Published online before print September 13, 2004, doi: 10.1161/01.CIR.0000142049.14227.AD
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(Circulation. 2004;110:1632-1637.)
© 2004 American Heart Association, Inc.
Imaging |
Quantitative 3-Dimensional Echocardiography for Accurate and Rapid Cardiac Phenotype Characterization in Mice
From the Departments of Cardiovascular Medicine (D.D., C.A.G., J.E.S., K.H., S.N.) and Engineering Science (J.S., X.Y., J.A.N.), University of Oxford, Oxford, England.
Correspondence to Prof Stefan Neubauer, MD, FRCP, Department of Cardiovascular Medicine, Level 5, John Radcliffe Hospital, Oxford, OX3 9DU, UK. E-mail stefan.neubauer{at}cardiov.ox.ac.uk
Received December 8, 2003; de novo received February 11, 2004; revision received April 6, 2004; accepted April 20, 2004.
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Abstract |
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Background— Insufficient techniques exist for rapid and reliable phenotype characterization of genetically manipulated mouse models of cardiac dysfunction. We developed a new, robust, 3-dimensional echocardiography (3D-echo) technique and hypothesized that this 3D-echo technique is as accurate as magnetic resonance imaging (MRI) and histology for assessment of left ventricular (LV) volume, ejection fraction, mass, and infarct size in normal and chronically infarcted mice.
Methods and Results— Using a high-frequency, 7/15-MHz, linear-array ultrasound transducer, we acquired ECG and respiratory-gated, 500-µm consecutive short-axis slices of the murine heart within 4 minutes. The short-axis movies were reassembled off-line in a 3D matrix by using the measured platform locations to position each slice in 3D. Epicardial and endocardial heart contours were manually traced, and a B-spline surface was fitted to the delineated image curves to reconstruct the heart volumes. Excellent correlations were obtained between 3D-echo and MRI for LV end-systolic volumes (r=0.99, P<0.0001), LV end-diastolic volumes (r=0.99, P<0.0001), ejection fraction (r=0.99, P<0.0001), LV mass (r=0.94, P<0.0019), and infarct size (r=0.98, P<0.0001). Also, excellent correlations were found between the 3D-echo–derived LV mass and necropsy LV mass in normal mice (r=0.99, P<0.0001), as well as for 3D-echo–derived infarct size and histologically determined infarct size (r=0.99, P<0.0001) in mice with chronic heart failure. Bland-Altman analysis showed excellent limits of agreement between techniques for all measured parameters.
Conclusion— This new, fast, and highly reproducible 3D-echo technique should be of widespread applicability for high-throughput murine cardiac phenotyping studies.
Key Words: echocardiography • magnetic resonance imaging • mice • myocardial infarction
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Introduction |
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New transgenic mouse models of cardiac dysfunction are produced at a rapid pace, but insufficient techniques exist for characterization of the structural and functional consequences of gene alteration. Magnetic resonance imaging (MRI) is currently the gold standard for measurement of myocardial function, having shown excellent reproducibility in both human1 and murine2,3 studies. However, as desirable as the MRI approach for phenotype characterization in mice is, its widespread use is limited by a number of factors: MRI experiments are costly, relatively time consuming, and therefore, difficult to use for large series of studies.
Two-dimensional echocardiography (2D-echo) has so far been the routine noninvasive cardiac phenotyping method in normal and gene-targeted mice,4–10 but this technique requires geometric assumptions for calculation of left ventricular (LV) mass and volumes. Therefore, 2D-echo has proven unreliable when the LV is of asymmetric shape, such as after myocardial infarction. 3D echocardiography (3D-echo) would overcome this limitation, and previous attempts at this11,12 have paved the way to the approach we propose here. Thus, we developed a new, robust, highly accurate, reconstructive 3D-echo technique for noninvasive, rapid phenotyping of the mouse heart. We hypothesized that this new method is superior to conventional 2D-echo methods and approaches the accuracy of MRI and histological examination for determining LV parameters and infarct size, respectively. If feasible, such a technique could find widespread use in basic cardiovascular research.
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Methods |
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3D Echo
A total of 18 normal (18 to 38 g) and 7 chronically infarcted (29 to 38 g) male C57B1/6 mice were anesthetized with 1.25% to 1.5% isoflurane in O2 and placed in the left lateral decubitus on a heated platform, designed with micrometer precision rotation and translation capabilities (Figure 1). An Agilent Sonos 5500 system was used, equipped with a 7/15-MHz, linear-array probe secured in a holder device with 360° freedom of movement. ECG and respiratory gating was obtained by using electrodes adapted with fine needles and secured on the mouse limbs. The gain, compression, depth, and zoom were optimized at the beginning of each experiment and kept constant. Between 10 and 18 consecutive short-axis views were acquired for the duration of a cardiac cycle at a minimum of 185 Hz by translating the mouse platform in 500-µm increments along the long axis of the heart. A single, parasternal, long-axis view was also obtained. The duration of imaging was 4 minutes; an entire experiment could be completed in 10 minutes. Heart rate was within 5% of 500 beats per minute in all mice, and the basal rectal temperature was constant. All images were stored digitally.
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MRI Validation Study
An MRI validation study was performed in 7 normal and 7 chronically infarcted mice on a 11.7-T experimental MR system (Bruker) as previously described.13 Cine MR images with 6 to 9 1-mm-thick, contiguous short-axis slices were acquired, comprising between 20 and 31 frames per cardiac cycle (echo time of 1.43 ms, repetition time of 4.6 ms, 2 averages per slice, matrix size of 256x256, and a field of view of 2.56 cm, giving an inplane resolution of 100x100 µm). Finally, a single, long-axis, cine dataset was acquired. Total time for an MRI study was 40 to 60 minutes.
Data Analysis
The 3D-echo and MRI short-axis movies were processed off-line. These were reassembled into a 3D matrix by using either the measured 3D platform locations for 3D-echo or the slice thickness for MRI to position each image slice in 3D. The 3D matrix was then analyzed with custom-designed software (MV1) by manually delineating the heart chamber borders and fitting a B-spline surface to the delineated image curves.14 The B-spline surface fit was initialized manually by using a sphere, defined as a regularly tessellated volume mesh. The surface nodes of the mesh were then deformed to best fit the delineated contour points by using an iterative, closest point–based surface mesh fitting algorithm. The volume enclosed by the surface could thus be calculated by summing the pyramidal volume elements defined by the final B-spline surface fit, with each pyramid having the apex in the center of the LV and the base on the surface. Thus, end-systolic (ES) and end-diastolic (ED) endocardial contours (including papillary muscles) and end-diastolic epicardial (EP) contours were traced for each slice, and the ES, ED, and EP surfaces were reconstructed. For LV mass calculation, the LV myocardial tissue volume obtained at end-diastole2 was multiplied by the myocardial density (1.05 g/mL); this was compared with the anatomic heart weight obtained by dissection of the LV after each experiment. 2D-echo LV myocardial mass was also obtained using both the area-length method (AL)15 and the truncated ellipsoid method (TE)16 in the normal group.
The 3D-echo measurements were performed by one observer for all mice, repeated a second time by the same observer for calculation of intraobserver variability, and performed by a second observer for interobserver variability. To obtain interstudy variability data, 5 mice were imaged a second time after 3 days.
Mouse Model of Chronic MI
Myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery (LAD). General anesthesia was maintained with 2% isoflurane in O2. Mice were intubated and ventilated with a tidal volume of 250 µL and respiratory rate of 150/min (Hugo-Sachs MiniVent type 845, Harvard Apparatus). A left thoracotomy was performed in the fourth intercostal space, the intercostal muscles dissected, and the pericardial sac opened. An intramyocardial suture was placed 1 to 2 mm below the atrioventricular groove with an atraumatic needle and a 7-0 polyethylene suture. The lungs were reexpanded and the thorax closed. Long-term survival after LAD ligation was 68%. All imaging in the infarct group was performed 6 weeks after surgery, with 3D-echo and MRI performed within 48 hours of each other.
Infarct Size Determination
After the second imaging protocol, the heart was fixed in formaldehyde at 100 mm Hg pressure. Immediately after explantation, the heart was suspended at the tip of a butterfly needle connected to a running column of 4% formal-saline for 1 hour to maintain aneurysm shape and then embedded in paraffin. Infarct size was determined histologically by using Picrosirius red as previously described for the rat,17 with one adaptation: Sections were taken at 250-µm intervals to allow for smaller cardiac dimensions. For in vivo determination of infarct size, end-diastolic epicardial and endocardial contours were traced on the 3D-echo and MRI short-axis slices; only akinetic and dyskinetic segments were considered infarcted. This investigation conformed with the UK Home Office Guidance on the Operation of the Animals (Scientific Procedures) Act, 1986 (HMSO).
Statistical Analysis
All results are given as mean±SD. Linear regression analysis and unpaired Student’s t test were performed for comparisons between groups. Bland-Altman analysis, shown as the mean of differences ±1SD, was used to assess the limits of agreement between techniques. Variabilities were calculated as mean±SD of the percentage ratios between differences and means of the 2 independently measured variables. Results were considered statistically significant at P<0.05.
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Results |
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As demonstrated in Table 1, 3D-echo, MRI, and histology yielded excellent agreement for measurements of LV mass, volume, ejection fraction, and infarct size, both in normal and chronically failing mouse hearts. No significant differences could be detected within groups for measurements made with different techniques. Both 3D-echo and MRI demonstrated the same degree of LV dysfunction (decreased ejection fraction) and dilatation (increased volumes) in chronically failing hearts.
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Data from Table 2 demonstrate that intraobserver, interobserver, and interstudy variabilities of 3D-echo–derived parameters were all low, ranging from 3% to 7%. These variabilities are similar to those reported for MRI.2 Thus, 3D-echo measurements were highly reproducible.
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Figures 2 and 3
show examples of original short-axis imaging recordings as well as reconstructed LV volumes. Figure 2 represents a normal heart (for selected cine movie, see the Data Supplement at http://www.circulationaha.org), and Figure 3A and 3B depicts 2 hearts with infarcts of different size. Figure 3A is an example wherein the infarcted territory was seen in just 3 slices on 3D-echo and on 2 slices on MRI, demonstrating a 1.5- to 2-mm infarct length measured in the long axis of the heart. (For corresponding cine movies, see Data Supplement at http://www.circulationaha.org.) In contrast, Figure 3B shows an example in which the aneurysmal territory extended over the anterior, lateral, posteroinferior, and apical walls, sparing the interventricular septum. (For corresponding cine movies, see the Data Supplement at http://www.circulationaha.org.)
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Figure 4A-D demonstrates the close linear correlations between 3D-echo and MRI-derived parameters of LV function and mass. Figure 4E and 4F shows data from an extended cohort of 18 normal mice imaged by ultrasound only; for these, the necropsy LV mass (79.9±17 mg) was compared with the calculated LV mass derived by both 3D-echo (79.6±18 mg) and 2D-echo (75.5±17 mg by the AL method and 89±19 mg by the TE method) measurements. The correlation coefficient for 3D-echo and necropsy mass was 0.99, but for both 2D-echo methods, it was lower (0.91 for AL and 0.90 for TE), a value consistent with 2D-echo data previously reported in murine studies.10,18,19
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Finally, Figure 5 shows the correlations of 3D-echo and MRI-derived infarct size, respectively, with histologically derived infarct size. The 2 imaging techniques showed very close agreement with each other for infarct size measurement (r=0.98, P<0.0001; Bland-Altman mean of differences, 0.07±3%), and both correlated well with histology.
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Discussion |
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We report on a new, quantitative, and highly accurate 3D-echo method for phenotype characterization in mice. Because of the simplicity and speed of acquisition (10 minutes per complete study), the method is applicable as a high-throughput, accurate, and reproducible technique to assess LV function in vivo in normal and chronically infarcted mice without need for geometric assumptions. Our new method was successful in all 25 mice that we attempted to image, and no animal was excluded from the study. A very light anesthetic protocol was used (1.25% to 1.5% isoflurane), which as shown previously, has virtually no cardiodepressant effects in both normal and infarcted mice.20
Although the MRI technique provided a higher spatial inplane resolution than echocardiography, slice positioning at 1-mm thickness had to be carefully adjusted to avoid cutoff at the cardiac apex. Using a smaller slice thickness would either decrease the signal-to-noise ratio or prolong the scan time substantially to obtain the same signal-to-noise ratio.
Three-dimensional-echo has the advantage of fast data collection and high temporal resolution. Our method represents a substantial gain in both precision and reproducibility compared with previous echocardiography studies11,12 due to the use of ECG and respiratory gating, fine sampling at 500 µm, and the spatial registration relative to the imaged object (as opposed to a hand-held probe, which is prone to angle error). This is the first murine echocardiography study that provides MRI validation data for LV volumes in normal and infarcted mice and MRI and necropsy data for LV mass in normal mice. The ECG and respiratory gating ensured that true end-diastolic and end-systolic frames were selected, without having to average over several frames, such as done by Scherrer-Crosbie et al,12 which is not only time consuming for the analysis but also prone to ambiguity. Image quality varied among animals, but border definition was sufficient in all mice for satisfactory contour tracing, such that echocardiographic contrast agents were not required and the study was fully noninvasive. The detailed spatial data sampling of the echocardiographic data led to smooth LV reconstruction shapes and improved the accuracy of volume and mass calculations to approach that of MRI and necropsy data. Indeed, in infarcted mice, we were able to image very small anterolateral infarcts (see Figure 3A) that would otherwise have been missed by 2D-echo studies, as previously noted by others.11 Importantly, quantitative analysis showed excellent agreement with the results obtained by MRI. Using Bland-Altman analysis, the mean of differences was calculated as a measure of systematic bias. For all parameters except infarct size, the values derived were close to zero and could not be considered physiologically significant. 3D-echo required a 4- to 6-fold shorter acquisition time than MRI but analysis time was longer, because twice the number of slices were obtained for analysis.
The correlation between imaging and histological results with regard to infarct size obtained by our 3D-echo analysis is superior to the ones previously reported in the literature.11,21 Nevertheless, in contrast to the aforementioned authors as well as others who used different imaging modalities,22 we found that both 3D-echo and MRI underestimate infarct size to the same degree in comparison with histology. It is important to point out, however, that the authors cited11,21,22 studied an acute model of LAD ligation, whereas our model was a chronic model of coronary occlusion, wherein scar healing was much more advanced, so some differences may be due to this fact. A similar underestimation has been reported by Nahrendorf et al23,24 in a rat model of chronic heart failure. The most obvious explanation for this is that normal myocardial tissue shrinks to a greater extent than infarcted tissue does during the dehydration process of histological preparation. This concept is supported by the observation that the larger the infarct size, the greater degree of underestimation.
There are several limitations to our study. First, we were unable to provide infarcted LV mass measurements from our imaging techniques. In our model of chronic heart failure, at 6 weeks after LAD ligation, the infarct scar is extremely thin. Thus, the endocardial and epicardial contours of this akinetic, aneurysmal area are in practice inseparable from one another on both echocardiography and MRI. Therefore, currently no in vivo imaging technique has sufficient resolution for quantification of the extremely thin scar in mice. Although others have previously provided infarcted LV mass measurements (eg, Yao et al21 in a canine model or Kanno et al11 in a mouse model), these were obtained from images at 3 hours and 1 week after occlusion, respectively, when the postinfarct remodeling process was not advanced and the epicardial and endocardial contours were still distinguishable from one another. Second, we were unable to provide 2D estimates of LV volumes and mass for incremental comparison with 3D-derived parameters in the infarct group because we thought that both the AL15 and the TE16 formulas would introduce an unacceptable degree of error after the ventricle had lost its normal shape. Third, although we acknowledge that our sample sizes are small, the high accuracy of the method permitted this to be the case, which we see as an advantage. However, independent confirmation of our results at other centers should be obtained.
In summary, we describe the most accurate echocardiography technique for LV assessment in mice reported so far, as demonstrated by comparison with the current gold standard volumetric technology (MRI) and histology. Because heart rate in mice is much faster than in humans, it is unlikely that real-time 3D-echo will be applicable for murine studies in the near future. Our reconstructive, quantitative, gated 3D technique should be of widespread applicability for groups planning serial, large-scale screening and high-throughput, cardiac phenotyping studies in genetically modified mice.
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Acknowledgments |
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This study was supported by the British Heart Foundation and the Medical Research Council, UK. We thank John Hastings and Graham Haynes in the Department of Engineering Science Main Workshop for their help with building the imaging platform.
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Footnotes |
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*Drs Dawson and Lygate contributed equally to this work.
The online-only Data Supplement, which contains cine movies, is available with this article at http://www.circulationaha.org.
Presented in part at the 75th American Heart Association Scientific Sessions, Chicago, Ill, November 17–20, 2002, the 76th American Heart Association Scientific Sessions, Orlando, Fla, November 9–12, 2003, and the 14th Annual Scientific Sessions of the American Society of Echocardiography, Las Vegas, Nev, June 2003, and published in abstract form (Circulation. 2002;106(suppl II):II-422–II-423; Circulation. 2003;108(suppl IV):IV-2706; J Am Soc Echocardiography. 2003;16:512).
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