Imaging of Pulmonary Hypertension 43

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K. Nikolaou, MD; A. Huber, MD

Department of Clinical Radiology, University Hospitals – Gross hadern, Ludwig Maximilian University of Munich, Marchioni nistr. 15, 81377 Munich, Germany

C O N T E N T S

43.1 Clinical Background 481 43.2 Methods 482

43.2.1 MR Angiography and MR Perfusion Imaging

with Parallel Acquisition Techniques 482 43.2.1.1 High-Spatial-Resolution

Magnetic Resonance Angiography 482 43.2.1.2 Magnetic Resonance Perfusion

Imaging 482

43.2.1.3 Pulmonary MRA and MR Perfusion:

Protocol Parameters 483

43.2.2 Multi-planar Imaging of the Right Ventricle with Parallel Imaging 484

43.3 Results 485

43.3.1 Differentiation of Primary and Secondary Pulmonary Hypertension with

High-Resolution

MRA and Perfusion Measurements Using Parallel Imaging 485

43.3.1.1 Results of MR Angiography 486 43.3.1.2 Results of MR Perfusion Imaging 487 43.3.1.3 Results of the Combined MR Perfusion

and MRA Approach 487

43.3.2 Staging of Pulmonary Hypertension by Comprehensive Protocol of Right- Ventricular Functional Analysis

and Flow Analysis

Compared to Clinical Staging (Wood Units, Echo, ECG) 488 43.4 Future Perspectives 489 43.4.1 Oxygen Imaging in PH 489

43.4.2 Quantitative Assessment of Pulmonary Perfusion in PH 491

43.5 Conclusion 492

References 493

Imaging of Pulmonary Hypertension 43

Konstantin Nikolaou and Armin Huber

43.1

Clinical Background

Pulmonary hypertension (PH) is a devastating disease characterized by the progressive elevation of pulmonary artery pressure leading to right ventricular failure and eventually death. However, it is not a single disease entity, but a common clinical end point for a host of diseases that are still being actively investigated. Tra- ditionally, pulmonary hypertension was classifi ed into primary pulmonary hypertension (PPH) and secondary pulmonary hypertension (SPH). The major dif- ference between these two groups of patients is that patients with SPH have a clear etiology or associated underlying disorder, which directly leads to elevated pulmonary artery pressure, while those with PPH are seemingly without a clear underlying cause. A newer, clinically more useful, treatment-based classifi cation of pulmonary hypertension was put forth by a team of experts in the World Health Organization (WHO) meeting on the diagnostic classifi cation of pulmonary hypertension in 1998 (Rich 1998). Five categories of pulmonary hypertension were recognized, including primary pulmonary arterial hypertension, pulmonary venous hypertension, pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia, pulmonary hypertension due to chronic thrombotic and/or embolic diseases, and pulmonary hypertension due to disorders directly affecting the pulmonary vasculature. The pathobiology of PPH includes endothelial and smooth muscle cell dysfunction, abnormal activation and release of vasoac- tive mediators, vascular remodeling, microvascular thrombosis, increased proinfl ammatory cytokines and abnormal ion channels (Loscalzo 2001). Recurrent pulmonary thromboembolism is one of the secondary etiologies leading to PH, classifi ed as chronic thromboembolic pulmonary arterial hypertension (CTEPH), and may be treated surgically (Fedullo et al. 2001), whereas PPH is typically treated using vasodilating drugs (Rich 2000). Comprehensive workup to differ- entiate the various etiologies of pulmonary hyperten-

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sion and especially CTEPH typically requires a series of clinical examinations and imaging procedures.

However, because treatment of CTEPH differs signiﬁ - cantly from other causes of pulmonary hypertension, an accurate diagnosis is essential.

The use of MRI in the assessment of cardiovascular diseases is a rapidly growing ﬁ eld. However, detection of chronic occlusive and non-occlusive changes of the pulmonary arteries at a segmental or subsegmental level requires high spatial resolution, which is limited by the scan time of a single breath-hold. Another relatively new potential clinical application of MRI in the diagnostic workup of PH has been the assessment of right-ventricular (RV) dysfunction. Recently, parallel-imaging techniques have become widely available. With implementation of parallel imaging, the temporal and spatial resolution of MR angiographic techniques and cardiac MR can be improved substantially (Griswold et al.

2002), giving magnetic resonance imaging an important role in the comprehensive assessment of the pulmonary circulation and consecutive right-heart changes.

43.2 Methods

43.2.1

MR Angiography and MR Perfusion Imaging with Parallel Acquisition Techniques

43.2.1.1

High-Spatial-Resolution Magnetic Resonance Angiography

Pulmonary MR angiography has been reported to have a high sensitivity and specifi city in the diagnosis of acute PE without the need for ionizing radiation or iodinated contrast material (Meaney et al. 1997; Stein et al. 2003). Oudkerk et al. (2002) have reported an excellent sensitivity of MRA in the diagnosis of pulmonary embolism. It could be shown that maximized spatial resolution of MRA is necessary for a reliable diagnosis. To achieve this goal, Oudkerk et al. (2002) used a double-bolus injection protocol and a small fi eld of view with sagittal orientation of the 3D slabs to depict both lungs with a high, sub-millimeter spatial resolution while maintaining a suffi cient signal- to-noise ratio. With parallel imaging, a similarly high spatial resolution can be achieved, applying only one contrast injection for MR angiography and covering

both lungs with a larger ﬁ eld of view and coronal orientations of the 3D slab; cf. also Chap. 28. This way, a nearly isotropic voxel size of 1.0×0.7×1.6 mm³ can be realized (Table 43.1). This should result in a higher overall accuracy of pulmonary MRA for detection of occlusive and non-occlusive changes of the pulmonary arteries as compared to conventional MRA techniques.

However, the usefulness of MRA as a sole modality in the diagnostic workup of pulmonary diseases other than PE has not been studied extensively.

43.2.1.2

Magnetic Resonance Perfusion Imaging

MR perfusion imaging might add additional valu- able information in the clinical workup of PH, such as demonstration of the exact extent of perfusion defects, and could increase diagnostic accuracy in the differentiation of various PH etiologies, depending on speciﬁ c patterns of perfusion defects (Fink et al.

2003). First studies on time-resolved, dynamic imaging of the pulmonary circulation have shown promising results (Sonnet et al. 2002). MRI of lung perfusion is realized by rapid imaging of the fi rst pass of contrast material through the lungs after bolus injection into a peripheral vein. Despite substantial improvements of the gradient technique over the past few years, the 3D imaging techniques used have been limited with regard to spatial and temporal resolution (Matsuoka et al. 2002). However, a suffi cient temporal resolution is critical in visualizing peak enhancement of the lungs, since the transit time of a contrast bolus through the lungs usually ranges between 3 and 4 s (Fishman 1963). Compared to applications of conventional MRI sequences, parallel-imaging techniques only acquire a fraction of the phase-encoding lines and reconstruct the missing information to a full fi eld-of-view image using the inherent spatial encoding of the different receiver coils (Dietrich et al. 2002); cf. Chap. 2. This way, a temporal resolution of about 1 s per phase can be obtained (Table 43.1). Still, as breath-hold times can add up to 20 to 25 s to acquire a suffi cient number of datasets, the readout scheme of MR perfusion scans should be centrically re-ordered. By this type of data acquisition, the central lines of the k-space are read out at the beginning of the scan, attributing to suffi cient contrast of the image, and peripheral lines of the k-space are read out towards the end of the scan, attributing to high-resolution data of the images.

To maintain a sufﬁ cient signal-to-noise ratio in spite of an improved spatial resolution, the bolus timing has to be optimized. To achieve a sharp bolus

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proﬁ le of the perfusion study, a high injection rate of contrast, e.g., 5 ml/s, should be used. A further improvement of signal-to-noise ratio can be gained from the use of contrast agents with higher relaxiv- ity, either due to a higher gadolinium concentration (Gadobutrol, 1.0 mol/l) (Tombach and Heindel 2002), or due to weakly or strongly protein-binding substances (e.g., Gadobenate Dimeglumine, Multi- hance, Bracco, Italy, or Gadovosveset Trisodium, Vas- ovist, Schering AG, Germany). Finally, MRI of lung perfusion has various advantages. Three-dimensional MRI offers a higher spatial resolution and better ana- tomic information than radionuclide perfusion scintigraphy and offers the advantage of reconstructing the data in any desired imaging plane. Additionally, MRI lacks any radiation exposure.

43.2.1.3

Pulmonary MRA and MR Perfusion:

Protocol Parameters

In the following sections, typical protocol parameters for high-spatial-resolution MRA and MR perfusion imaging of the lung with parallel acquisition techniques are given. These protocol parameters have been implemented on a 1.5-T MR system with high- performance gradients (40 mT/m, 200 T/m/s slew rate, 200 µs rise time) and eight receiver channels (Magnetom Sonata Maestro Class, Siemens Medical Solutions, Erlangen, Germany). MR perfusion imaging has to be performed before MRA to avoid residual contrast in the pulmonary parenchyma after MRA.

Table 43.1 gives a comprehensive overview of these protocol parameters compared to conventional MRA techniques.

MR Perfusion Protocol

Patients are positioned in the supine position, head fi rst. A special 12-channel receiver coil, dedicated for parallel imaging, is used. Eight of the 12 receiver channels of this coil are combined in pairs of two to fi t the eight receiver channels of the MR system. With this coil, the receiver channels are arranged circularly around the patient’s chest to optimize the spatial sensitivity profi les of the receiver coils for parallel imaging.

After initial localizer sequences, a test-bolus sequence is performed, injecting 2 ml of a 1.0-molar gadolinium-chelate gadobutrol (Gadovist, Schering AG, Berlin, Germany) at a ﬂ ow rate of 5.0 ml/s, acquiring a series of coronal images of the right heart. For the dynamic perfusion study, an ultra-fast FLASH (fast low angle shot) gradient-echo sequence [repetition time (TR)/

echo time (TE), 1.7 ms/0.6 ms; ﬂ ip angle, 25°] with a generalized auto-calibrating partially parallel acqui- sition technique (GRAPPA, acceleration factor R=2) (Griswold et al. 2002) is applied. Further sequence parameters for the MR perfusion protocol are: readout bandwidth: 1,220 Hz/pixel; reference k-space lines (auto-calibration signals) for coil calibration: 24; slice thickness: 4.0 mm; partitions: 24; resulting slab thickness: 96 mm; acquisition matrix 133×256 (52% phase resolution); ﬁ eld of view: 400 mm, resulting in a spatial resolution of 1.6×3.0×4.0 mm³; k-space readout scheme: centrically re-ordered. Acquisition time for one 3D data set of 24 slices is 1.1 s. A total of 25 slabs are acquired for each perfusion study, resulting in a total breath-hold time of 27.5 s (inspiration). Acquisition is started 4 s before the estimated arrival time of the contrast to acquire non-contrast-enhanced studies for subtraction purposes. Injections have to be performed

Table 43.1. Comparison of acquisition parameters of MR angiography and MR perfusion imaging with and without parallel imaging

MR angiography MR perfusion

Without parallel imaging

With parallel imaging

Without parallel imaging

With parallel imaging

TR/TE (ms) 3.3/1.2 2.9/1.2 1.7/0.7 1.7/0.6

Spatial resolution (mm³) 1.4×0.7×2.0 1.0×0.7×1.6 2.9×1.5×5.0 2.9×1.5×4.0

Slice thickness (mm) 2.0 1.6 5.0 4.0

Number of slices 64 88 16 24

Slab thickness (mm) 128 144 80 96

Number of phases 1 1 24 25

Acquisition time per phase (s) 21 22 1.2 1.1

Total acquisition time(s) 21 22 29 28

[Modiﬁ ed from (Nikolaou et al. 2005), with permission]

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with a power-injection system, using a contrast-agent dosage of 0.1 mmol/kg body weight of gadobutrol fol- lowed by a saline ﬂ ush of 25 ml. To ensure an optimized bolus proﬁ le, a high injection rate of 5.0 ml/s is used in combination with a 16-gauge intravenous catheter, which should be placed into an antecubital vein. For each phase (n=25), maximum intensity pro- jections (MIP) of the subtracted data sets over all 24 slices are performed for three-dimensional display.

MR Angiography Protocol

To determine the exact circulation time of the contrast bolus from the injection site to the pulmonary arteries, the test-bolus study has to be repeated, as different fl ow rates of the contrast agent are used for the high- spatial-resolution angiography study. The second test bolus for MRA is performed applying identical sequence parameters, plane orientation and contrast agent (2.0 ml of gadobutrol), but using a fl ow rate of 2 ml/s to ensure a longer, more homogeneous contrast bolus for MRA. Subsequently, a breath-hold contrast-enhanced, three-dimensional FLASH study (TR/TE/fl ip angle:

2.9 ms/1.2 ms/25°) is performed in coronal slice orientation, using the same parallel imaging technique as for the MR perfusion study (GRAPPA, acceleration factor R=2).

Further sequence parameters for the MRA protocol are:

readout bandwidth: 650 Hz/pixel; reference k-space lines for coil calibration: 24; slice thickness: 1.6 mm; partitions:

88; resulting slab thickness: 141 mm; acquisition matrix:

410×512 (80% phase resolution); ﬁ eld of view: 400 mm, resulting in a spatial resolution of 1.0×0.7×1.6 mm³. Acquisition time for one 3D data set of 88 slices is 22 s, acquired during breath-hold (inspiration); the k-space readout scheme is centrically re-ordered. Due to this asymmetric sequential read-out scheme of the k-space, acquisition is started 5 s before the estimated arrival time of the contrast bolus. A non-contrast-enhanced MRA dataset, which is acquired before any administra- tion of contrast at the beginning of the examination, is subtracted from the contrast-enhanced images, and for image analysis, single coronal slices and MIP reconstruction of the complete dataset (88 slices) are stored.

43.2.2

Multi-planar Imaging of the

Right Ventricle with Parallel Imaging

Right-ventricular hypertrophy and right-ventricular heart failure are commonly caused by pulmonary hypertension and are a major cause of death in this

patient population. Accurate and reproducible assessment of right-ventricular function including ejection fraction as well as chamber volumes during end-diastole and end-systole is important to the care of these patients (Hunt 1997). However, exact right-ventricular volumes are not routinely obtained even in settings in which quantitative data are useful, partly due to the measurement inaccuracy of established modalities such as echocardiography (Bottini et al. 1995;

Teichholz et al. 1976). While previous authors have validated the accuracy of cardiac MRI-derived volume and functional data (Bellenger et al. 2000), existing strategies can suffer from measurement variability and decreased clinical robustness in heart-failure patients (Grothues et al. 2002). Current techniques require ill, dyspneic patients to undertake multiple, prolonged breath holds in the exact same diaphragmatic position. They also collect and assemble data over multiple cardiac cycles, causing image degradation during arrhythmias. In addition, the process of complete volu- metric imaging of the entire right ventricle (RV) and left ventricle (LV) can take as long as 10 to 15 min, during which time patient motion will compromise image quality and quantitative accuracy.

Current techniques are thus ill-suited for routine application in heart failure patients and have hampered the clinical utility of cardiac MRI. Recently, steady-state free precession (SSFP) sequences have been introduced to cardiac MR imaging (Thiele et al. 2001). While their increased signal-to-noise ratio and blood-to-myocar- dial contrast have improved image quality, the quantifi cation of cardiac function continues to suffer from prolonged image acquisition times and the need for multiple breath-holds. The incorporation in faster, real- time imaging strategies has been hampered by the rela- tive ineffi ciency of k-space sampling techniques, with resultant poor temporal and spatial resolution (Hori et al. 2003; Spuentrup et al. 2003). Some investigators have advocated combining real-time techniques with a free-breathing strategy to assess LV and RV volumes quantitatively. Narayan et al. (2005) suggested using a high-resolution spiral sequence that provides effi cient k-space sampling for real-time imaging with SSFP. This strategy provides complete coverage of RV and LV function in a single breath hold by employing a multislice strategy in which one slice is imaged every heartbeat.

This single-breath-hold strategy was assessed in 20 patients with congestive heart failure and validated with the gold standard: gated, segmented k-space, multiple- breath-hold acquisition. A good correlation for LV and RV parameters between the real-time technique and the segmented-k space technique was found.

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An alternative method was used for real-time imaging of ten slices, one per RR cycle, during a single breath hold with sufﬁ cient temporal resolution: A shared- echo technique was combined was parallel imaging for improvement of temporal resolution with a time window per frame below 50 ms (Wintersperger et al. 2003). Results for the ventricular parameters EDV (r=0.93), ESV (r=0.99), SV (r=0.83), and EF (r=0.99) of real-time multi-slice SSFP imaging showed a high correlation with results of segmented SSFP acquisitions.

Systematic differences between both techniques were statistically non-signiﬁ cant. Single-breath-hold multislice techniques using GRAPPA allow for improvement of temporal resolution and for accurate assessment of global ventricular functional parameters (Wintersperger et al. 2003).

This imaging technique can be used in a comprehensive evaluation of patients with pulmonary hypertension to image lung perfusion, lung arteries and the right heart within one examination. A complete coverage of the right and left ventricle can be achieved within one breath hold. With two breath holds, one stack of ten cine slices can be acquired in the short- axis orientation and a second stack of ten slices can be acquired in transverse orientation. Typical imaging parameters of a real-time cine technique including echo-sharing and parallel imaging are shown in Table 43.2. The quantitative assessment with post- processing software can be performed on the short- axis images; the transverse images allow for an additional visual evaluation of typical right-heart changes.

Both the short-axis images and the transverse images allow detecting right-heart dilatation, hypertrophy of the myocardium, pathological movement of the septum – ﬂ attening or convex shape in relation to the left ventricle – and a jet into the right atrium caused by secondary regurgitation of the tricuspid valve.

Table 43.2. Typical imaging parameters of a real-time cine TrueFISP (GRAPPA, R=2, 12 reference lines) pulse sequence using parallel imaging and echo sharing for assessment of right heart function

TR 0.8 ms

TE 0.9 ms

Flip angle 50°

Temporal resolution 48 ms

Bandwidth 1,395 Hz/pixel

Field of view 350×265 mm²

Acquisition matrix 128×80 Spatial resolution 3.1×3.3 mm²

Slice thickness 8 mm

Inter-slice gap 2 mm

In addition to cine imaging, fl ow measurements can be carried out with a free-breathing technique to quantify the volume of secondary regurgitation of the tricuspid valve. A fl ow measurement with coverage of the pulmonary trunk and the ascending aorta can be used to exclude or detect intra- or extra-cardiac shunts and quantify the shunt volume, as the presence of vascular or cardiac shunts can be a reason for secondary pulmonary hypertension. Figure 43.1 demonstrates the diastolic and systolic cine images acquired with a real-time technique during a single breath-hold. With acquisition of one slice per breath- hold, a change of the respiratory position during the duration of the cine examination has a minor impact on image quality. The use of an averaging technique during free breathing for the velocity-encoded phase- contrast measurements in the position of the tricuspid valve and in a transverse orientation including the two large arteries, ascending aorta and pulmonary trunk, does not require breath-holding, and allows for reconstruction of images with adequate temporal resolution of 20 ms. The scan time per fl ow measurement with retrospective ECG gating is between 1 1/2–2 min. Figure 43.2 shows phase-contrast images of the tricuspid valve and the aorta and the pulmonary trunk.

43.3 Results

43.3.1

Differentiation of Primary and Secondary Pulmonary Hypertension with High-Resolution MRA and Perfusion Measurements Using Parallel Imaging

In the following sections, results from a pilot study are reported (Nikolaou et al. 2005). The pur- pose of this study was the assessment of a combined approach for the correct differentiation of PPH and CTEPH, subsequently performing time- resolved, dynamic MR perfusion imaging and MR angiography in one study with parallel-imaging techniques (using the protocol parameters given in Sect. 43.2.1.3). During this study, 29 consecutive patients (mean age, 55±16 years; 16 female patients, mean age 54±17 years; 13 male patients, mean age 57±15 years) with known pulmonary arterial hypertension were examined.

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reference modalities. Table 43.3 shows the diagnostic imaging criteria for MRA datasets, differentiating non-occluding and occluding imaging ﬁ ndings. For non-occlusive image criteria, MRA showed high sensitivities for changes of the central pulmonary arteries (dilated main stem, pruned tree, 100% and 94%, respectively), but lower sensitivities for non-occlusive changes involving more peripheral vessels (57%–89%).

43.3.1.1

Results of MR Angiography

Analysis of the MR angiographic images alone (without knowledge of the MR perfusion results) allowed differentiation of typical obstructive and non-obstructive imaging ﬁ ndings, as compared to digital subtraction angiography (DSA) and/or CT angiography (CTA) as

Fig. 43.1. a Eight cine images in a short-axis orientation acquired during the end-diastolic phase with a real-time SSFP pulse sequence. Ten slices can be acquired during a single breath hold with a temporal resolution of 47 ms using parallel imaging and shared-echo technique. b Eight cine images in a short-axis orientation acquired during the end-systolic phase with a real-time SSFP pulse sequence. Ten slices can be acquired during a single breath hold with a temporal resolution of 47 ms using parallel imaging and a shared-echo technique

b a

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For occlusive image criteria, sensitivities were high for complete vessel occlusion and free-ﬂ oating thrombi (83% and 86%, respectively), but lower for older and/

or organized thrombi (wall adherent thrombi, webs and bands, 71% and 50%, respectively). Accordingly, kappa-values (κ) (inter-observer agreement) ranged from 0.79 to 0.26 and inter-modality agreement ranged from 97% to 72%. Using MRA data alone, correct differentiation of PPH and CTEPH succeeded in 83% of the cases (24/29) (Table 43.4).

43.3.1.2

Results of MR Perfusion Imaging

The analysis of the time-resolved MR perfusion data sets alone (without knowledge of the MRA results) allowed differentiation of perfusion abnormali-

ties from normally perfused lungs in most cases, as compared to perfusion scintigraphy as the reference modality (for n=24 patients). In detail, MRI showed a sensitivity of 77% for the detection of any perfusion defect on a per-patient basis (17 of 22 patients with perfusion abnormalities detected). Two patients with normal ﬁ ndings in perfusion scintigraphy were also assessed as normal in MR. When the results of the MR perfusion data were compared with the conventional perfusion scintigraphy for all 24 patients undergoing both modalities, an inter-modality agreement, i.e., congruent diagnosis on a per-patient basis, of 79%

(19/24) was observed. Inter-observer agreement for the detection of perfusion defects was high (κ=0.64, good agreement). For the differential diagnosis of PPH and CTEPH, reviewers had to make the following decision: If a perfusion defect is present, is it:

(1) patchy/diffuse? Æ indicative for PPH or

(2) segmental/circumscribed? Æ indicative for CTEPH Comparing MR perfusion data of all patients (n=29) with the ﬁ nal reference diagnosis, a correct diagnosis (PPH or CTEPH) was made in 69% of the cases (20/29) (Table 43.4).

43.3.1.3

Results of the Combined MR Perfusion and MRA Approach

While the interpretation of MR-perfusion and MRA data alone led to a correct diagnosis (PPH or CTEPH) in 69% and 83% of the cases, respectively, the combi-

a

Table 43.3. Imaging criteria in the assessment of MR angiography

Imaging criteria:

non-occluding

Imaging criteria:

occluding Dilatation of the pulmonary

arterial main stem

Complete vessel occlusion

Proximal caliber changes (pruned-tree sign)

Free-ﬂ oating thrombus

Peripheral vessel reduction Wall-adherent/endothelial- ized thrombus

Focal vessel ectasia Webs and bands Presence of the corkscrew

phenomenon

Fig. 43.2a,b. Phase-contrast imaging: a The pulmonary trunk and the ascending aorta reveal bright signal. b After drawing regions of interests, the forward volumes can be determined

b Net ﬂ ow vs time

23 90 157 224 291 358 425 492 559 626 693 59

53 47 41 35 29 23 17 11 5 –1

Slice position: SP H116.0 Venc adjustment–150:150

Time (ms) Legend:

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nation of the data led to a correct diagnosis in 90% of the cases, i.e., 26 of 29 patients were diagnosed cor- rectly for suffering from PPH or CTEPH, as compared to the ﬁ nal reference diagnosis (Table 43.4). This way, it was proven that combining the information of MR perfusion and MR angiography in a comprehensive evaluation, the diagnostic information can be used complementarily, increasing the diagnostic value of pulmonary MRI. Figures 43.3 and 43.4 display typical imaging ﬁ ndings of MR angiography and MR perfusion imaging in patients with CTEPH and PPH.

43.3.2

Staging of Pulmonary Hypertension by Comprehensive Protocol of Right-Ventricular Functional Analysis and Flow Analysis Compared to Clinical Staging (Wood Units, Echo, ECG) The early diagnosis of PAH is diffi cult because present- ing symptoms are often mild and non-specifi c. By the time patients develop signifi cant dyspnea, the disease is usually advanced. Accurate diagnosis depends on right-heart catheterization; however, thisis an invasive and costly test and thus is not appropriate for screening. Right-ventricular dysfunction and pulmonary hypertension often are diagnosed serendipitously by echocardiography; however, echocardiography may not detect pulmonary hypertension unless the diagnosis is specifi cally sought or if there is not adequate tricuspid regurgitation. The latter scenario may occur in up to 10% of patients with pulmonary hypertension.

The ECG is easily performed, is inexpensive, and is widely available. Its diagnostic utilityhas been established for ischemic heart disease, but it hasnot been widely evaluated as a screening tool with which to exclude pulmonary vascular disease associated with PAH. Ahearn et al. (2002) found that ECG parameters do not correlate well with hemodynamic or echocardiographic ﬁ ndings in patients with suspected pulmo-

nary hypertension. The amplitude of the P-wave in lead II had a negative correlation with the cardiac index of 0.3. It correlated poorly with other hemodynamic, echocardiographic, and exercise parameters, with correlation coefﬁ cients ranging from 0.26 to 0.39. The frontal QRS axis correlated best of all ECG parameters with hemodynamic and echocardiographic parameters, with a coefﬁ cient of –0.46 with the cardiac index.

The pulmonary vascular resistance (PVR) is determined by right heart catheterization and quantiﬁ ed by Wood units. An increased pulmonary vascular resistance can be caused by lung embolism, various parenchymal lung diseases or secondary to cardiac or extra-cardiac shunts and congenital vascular and cardiac anomalies and heart-valve disease.

For cine MRI of the left and right ventricles, gender and age-specifi c reference values for the functional parameters ejection fraction, end-diastolic and end- systolic volume and ventricular mass have been available since 1999 (Lorenz et al. 1999). However, they are somewhat different depending on the MRI technique that is used. For assessment of right-ventricular functional parameters, MRI is superior compared to echocardiography. A main limitation of echocardiography of the right ventricle is the lack of clear landmarks. Therefore, the most suffi cient parameter for quantifying the right-ventricular failure and pulmonary hypertension is assessment of the extent of regurgitation of the tricuspid valve by echocardiography either by direct visualization or determination of the pressure gradient. In contrast to echocardiography, MRI is not only able to visualize the regurgitation jet (Fig. 43.5) and determine the pressure gradient of the jet, but also the regurgitated volume can be determined exactly and quantifi ed in relation to the right ventricular stroke volume. Cine images in the short-axis orientation near the atrioventricular valves demonstrate pathological movement of the septum towards the left ventricle during diastole. Either fl attening or inver- sion of the normal curvature of the septum can be

Table 43.4. Diagnostic accuracy of MR angiography, MR perfusion imaging, and the combined assessment of MRA and MR perfusion imaging

Modality Detection and correct classiﬁ cation of any defect (n=29)

Detection and correct classiﬁ cation of secondary defects (n=10)

Inter-modality agreement Inter-observer agreement (κ)

MR angiography 83% 60% Vs. CTA/DSA: 86% 0.70

MR perfusion 69% 70% Vs. scintigraphy: 86% 0.63

MRA and MR perfusion 90% 80% Vs. ﬁ nal diagnosis: 90% 0.73

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observed (Fig. 43.5). In patients with intra- or extra- cardiac shunts, the shunt volume can be determined in relation to the right-ventricular stroke volume by ﬂ ow measurements. The percentage of shunt volume (Fig. 43.6) is important for the therapeutic decision of surgical or interventional repair. The most established alternative method for shunt quantiﬁ cation is right- heart catherization, which is an invasive examination.

Pulmonary hypertension in intra- or extra-cardiac shunts except for larger ventricular septum defects usually develops slowly when Eisenmenger’s reaction is beginning. With a shunt volume of more than 50%, surgical or interventional therapy is indicated.

43.4

Future Perspectives

43.4.1

Oxygen Imaging in PH

A major impact on the comprehensive assessment of PH using MRI might arise from the combination of pulmonary MR angiographic techniques with functional imaging of lung ventilation, using either hyperpolarized gases such as helium-3 (Kauczor et al. 2002; Rizi et al. 2003) or simply oxygen (Muller

c

b a

Fig. 43.3. a Contrast-enhanced MR perfusion imaging (GRAP- PA technique) of a 53-year-old male patient with secondary, chronic thromboembolic pulmonary arterial hypertension (CTEPH): A maximum intensity projection (MIP) of a single perfusion phase of the MR perfusion dataset (25 phases) clear- ly shows segmental perfusion defects in the left upper lobe and right lower lobe due to thromboembolic occlusions (arrows). b MR angiography (GRAPPA) of the same patient: In the single coronal image of the high spatial resolution MRA dataset, the dark, thromboembolic material can be identiﬁ ed in the lower right lobe pulmonary artery (long arrow), causing the perfu- sion defect seen in the perfusion image. c Digital subtraction angiography proves segmental perfusion defects in identical lung areas as shown by MR perfusion imaging (arrows). [Mod- iﬁ ed from (Nikolaou et al. 2005), with permission]

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Fig. 43.4. a Contrast-enhanced MR perfusion study (GRAPPA technique) of a 55-year-old male patient with primary pulmonary arterial hypertension (PPH). From the dynamic dataset of MR perfusion (25 phases, 1.1 s acquisition time per phase), a single, late parenchymal perfusion phase is displayed. Dif- fuse, non-segmental peripheral perfusion defects are shown on both sides (arrows). b and c The diagnostic reference mo- dalities, i.e., digital subtraction angiography b, after selective catheterization of the right pulmonary artery and perfusion scintigraphy c, demonstrate the identical diffuse peripheral perfusion defects without proof of occluding thrombotic ma- terial or segmental perfusion defects (arrows). [Modiﬁ ed from (Nikolaou et al. 2005), with permission]

c a b

et al. 2002; Dietrich et al. 2005). Using either MR imaging technique of pulmonary ventilation, and combining information with the MR perfusion data, a differentiation of perfusion defects arising from thromboembolic origin or from atelectasis/

dystelectasis can be made (Ley et al. 2004), further helping in the complex differential diagnosis of PH.

Oxygen imaging of the lung has the advantage of being easier to perform and less expensive than helium imaging. Since oxygen imaging is based on the T1-shortening of molecular oxygen dissolving in blood, it represents the combined physiologic processes of ventilation, diffusion and, to a lesser degree, perfusion. However, the signal-to-noise ratio of oxygen imaging is considerably lower than applying helium, and if respiratory and/or cardiac trigger-

ing are employed for optimized image quality, oxygen imaging of pulmonary ventilation has been reported to be very time-consuming (Ohno et al. 2002). With implementation of parallel-acquisition techniques, using slice-selective pulses and combined respiratory and ECG triggering, oxygen-enhanced lung MRI with the acquisition of six slices and 80 repetitions can be performed in 8 to 13 min, depending only on the respiratory frequency of the examined subject (Dietrich et al. 2005); cf. Chap. 38. Thus, using parallel imaging, oxygen-enhanced lung imaging becomes sufﬁ ciently fast to be integrated into a clinical routine MRI examination of the lung consisting of other morphologic and functional methods such as lung perfusion MRI and pulmonary MR angiography.

Future studies will have to prove if oxygen imaging

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with parallel acquisition techniques integrated into a comprehensive MRI protocol will further improve the diagnostic and clinical workup of PH.

43.4.2

Quantitative Assessment of Pulmonary Perfusion in PH

Apart from the distinct determination of the peak enhancement of the lung tissue, the temporal information achieved by parallel imaging could be used for the temporal analysis of tissue perfusion and ultimately for the calculation of semi-quantitative or quantitative parameter maps of parenchymal perfusion (Nikolaou et al. 2004). If a correct contrast- agent dose and fast sequences with high temporal

resolution are used, MRI is able to evaluate regional differences in pulmonary perfusion (Fink et al. 2004);

cf. Chap. 37. By assessing the arterial input function and the parenchymal response curve, quantitative perfusion parameters can be derived, applying a simpli- ﬁ ed one-compartment model (Fig. 43.7) (Nikolaou et al. 2004). Such a quantitative MR approach would be of high potential clinical value, because intra- and interindividual differences in pulmonary blood ﬂ ow and volume would be detectable. In combination with recent MR ventilation/diffusion techniques, such as oxygen-enhanced imaging, it might also be attrac- tive to estimate ventilation/perfusion ratios. Ideally, a quantitative method of perfusion assessment would enable the detailed follow-up of PH patients and help in the assessment of treatment effects of vasodilative drug therapy in patients suffering from PPH.

Fig. 43.5. a Real-time cine images demonstrate a pathological movement of the septum towards the left ventricle during di- astole caused by primary pulmonary hypertension. b Cine SSFP image after contrast-material injection shows a jet from the secondary insufﬁ cient tricuspid valve into the right atrium

a

b

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minutes to even breath-holds. This allows the combined use of different morphologic and functional MRI techniques within a reasonable total scan time.

MR angiography of the pulmonary vasculature can be complemented by additional functional measurements such as ﬂ ow measurements and assessment of right-heart cardiac function. In the future, potential clinical applications of pulmonary MRI in the diagnosis of pulmonary hypertension could include ventilation imaging using oxygen, or quantitative assessment of pulmonary perfusion, enabling a truly comprehensive workup of PH using MRI alone.

c

b a

d Fig. 43.6. a Phase-contrast images of the ascending aorta and pulmonary trunk. b The quantiﬁ cation of the net ﬂ ow demonstrates a shunt volume of 70%. A secondary pulmonary hypertension is caused by an anomalous return of the right upper lobe vein into the superior vena cava c and by a large sinus venous defect d. Surgical repair is indicated

43.5 Conclusion

In patients with pulmonary hypertension, MR imaging of the pulmonary circulation using the combination of MR perfusion imaging and MR angiography with parallel-imaging techniques provides a high diagnostic accuracy in differentiating PPH and CTEPH. Further larger-sample studies will be needed for validation. Besides improving temporal and spatial resolution of these techniques, also their required scan time can be substantially reduced from several

Net ﬂ ow vs time

47 114 181 248 315 382 449 516 583 615 717 130

123 110 97 84 71 58 45 32 19 0

Slice position: SP H116.0 Venc adjustment–150:150 Legend:

Data Spline

(13)

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