PH, seen in approximately one-third of patients.122 Causes include distal inoperable subsegmental disease and/or coexisting small vessel arteriopathy.122 Recurrent PH is less common and is due to a new thromboembolic event after successful PTE.116 CTA and MRI are promising tools for assessing residual/recurrent PH, with both having their respective strengths. DECT with its ability to provide perfusion information along with excellent depiction of thrombotic disease might evolve as a frontline test for evaluation of complications.

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The role of imaging in the diagnosis and management of CTEPH continues to expand rapidly. With the success of newer minimally invasive therapies such as BPA, a variety of therapy options are available. One of the holy grails in the imaging of CTEPH remains the identification of microvascular disease. So far, there is no gold standard for direct identification of microvascular disease. Angiography-based partitioning of PVR by a PA occlusion technique may allow the identification of patients with small vessel disease but is invasive and technically demanding.111 A handful of studies have shown the potential role of echocardiography and MRI in identifying these patients. Using Pulsed Doppler and PC-MRI, the PA systolic profile is mapped and assessed for the presence of systolic notching. The timing of the systolic notch is used as a predictor of the site of obstruction, with a late systolic notch indicating the presence of microvascular disease.123 Although such advances are promising, larger studies are needed to fully assess the benefit of these noninvasive markers of microvascular disease.

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Imaging plays an important role in the diagnosis of CTEPH, its preoperative evaluation, and in the assessment of a patient’s response to therapy. Although V/Q scanning continues to be favored as the initial screening test of choice, CT has emerged as the definitive imaging test of choice in depicting the structural and vascular abnormalities in CTEPH. MRI plays a complementary role, providing crucial functional and physiological information that carries prognostic value. The emergence of new methods such as DECT, SPECT V/Q, SPECT-CT V/Q, and newer MRI techniques heralds an exciting and promising shift in imaging paradigms that may improve clinical decision making and ultimately lead to more favorable patient outcomes.

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chronic thromboembolic pulmonary hypertension; computed tomography; ventilation-perfusion scan; magnetic resonance imaging

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