Assessment of Pulmonary Hypertension

Assessment of Pulmonary Hypertension: What CT and MRI Can Provide Yuka Okajima, MD, Yoshiharu Ohno, MD, PhD, George R. Washko, MD, Hiroto Hatabu, MD, PhD Rationales and Objectives: Pulmonary hypertension (PH) is a life-threatening condition, characterized by elevated pulmonary arterial pressure, which is confirmed based on invasive right heart catheterization (RHC). Noninvasive examinations may support diagnosis of PH before proceeding to RHC and play an important role in management and treatment of the disease. Although echocardiography is considered a standard tool in diagnosis, recent advances have made computed tomography (CT) and magnetic resonance (MR) imaging promising tools, which may provide morphologic and functional information. In this article, we review image-based assessment of PH with a focus on CT and MR imaging. Conclusions: CT may provide useful morphologic information for depicting PH and seeking for underlying diseases. With the accumulated technological advancement, CT and MRI may provide practical tools for not only morphologic but also functional assessment of patients with PH. Key Words: Pulmonary hypertension; CT; MRI; assessment. ªAUR, 2011

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ulmonary hypertension (PH) is a life-threatening condition, characterized by elevated pulmonary arterial pressure (PAP) and secondary right ventricular (RV) failure. It has been defined as a mean PAP greater than or equal to 25 mm Hg at rest, based on right heart catheterization (RHC) (1). Numerous causes of PH exist. The latest clinical classification—Dana Point classification—comprises five major categories that share pathologic, clinical, and therapeutic features and is intended to standardize diagnosis and treatment and to conduct clinical trials in a well-characterized group of patients (Table 1) (2). Patients with PH often present dyspnea, fatigue, chest pain, syncope, and abdominal distension (3), which may precede RV dysfunction and death. These nonspecific symptoms are often obscured by manifestations of underlying diseases, such as interstitial lung disease and chronic obstructive pulmonary disease, and patients with mild PH may often be asymptomatic. This may lead to delays in diagnosis, although diagnosis of mild PH may be more important for therapeutic reasons.

Acad Radiol 2011; 18:437–453 From the Department of Radiology (Y.O., H.H.), Center for Pulmonary Functional Imaging (Y.O., G.R.W., H.H.), and Pulmonary and Critical Care Division (G.R.W.), Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115; Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (Y.O.). Received November 12, 2010; accepted January 12, 2011. Address correspondence to: Y.O. e-mail: [email protected] ªAUR, 2011 doi:10.1016/j.acra.2011.01.003

The initial diagnostic process for patients with suspected PH requires a series of evaluations, including electrocardiogram (ECG), 6-minute walking test, cardiopulmonary exercise test, brain natriuretic peptide or N-terminal pro-brain natriuretic peptide test, echocardiography, and RHC. These are to 1) confirm the diagnosis of PH, 2) clarify the clinical PH group and specific etiology within a pulmonary arterial hypertension (PAH) group, and 3) evaluate functional and hemodynamic impairments (1). The goals of this process are to determine the severity of disease, its prognosis, and to establish an appropriate treatment strategy according to the precise category. RHC is the gold standard for this initial assessment, and is also recommended for follow-up evaluation (1). Although the morbidity and mortality related to RHC have become low when performed at experienced centers (1.1% and 0.055%, respectively) (4), noninvasive imaging evaluations may be desired to support carrying out this invasive procedure. Transthoracic echocardiography is recommended in the diagnostic workup for suspected PH (5). However, recent progress in both computed tomography (CT) and magnetic resonance (MR) technology has extended their roles in disease diagnosis and management. Although morphologic and hemodynamic parameters from CT and magnetic resonance image (MRI) have not yet replaced those from echocardiography or RHC, they may add weight to a diagnosis of PH and assessment of severity (3). In this article, we review general roles of CT and MRI in diagnostic strategy for PH, and discuss their potential roles and future directions. 437

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TABLE 1. Clinical Classification of Pulmonary Hypertension (Dana Point, 2008) 1. Pulmonary arterial hypertension 1.1. Idiopathic 1.2. Heritable 1.2.1. BMPR2 1.2.2. ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia) 1.2.3. Unknown 1.3. Drug- and toxin-induced 1.4. Associated with 1.4.1. Connective tissue diseases 1.4.2. HIV infection 1.4.3. Portal hypertension 1.4.4. Congenital heart diseases 1.4.5. Schistosomiasis 1.4.6. Chronic hemolytic anemia 1.5. Persistent pulmonary hypertension of the newborn 10 . Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 2. Pulmonary hypertension from left heart disease 2.1. Systolic dysfunction 2.2. Diastolic dysfunction 2.3. Valvular disease 3. Pulmonary hypertension owing to lung diseases and/or hypoxia 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4. Sleep-disordered breathing 3.5. Alveolar hypoventilation disorders 3.6. Chronic exposure to high altitude 3.7. Developmental abnormalities 4. Chronic thromboembolic pulmonary hypertension 5. Pulmonary hypertension with unclear multifactorial mechanisms 5.1. Hematologic disorders: myeloproliferative disorders, splenectomy 5.2. Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4. Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis ALK-1, activin receptor-like kinase 1 gene; BMPR2, bone morphogenetic protein receptor, type 2; HIV, human immunodeficiency virus. Adapted from Simonneau et al (2).

COMPUTED TOMOGRAPHY The main role of CT is to explore associated underlying diseases, such as diffuse lung disease, to determine PH clinical classification (1). CT has an advantage in clearly demonstrating lung parenchymal changes with good reproducibility. CTequipment is easily accessible in daily clinical practice, and 438

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short acquisition time enables CT to scan patients with a short breath hold. Because clinical manifestation of PH is often difficult to depict in patients at high risk for PH, the radiological suggestion of PH sometimes plays an important role in clinical practice. Therefore, knowledge of general CT findings of PH and PH-associated diseases is essential. CT Findings of PH

PH is hemodynamically classified into two categories: precapillary and postcapillary. Precapillary PH is defined as PH with pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mm Hg based on RHC, which includes PH with pathological changes limited to the arterial side of the pulmonary circulation, especially at the level of the muscular arteries. Postcapillary PH is defined as PH with PCWP of more than 15 mm Hg, which includes PH attributed to primary changes within pulmonary venous circulation between the capillary bed and the left atrium (6). This classification is of value, because it corresponds to a different therapeutic strategy; reduction of PCWP is the primary goal for treatment of postcapillary PH, whereas treatment of precapillary PH includes therapy to decrease pulmonary vascular resistance (PVR) as well as specific therapy for underlying diseases if present. Precapillary PH. The important feature in precapillary PH is vasoconstriction, predominantly at subsegmental levels, caused by vascular remodeling, which increases vascular resistance, resulting in dilation of the central pulmonary arteries (5). Thus, common CT findings in precapillary PH include 1) central pulmonary arterial enlargement and 2) ‘‘pruning’’ or loss of the peripheral vascularity (7). Elevated PAP increases RV pressure, which leads to RV hypertrophy. More increase in PAP may cause dilation of the RV and tricuspid valve, accompanied by tricuspid regurgitation, resulting in dilation of the right atrium (RA). Therefore, patients with severe PH present 3) RV hypertrophy; 4) RV dilation; and 5) flattening and bowing to left of the interventricular septum (Fig 1), which may be followed by 6) dilation of RA, superior vena cava (SVC), and inferior vena cava (IVC); and 7) regurgitation of contrast media into RA, SVC, and IVC from secondary tricuspid regurgitation (8,9). A mosaic parenchymal attenuation pattern is sometimes present, reflecting inhomogeneous perfusion. A large amount of fluid within the anterior pericardial recess is also seen more frequently in patients with PH than in normal individuals (10,11). Precapillary PH includes many causes. CT can demonstrate both intrapulmonary and extrapulmonary findings of PH-associated diseases. Among these causes, identification of chronic thromboembolic pulmonary hypertension (CTEPH) is especially crucial for therapeutic reasons: treatment for CTEPH includes thromboendarterectomy, whereas other forms of PH should be treated with medical therapy, or lung or heart-lung transplantation (1). Thus, we focus on CT

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CT AND MRI OF PULMONARY HYPERTENSION

Figure 1. Contrast enhanced chest computed tomography images of a 38-year-old female with pulmonary veno-occlusive disease with pulmonary hypertension. (a) The main pulmonary arterial diameter is dilated and the pulmonary artery/ascending aorta ratio is larger than 1. (b) The dilated right atrium and ventricle and the right ventricle hypertrophy are seen. The intraventricular septum is bowing toward the right. (c) The diameter of the segmental pulmonary artery is larger than the outer diameter of the adjacent bronchiole. There are diffuse illdefined centrilobular ground-glass opacities and subpleural septal thickening.

findings of CTEPH and discuss the roles that CT may play in diagnostic strategy. CTEPH (Group 4). The prevalence of CTEPH after acute pulmonary embolism (PE) is suggested to be 0.5–2% (1), but up to 63% of patients diagnosed with CTEPH give no previous history of definite acute PE (12). Therefore, examinations to exclude CTEPH should be performed in all patients with suspected PH. The best screening test to exclude CTEPH remains the ventilation-perfusion (V/Q) lung scans; a normal or very low probable result on V/Q scans essentially excludes CTEPH, with sensitivity of 90–100% and specificity of 94–100% (1). However, positive V/Q results may include various diseases, such as pulmonary artery (PA) sarcoma, large-vessel pulmonary vasculitis, extrinsic vascular compression, pulmonary veno-occlusive disease (PVOD), or pulmonary capillary hemangiomatosis (PCH) (13). Thus, computed tomography pulmonary angiography (CTPA) is indicated when a V/Q lung scan shows indeterminate possibility or reveals perfusion defects (1,3). CT findings in patients with CTEPH include 1) complete obstruction of a vessel that is smaller than adjacent patent vessels; 2) chronic thromboembolic material within the pulmonary arteries, such as mural defects indicating thrombi along the arterial wall, railway track signs indicating floating thrombi, contrast material flowing through thickened smaller arteries indicating recanalization, or a web or flap within a contrast material-filled artery; 3) subpleural opacities, representing prior infarcted areas; and 4) mosaic attenuation of the pulmonary parenchyma (1,14–16), in addition to findings of precapillary PH discussed previously. A marked variation in size of segmental vessels seems specific for CTEPH (15). Image reformations derived from multidetector row CT (MDCT) with nearly isotropic voxels with high spatial resolution, such as maximum intensity projections (MIP), multiple planar reformations (MPR), and three-dimensional images,

have improved detection of thromboemboli in distal pulmonary arteries, and provide a useful overview of the entire PA tree (17). Recent studies reported that multidetector row CTPA enabled accurate evaluation of distal pulmonary arteries down to the fifth order (18), and improved detection of segmental and subsegmental PE in patients with acute PE, with higher interobserver agreement compared to conventional digital subtraction angiography of pulmonary arteries (19). However, few studies have evaluated chronic PE (5,16,20). The sensitivity and specificity for depiction of chronic PE have been reported to vary widely compared with conventional pulmonary angiography: one study reported a higher sensitivity and specificity of 98.3% and 94.8% at main/lobar level, and 94.1% and 92.9% at segmental level (17,21), and another reported a sensitivity of 70.4% for segmental and 63.6% for subsegmental arteries (17,21). On the other hand, V/Q scans tends to correlate poorly with the severity of obstruction (22), and to underestimate the severity of large-vessel obstruction in CTEPH (23). Thus, multidetector row CTPA is useful to depict surgically accessible PE, which is essential for preoperative assessment (1), whereas the main utility of V/Q scans may be limited to depiction of thromboemboli at the subsegmental PA level where CT often fails to detect. A mosaic attenuation pattern has been a well-recognized feature of CTEPH (15), described as the coexistence of sharply demarcated parenchymal areas of increased attenuation with normal or increased-in-size segmental arteries, and those of decreased attenuation with relatively small segmental arteries (16). It may also be seen in patients with other forms of PH, especially PAH due to vascular disease (24), which tends to present diffusely distributed, whereas it may be limited to a few segmental or subsegmental vessels in patients with CTEPH. It may also be seen in patients with small airway diseases, in whom it reflects air trapping, 439

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tends to be emphasized on expiratory CT, and is often accompanied by bronchial dilation. Although the mechanism of mosaic perfusion is still unclear, it is suggested to represent hyperperfused and hypoperfused parenchyma, reflecting small vessel obliteration (15). Some studies showed that hyperattenuated areas on CT were compatible with perfused lung on V/Q scans and better enhanced with contrast media, and that mosaic attenuation disappeared after thrombectomy in patients with CTEPH (25). Dilated bronchial artery collaterals or other systemic collateral vessels, indicating compensatory pulmonary perfusion through these systemic arteries, may also support diagnosis of PH with embolic causes, although these collaterals are nonspecific, and also seen in some cases associated with congenital heart disease, idiopathic pulmonary arterial hypertension (IPAH), veno-occlusive disease, and bronchiectasis (26–30). Total cross-sectional area of bronchial arteries was reported to correlate strongly with the extent of central PE in patients with CTEPH, indicating a favorable predictor for postsurgical outcome (31).

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causes of postcapillary PH, or left heart diseases. Patients with PVOD may also present characteristic CT findings: subpleural smoothly thickened septal lines, gravity-dependent ill-defined centrilobular ground-glass opacities and mediastinal lymphadenopathy, as well as pleural effusion (33,34) (Fig 1). The presence of these three findings was reported to have sensitivity and specificity of 66% and 100%, respectively, for diagnosing PVOD in patients with PAH (34). These findings may also be clinically important, because their presence shows a close correlation with the risk of pulmonary edema due to epoprostenol (prostaglandin I2) therapy (35,36). PCH may demonstrate similar histological and radiographic features to PVOD, and differentiation of these diseases is often difficult. There has been controversy as to whether PCH is a distinct entity or a sequel of PVOD (33,37). Patients with PCH may have well-defined ground-glass opacities as well as illdefined opacities, and tend to show nodular septal thickening (33,38,39).

Evaluation of the Presence and Severity of PH

Postcapillary PH. CT findings of postcapillary PH typically demonstrate features of interstitial pulmonary edema, such as 1) interlobular septal thickening, 2) centrilobular nodular opacities, 3) pleural effusions, and 4) increased opacities in lung, which may be accompanied by a wedge-shaped consolidation when macroscopic venous infarction is present. With severe pulmonary vein hypertension, findings derived from precapillary PH may also present. The most common causes of postcapillary PH are left heart diseases (Group 2). Although conventional CT cannot identify left heart diseases, it may indicate the presence of left heart dysfunction, based on CT findings such as left ventricular (LV) hypertrophy, caused by elevated LV pressure, and dilation of the left atrium and central pulmonary vein, due to elevated pressure of pulmonary veins and capillaries (5). To recommend further evaluation for left heart disease is important when these findings are depicted on CT. PVOD and PCH are uncommon diseases caused by obstruction of pulmonary veins and capillaries, respectively. To identify patients with these diseases is clinically essential; not only may they not respond to standard antipulmonary hypertensive medications, such as pulmonary vasodilators and PAH-specific agents, but these treatments may cause critical and potentially fatal acute pulmonary edema (1,32,33). Although surgical lung biopsy is considered to provide the definite diagnosis, it is not recommended due to the associated risk. CT may play an important role in an integrated diagnostic process based on less invasive examinations, including arterial blood gas analysis, pulmonary function test, and bronchoalveolar lavage, where occult alveolar hemorrhage may be demonstrated in cases with PVOD. PVOD and PCH (Group 10 ). CT findings of marked narrowing of the central pulmonary vein and a normal-sized left atrium are suggestive of PVOD and PCH, in contrast to other 440

Many investigations have evaluated the reliability of CT in detecting and estimating the severity of PH. There are two main approaches for evaluation of PH: morphologic and functional evaluation. Morphologic evaluations Evaluation of the pulmonary vasculature. Numerous studies evaluated the main PA diameter, which was measured at the level of the bifurcation lateral to ascending aorta (AA) or as the maximum dimension of the PA perpendicular to its long axis on two-dimensional axial images. The reported upper limit of the main PA diameter in normal individuals varied widely from 25 mm to 36 mm (40–42). A main PA diameter greater than 28.6 mm was first reported to have specificity of 100% with sensitivity of 69% for PH in patients with cardiovascular diseases without evidence of pulmonary fibrosis, using a comparatively low-mean PAP criterion for PH (18 mm Hg) (42). However, subsequent studies using different study subjects including patients with pulmonary parenchymal diseases, or patients referred to lung or cardiopulmonary transplantation, found that a main PA diameter greater than 29 mm had much lower specificity of 61–89% (43). Thus, there may be a considerable overlap in the absolute diameter of the main PA between patients with PH and normal individuals. The CT measurement of the main PA diameter has also been used to roughly estimate the severity of PH. Correlation coefficients between the CT-measured main PA diameter and RHC-derived mean PAP vary widely from 0.43 to 0.83 (42,44–47). Others have reported no correlation between them (43,48). These inconsistencies may derive from the wide variety of study populations. Although the size of pulmonary vessels may indirectly reflect PAP, it may also depend on complex factors including physiologic factors, such as sex, body constitution, blood flow, vessel

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compliance, and peripheral vessel resistance, pathologic factors such as underlying diseases, and the stage of the cardiac cycle at which images are obtained. A stronger correlation was shown in patients with more severe PH than in patients with mild PH (46). It is worth noting that no correlation was reported between the CT-measured main PA diameter and mean PAP in patients with pulmonary fibrosis and that considerable dilation of the main PA was observed in these patients even without PH, without relation to the extent of fibrosis (49,50). However, a significant decrease in CTmeasured main PA diameter was observed in patients with CTEPH after thrombectomy according to decrease in mean PAP, suggesting that CT measured-main PA diameter may be a useful marker for follow-up evaluation (44). Using refined measurements, such as cross-sectional area produced by two-dimensional diameters, instead of using a simple diameter, have not improved diagnostic accuracy (42,51). Furthermore, some studies also examined the diameter of the proximal PA other than the main PA, such as right and left main PA and right interlobar artery, and found that they did not strengthen the correlation with RHC-derived mean PAP (42,44,46). The ‘‘ratio of the PA to AA diameter (PA/AA ratio) >1’’ has become a widely accepted reliable sign to identify PH, which can easily be assessed on a single slice by just comparing the PA and AA diameter. It was reported to have a high specificity of 92% for PH with a definition of a mean PAP greater than 20 mm Hg for PH and also to demonstrate a strong correlation with RHC-derived mean PAP (correlation coefficient, 0.74), although the negative predictive value was reported relatively low (52%) (47). A multivariate analysis revealed that the PA/AA ratio was confounded only by age (47). The PA/AA ratio is suspected to internally normalize not only to other confounding factors but measurement techniques including window settings and cardiac cycles. To be noted, the PA/AA ratio may be more valuable to depict PH in patients with pulmonary fibrosis, because the ratio showed markedly stronger correlation with mean PAP than the main PA diameter alone in patients with pulmonary fibrosis, whereas that was not the case with patients without pulmonary fibrosis (50). Furthermore, the PA/AA ratio may possibly reflect PAP better than the main PA diameter in patients with severe PH, considering the fact that increase in PAP may lead to reduction of cardiac output (CO), resulting in decrease in size of the aorta (52). Other attempts to normalize CT measurements of the main or left PA using other confounding factors have failed to improve the correlation with mean PAP (42,46,51). Concerned with distal PA, limited studies have reported the segmental PA diameter as a reliable marker of PH (20,43,51,53), where its correlation with mean PAP was not superior to that of the PA/AA ratio (correlation coefficient, 0.44 and 0.67, respectively) (51). A recent study reported the presence of ‘‘the enlarged ratio of the segmental PA diameter to the outer diameter of the adjacent bronchus (segmental

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artery-to-bronchus ratio), defined as the ratio greater than 1.25, in three out of two upper and two lower lobes.’’ This ratio had sensitivity of 68% with a specificity of 87% for PH, and that it also corresponded to the severity of PH with high reproducibility (51). It should be noted that multiple lobes need to be evaluated; some normal individuals may show the enlarged segmental artery-to-bronchus ratio in a single branch, and localized dilation of the segmental arteries may also be present in patients with pulmonary fibrosis from blood redistribution. Limited studies have evaluated combined non-invasive measurements. In patients with parenchymal lung disease, a combination of ‘‘a CT-derived main PA diameter of 29 mm or more’’ and ‘‘a segmental artery-to-bronchus ratio greater than 1 as measured with CT in at least three out of two upper and two lower lobes’’ increased specificity for PH up to 100%, compared to the single criteria of the main PA diameter (43). A more recent study revealed that a combination of the CT-derived main PA/AA ratio and echocardiography-derived RV systolic pressure was a better predictor for PH and had stronger correlation with RHCderived mean PAP (correlation coefficient, 0.74) than either single measurement (correlation coefficient, 0.67 and 0.66, respectively) (51). MDCT allows for the identification and evaluation of the PA distal to segmental PA (18). The simple subsegmental PA diameter was reported to have no significant correlation with RHC-derived mean PAP (51). A recent study measured cross-sectional areas of subsegmental and sub-subsegmental pulmonary vessels with a unique semiautomatic method on two-dimensional axial CT images, defining vessels with a cross-sectional area of 5–10 mm2 as subsegmental vessels and those with a cross-sectional area less than 5 mm2 as subsubsegmental vessels, and found that the percentage of the total cross-sectional area of the sub-subsegmental vessels had an inverse correlation with RHC-derived mean PAP in patients with severe emphysema (correlation coefficient, 0.512) (Fig 2) (54). Cardiac evaluation. Increase in PAP may usually be followed by morphologic changes in the heart. Depicting these CT findings in clinical practice may be essential in order to not overlook critical diseases. Several studies have reported upper limits of normal cardiac structures measured on ECG-gated CT (Table 2) (55). Although conventional axial thoracic CT is not suitable for morphologic cardiac evaluation, these variables may serve to depict cardiac abnormalities even on conventional CT. The ratio of the RV diameter to LV diameter (RV/LV ratio), by measuring the widest short-axis diameter on transverse images and the presence of the interventricular septal deviation are used for evaluating RV dilation. An RV/LV ratio greater than 1 and 1.5 on nongated MDCT was reported to represent modest and severe RV dilation, respectively, in patients with acute PE (56–58). Although the same may be suggested for patients with PH, further study is needed for the utility of the RV/LV ratio in those patients. 441

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TABLE 2. Approximate Partition Values for Upper Limits of Normal for the Assessment of Cardiac Morphology Parameter Diameter of main pulmonary artery Transverse diameter of right ventricle Thickness of right ventricular free wall Transverse diameter of right atrium Thickness of interventricular septum Transverse diameter of left ventricle Thickness of left ventricular free wall Anteroposterior diameter of left atrium

Value (mm) 29 45 3 35 13 55 11 45

Adapted from Hoey et al (55).

high injection rate of contrast media was an independent factor for increasing the likelihood of reflux, as well as tricuspid regurgitation, RV systolic dysfunction, and PH, higher injection rate may lead to a higher sensitivity and lower specificity for depicting right heart dysfunction (59). It may be important to look for right heart diseases when reflux of contrast media into the IVC or hepatic vein is demonstrated on CT. Pulmonary parenchyma. The presence of subpleural opacities in patients with CTEPH showed a positive correlation with a poor outcome after endarterectomy (correlation coefficient, 0.32) (60). It was reported that decreased attenuation areas with normal or increased-in-size segmental arteries without diminished-in-size arteries correlated with a less favorable outcome in patients with CTEPH after surgical thromboendarterectomy, which may suggest small vessel disease (61). Limited studies have evaluated pulmonary parenchymal findings related to the severity of PH in patients with PH of other causes. Recent studies found no correlation between the extent of emphysema on CT and RHC-derived PAP (62,63), nor between the severity of pulmonary fibrosis and mean PAP (50,64).

Figure 2. The method of measuring the cross-sectional area of small pulmonary vessels using ImageJ software. (a) Computed tomography image of lung field segmented within the threshold values from 500 Hounsfield units (HU) to 1024 HU. (b) Binary image converted from segmented image (a) with window level of 720 HU. Pulmonary vessels are displayed in black. (c) Mask image for particle analysis after setting vessel size parameters within 0 to 5 mm2 and the range of circularity within 0.9 to 1.0. Reprinted with permission from Matsuoka et al (54).

Reflux of contrast media into IVC was reported to have specificity of 100% and sensitivity of 90.4% for detection of tricuspid regurgitation on CTPA with an injection rate of up to 4 mL/second. Reflux grading on CT also showed close correlation with RHC-derived mean PAP (correlation coefficient, 0.685) (8). Although a multivariable analysis found that 442

Functional evaluation. Although insufficient temporal resolution limited earlier conventional CT to cardiac imaging, recent MDCT techniques have made it possible to scan the entire heart within a single breath hold. Using retrospective ECG gating, cardiac MDCT provides several datasets at different cardiac phases within the response rate interval, which allows for quantitative functional analysis (65). The feasibility of deriving LV functional parameters from ECGgated MDCT has been demonstrated, and these correlated well with indices produced by other established modalities such as echocardiography and MRI (66,67). RV function is an especially important prognostic indicator in PAH (68). Several investigations have validated the utility of ECG-gated MDCT for estimation of RV function using various parameters such as RV ejection fraction (EF) and RV mass (69). Although ECG-gated RV measurements have been proposed for evaluating RV function in patients with acute PE (70), limited investigations have evaluated them in patients with chronic PH (71). Recent investigations using ECG-gated MDCT found that among parameters such as

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RV outflow tract diameter, cross-sectional area, and wall thickness, right PA distensibility, defined as the change in a cross-sectional area of the right PA between diastolic and systolic phase, was not only the most reliable to identify patients with PH but also had the strongest correlation with mean PAP (71). However, radiation exposure still makes ECG-gate MDCT questionable as a follow-up examination for assessment of hemodynamic function, although recent technical advances have reduced the radiation exposure of ECG-gated chest MDCT down to the lower level recommended for nongated chest MDCT (72). New Investigations and Future Directions

Most prior investigations have non-invasively evaluated the severity of PH based on two-dimensional measurements. Recent progress in CT hardware and software has allowed for three-dimensional measurement and volumetry of various structures. An investigation of 16 patients with chronic sleep apnea with semiautomatic three-dimensional volumetry of PAs on contrast-enhanced MDCT showed that the volumes of PAs removed of their mediastinal portion and normalized for body mass index, strongly correlated to mean PAP derived from RHC (correlation coefficient, 0.89) (45). Threedimensional measurements may provide more useful indices than two-dimensional CT images, because the PA may change in shape and relative correlation with surrounding structures as the disease progresses. Although current imaging examinations cannot yet directly demonstrate thromboemboli in the small PAs distal to the subsegmental PAs, pulmonary perfusion imaging reflecting microcirculation may compensate for this limitation. Microvascular obstruction is another critical prognostic factor to be assessed preoperatively for CTEPH (73). One approach to obtain perfusion imaging is to emphasize lung densitometry derived from CTPA scans with an optimized display of the density distribution. Thin slab minimum intensity projection reconstructions enhance mosaic attenuation patterns, which correlated well with scintigraphic perfusion patterns in 81.3% of patients with PH (74). Perfusion-weighted color maps to visualize parenchymal enhancement using color coding were reported to provide additional information to CTPA alone (75). Subtraction images between precontrast and postcontrast images may also emphasize perfusion images, and the technique was validated on an animal model (76). However, these techniques have the same disadvantages as original images: they are affected by underlying lung diseases and are unable to exclude mosaic attenuation due to other causes. Furthermore, double radiation subtraction technique requirements may also limit the clinical feasibility. These disadvantages may be overcome by techniques such as dual energy CT (DECT) and MR perfusion imaging. DECT with two X-ray tubes at different potentials can depict iodine, due to its demonstrating higher X-ray attenuation at low photon energies than most materials composing the body (77). Initial studies showed that lung perfusion studies on

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DECT were comparable to perfusion scintigraphy (77,78), and increased sensitivity for tiny distal thromboemboli, compared with CTPA alone (78). It could also depict perfusion defects beyond non-occlusive proximal thromboemboli (79,80). DECT scans can provide CTPA, a high-resolution morphologic image, and a spatially matched perfusion image simultaneously in a single scan, with a radiation dose comparable to that reported for conventional single-energy chest CTPA (80). However, the limited size of the B-detector system may lack peripheral information, especially in patients with a large body frame or with increased lung volume. Further optimization of the display settings and the injection protocols to reduce beam-hardening artifacts from dense contrast material may be required as well. Area-detector CT may be another promising tool. A new CT hardware with 320-detector rows provides volumetric imaging with an increase in the width of the detector of up to 16 cm, although it cannot cover the entire lung yet. Clinical feasibility has been validated in limited organs, such as brain, heart, and abdomen (81–83), but not yet in the lung. Areadetector CT may be expected to differentiate pulmonary arteries from pulmonary veins, and provide perfusion images (Figs 3, 4). Its use, however, includes radiation exposure. MAGNETIC RESONANCE IMAGING The main advantage of MRI, at present, is evaluation of the great vessels and the heart, where both anatomic and functional evaluation is possible without radiation exposure. Recent studies have reported that MRI is good at evaluating the heart, even the right heart, and that it has better reproducibility compared to echocardiography (84,85). Cardiac MRI has now become a well-established imaging modality for diagnosis and follow-up of various heart diseases, and is considered a gold standard, especially, for evaluation of the right heart (86,87), which plays a central role in diagnosis and management of patients with PH. Large Vessels

MRI is good at demonstrating anatomic abnormalities of the PAs. Early investigations have demonstrated that ECG-gated spin echo (SE) MRI may be useful for evaluating the central cardiovascular system, as rapidly flowing blood within the great vessels is seen as a signal void in high contrast to their walls or mediastinal structures (88–90). The main, left, and right PA diameters measured on ECG-gated SE MRI were reported to have strong correlations with those derived from conventional pulmonary angiography (correlation coefficient, 0.96, 0.96, and 0.93, respectively) (91). However, along with CT measurements, correlation of the main PA diameter and the ratio of the main PA to thoracic aortic diameter on ECG-gated SE MRI with RHC-derived mean PAP varies (correlation coefficient, 0.48–0.76 and 0.59–0.7, respectively) (92–94), and some investigations reported no correlation between them (94). 443

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Figure 3. A 70-year-old normal male. (a) Axial first-pass perfusion computed tomography (CT) map from 320-detector row CT data shows that pulmonary blood flow is increased in the dorsal region compared to the ventral region, reflecting gravity effect. (b) 320-detector row CT so-called area-detector CT obtains volumetric dynamic CT data without helical scan, and can also provide coronal perfusion map from same data set. On the coronal plane, regional difference of perfusion parameters is not observed in both lungs as compared with the axial plane.

Another important role in evaluating large vessels in patients with PH is to depict PE. Two different approaches have been developed to demonstrate thromboemboli: MR direct thrombus imaging and MR angiography (MRA). SE techniques positively enhance thromboemboli on T1-weighted images as intraluminal signal structures (95– 97). Besides thromboemboli, abnormal slow flow due to elevated PAP may also cause the presence of intraluminal signal in both systolic and diastolic phase (92,93,98). SE techniques are, at present, not of practical use due to their susceptibility to motion artifacts and flow artifacts. Cine (dynamic) gradient echo (GRE) techniques are sensitive to flow and have demonstrated the feasibility of the differentiation (99). However, they have limitations of in-plane spatial resolution and susceptibility artifacts. Inversion recovery (IR) techniques, which enhance intravascular emboli with selective nulling of blood signal, applied to GRE techniques are still unable to identify thromboemboli in distal to lobar PA branches (99). MRA is performed with and without intravenous injection of contrast media. Although noncontrast MRA, such as timeof-flight MRA, has successfully demonstrated the proximal pulmonary arteries (100,101), it has not been applied to clinical practice due to inferior spatial resolution, insensitivity to slow flow, and motion sensitivity. Contrast MRA works much better at present, and is used in clinical practice. Contrast-enhanced MRA has become well accepted for the evaluation of various pulmonary vascular diseases (5,102–105). Three-dimensional GRE sequences with short repetition time (TR) have made it possible to obtain MRA with a single breath hold (106,107). Few studies have evaluated CTEPH (108–111), although MRA with MPR and MIP visualizing the entire vascular tree has reported to detect acute PE as accurately as CTPA 444

(112), with high sensitivity of 68–100% and specificity of 95–99.7%, compared with conventional pulmonary angiography (102,103,112). Two-dimensional MRA has been reported to have sensitivity and specificity of 82–83% and 93–96% for chronic PE at lobar and 68–76% and 93–95% at segment arteries, compared with conventional pulmonary angiography (110). It has also been shown to differentiate CTEPH from IPAH with sensitivity of 92%, compared with V/Q scans (109). Three-dimensional MRA in patients with CTEPH has demonstrated all patent PAs down to a segmental level and 93% of patent subsegmental vessels, compared with pulmonary angiography (108). Another investigation found that three-dimensional MRA was as accurate as CTPA in detection of segmental occlusions of PAs and superior in demonstrating abnormal proximal-to-distal tapering in patients with CTEPH, although it was inferior in demonstrating patent segmental and subsegmental PAs (111). Recently introduced parallel imaging techniques and highfield-strength MRI may be expected to improve image quality. Although the number of phase-encoding steps reduces the signal-to-noise ratio in parallel imaging techniques, threedimensional pulmonary time-resolved MRA, combined with the sensitivity encoding and a sharp bolus injection of contrast media, has demonstrated simultaneously high spatial and temporal resolution with sensitivity and specificity of 83% and 97% for PE, compared with pulmonary angiography (113,114) (Fig 5). High-field strength MRI may increase signal-to-noise ratio, whereas it may also increase the susceptibility effects, leading to inferior image quality (115). However, a recent study has demonstrated that timeresolved MRA at 3 Tesla was feasible and provided high resolution of vascular structures (116). Increased PAP and dilation of the PAs may lead to stiffness and indistensibility of the proximal PAs (117). Some investigations evaluated PA distensibility on MRI, calculated from the

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Figure 4. A 73-year-old male with pulmonary emphysema and organizing pneumonia. Left: Computed tomography (CT) image shows severe pulmonary emphysema in both lungs and a mass in the right upper lobe (segment 2), which was diagnosed as organizing pneumonia with biopsy and follow-up CT examinations. Right: Axial first-pass perfusion CT map from 320-detector row CT data shows decreased pulmonary blood flow in the areas corresponding to pulmonary emphysema, compared to that of normal lung parenchyma.

change in cross-sectional area of the PA between systole and diastole: ðdiastolic cross  sectional areaÞ  ðsystolic cross  sectional areaÞ  100 systolic cross  sectional area

Patients with PH showed a significantly lower PA distensibility compared to normal subjects (118–120). MRI-derived PA distensibility may also reflect acute response to vasodilator therapy in patients with IPAH: a recent prospective study found that responders to acute vasodilator tests showed a significantly higher PA distensibility than nonresponders, and that a cutoff value of 10% PA distensibility may differentiate between them with sensitivity and specificity of 100% and 56% (120). However, correlation between PA distensibility and RHC-derived mean PAP has been controversial (119,120). Phase-encoding velocity mapping is another functional approach to evaluate blood flow in large vessels. Patients with PH show changes in blood flow patterns: inhomogeneous flow profiles with lower peak systolic velocity and higher retrograde flow after middle to late systole in the PAs (118,121,122). However, both retrograde flow and peak systolic velocity has no or poor relationship with RHCderived mean PAP (121–123). In a more recent study using time-resolved three-dimensional phase-contrast MRI, all patients with definite PH showed a vortex of blood flow in the main PAs with sensitivity and specificity of 100% and 100%, and the relative duration of the vertical flow in the main PA correlated with mean PAP (correlation coefficient 0.94) (124). Patients with PH also showed shorter time-topeak PA velocity and a steeper velocity increase gradient on phase-contrast MRI, compared with normal subjects (123). Another study found a significant decrease in peak velocity in the right and left PAs, but not in the main PA in patients with PH secondary to cystic fibrosis, which raises the possibility that phase-contrast MRI may reflect early hemodynamic abnormalities prior to RV dysfunction (125). Cardiac Evaluation

MRI pulse sequences have contributed to delineating anatomic structures, demonstrating intravascular lumen darker or brighter (black blood turbo SE techniques or bright blood

GRE techniques, such as steady-state free-precession pulse sequences) than surrounding structures. Conventional gradient-recalled echo or steady-state free-precession pulse sequences have been used to obtain cine images, or movies of 15–20 frames per cardiac cycle with temporal resolution of 30–40 ms per frame with breath hold of 5–18 seconds (87,126). Cine mode cardiac MRI can demonstrate regional and global abnormalities of wall motion and provide quantitative measurements, such as ventricular volumes, EF, and myocardial masses by drawing contours of endocardium and epicardium on short axis or transverse images at enddiastolic and end-systolic phase with postprocessed calculation (127). Although the complex geometry of the RV makes it difficult to identify it on short axis images, its assessment has been proven feasible (127). Several investigations have demonstrated that cardiac MRI-derived measurements are accurate (128–130) and have a higher reproducibility than those derived from echocardiography (84,85), although the reproducibility of the RV function is still inferior to that of LV function (131). Cardiac MRI in patients with PH shows RV dilation with hypertrophy, RA dilation, and flattening or bowing toward left of the interventricular septum (92,93). Some investigations have revealed that patients with PH show significantly thicker diastolic RV walls (92,93), larger RV mass, which is the product of myocardial volume and muscle-specific density, higher RV end-diastolic and endsystolic volumes, more dilated RV, and lower RVEF, RV stroke volume (SV), and RV CO, compared with normal subjects (132–135). Diastolic RV wall thickness and RV mass measured on cardiac MRI were reported to linearly correlate with RHC-derived mean PAP in patients with PH (correlation coefficient, 0.79–0.90 [92,93,136] and 0.75 [130], respectively). A ventricular mass index (VMI) greater than 0.6, obtained by dividing RV mass by LV mass, had sensitivity and specificity of 84% and 71% for detecting PH, and better correlation with RHC-derived mean PAP (correlation coefficient, 0.81) than RV mass alone and mean PAP derived from echocardiography (137). Another study showed much weaker correlation between them (correlation coefficient, 0.56) (138). Furthermore, a recent investigation demonstrated that the curvature ratio of the LV septal wall to the free wall measured on cardiac MRI had sensitivity and specificity of 87% and 100% for depicting elevated RV systolic pressure 445

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Figure 5. A 66-year-old male with acute pulmonary embolism. (a) Contrast-enhanced multidetector computed tomography demonstrates thrombi (arrows) in right main pulmonary artery, and bilateral interlobar, segmental, and subsegmental pulmonary arteries. (b) Source images of time-resolved contrast-enhanced magnetic resonance angiography (L to R: ventral to dorsal) show thrombi in bilateral main, interlobar, segmental and subsegmental pulmonary arteries, and heterogeneously reduced pulmonary parenchymal perfusion in both lungs.

and that estimated RV systolic pressure had a moderate agreement with that derived from RHC with high intraobserver and interobserver reproducibility (139). Evaluation of interventricular septal curvature also found that the curvature was correlated to systolic PAP (correlation coefficient, 0.77) and patients with bowing of the interventricular septum toward left tended to have a systolic PAP greater than 67 mm Hg (140). Patients with severe PH also show LV dysfunction, which may be derived from impaired LV filling because of decreased RVSV following increased PVR and interventricular septal bowing (141). MRI showed significantly lower LV enddiastolic volume (LVEDV) and LVSV in patients with PH (132), and a close relationship between LVEDV and SV (141). Isovolumetric relaxation time may be a marker of RV diastolic dysfunction, which is relatively easily obtained by normalization of the time interval between pulmonary valve closing and tricuspid valve opening for the R-R interval. RV diastolic dysfunction may indicate an early sign of ventricular dysfunction, which has now become a therapeutic target. Isovolumetric relaxation time was reported to have a good correlation with RV mass and RV afterload and, furthermore, better response to medication to decrease RV afterload (142). Phase-contrast MRI techniques may provide reliable quantitative measurements of blood flow: velocities and flow volumes passing through blood vessels and cardiac valves, such as SV, CO, EF; valvular regurgitant fractions; and the extent of cardiac shunts, which correlate well with ex 446

vivo measurements and in vivo measurements derived from RHC and Doppler echocardiography (108,121,122,143,144). They may also produce ventricular diastolic filling patterns, PVR, acceleration time (AT, defined as time from onset to the peak velocity of flow in the main PA), and acceleration volume by assessing the time-velocity curve. Some of these values can also be obtained by volumetric methods. For example, RVSV can be calculated using both phase-contrast techniques and volumetric methods. With considerable tricuspid regurgitation, volumetric methods may overestimate CO, and flow measurements are regarded more reliable (132), although these two estimates have demonstrated good correlations in normal subjects. However, flow measurement may be less accurate in patients with arrhythmia. MRI has been expected to be an accurate alternative for echocardiography and invasive RHC in estimating PAP. Several investigations on phase-contrast MRI have evaluated the ability of time-velocity curves to estimate PAP and PVR (122,145). A ratio of AT/ejection time (ET) and pressure wave velocity showed a linear correlation with RHCderived mean PAP (correlation coefficient, 0.68 and 0.82, respectively) (145,146). A ratio of maximal change of pulmonary inflow rate during ejection over acceleration volume had direct correlation (correlation coefficient, 0.89), and AT and acceleration volume had inverse correlations with PVR (correlation coefficient, 0.65 and 0.78, respectively) (122). However, the correlations between

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phase-contrast MRI measurements and RHC-derived indices vary among different subjects and different investigations. The VMI was reported to have the best correlation with RHCderived mean PAP (correlation coefficient, 0.55) among five different MRI-based methods, including AT, AT/ET ratio, pulse wave velocity, VMI, and cross-sectional area of the PA (138). A different approach on phase-contrast MRI for estimation of PAP, measuring the pressure gradient of the tricuspid valve based on the modified Bernoulli’s equation, which has been a well-established method in echocardiography (147), found that systolic PAP derived from MRI had a better correlation with RHC-derived PAP than that obtained by echocardiography (148). Another investigation found that other values derived from MRI, such as a large RV end-diastolic volume, and low SV and LVEDV measured at baseline were strong independent predictors of mortality and treatment failure in patients with IPAH (149), and that a further decrease in SV and LVEDV, and progressive RV dilation at 1-year followup, were the strongest predictors of mortality (149). Although, so far, there is a consensus that an accurate estimation of PAP based on MRI is still not feasible (138), these recent investigations suggest that MRI could be a promising non-invasive tool in clinical practice. New Investigations and Future Directions

Regardless of the etiology, patients with PH demonstrate some common pathological features: vascular remodeling, such as medial hypertrophy of both muscular and elastic arteries, and dilation and intimal atheromas of elastic PAs (150). These pathological changes are considered to cause and advance increased PVR and have recently been targets of specific drug therapy. Therefore, pulmonary perfusion, especially in the peripheral zone, may represent the severity of PH and also provide additional important functional information for diagnosis and management of PH. Recent advances in MR techniques have allowed for visualization of lung parenchyma and perfusion imaging. Two major MR techniques have been invented for evaluating pulmonary perfusion: dynamic contrast-enhanced MR perfusion imaging and arterial spin labeling (ASL), or spin tagging without contrast media. Contrast-enhanced MRI with a breath hold using short TR and echo time has proved to be clinically feasible to qualitatively assess pulmonary perfusion in healthy human subjects (151,152). Although early MRI techniques were limited in temporal and spatial resolution, pulmonary circulation is presently clearly differentiated from systemic circulation of pulmonary parenchyma with the rapid injection of contrast media at the rate of greater than 3 mL/second (153). Several investigations have revealed the feasibility of dynamic contrast-enhanced MR perfusion for depicting perfusion defects in patients with PE or suspected PE (103,154,155), and demonstrated sensitivity and specificity of 69% and 91%, compared with perfusion scintigraphy (155). Parallel

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imaging techniques have enabled contrast-enhanced perfusion MRI to obtain one phase with a temporal resolution of 1.1 seconds, as well as improved spatial resolution, resulting in better depiction for perfusion defects. Contrast-enhanced perfusion MR images with parallel imaging techniques showed a better agreement with perfusion scintigraphy for depicting perfusion defects (kappa value, 0.74) (156) than those without parallel techniques (kappa value, 0.52–0.63) (155,157). Contrast-enhanced perfusion MRI may be of value for depicting abnormal findings in peripheral vasculature and tiny thromboemboli, given that MRA with parallel imaging techniques, despite of improvement in spatial resolution, is still unable to do so. An investigation using combined contrast-enhanced perfusion MR images and MRA with parallel imaging techniques successfully differentiated CTEPH from IPAH with a high accuracy of 90% in patients with PH (158). In addition, contrast-enhanced MR perfusion studies may also provide quantitative measurements of regional pulmonary perfusion in the entire lung, such as relative regional mean transit time (MTT), pulmonary blood volume (PBV), and pulmonary blood flow (PBF), based on the indicator dilution principle and fuzzy cluster analysis (153,159). These parameters showed a good correlation with absolute pulmonary perfusion derived from microspheres in a pig model of PE (153). Subsequently, quantitative assessment of regional pulmonary perfusion in human subjects, including patients with PH, using three-dimensional dynamic contrast-enhanced MRI, has been shown to be feasible (160). Patients with IPAH showed significantly decreased PBF and prolonged MTT in the entire lung (160,161); PBF and MTT in patients with IPAH, and PBF and PBV in patients with PH secondary to connective tissue diseases correlated with RHC-derived PVR and mean PAP with statistically significant differences (64,161) (Fig 6). Thus, contrast-enhanced perfusion MRI may be a promising tool for assessing PH, because it may be the only diagnostic tool that can qualitatively and quantitatively demonstrate regional perfusion changes in the peripheral lungs without radiation exposure. However, the acquisition time of more than 20 seconds may still be too long for patients with dyspnea. ASL techniques use proton spins in blood as an internal diffusible tracer to demonstrate pulmonary perfusion without intravenous injection of contrast media. ASL techniques are divided into two techniques: pulsed techniques and steady state techniques. Pulsed ASL, such as signal targeting alternating radiofrequency and flow-sensitive alternating inversion recovery (FAIR) with an extra radiofrequency pulse (FAIRER), uses IR radiofrequency (RF) pulse to magnetically label proton spins in arterial water (162). Instead of echo-planar, fast GRE (such as ultrashort turbo fast low angle shot) and halfFourier single-shot turbo spin-echo (HASTE) have been used in combination to overcome the extremely 447

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Figure 6. Quantitative pulmonary perfusion parameter maps for a 69-year-old female patient with collagen tissue disease and pulmonary arterial hypertension. (a) Image maps (L to R: ventral to dorsal) of pulmonary blood flow (PBF) from coronal three-dimensional (3D) dynamic magnetic resonance (MR) data show heterogeneously and markedly reduced regional PBF in the gravitational and isogravitational directions. The mean PBF was 118.0  34.2/100 mL/min. (b) Image maps (L to R: ventral to dorsal) of pulmonary blood volume (PBV) from coronal 3D dynamic MR data show heterogeneously and markedly reduced regional PBV in the gravitational and isogravitational directions. The mean PBV was 12.5  5.2/100 mL. (c) Image maps (L to R: ventral to dorsal) of mean transit time (MTT) from coronal 3D dynamic MR data show heterogeneously prolonged regional MTT in the gravitational and isogravitational directions. The mean MTT was 6.4  2.8 seconds. Adapted from Ohno et al (64).

heterogeneous susceptibility of the lung and improve images, which has proved feasible in normal human subjects (163,164). Subtraction of images with and without IR-RF may extract perfusion images from the background. Limited investigations have evaluated pulmonary perfusion using pulsed ASL sequences; most have used animal models or normal human subjects (163–165). A recent investigation 448

showed that pulsed ASL using FAIR demonstrated similar perfusion defects to those obtained by dynamic contrast perfusion MRI in patients with PE and lung cancer, as well as in normal subjects (166). In addition, pulsed ASL may provide quantitative assessments of perfusion using an appropriate kinetic model and has also been applied to evaluation of pulmonary perfusion

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(164,167). Spatial pulmonary perfusion heterogeneity can be evaluated by quantifying regional PBF with ASL using FAIRER in normal human subjects (168). This method showed that subjects with a history of high-altitude pulmonary edema had increased heterogeneity of PBF with acute hypoxia, which is consistent with uneven hypoxic vasoconstriction (169). However, absolute signal measurements may be affected by several physiological and technical factors, and the ASL image could also reflect blood volume rather than blood flow, because it includes signals from larger vessels if the vessels are filled with tagged blood. Another approach to assess pulmonary perfusion uses noncontrast MRI techniques such as HASTE or short-echo spacing half-Fourier fast SE techniques. These sequences demonstrate a gradual increase in signal intensity during diastolic phase and a decrease during systolic phase. Thus, subtraction of signal intensity between diastolic and systolic phases may be considered to represent pulmonary perfusion (170,171). The application of these techniques has proven feasible for qualitatively and quantitatively assessing pulmonary perfusion in patients with pulmonary diseases, including PE and chronic obstructive pulmonary disease, as well as in animal models and normal human subjects (170–172). Some investigations have also demonstrated the feasibility of using combined MRV/Q images for assessment of pulmonary ventilation and perfusion in normal human subjects and patients with various lung diseases (173,174). Regional perfusion defects without ventilation abnormalities have been successfully demonstrated in all patients with PE (173). Although the best combination of each method for assessing pulmonary ventilation and perfusion and the ideal image registration still need more consideration, these combined methods may be promising tools for evaluating pulmonary physiology.

CONCLUSION Recent advances in CT and MRI have improved spatial and temporal resolutions and allowed for functional imaging. CT may provide useful morphologic information for depicting PH and seeking underlying diseases at primary diagnosis. However, there has not yet been enough evidence to rely solely on morphologic CT evaluation for diagnosis of PH. Cardiac MRI is considered a gold standard for evaluation of the right heart, which is indispensable in diagnosis and management of PH. Furthermore, advances in treatment may require more accurate and less invasive assessment of the severity of the disease and the response to therapy. Functional CT and MRI evaluation may be expected to serve well in this aspect. With the accumulated technological advancement and knowledge of potential clinical applications, the time has come for CT and MRI to be practical tools for morphologic and functional assessments of patients with PH.

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