Quantitative Magnetic Resonance Imaging of Pulmonary Hypertension: A Practical Approach to the Current State of the Art

Swift, Andrew J. PhD*; Wild, Jim M. PhD*; Nagle, Scott K. MD, PhD†,‡,§; Roldán-Alzate, Alejandro PhD; François, Christopher J. MD; Fain, Sean PhD†,§; Johnson, Kevin PhD; Capener, Dave MSc*; van Beek, Edwin J.R. MD, PhD; Kiely, David G. MD#; Wang, Kang PhD**; Schiebler, Mark L. MD

Journal of Thoracic Imaging:
doi: 10.1097/RTI.0000000000000079
Symposium Review Articles
Abstract

Pulmonary hypertension is a condition of varied etiology, commonly associated with poor clinical outcome. Patients are categorized on the basis of pathophysiological, clinical, radiologic, and therapeutic similarities. Pulmonary arterial hypertension (PAH) is often diagnosed late in its disease course, with outcome dependent on etiology, disease severity, and response to treatment. Recent advances in quantitative magnetic resonance imaging (MRI) allow for better initial characterization and measurement of the morphologic and flow-related changes that accompany the response of the heart-lung axis to prolonged elevation of pulmonary arterial pressure and resistance and provide a reproducible, comprehensive, and noninvasive means of assessing the course of the disease and response to treatment. Typical features of PAH occur primarily as a result of increased pulmonary vascular resistance and the resultant increased right ventricular (RV) afterload. Several MRI-derived diagnostic markers have emerged, such as ventricular mass index, interventricular septal configuration, and average pulmonary artery velocity, with diagnostic accuracy similar to that of Doppler echocardiography. Furthermore, prognostic markers have been identified with independent predictive value for identification of treatment failure. Such markers include large RV end-diastolic volume index, low left ventricular end-diastolic volume index, low RV ejection fraction, and relative area change of the pulmonary trunk. MRI is ideally suited for longitudinal follow-up of patients with PAH because of its noninvasive nature and high reproducibility and is advantageous over other biomarkers in the study of PAH because of its sensitivity to change in morphologic, functional, and flow-related parameters. Further study on the role of MRI image based biomarkers in the clinical environment is warranted.

Author Information

*Academic Unit of Radiology, Department of Cardiovascular Science, University of Sheffield

#Sheffield Pulmonary Vascular Disease Unit, Royal Hammashire Hospital, Sheffield

Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

Department of Radiology, University of Wisconsin-Madison School of Medicine and Public Health

Departments of Pediatrics

§Medical Physics

Biomedical Engineering, University of Wisconsin-Madison

**General Electric Medical Systems, Advanced Science Laboratory, Madison, WI

Kang Wang is an employee of General Electric Medical Systems. The remaining authors declare no conflicts of interest.

Reprints: Jim M. Wild, PhD, Academic Unit of Radiology, University of Sheffield, C Floor, Royal Hallamshire Hospital, Sheffield S10 2JF, UK (e-mail: j.m.wild@sheffield.ac.uk).

Article Outline

Pulmonary hypertension (PH) is clinically defined as the presence of mean pulmonary artery pressure (mPAP) ≥25 mm Hg at rest measured at right heart catheterization (RHC).1 RHC is an invasive investigation in which pressure and flow are directly measured by insertion of a catheter through the jugular or femoral vein into the right side of the heart and pulmonary artery (PA). Further detailed assessment using blood testing, echocardiography, lung function, and multimodality imaging is key to identifying the cause of PH, which defines both prognosis and treatment.2,3

The modern classification of PH was introduced with the rationale of bringing together similar conditions on the basis of common pathophysiological, clinical, radiologic, and therapeutic patterns.1,4 There are 5 major forms of PH: group 1—pulmonary arterial hypertension (PAH), which can be idiopathic or associated with other conditions, most commonly systemic sclerosis or congenital heart disease; group 2—PH due to left heart disease (PH-LHD); group 3—PH due to lung disease and/or hypoxia (PH-Lung); group 4—chronic thromboembolic PH (CTEPH); and group 5—unclear or multifactorial etiologies.

PH ranges from an uncommon progressive condition of PAH, which is characterized by a vasculopathy affecting the small pulmonary arteries, to usually mild elevations of PA pressure that are more commonly associated with severe cardiac or respiratory disease. In patients with idiopathic PAH (IPAH), prolonged elevation of the right ventricular (RV) afterload results in RV failure and eventually in death, occurring typically within 3 years in untreated patients with IPAH.5 Significant progress has been made in the treatment of IPAH over the last 20 years, and the UK and Ireland Pulmonary Hypertension Registry identified a 5-year survival rate of approximately 80% for patients under the age of 50.6

Patients with PH usually present with dyspnea and fatigue, with syncope and angina-like pain more frequent in advanced disease. Symptoms are nonspecific, and the delay from initial symptoms to diagnosis is often up to 2 years. As a result, damage to the pulmonary arterial vasculature is already quite advanced by the time of diagnosis.

The survival of patients with PAH is dependent on the form of PAH. Hurdman and colleagues demonstrated the importance of systematic evaluation in 600 treatment-naive patients with PAH diagnosed at a PH referral center with an overall 3-year survival rate of 68%, which is significantly better in patients with PAH associated with congenital heart disease (85%) compared with IPAH patients (63%), which in turn is significantly better than the rate among patients with PAH-systemic sclerosis (53%) (P<0.01). Kane et al7 studied important variables associated with outcome in 484 patients and demonstrated that variables associated with poor RV function increased the risk of death. Several studies have now demonstrated that a number of hemodynamic and echocardiographic measures associated with impaired RV function identify patients with a poor prognosis, including increased right atrial pressure, reduced cardiac index, mixed venous oxygen saturation, reduced TAPSE, and severe tricuspid regurgitation.

Van de Veerdonk and colleagues have shown that baseline measurement of RV ejection fraction (RVEF) using MRI predicts mortality in a group of patients with PAH, and an improvement in RVEF at follow-up has been associated with better outcome independent of hemodynamic indices including pulmonary vascular resistance. This adds weight to the argument that direct visualization of changes in the RV may be more important than monitoring of invasive hemodynamics.8 This would seem logical given that the cause of death is RV failure.

The current diagnostic paradigm for the diagnosis of PAH includes a clinical examination, a 6-minute-walk test, multiple blood tests including brain natriuretic peptide, lung function, and radiologic investigations.4 The common radiologic tests include chest x-ray, echocardiography, nuclear medicine perfusion scan, computed tomography (CT) pulmonary angiography, and, in certain centers, cardiac MRI. The purpose of this review is to showcase and explain the pathophysiological stages of this disease and the use of various cardiopulmonary vascular MRI methods that can be used in daily practice to help diagnose, evaluate, and follow up treatment response in this group of patients. Whereas “estimates” of systolic PA pressure (sPAP) can be determined from the velocity of the tricuspid regurgitation jet,9 the gold standard for clinical diagnosis of this disease remains a direct measurement of pulmonary arterial pressure at RHC.

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THE CLINICAL ROLE OF QUANTITATIVE CARDIAC MRI METHODS IN PAH

MRI has several inherent advantages, including high contrast resolution, absence of ionizing radiation, and sequences with multiple aspects of sensitivity to cardiopulmonary form and functional changes. A range of pulse sequences are utilized in a routine cardiopulmonary examination for suspected PH, detailed below, each with its own benefits in the diagnostic and prognostic evaluation of patients with suspected PH. Imaging of the anatomic structure for structural assessment requires high spatial resolution, whereas accurate imaging of cardiac function requires high temporal resolution and exploitation of the high sensitivity of MRI for assessment of wall motion and blood flow. The review of the imaging protocol allows for a comprehensive assessment of the heart and pulmonary vasculature in terms of form and function.

Biomarker assessment with imaging in patients with PAH is very important. To establish a difference in treatment methodology, drug companies rely on accurate and reproducible markers that detect changes with therapy.10 The precision of measurement means that fewer patients need to be imaged with MRI compared with transthoracic echocardiography11: for instance, there is higher interobserver and intraobserver agreement when using MRI to measure the RV parameters of RV end-diastolic volume index and tricuspid regurgitant volume12 when compared with transthoracic echocardiography.13 The saving in terms of cost when using a more precise and reproducible imaging method is significant, and clinical practice is rapidly acknowledging this fact.

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OVERVIEW OF CARDIOPULMONARY VASCULAR MRI METHODS FOR IMAGING PH

A standard protocol in the clinical assessment of patients with suspected PH based on current evidence includes a lung volume anatomic scan at breath-hold for localization, volumetric cardiac imaging for assessment of biventricular mass, volume, and function, and stroke volume (SV) and cardiac output derived by phase-contrast MRI at the PA and aorta. If the diagnosis of pulmonary thromboembolic disease is suspected, an MR angiogram (MRA) of the pulmonary arteries and a time-resolved contrast-enhanced lung perfusion scan should also be undertaken.14,15 Chronic pulmonary thromboembolism can be identified using these methods in patients with high sensitivity and specificity.14,16 The time-resolved nature of the dynamic contrast-enhanced (DCE) perfusion angiography scan also allows for assessment of left-right heart shunts and collateral bronchial circulation. Finally, late gadolinium enhancement (LGE) imaging (following this contrast dose) is performed to assess for abnormal uptake of gadolinium suggesting myocardial infarction or cardiomyopathy and to look for the presence of gadolinium accumulation at the RV interventricular septal insertion points.17

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THE COMPREHENSIVE CARDIOPULMONARY VASCULAR MRI PROTOCOL

Localizers

Cardiac and lung morphology should first be determined with breath-hold rapid imaging sequences. Short echo time (TE) balanced steady-state free precession (bSSFP: True FISP, FIESTA, bFFE) imaging provides good signal from the parenchyma if the TE is minimized to around 1 ms, allowing lung pathology such as interstitial fibrosis, which is related to PH in patients with pulmonary fibrosis and scleroderma, to be assessed alongside CT.18 The high signal to noise ratio (SNR) from the blood provides good contrast with the vessel lumen and thus serves as a non–contrast-enhanced angiogram, which can be useful in the delineation of adherent material in the central pulmonary arteries in CTEPH.14

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Black-blood Imaging

Cardiac-gated black-blood imaging is a technique that nulls the signal from flowing blood19 using a cardiac-gated dual inversion recovery fast spin-echo sequence. Typical imaging parameters are 4 to 6×8 mm slices through the pulmonary arteries, spacing 2 mm, axial orientation, inversion time (TI)1 50 ms, TI2 551 ms, echo train length 32, bandwidth 31.2 kHz, parallel imaging acceleration factor 2, field of view (FOV) 40 cm (36 cm FOV in phase direction), TE 42 ms, and matrix 256×256. The high–spatial resolution images allow for the morphologic assessment of boundaries between the lumen and vessel walls of the cardiac chambers and vascular structures. Vessels with fast flowing blood appear black, resulting in high contrast resolution between the vessel lumen and the vessel wall. Good suppression is achieved with fast blood flow such as in the aorta. However, it is less effective in the presence of turbulent or slow-flowing blood such as that observed near vessel bifurcations and in the pulmonary arteries particularly of patients with PH.20 Frank et al21 studied the slow-flow phenomenon in patients with PH and showed that slow-flow artifacts were observed in those patients with sPAP>70 mm Hg. Furthermore, several groups have reported a correlation between the slow flow phenomenon and sPAP and pulmonary vascular resistance. In addition, an association between a qualitative score of the extent of slow-flow artifact and outcome has been identified, with the presence of artifacts within the proximal pulmonary main pulmonary arteries predicting mortality in a cohort of patients with PH (Fig. 1).22

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Cine Cardiac MRI
Biventricular Volume, Function, and Mass

Images of the beating heart are captured with cine MRI by gating the acquisition to the cardiac cycle. One significant advantage over echocardiography is that the plane of imaging can be positioned in an accurate and reproducible manner. Balanced steady state free precession (bSSFP) imaging is again the sequence of choice for cine cardiac MRI.23 This technique utilizes a high flip angle with short repetition time (TR) delivering high temporal resolution.13 The key difference of bSSFP over simple gradient echo imaging is that gradient waveforms are balanced, and as such the refocused magnetization between RF pulses results in improved blood-myocardial contrast resolution with T2/T1 weighting, SNR, and temporal resolution (Fig. 2). Typical parameters are as follows: TR/TE 3.7/1.6 ms, 20 phases per cardiac cycle, slice thickness 8 mm, FOV 48, matrix 256×256, and bandwidth 125 kHz/pixel. A stack of images in the short-axis plane with a slice thickness of 8 mm (2 mm interslice gap) or 10 mm (0 mm interslice gap) are typically acquired, covering both ventricles from the base to the apex. bSSFP cine imaging is usually performed with retrospective gating, but when imaging patients with arrhythmia prospective gating may be beneficial.

Accurate and reproducible biventricular volume, function, and mass measurements can be derived from cine bSSFP imaging,13 and such measurements can provide useful clues in the clinical assessment of patients with suspected PH.24,25 Volumetric imaging of the ventricles for quantification is typically performed in the short-axis plane. There are difficulties with this approach; in particular, determining the anatomy at the most basal slice is challenging. The most common approach is to use the smallest chamber size as end-systole and the largest as end-diastole. From end-systolic and end-diastolic images, measurements such as end-diastolic volume, end-systolic volume, ejection fraction, SV, and mass can be calculated for both ventricles.13 Identification of end-systole can be difficult in patients with PH because of dysynchrony of left ventricle (LV) and RV contraction.26 In patients with PH the RV contraction is prolonged with respect to the LV. This accounts for the lengthening (and a louder) second heart sound (P2) in these individuals. Bowing of the interventricular septum toward the LV at the end of the RV systole is obvious in a short-axis view and is indicative of the pressure differential between the RV and LV and results in a diminished RVEF.27

Measurement of RV mass is similarly challenging; RV mass measurements typically include trabeculations and the papillary muscles. The interventricular septum is not considered part of the RV in mass analysis; however, trabeculations that project into the RV from the interventricular septum are included in the analysis. It has been shown that a manual approach to RV analysis offers higher accuracy and reduced interobserver variability compared with a semiautomated segmentation method.10 Another practical challenge is that RV and LV volumes and function vary with age, sex, and body surface area.28 Correction for all 3 variables may be important for identifying small yet clinically significant cardiac volumetric abnormalities in an individual patient.29 Despite the challenges, cardiac MR volume and functional measurements are being increasingly recognized as important in the clinical assessment of patients with PH, having the sensitivity to evaluate change at follow-up examinations and identify treatment failure.24,30 Further development and validation of the methodologies is warranted to promote wider dissemination.

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Interventricular Septum and LV Eccentricity

Elevated RV pressure causes the interventricular septum to bow to the left in patients with PH.31 This leftward motion of the interventricular septum causes the deformation of the LV into a “D shape” as a result of the pressure differential between LV and RV chambers (Fig. 3). Beyar et al32 demonstrated that interventricular septal bowing is present in an animal model when the pressure differential (RV pressure−LV pressure) exceeds 5 mm Hg, and a strong association between interventricular septal curvature and the RV−LV pressure gradient was demonstrated as RV pressure increases. Previous studies using MRI have attempted to quantify paradoxical interventricular septal position by measuring the curvature of the septum and have shown strong correlations with the severity of PH.31

Roeleveld et al31 found a strong correlation between the radius of curvature of the interventricular septal position at the point of maximal septal deviation with PA systolic pressure. Also, Dellegrottaglie et al33 demonstrated in a similar manner that, in patients with PH or suspected of having PH, septal curvature derived from cardiac MR is comparable to RHC measurements and is an accurate metric for estimation of RV systolic pressure. As the disease progresses, the RV dominates the interaction between the cardiac chambers, resulting in a change in LV contour. To quantify this resultant LV deformation, echocardiographic indices such as the LV systolic and diastolic eccentricity indices (sEI, dEI) can be computed from the MRI. The sEI correlates with mPAP in patients with PH, and its routine measurement using echocardiography has been recommended for the identification of RV dysfunction in patients with suspected PH.34 Raymond et al35 studied the prognostic importance of echocardiographic indices in patients with PAH. dEI was identified as a potential prognostic indicator, predicting mortality from Kaplan-Meier log rank analysis, although it is noted that dEI had marginal statistical significance (P=0.074) on Cox proportional hazard regression analysis. Thus, from these studies on septal curvature and LV eccentricity in patients with PH, it is clear that the configuration of the interventricular septum and its effect on the LV are important measurements in the noninvasive hemodynamic assessment of the severity of PH.

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Phase-contrast MRI
Cardiac Output and Flow Profile

In the main PA, blood flow can be measured with phase-contrast imaging with gradient echo imaging and velocity-encoding gradients.36 Hemodynamic measurements such as forward flow, retrograde flow, average velocity, and peak velocity can be determined. Cardiac output has been shown in several studies as an independent marker of adverse outcome in patients with PAH.5,37 Several MRI methodologies are well suited for the evaluation of cardiac output and SV. MR volumetry can accurately and reproducibly evaluate the change in volume of the RV and LV chambers in healthy and diseased states,38 and phase-contrast imaging is a robust technique for the evaluation of pulmonary arterial and aortic blood flow.39,40 Phase-contrast MRI–derived flow measurements have been shown to correlate with invasive measurements of pressure and resistance; for instance, PA pressure is negatively correlated with average velocity of blood flow in the main PA,40 and PVR can be estimated by calculating the ratio of the maximal change in flow rate during ejection by the acceleration volume.41 Moreover, a recent study has identified that early retrograde flow in the pulmonary trunk is a characteristic feature in patients with PH.42 Measurements are typically acquired in clinical practice in the PA with a 2-dimensional (2D) gated cine sequence with velocity encoding in 3 dimensions. Phase-contrast imaging parameters are as follows: TR 5.6 ms, TE 2.7 ms, FOV 48×28.8, slice thickness 10 mm, bandwidth 62.5 kHz, matrix 256×128, and 20 reconstructed cardiac phases. Typically, the velocity-encoding value for flow sensitization in the PA in PH patients is 150 cm/s.

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PA Stiffness and Pulsatility

Pulsatile blood flow is produced from RV contraction driving blood through the main PA toward the capillary bed. In patients with PH, increased pulmonary vascular resistance is associated with increased vascular stiffness,43 dilatation of the pulmonary arteries, and reduced flow velocity.44,45 This impacts the RV-PA coupled system, with elevated RV workload resulting in RV remodeling with hypertrophy and dilatation, eventually resulting in RV failure and death.38 PA stiffness has been assessed in previous studies of patients with PH.43 Typically, the same bSSFP cine sequences as used for myocardial motion are used. In a study of 134 patients with PH, a moderate relationship between PA stiffness, as measured both by and by relative area change (RAC) of the pulmonary trunk (during the cardiac cycle), and pulmonary vascular resistance was observed (Fig. 4). RAC was correlated with adverse outcomes (P<0.05) and may be sensitive to mild PH given that compliance and resistance have an inverse linear relationship and that small increases in pulmonary vascular resistance are associated with larger proportional reductions in compliance.46 Reduced RAC measured at the main PA and the right main PA has been shown to predict mortality in patients with PAH.47 This mirrors the physiology found in the systemic circulation in which reduced pulsatility of the aorta (stiffening of the wall and an increase in the pulse wave velocity) is independently linked to cardiovascular events and all-cause mortality.48

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LGE

LGE imaging is a technique whereby T1-weighted inversion recovery gradient echo images are acquired approximately 10 to 15 minutes after intravenous injection of gadolinium-based contrast agents. The typical pulse sequence parameters are as follows: TR 7.7 ms, TE 3.6 ms, slice thickness 8 mm, FOV 45×40.5, and matrix 256×224. A selective 180-degree inversion recovery triggered to end-diastole was acquired in the short axis. The inversion time can be optimized by measuring the non–contrast-enhanced myocardial T1 with a modified Look-Locker sequence.49 Abnormal myocardium is permeable to contrast, effectively delaying the washout of the contrast from the surrounding interstitium, scar, or dead myocytes. These damaged myocardial tissues represent in effect a different cellular compartment for which the transit times are distinct from the blood pool and the normally enhancing myocardium. Pathologies such as infarction or fibrosis, in which there is abnormal myocardial architecture, increase the local concentration of the contrast agent causing shorter T1 relaxation time compared with normal myocardium. This phenomenon is referred to as late or “delayed” enhancement.50 In the left heart, LGE imaging was developed primarily for assessment of scarring after myocardial infarction, with areas of scarring or fibrosis appearing as areas of high signal intensity. However, this feature is not specific to myocardial infarction. Other cardiovascular disorders in which fibrosis is present can be detected with this method: for example, hypertrophic cardiomyopathy, myocarditis, amyloid infiltration, and PH.51 LGE has been noted at the insertion points of the interventricular septum in patients with PH (Fig. 5), and the amount of late enhancement has been shown to be related to RV volume, mass, and interventricular septal position.52 It is postulated that the degree of LGE relates to mechanical strain caused by elevated RV pressure and structural deformation at the insertion points.52 Thus, LGE in PH is thought to represent pooling of contrast agents within an area of myocardium whose architecture has been affected by mechanical stress and hypertrophy. In a report of a case, the LGE was found to be related to contrast pooling at the septal insertion points, where myocardial disarray (not fibrosis) of the interdigitating fibers of the RV and LV was found.53 A recent study has shown that the presence of LGE on the myocardium of patients with PH is of prognostic value,54 with patients with LGE having worse outcome. However, further research is required to establish the independent prognostic value of LGE as a predictor over clinical, RV, and hemodynamic indices.

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Magnetic Resonance Angiography (MRA)

Contrast-enhanced MRAs can provide an overview of vessel pruning in IPAH and the delineation of thromboembolic material in CTEPH. Distinct angiogram patterns are evident in the PH subgroup types (Fig. 6) with characteristic dilated arteries with distal vessel pruning in IPAH and the pattern of splayed vessels evident in PH associated with chronic obstructive pulmonary disease/emphysema. Images can be acquired with single breath-hold short TE (∼1 ms) 3D spoiled gradient echo sequences with moderate parallel imaging (R≤2 in both phase directions) in breath-holds <12 s. The dose and molarity of contrast agents needed for pulmonary MRA55 will depend upon the pulse sequence timing and flip angle. The use of 10 mL of Gadovist© (Schering Gd-BT-D3OA) at an injection rate of 5 mL/s, followed by a 10 mL saline flush, will provide good delineation of the pulmonary vessels, and bolus timing can be synchronized with central k-space acquisition to bias the arterial-phase or venous-phase intensity. As in CT angiography, MRA is used in the setting of the acute onset of dyspnea for the determination of pulmonary embolism. Similar findings can be seen in the right heart.

These include the following: (a) an increase in the short axis of the RV when compared with the LV (RV/LV diameter); (b) hepatic venous reflux on bolus phase; (c) azygous reflux on the bolus phase; (c) inferior vena cava distension; (d) determination of the degree of obstruction; (e) pulmonary infarction; and (f) pleural effusion.

Furthermore, MRA has the ability to reveal perfusion defects on the bolus phase. The absolute amount of pulmonary perfusion may become an important prognostic tool in the future, as there are some early reports on the use of this simple metric from dual-energy CT,56 wherein the obstruction index and RV/LV diameter were found to be highly correlated with the percentage of nonperfused lung.

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Time-resolved Contrast-enhanced Angiography and Pulmonary Perfusion MR

DCE imaging allows for visualization and measurement of the dynamic passage of a contrast bolus through the heart and lungs. For a typical MRI protocol, 0.05 to 0.1 mmol/kg of gadolinium contrast agent (at a dose approximately 4 times weaker than that for an MRA) is injected intravenously at 2 to 4 mL/s, followed by a saline flush of 10 mL. Continuous imaging immediately after contrast injection allows for a time-resolved analysis of the transit of the contrast bolus through the cardiopulmonary system (Fig. 7).57 Typically, T1-weighted gradient echo imaging is the sequence of choice with rapid data acquisition, and the use of parallel imaging acceleration (acceleration factor of 2 to 4 times) allows the MR perfusion acquisition to be acquired within a single breath-hold (10 to 20 s) with 10 to 30 time-resolved images. Recent advances in parallel imaging and MR sampling strategies have improved the spatial-temporal resolution of dynamic MRI. For example, interleaved variable density sampling58 combined with parallel imaging acceleration in 2D allows a single breath-hold (∼23 s) acquisition to achieve full chest coverage with sufficient (4.0 mm isotropic) spatial resolution and a very high temporal frame rate (1.0 s/frame).59 The acquired data can be reconstructed using either conventional view-sharing methods60 or more sophisticated constrained reconstruction methods.58 These show improved temporal fidelity without blurring at locations where contrast dynamics change rapidly, such as the start of contrast arrival and the peak arterial phase.

Although the bolus protocol and injection rate have been studied,61 the choice of contrast agent and its influence on DCE imaging of the lung have been less well studied. It should be stated, however, that, unlike iodine-based contrast material and CTA perfusion imaging, absolute quantification of lung perfusion is problematic as the concentration of contrast agent and T1 shortening on which the signal intensity is measured do not scale in a linear manner. In other words, the signal intensity of a voxel is not directly correlated to the concentration of contrast, and in the PA, for example, there is limited mixing of contrast agent, and the concentration can be quite high, leading to saturation or “clipping” of the measured signal that underestimates the concentration-time profile of the measured arterial input function. One solution is to inject with a lower dose of contrast; however, lower concentrations of contrast reduce the SNR and sensitivity to perfusion defects in the lung parenchyma.57 One compelling alternative approach is the so-called “dual-bolus” method used by Risse et al62 to overcome the issue of nonlinearity in the calculation of the arterial input function and improve SNR in the lung parenchyma. However, variations in the dual-bolus method remain an area of active research.

The simplest means of analyzing DCE pulmonary perfusion is qualitative inspection of the peak signal enhancement images from the time series, which give a regional picture of pulmonary perfusion heterogeneity. The precontrast baseline images can be subtracted from the peak intensity image to give a qualitative perfusion image (see examples in Fig. 6). MR perfusion images like these provide a high-resolution robust and nonionizing alternative to nuclear medicine perfusion scintigraphy and have been shown to be of equal or greater sensitivity to perfusion scintigraphy in the screening of CTEPH.16 The time-resolved nature of DCE perfusion MRI allows further quantitative interpretation of regional blood flow, volume, and contrast transit time, and several studies have investigated the value of these quantitative parameters in the clinical environment.63 The association of DCE-MR cardiopulmonary transit times with cardiac function has been investigated in patients with left heart disease. Cardiopulmonary transit times are significantly prolonged in patients with LV failure, correlating directly with LV volume and inversely with LV ejection fraction.64 Previous studies have assessed DCE-MR in patients with PH by measuring transit times at pulmonary arterial and lung regions of interest. Skrok et al65 studied the relationship of DCE transit times in comparison with RV function and invasive pulmonary hemodynamics, showing significant associations with pulmonary vascular resistance and right atrial pressure. It should be noted that such measurements may prove to be useful in the prognostic evaluation and follow-up of patients with PAH,65 with a recent study showing prognostic significance of pulmonary transit times in patients with PAH. In this study, transit time measurements predicted mortality independent of age, sex, and World Health Organization functional class; however, invasive hemodynamic indices such as cardiac output, pulmonary vascular resistance, and DCE measurements were not independent of one another, suggesting that they are closely related.66

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ADVANCED IMAGING AND MODELING METHODS IN DEVELOPMENT FOR IMAGING PULMONARY VASCULAR DISEASE

The following methods have recently been attempted in patients with PAH/PH. Pulse wave velocity can be calculated directly using the transit time technique by determining flow wave arrival time at 2 points in the proximal PAs using a high–temporal resolution flow-mapping sequence and dividing the difference by the distance between them.67 Pulse wave velocity not only indicates that there is transmission of flow but also gives the velocity of propagation of the pulse along the vessel. This impact wave travels more quickly than the flow of blood within the vessel. With aging and stiffening of the vessel wall, loss of elasticity, and compliance, the pulse wave velocity increases. With loss of compliance, the normal “windkessel effect” of energy storage by the compliant proximal pulmonary arteries is lost, decreasing the efficiency of energy storage and reducing SV in the face of high pressure defined by the pulmonary vascular resistance.68 Thus, a high pulse wave velocity is an indication of worsened vessel compliance and increased ventricular work that is exacerbated by increased stress and oxygen demand.

A recent study assessing 4D MR flow patterns along the axis of the PA showed vortex pulmonary flow in all patients with PH. Furthermore, the characteristics of the vortex, including the relative period of existence of the vortex, correlated well with PA pressure.69 Truong and colleagues have very recently published some early results in the use of wall sheer stress and compliance in the analysis of children with PAH. They show through 4D flow imaging with wall sheer stress analysis of the right lower lobe PA that children with PAH have lower wall sheer stress compared with children without PAH (P<0.018). Also, as expected, the size of the main PA indexed to body surface area was significantly larger in those children with PAH (P<0.003).70

Despite the promising nature of these findings, further validation of 4D flow MRI is required. Another emerging yet challenging MR methodology is cardiac MR spectroscopy. Clinical 31P-NMR spectroscopy has been applied to the left heart, but there is only scant evidence of its use in the RV,71 likely owing to technical challenges. Further technical development and assessment of the feasibility of spectroscopy for the RV and the interventricular hinge point may be of value in the study of RV metabolism.

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NONINVASIVE ASSESSMENT OF HEMODYNAMICS WITH MRI

The ability to noninvasively and reliably estimate pulmonary arterial pressure is a key objective, as this would permit the diagnosis of PH. Systolic pulmonary arterial pressure can be estimated with echocardiography using tricuspid regurgitant jet velocity. The regurgitant jet is manually interrogated by the user at multiple angles72 until the maximum velocity is achieved. This is more challenging with MRI, as typically a single slice is prescribed with phase-contrast imaging and due to motion of the valve during the cardiac cycle. Pulmonary arterial pressure has been estimated previously by measuring the effects of PH on the heart using MRI. Initial results support the measurement of the ventricular mass index.25 For cardiac MRI to provide a complete hemodynamic assessment, in addition to right heart pressure, left-sided cardiac pressure must be estimated to determine the transpulmonary gradient, a measurement that is necessary to derive pulmonary vascular resistance. In a recent study, mPAP has been accurately estimated using multivariate regression analysis of MRI indices, identifying ventricular mass index along with the angle of the interventricular septum as having additive value for the estimation of mPAP. Furthermore, using left atrial volume and phase-contrast flow measurements as surrogates of left-sided cardiac pressures and cardiac output, pulmonary vascular resistance could be estimated showing the feasibility of MRI to estimate key pulmonary hemodyamic biomarkers.73 There is tremendous potential for the estimation of left-sided heart pressure through the measurement of transmitral flow and myocardial tissue velocity, which when performed with MRI may improve the reliability of the estimations.74 Table 1 presents several MR methods for estimating pulmonary arterial pressure and pulmonary vascular resistance. Validation of current and development of new MR biomarkers encompass improvement of image acquisition and validation of image analysis methods that are crucial to further solidify the importance of MRI as a robust, precise, and reproducible tool for imaging of the right heart in patients with PAH and other causes of PH. The combination of invasive pressure measurements, venous oxygen saturation, pulmonary capillary wedge pressure, and pulmonary vascular resistance during MRI has been recently shown to be feasible in a porcine model of acute pulmonary embolism.78 This ability to simultaneously measure these invasive clinical reference standards in patients during an MRI scan would be very useful and could entirely eliminate the need for a separate RHC.

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MRI PROGNOSIS MARKERS

Despite the continued development of effective treatment options, PAH remains an incurable disease with high morbidity and mortality. Established predictors of adverse outcome in PH include low cardiac output, elevated right atrial pressure, high pulmonary vascular resistance, and reduced mixed venous oxygen saturations as measured at RHC.37,79 There is growing evidence for the role of MRI as a reliable, reproducible, and sensitive biomarker for patient follow-up in the context of risk stratification and for assessment of treatment response.8,80 Cardiac MRI–determined RV volume, SV derived from phase-contrast MRI, ejection fraction, and LV volume independently predict mortality and treatment failure in IPAH.8 In addition, studies evaluating the prognostic value of pulmonary arterial stiffness in patients with PAH have shown that MRI determined pulmonary arterial RAC predicts mortality in PAH and in unselected patients with PH.46,47 Table 2 outlines the studies that have assessed MRI measurements in the prognostic evaluation of patients with PAH/PH.

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FUTURE ROLE OF NONINVASIVE IMAGING IN THE SETTING OF PULMONARY VASCULAR DISEASE

This review has illustrated the potential of MRI in the assessment of patients with suspected PH, with accuracy at least comparable to that of echocardiography. Furthermore, key hemodynamic measurements of pressure, resistance, and flow can be estimated using a noninvasive approach combining multiple MR indices.7 Moreover, several studies have shown that directly visualizing and quantifying the changes in RV function with MRI at follow-up predict mortality independent of clinical and invasive hemodynamic measurements. These facts bode well for the future of MRI in the initial workup and longitudinal follow-up of this group of diseases, as MR metrics of RV function and the associated morphometric indices are more precise and reproducible than echocardiography and also have less interobserver and intraobserver variability.

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REFERENCES

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Keywords:

pulmonary hypertension; magnetic resonance imaging; multidetector computed tomography; thromboembolism; heart catheterization

© 2014 by Lippincott Williams & Wilkins