June 2012, VOLUME 198
NUMBER 6

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June 2012, Volume 198, Number 6

Cardiopulmonary Imaging

Review

Current Role of Imaging in the Diagnosis and Management of Pulmonary Hypertension

+ Affiliation:
1 All authors: Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104.

Citation: American Journal of Roentgenology. 2012;198: 1320-1331. 10.2214/AJR.11.7366

ABSTRACT
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OBJECTIVE. The purpose of this review is to describe classification schemes and imaging findings in the diagnosis and management of pulmonary hypertension.

CONCLUSION. Pulmonary hypertension is a complex pathophysiologic condition in which several clinical entities increase pressure in the pulmonary circulation, progressively impairing cardiopulmonary function and, if untreated, causing right ventricular failure. Current classification schemes emphasize the necessity of an early, accurate etiologic diagnosis for a tailored therapeutic approach. Imaging plays an increasingly important role in the diagnosis and management of suspected pulmonary hypertension.

Keywords: diagnosis, management, noninvasive imaging, pulmonary hypertension

Classification
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In its broadest sense, pulmonary hypertension is a pathophysiologic condition in which the hemodynamics in the pulmonary circulation are altered. An increase in pulmonary vascular resistance increases mean pulmonary arterial pressure to greater than 25 mm Hg [1]. This definition encompasses several distinct clinical entities with variable pathologic mechanisms and prognoses. Many classification schemes have been devised in an attempt to devise a conceptual frame-work for clinical and research purposes. Initially, a division was made between primary and secondary pulmonary hypertension [2]. The former comprised diseases that primarily affect the pulmonary vasculature, and the latter, diseases primarily involving the heart and lung parenchyma. Improved understanding of molecular pathophysiologic mechanisms led to more-detailed classification schemes. A scheme that originated at the second World Health Organization (WHO) symposium [3] led to the current classification, which was proposed at the third WHO symposium in 2003 and modified in 2008 [4, 5]. The WHO classification divides pulmonary hypertension into the five groups shown in Appendix 1.

Because of the complex interplay between the right heart, lungs, and left heart as a functional cardiorespiratory unit, clinical diagnosis and classification according to the WHO scheme can be challenging. From a diagnostic standpoint, the hemodynamic distinction between precapillary pulmonary hypertension (mean pulmonary arterial pressure > 25 mm Hg, pulmonary capillary wedge pressure ≤ 15 mm Hg) and postcapillary pulmonary hypertension (mean pulmonary arterial pressure > 25 mm Hg, pulmonary capillary wedge pressure > 15 mm Hg) may be more practical, particularly for clinical use. Precapillary pulmonary hypertension includes pulmonary arterial hypertension (WHO class 1), pulmonary hypertension due to lung parenchymal disease (WHO class 3), chronic thromboembolic pulmonary hypertension (WHO class 4), and miscellaneous causes (WHO class 5). Postcapillary pulmonary hypertension includes pulmonary venous hypertension associated with left-heart disease (WHO class 2).

The epidemiology, clinical presentation, pathophysiologic mechanisms, and therapeutic strategies are discussed in detail elsewhere. This focuses on the modern diagnostic approach to pulmonary hypertension, emphasizing the crucial role played by imaging. The emerging role of noninvasive imaging is discussed.

Role of Imaging in Diagnosis and Management
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Notwithstanding the vast number of conditions that lead to pulmonary hypertension, the clinical presentation is consistent: dyspnea, initially with exertion, with or without signs and symptoms of the underlying condition. If pulmonary hypertension is left untreated, the clinical course is progressive nonlinear deterioration resulting in severe right-heart dysfunction with dyspnea at rest [6, 7]. The role of the clinician is to make the diagnosis of pulmonary hypertension as early as possible. It also is critical to correctly classify the type of pulmonary hypertension according to the modified WHO classification so that effective tailored therapy can be instituted [5].

The definitive hemodynamic diagnosis of pulmonary hypertension requires right-heart catheterization [8, 9], an invasive diagnostic procedure used for direct measurement of right ventricular pressure and pulmonary arterial pressure and indirect measurement of pulmonary venous pressure through pulmonary capillary wedge pressure throughout the cardiac cycle [10]. Nonetheless, because of the costs and risks associated with right-heart catheterization, this modality is rarely used as a first-line test. Several evidence-based diagnostic algorithms have been devised that emphasize judicious use of invasive imaging and an initial approach that combines noninvasive imaging, clinical assessment, and nonimaging tests [1, 11].

The pivotal elements of the initial assessment are history and physical examination, chest radiography, ECG [12, 13], and transthoracic echocardiography [1, 14]. The initial goals are not only to establish a tentative diagnosis of pulmonary hypertension but also to diagnose or exclude the most common causes of pulmonary hypertension: left-heart failure and lung parenchymal diseases that lead to hypoxemia (formerly categorized as secondary pulmonary hypertension) [15-17]. Contingent on the results of initial tests, additional, more specific tests are ordered. For instance, abnormal results of transthoracic echocardiography would lead to transesophageal echocardiography; abnormal findings at chest radiography would lead to chest CT or ventilation-perfusion (V/Q) scanning; and abnormal findings at physical examination would lead to pulmonary function testing.

If the diagnosis of left-heart failure or a lung parenchymal disease that leads to hypoxemia is confirmed and the degree of pulmonary hypertension is deemed proportionate to the severity of the underlying condition, the diagnostic workup is terminated, and proper treatment is instituted. If not, V/Q scanning or contrast-enhanced chest CT should be performed to evaluate for suspected thromboembolic disease. If thromboembolic disease is present, anticoagulation and other preventive measures, such as placement of an inferior vena caval filter, are instituted. If no pulmonary arterial filling defects or other direct or indirect findings suggesting pulmonary embolism, either acute or chronic, are detected at chest CT but segmental perfusion defects are found at V/Q scanning, pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis should be considered if otherwise concordant chest CT findings are present (see later). If no filling defects are seen in the pulmonary arterial circulation at chest CT and V/Q findings are normal, a tentative diagnosis of pulmonary arterial hypertension (formerly categorized as primary pulmonary hypertension) is made and confirmed with invasive right ventricular catheterization. Additional specific imaging and laboratory tests are performed as needed to classify the condition into one of the following groups: congenital heart disease, connective tissue disease, HIV infection, portal hypertension, chronic hemolysis, drug toxicity, or idiopathic or familial disorder [1, 11, 18-21].

Imaging plays a crucial role throughout the complex diagnostic algorithm. Every patient with suspected pulmonary hypertension should generally undergo chest radiography and transthoracic echocardiography. Chest radiography is a universally available, safe, and cost-effective study that can be used to answer two fundamental questions: Does the patient have substantial cardiomegaly (indicating possible left-heart failure or congenital heart disease)? Does the patient have evidence of clinically significant chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD)?

Chest Radiography

Chest radiography is not sensitive in the detection of mild cardiomegaly, mild COPD, or mild ILD, but the findings are almost never normal in the presence of moderate to severe manifestations of any of these conditions. If a finding is borderline normal or a precise diagnosis is elusive, chest CT is the recommended subsequent test because it is more sensitive and specific than radiography. Chest radiographic findings may suggest the presence of pulmonary hypertension, but the sensitivity and specificity are not high enough for a definitive diagnosis. The following chest radiographic findings may indicate the presence of pulmonary hypertension: enlargement of the right and left main pulmonary arteries; hilar enlargement; tapering or pruning of peripheral pulmonary arteries; enlargement of the right interlobar artery (greater than 15-mm diameter on a posteroanterior frontal radiograph); right atrial and right ventricular enlargement; and areas of oligemia, which appear as increased lucency and decreased vascularity [22, 23] (Figs. 1A, 1B, 2, 3A, 3B, 3C, 4A, 4B, 4C, 5A, and 5B). Pulmonary venous pressure can be measured as pulmonary capillary wedge pressure (PCWP), which reflects left atrial pressure and left ventricular diastolic filling pressure. PCWP can be estimated by observing the vascular pattern and the presence of interstitial or alveolar edema on chest radiographs. It has been suggested that PCWP greater than 13 but less than 18 mm Hg indicates the presence of vascular redistribution with relative hypervascularity of the upper lung fields; 18-25 mm Hg, interstitial pulmonary edema; and greater than 25 mm Hg, alveolar edema and, often, pleural effusions. If pulmonary hypertension is present in these clinical situations, strong consideration should be given to left ventricular failure as a causal factor [24-26].

Transthoracic Echocardiography

Transthoracic echocardiography is a noninvasive, safe, and relatively readily available modality that plays a major role in the evaluation of the heart, complementing chest radiography. It yields semiquantitative functional and anatomic information and is an invaluable tool for the diagnosis of systolic and diastolic dysfunction of the left and right ventricles, of intracardiac shunt, and of valvular stenosis and regurgitation. Because assessment of right ventricular function is essential for determining prognosis and response to therapy, transthoracic echocardiography should be performed early in the diagnostic workup of pulmonary hypertension [27]. If there are limitations to the transthoracic approach, transesophageal echocardiography should be considered.

Doppler Echocardiography

Echocardiography also can be used to estimate pulmonary arterial pressure, although precise measurement requires right ventricular catheterization [1, 5, 11]. Pulmonary arterial pressure is estimated with Doppler sonography by measurement of the velocity of the regurgitant jet from the tricuspid valve during systole. Because pressure cannot be directly measured with Doppler sonography, right atrial pressure must be assumed, usually to be 7-8 mm Hg. Central venous pressure is estimated by physical evaluation of neck vein distention [28]. Tissue Doppler imaging has been proposed to better characterize right ventricular performance in the presence of pulmonary hypertension. It has been found that delayed contraction of the right ventricular free wall in relation to that of the interventricular septum (right ventricular dyssynchrony) correlates with pulmonary hypertension (delay > 25 milliseconds) and with right ventricular dysfunction (delay > 37 milliseconds) [29]. Echocardiography is currently the chief noninvasive imaging modality in clinical use for the assessment of WHO group 2 pulmonary hypertension (associated with left-heart disease) [30, 31].

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Fig. 1A52-year-old woman with chronic dyspnea and smoking history.

A, Posteroanterior (A) and lateral (B) chest radiographs show hyperinflation of lungs and enlargement of central pulmonary arteries, representing pulmonary hypertension secondary to chronic obstructive pulmonary disease, which is the second most common cause of pulmonary hypertension worldwide.

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Fig. 1B52-year-old woman with chronic dyspnea and smoking history.

B, Posteroanterior (A) and lateral (B) chest radiographs show hyperinflation of lungs and enlargement of central pulmonary arteries, representing pulmonary hypertension secondary to chronic obstructive pulmonary disease, which is the second most common cause of pulmonary hypertension worldwide.

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Fig. 2 —64-year-old man with ST-segment elevation myocardial infarction and progressive respiratory failure. Anteroposterior chest radiograph shows typical appearance of pulmonary alveolar edema secondary to left ventricular congestive failure with postcapillary pulmonary hypertension. Left ventricular failure is the most common cause of pulmonary hypertension worldwide.

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Fig. 3A33-year-old man with mild dyspnea on exertion.

A, Posteroanterior (A) and lateral (B) chest radiographs show moderate pulmonary arterial dilatation in association with known pulmonary hypertension secondary to left to right shunt due to longstanding atrial septal defect (ASD).

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Fig. 3B33-year-old man with mild dyspnea on exertion.

B, Posteroanterior (A) and lateral (B) chest radiographs show moderate pulmonary arterial dilatation in association with known pulmonary hypertension secondary to left to right shunt due to longstanding atrial septal defect (ASD).

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Fig. 3C33-year-old man with mild dyspnea on exertion.

C, Axial balanced steady-state free precession gradient-recalled echo cardiac MR image shows secundum ASD (arrow).

Chest CT

Chest CT is an invaluable noninvasive imaging modality in the workup of pulmonary hypertension. It is the reference standard for noninvasive diagnosis of ILD, either idiopathic or secondary to connective tissue disease, and of COPD, particularly emphysema predominant, in combination with pulmonary function testing [32-35]. Although the diagnosis of small airways disease-predominant COPD is challenging with standard chest CT, expiratory imaging coupled with quantitative analysis of imaging metrics and volumes facilitates accurate diagnosis and quantification of disease severity, there being a strong correlation between the imaging findings and key pulmonary function testing parameters [36]. Normal chest CT findings in a patient with pulmonary hypertension imply that it is highly unlikely that ILD or emphysema is a significant etiologic factor [32-35]. Therefore, as the best method for evaluating the pulmonary parenchyma, chest CT is the best diagnostic modality for diagnosis of WHO group 3 pulmonary hypertension, which is caused by hypoxic vasoconstriction secondary to parenchymal lung disease.

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Fig. 4A57-year-old woman with progressive dyspnea on exertion.

A, Posteroanterior (A) and lateral (B) chest radiographs show marked pulmonary arterial dilatation representing longstanding severe pulmonary hypertension due to known patent ductus arteriosus and Eisenmenger physiology. Pulmonary arterial calcifications (arrow, B) are typical of chronic, severe pulmonary hypertension.

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Fig. 4B57-year-old woman with progressive dyspnea on exertion.

B, Posteroanterior (A) and lateral (B) chest radiographs show marked pulmonary arterial dilatation representing longstanding severe pulmonary hypertension due to known patent ductus arteriosus and Eisenmenger physiology. Pulmonary arterial calcifications (arrow, B) are typical of chronic, severe pulmonary hypertension.

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Fig. 4C57-year-old woman with progressive dyspnea on exertion.

C,Axial contrast-enhanced chest CT image confirms marked enlargement of central pulmonary arteries and mediastinal and chest wall edema suggesting right ventricular failure. Pulmonary artery catheter (Swan-Ganz) has been placed.

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Fig. 5A46-year-old man with holodiastolic murmur.

A, Arterial (A) and venous (B) phase pulmonary angiograms show postcapillary pulmonary hypertension secondary to mitral stenosis. Massive left atrial enlargement is evident.

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Fig. 5B46-year-old man with holodiastolic murmur.

B, Arterial (A) and venous (B) phase pulmonary angiograms show postcapillary pulmonary hypertension secondary to mitral stenosis. Massive left atrial enlargement is evident.

Contrast-enhanced chest CT performed with MDCT scanners that generate isotropic volumetric datasets is the reference standard for the diagnosis of acute and chronic thromboembolic disease [37-40]. Chest CT has intrinsic advantages over V/Q scanning in that it is tomographic (rather than planar), has submillimeter spatial resolution, and, on high-quality images, depicts thrombotic and embolic filling defects in the pulmonary arterial tree from the level of the main pulmonary artery (MPA) to the level of the subsegmental arteries [41-43]. V/Q scanning plays a role in the diagnosis of microvascular disease that manifests itself as perfusion defects on a perfusion scan but is not associated with directly detectable abnormalities on chest CT images [44, 45] (Fig. 6).

On the one hand, because of the immense functional reserve of the normal pulmonary vasculature, it is uncommon for acute pulmonary embolism to cause pulmonary hypertension or right ventricular dysfunction [46-48]. Poor clinical outcome after acute pulmonary embolism is nonetheless associated with right ventricular dysfunction and large embolic burden, as measured with an obstruction index of the pulmonary arterial circulation of 40% or greater at helical chest CT [49]. This situation generally occurs only with massive saddle emboli in the large proximal pulmonary arteries or with a large number of relatively small emboli occluding the more distal segmental or subsegmental arteries [50, 51] (Fig. 7). On the other hand, chronic pulmonary thromboembolism is far more prone to be associated with pulmonary hypertension, even in the absence of a substantial thromboembolic burden, because of molecular adaptation mechanisms that lead to remodeling of the pulmonary vasculature with medial hypertrophy and in situ small-vessel thrombosis [37, 52, 53] (Fig. 8).

Acute and chronic pulmonary thromboembolic disease can be differentiated on images by the morphologic features of the pulmonary arterial filling defects (usually closer to central in location and occlusive if acute; likely eccentric in location, nonocclusive, and sometimes calcified if chronic) and by the caliber and distribution of the pulmonary arterial branches (normal if acute, usually dilated centrally and pruned peripherally if chronic). The nonopacified pulmonary arterial branches tend to be dilated in acute thromboembolic disease but are generally smaller than adjacent patent vessels in chronic thromboembolic disease. Moreover, chronic thromboembolic disease tends to be associated with dilated central pulmonary arteries, indicating pulmonary hypertension. Acute thromboembolic disease, however, generally presents with normal-caliber central pulmonary arteries unless there is preexisting pulmonary hypertension. Other findings suggesting chronic thromboembolic disease include a mosaic perfusion pattern and the presence of dilated bronchial or other systemic collateral vessels [53, 54].

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Fig. 6 —37-year-old man with ventilation-perfusion (V/Q) scan findings of chronic pulmonary thromboembolism and pulmonary arterial hypertension. Planar ventilation images (top two rows) and planar perfusion images in different projections (bottom two rows) show multiple bilateral mismatched segmental perfusion defects. Diagnosis of pulmonary hypertension cannot be established with V/Q scan alone, nor can this method be used to differentiate acute from chronic pulmonary thromboembolism.

Dual-energy CT angiography has been proposed as a method of assessing both vascular anatomy and quantitative perfusion in the presence of chronic thromboembolic pulmonary embolism. The correlation between perfusion parameters derived with dual-energy CT and subjective assessment of mosaic attenuation pattern was strong (r > 0.6, p < 0.006), but there was no statistically significant correlation with vascular obstructive index, mean pulmonary artery pressure, or pulmonary vascular resistance [55]. Consequently, contrast-enhanced chest CT is the most useful diagnostic modality for WHO group 4 pulmonary hypertension (associated with acute and chronic thromboembolic disease) (Figs. 9, 10A, 10B, 11A, 11B, 11C, 12A, and 12B).

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Fig. 7 —50-year-old woman with acute dyspnea. Pulmonary angiogram shows extensive filling defects in right interlobar artery and its right lower and middle lobe branches, indicating acute pulmonary thromboembolism (PTE). Acute PTE is uncommonly associated with pulmonary hypertension, except if massive, in which case right ventricular failure generally ensues with worse prognosis. Caliber of pulmonary arterial tree is normal.

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Fig. 8 —54-year-old woman with recurrent pulmonary thromboembolism (PTE). Pulmonary angiogram shows dilatation and poor opacification of segmental and subsegmental arteries without occlusive filling defects, indicating presence of chronic PTE, which is commonly associated with pulmonary hypertension. Marked enlargement of central pulmonary arteries is evident, as are pacemaker leads and cardiomegaly. Measured mean pulmonary arterial pressure is 76 mm Hg.

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Fig. 9 —49-year-old man with chronic dyspnea on exertion. Axial contrast-enhanced chest CT image shows chronic pulmonary thromboembolism, eccentric filling defect in right pulmonary artery (arrow), and marked enlargement of main pulmonary artery to 4.9 cm, suggesting presence of pulmonary hypertension.

Other diseases that involve the pulmonary microvasculature, such as pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis (WHO group 1), and miscellaneous causes, such as sarcoidosis, hematologic disorders, neoplastic obstruction, fibrosing mediastinitis, and pulmonary Langerhans cell histiocytosis (WHO group 5), can also be diagnosed with chest CT, further augmenting the importance of this imaging modality in the diagnostic workup of pulmonary hypertension [56-59]. Chest CT is also an important ancillary modality for patients with WHO group 2 pulmonary hypertension (associated with left-heart disease) because it depicts pulmonary interstitial and alveolar edema, indicating the presence of congestive heart failure and pulmonary venous hypertension.

In addition to its dominant role in evaluation of the lung parenchyma and pulmonary thromboembolic disease, chest CT is useful for direct assessment of the pulmonary arteries when pulmonary arterial hypertension is suspected. It has been reported [60] that the finding of MPA caliber greater than 29 mm measured 2 cm from the pulmonary valve has 84% sensitivity, 75% specificity, and 97% positive predictive value for the presence of pulmonary arterial hypertension, as confirmed with invasive imaging. Moreover, if the MPA has a maximum transverse diameter greater than that of the proximal ascending thoracic aorta, sensitivity is 70%, specificity 92%, and positive predictive value 96% for the presence of pulmonary arterial hypertension [60]. One should be mindful to first determine that the ascending aorta is not aneurysmal when performing these measurements.

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Fig. 10A64-year-old man with recurrent deep venous thrombosis.

A, Axial (A) and coronal maximum-intensity-projection (B) contrast-enhanced chest CT images show chronic pulmonary thromboembolism, eccentric filling defect in right pulmonary artery (arrows, A), and marked enlargement of central pulmonary arteries. Small loculated right pleural effusion and hypertrophy of extrapleural fat on left also are evident.

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Fig. 10B64-year-old man with recurrent deep venous thrombosis.

B, Axial (A) and coronal maximum-intensity-projection (B) contrast-enhanced chest CT images show chronic pulmonary thromboembolism, eccentric filling defect in right pulmonary artery (arrows, A), and marked enlargement of central pulmonary arteries. Small loculated right pleural effusion and hypertrophy of extrapleural fat on left also are evident.

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Fig. 11A71-year-old man with chronic exertional dyspnea.

A, Axial contrast-enhanced chest CT image shows semiocclusive filling defect and intravascular web (arrow) in right lower lobe proximal lobar artery characteristic of chronic pulmonary thromboembolism.

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Fig. 11B71-year-old man with chronic exertional dyspnea.

B,Coronal maximum-intensity-projection image shows variable caliber of lobar, segmental, and subsegmental arteries in different lobes. Dilated branches are evident in right upper lobe and mid left upper lobe. Narrowed branches are present in apical left upper lobe, another finding that is commonly seen in chronic pulmonary thromboembolism.

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Fig. 11C71-year-old man with chronic exertional dyspnea.

C,Axial chest CT image shows mosaic perfusion pattern secondary to chronic pulmonary thromboembolism.

Another chest CT finding suggestive of pulmonary arterial hypertension is enlargement of the segmental arteries greater than 1.25 times the caliber of the adjacent bronchus. A combination of positive findings increases diagnostic confidence. For instance, the finding of an enlarged MPA (> 29 mm) and concomitant enlargement of three of four segmental arteries (arterial-to-bronchial diameter ratio, > 1.25) has 100% specificity for the diagnosis of pulmonary arterial hypertension [60]. If pulmonary fibrosis or emphysema is present, however, the correlation between pulmonary artery dimension and severity of pulmonary hypertension is substantially weaker [61]. In the latter clinical situations, a combination of findings is warranted to suggest the diagnosis.

A prospective study [62] in which the subjects were 134 patients who underwent right-heart catheterization and chest CT within 72 hours of each other showed that CT-derived measurement of the MPA diameter has stronger correlation with the presence of pulmonary hypertension in patients without ILD (MPA diameter > 31.6 mm had a positive predictive value of 90.0% and a negative predictive value of 58.3%) than in patients with ILD (MPA diameter > 25 mm had a positive predictive value of 46.3% and a negative predictive value of 83.8%). In both groups, however, the MPA diameter was significantly greater in patients with pulmonary hypertension than in those without. One conclusion is that pulmonary hypertension is more likely to be present even with normal-caliber pulmonary arteries if the underlying diagnosis is ILD [62]. The presence of bronchial artery hypertrophy greater than 1.5 mm has also been implicated in pulmonary arterial hypertension, although this sign is probably far more common in chronic pulmonary thromboembolic disease [63].

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Fig. 12A49-year-old man with long-standing pulmonary hypertension.

A, Unenhanced axial chest CT images show marked enlargement of central pulmonary arteries (A) and hypodense eccentric thrombus in dilated right pulmonary artery (short arrow) with linear wall calcifications (long arrow) (B). Linear calcifications in pulmonary arterial walls represent atheromatous plaques, which can be seen in severe longstanding pulmonary hypertension.

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Fig. 12B49-year-old man with long-standing pulmonary hypertension.

B, Unenhanced axial chest CT images show marked enlargement of central pulmonary arteries (A) and hypodense eccentric thrombus in dilated right pulmonary artery (short arrow) with linear wall calcifications (long arrow) (B). Linear calcifications in pulmonary arterial walls represent atheromatous plaques, which can be seen in severe longstanding pulmonary hypertension.

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Fig. 13A58-year-old woman with chronic cough and progressive dyspnea.

A, Unenhanced axial chest CT image shows enlargement of main pulmonary artery to 3.8 cm.

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Fig. 13B58-year-old woman with chronic cough and progressive dyspnea.

B,Unenhanced coronal chest CT image shows severe interstitial lung disease. Patient underwent bilateral lung transplant, and clinical and pathologic findings confirmed pulmonary hypertension secondary to chronic hypersensitivity pneumonitis.

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Fig. 14 —63-year-old woman with pulmonary hypertension. Unenhanced coronal chest CT image shows widespread centrilobular and peribronchovascular ground-glass opacities. Diagnosis of pulmonary capillary hemangiomatosis was confirmed with bronchoscopic biopsy.

Several pulmonary parenchymal findings are associated with pulmonary arterial hypertension, though individually they are not sensitive or specific enough to warrant the diagnosis [58]. These findings include mosaic attenuation (more commonly seen in pulmonary hypertension due to chronic pulmonary thromboembolic disease but also seen in small airways disease without pulmonary hypertension, among other possibilities) and widespread tiny centrilobular ground-glass nodules (similar to those observed in hypersensitivity pneumonitis but pathologically deemed to represent cholesterol granulomas or large plexogenic arterial lesions), which have been described in 7-47% of patients with pulmonary arterial hypertension. In a patient with pulmonary hypertension, the presence of widespread tiny centrilobular ground-glass nodules or interlobular septal thickening should suggest the presence of pulmonary capillary hemangiomatosis or pulmonary venoocclusive disease, respectively [64-70] (Figs. 13A, 13B, 14, and 15).

Direct evaluation of the heart is a relatively new capability with ECG-gated MDCT, which has high temporal and spatial resolution for 3D anatomic assessment of the heart combined with 4D cardiac functional assessment [71]. Several cardiac findings of pulmonary hypertension can be present even at routine non-ECG-gated chest CT, including right ventricular enlargement, flattening or leftward convexity of the interventricular septum, and reflux of IV contrast material from the right atrium into the inferior vena cava. In addition to dilation of the main, right, and left pulmonary arteries, quantitative measurements of the heart obtained at non-ECG-gated chest CT have been found predictive of pulmonary hypertension in hospitalized patients as estimated with Doppler echocardiography. In particular, right ventricular free wall thickness of 6 mm or greater (odds ratio, 30.5), right ventricular wall-to-left ventricular wall thickness ratio of 0.32 or greater (odds ratio, 8.8), right ventricular-to-left ventricular luminal diameter ratio of 1.28 or greater (odds ratio, 28.8), and main pulmonary artery-to-ascending aorta diameter ratio of 0.84 or greater (odds ratio, 6.0) have been associated with increased odds of pulmonary hypertension [72]. Calcifications may be present in the walls of the central pulmonary arteries, pathologically representing atheromatous plaques. However, this finding is usually seen only in late stage, severe pulmonary hypertension.

For evaluation of subtle cardiac findings associated with the diagnosis of mild to moderate pulmonary hypertension, ECG gating is necessary. Intracardiac shunts such as atrial septal defect causing left to right shunting can be diagnosed, as can details on the specific type of defect (sinus venosus, ostium primum, ostium secundum). Ventricular septal defect is less common in adults but when present can cause substantial left to right shunting. In an adult admitted to the hospital with a diagnosis of septal defect, the presence of a ventricular septal defect and pulmonary hypertension is associated with higher mortality than atrial septal defect [73]. Partial and total anomalous pulmonary venous return can cause marked left to right shunting that leads to right-heart volume overload and eventually pulmonary hypertension and right-heart failure, particularly if the left to right shunt fraction is greater than 2 [74, 75].

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Fig. 15 —44-year-old woman with pulmonary hypertension who underwent bone marrow transplant 5 years previously. Unenhanced coronal reformation chest CT image shows peripheral faint intralobular and interlobular septal thickening and associated heterogeneous attenuation of lung parenchyma due to mosaic perfusion. Diagnosis of pulmonary venoocclusive disease was proposed on the basis of clinical, imaging, and bronchoscopic findings.

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Fig. 16A34-year-old woman with idiopathic pulmonary arterial hypertension.

A, Balanced steady-state free precession gradient-recalled echo right ventricular outflow tract (A) and axial (B) cardiac MR images show enlargement of central pulmonary arteries.

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Fig. 16B34-year-old woman with idiopathic pulmonary arterial hypertension.

B, Balanced steady-state free precession gradient-recalled echo right ventricular outflow tract (A) and axial (B) cardiac MR images show enlargement of central pulmonary arteries.

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Fig. 16C34-year-old woman with idiopathic pulmonary arterial hypertension.

C, Midsystolic short-axis MR image shows leftward deviation with flattening of interventricular septum due to increased right ventricular pressure.

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Fig. 16D34-year-old woman with idiopathic pulmonary arterial hypertension.

D, Velocity-encoded phase-contrast magnitude (D) and phase (E) MR images can be used to measure the velocity in main pulmonary artery (arrow, E), which correlates with pulmonary arterial pressure.

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Fig. 16E34-year-old woman with idiopathic pulmonary arterial hypertension.

E, Velocity-encoded phase-contrast magnitude (D) and phase (E) MR images can be used to measure the velocity in main pulmonary artery (arrow, E), which correlates with pulmonary arterial pressure.

Patent ductus arteriosus is another potential cause of left to right shunting that can lead to severe pulmonary hypertension if uncorrected [76]. Regardless of the actual anatomic abnormality involved, any sustained clinically significant left to right shunting overloads the right-heart circulation, and molecular and cellular adaptation mechanisms lead to chronic right ventricular hypertrophy and dilation and pulmonary arterial hypertension [77-82]. If the patient is not treated, the arterial pressure in the right-side circulation can rise above the systemic arterial pressure, effectively reversing the direction of shunting (Eisenmenger physiology), worsening the prognosis. Complex congenital cardiomyopathy and valvular disease can also be diagnosed with ECG-gated chest CT, but cardiac MRI is the preferred diagnostic modality for these conditions. Because of the absence of cardiac motion artifacts, the transverse diameter of the central arteries can be more accurately measured with ECG-gated than with nongated chest CT [83, 84].

Right and left ventricular function can be quantitatively assessed with ECG-gated chest CT. The distensibility of the right pulmonary artery has the strongest correlation with mean pulmonary arterial pressure [85]. It is superior to right ventricular outflow tract wall thickness and systolic diameter, indicating that functional measurements obtained with ECG-gated chest CT add value to anatomic assessment of pulmonary arterial caliber in the diagnosis and management of pulmonary hypertension.

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Fig. 17 —22-year-old woman with continuous murmur and pulmonary arterial hypertension due to patent ductus arteriosus. Image from balanced steady-state free precession gradient-recalled echo four-chamber cardiac cine MRI loop at level of main pulmonary artery. Linear hypointense artifact (arrow) originates from proximal descending thoracic aorta and is directed toward proximal main pulmonary artery, corresponding to dephasing secondary to turbulent flow due to high-velocity left to right shunt in patent ductus arteriosus.

MRI

MRI is a powerful, noninvasive, flexible modality that has several advantages over CT and echocardiography in evaluation of the heart. The absence of ionizing radiation allows repeated examinations when necessary without accumulative radiation exposure. MRI has superior soft-tissue contrast resolution and spatial resolution compared with echocardiography and is operator independent because it is not limited by acoustic windows and large habitus. MRI also can be tailored for assessment of the heart (cardiac MRI) and great vessels (MR angiography of the chest) to generate both structural and functional information. The usefulness of MRI in assessing the pulmonary parenchyma, however, is substantially inferior to that of CT [86-92].

MRI is the reference standard for assessment of congenital heart disease because it accurately delineates structural changes, cardiac situs, intracardiac shunts, atrioventricular and ventriculoarterial relations, vascular dimensions, and wall motion and valvular abnormalities [93]. MRI also is the most useful modality for assessing right ventricular anatomy and function, which is critical in the prognosis of pulmonary hypertension [94, 95]. Contrast-enhanced MRI is unique in depicting the presence and extent of myocardial scarring related to previous infarction, myocarditis, and infiltrative disease of the myocardium through depiction of delayed enhancement, findings that can be associated with left ventricular dysfunction and pulmonary venous hypertension [96].

MRI, like Doppler echocardiography, can be used to quantify flow velocity with phase-contrast imaging, allowing estimation of arterial and intracardiac pressures. A major strength of MRI compared with echocardiography is that arbitrary planes can be set without limitation by available acoustic windows, leading to greater accuracy and reproducibility in comparison with Doppler echocardiography [97]. Further developments in MRI techniques will increase the clinical usefulness of this modality. It is conceivable that the combination of advanced CT and MRI techniques will effect thorough anatomic and functional assessment of the heart-lung unit in patients with suspected pulmonary hypertension, obviating invasive right-heart catheterization in selected patients. The introduction of PET/MRI systems may contribute further to noninvasive diagnostic imaging through the acquisition of anatomic, physiologic, and metabolic data in a single examination.

MRI is useful for comprehensive assessment of the right ventricle. The complex 3D structure of this chamber can be directly assessed with MRI to measure right ventricular systolic and diastolic volumes and mass. Four-dimensional functional assessment facilitates accurate evaluation of right ventricular ejection fraction, as well as detection and quantification of global and regional wall motion abnormalities. Moreover, the ability to repeat the study as often as clinically indicated can be invaluable in patient care. For example, a trial of a pulmonary vasodilator drug can be instituted, and MRI can be performed at sequential time points to assess for an objective response in right ventricular volume and mass because right ventricular end-diastolic volume is a strong predictor of mortality in pulmonary arterial hypertension [94, 95]. Moreover, if severe dilation of the right ventricle with increased pressure causing leftward bowing of the interventricular septum has occurred, left ventricular function may be compromised owing to impaired early diastolic filling. This finding can be accurately evaluated with cardiac MRI and has prognostic implications [86, 89, 90].

Phase-contrast MRI is increasingly used to measure flow velocity in any major artery because pulmonary arterial pressure can be estimated from pulmonary artery flow velocity. A study in which the subjects were 42 patients with pulmonary artery hypertension confirmed with right-heart catheterization [98] showed good correlation of average pulmonary artery velocity and mean pulmonary arterial pressure, systolic pulmonary arterial pressure, and pulmonary vascular resistance index, the correlation coefficients being -0.73, -0.76, and -0.86 (p < 0.001). An average velocity cutoff of 11.7 cm/s revealed pulmonary arterial hypertension with 92.9% sensitivity and 82.4% specificity. In another study [99], the correlation of right ventricular stroke volume and systolic pulmonary arterial pressure measured with cardiac MRI, echocardiography, and right-heart catheterization in 20 patients was assessed. The correlation between cardiac MRI and right-heart catheterization was 0.96 for stroke volume and 0.94 for systolic pulmonary arterial pressure, compared with 0.01 for stroke volume and 0.86 for systolic pulmonary arterial pressure between echo-cardiography and right-heart catheterization. These results highlight the superiority of cardiac MRI over echocardiography compared with the reference standard right-heart catheterization. A prospective study in which the subjects were 55 patients (22 with manifest pulmonary hypertension, 32 with latent pulmonary hypertension, and one without pulmonary hypertension) who underwent time-resolved 3D phase-contrast MRI of the MPA [100] showed this technique had 100% sensitivity and 91% specificity in the diagnosis of pulmonary hypertension when blood flow vortices were detected in the MPA.

Another approach involves measurement of pulmonary circulation time, which is usually prolonged in pulmonary hypertension. A study in which the subjects were 18 patients with combined pulmonary fibrosis and emphysema involved calculation of mean transit time through the pulmonary artery with MR angiography [101]. The result was correlated with mean pulmonary arterial pressure as measured by right-heart catheterization, and correlation of 0.71 was found (p < 0.001).

The foregoing results illustrate the broad applicability of MRI for quantitative assessment of hemodynamic parameters in pulmonary hypertension (Figs. 16A, 16B, 16C, 16D, 16E, and 17).

Conclusion
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Pulmonary hypertension is a complex, clinically relevant condition that causes substantial morbidity and mortality if undiagnosed and untreated. Several clinical entities converge into one of multiple pathobiologic pathways that lead to pulmonary hypertension and right-heart dysfunction, as delineated by the current classification schemes. Because of the increasing availability of effective therapies tailored to the specific mechanism leading to pulmonary hypertension, early and accurate etiologic diagnosis is paramount. In this scenario, imaging, particularly noninvasive imaging, plays a central role in the diagnosis and management of this challenging condition. Right ventricular catheterization remains the reference standard for diagnostic confirmation. Chest radiography and echocardiography are the cornerstones of initial assessment of suspected pulmonary hypertension. Chest CT and, increasingly, MRI are advanced noninvasive modalities that with minimum patient risk yield crucial detailed information on the pulmonary parenchyma, cardiac anatomy and function, and the status of the pulmonary vasculature. They are useful not only for precise etiologic diagnosis but also for effective treatment of patients with pulmonary hypertension.

APPENDIX 1: World Health Organization Classification of Pulmonary Hypertension

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Address correspondence to E. J. Mortani Barbosa Jr ().

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