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Acute Myocardial Infarction: Contrast-enhanced Multi–Detector Row CT in a Porcine Model¹

¹ From the Departments of Radiology (U.H., R.M., C.E., M.F., S.G., S.A., D.K., D.S., T.J.B.) and Cardiac Surgery (J.T.) and Division of Cardiology (D.S.), Massachusetts General Hospital and Harvard Medical School, 100 Charles River Plaza, Suite 400, Boston, MA 02114. Received February 6, 2003; revision requested April 23; final revision received September 26; accepted October 20. Supported in part by the Center for Integration of Medicine and Innovative Technology (CIMIT), Boston, Mass, and the New York Cardiac Center, New York, NY. Address correspondence to U.H. (e-mail: uhoffman@partners.org).

	ABSTRACT

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PURPOSE: To assess the role of contrast material–enhanced retrospectively electrocardiographically (ECG) gated multi–detector row computed tomography (CT) in the detection of acute myocardial infarction in a porcine model of total coronary occlusion.

MATERIALS AND METHODS: Seven Yorkshire farm pigs were studied with contrast-enhanced retrospectively ECG-gated multi–detector row CT 3 hours after total occlusion of the distal left anterior descending artery (n = 5) or the second diagonal branch (n = 2). Reformatted short-axis end-systolic and end-diastolic CT data sets were assessed for myocardial perfusion deficits, coronary occlusion, and abnormal myocardial wall motion. Perfusion deficits were compared with microsphere-determined blood flow and triphenyltetrazolium chloride (TTC)–stained tissue samples for infarct assessment by using Bland-Altman analysis and analysis of variance.

RESULTS: Myocardial perfusion deficits, occlusion of the left anterior descending artery or second diagonal branch, and akinesis of the infarcted segment were identified in all five animals that completed the study. One animal died, and one data set had nondiagnostic image quality. The CT end-diastolic (mean, 16.1% ± 4.8 [SD]; range, 8.6%–22.2%) and end-systolic (mean, 17.0% ± 6.4; range, 8.7%–26.8%) volume of perfusion deficit was similar to that of infarcted tissue at TTC staining (mean, 13.6% ± 6.0; range, 7.8%–30.9%). Infarcted myocardium at CT demonstrated a 76.1% reduction in microsphere-determined blood flow and a significant reduction of myocardial CT attenuation compared with normal myocardium (P < .01). Myocardial wall motion analysis demonstrated absence of systolic wall thickening in infarcted myocardium.

CONCLUSION: Multi–detector row CT with retrospective ECG gating permits the detection and further characterization of acute myocardial infarction in a porcine model of complete coronary occlusion.

© RSNA, 2004

Index terms: Animals • Computed tomography (CT), angiography, 51.12113, 51.12116 • Computed tomography (CT), experimental studies • Myocardium, infarction, 511.771

	INTRODUCTION

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Multi–detector row computed tomographic (CT) scanners with four parallel detectors, a gantry rotation time of 500 msec, and a section thickness of 1.00–1.25 mm permit noninvasive evaluation of coronary anatomy, detection of coronary stenosis, and evaluation of left ventricular function (1–4). Earlier studies (5,6) have demonstrated the general feasibility of conventional CT for infarct imaging in animal models. Multi–detector row CT with improved temporal and spatial resolution, increased signal-to-noise ratio, and the ability to image the entire heart during a single breath hold provides the technical prerequisites for comprehensive evaluation of myocardial infarction.

The purpose of our study was to assess contrast material–enhanced retrospectively electrocardiographically gated multi–detector row CT in the detection of acute myocardial infarction in a porcine model of total coronary occlusion.

	MATERIALS AND METHODS

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Animal Preparation
Open-heart surgery was performed (by R.M., J.T.) in seven healthy Yorkshire farm pigs (five females and two males; mean weight, 52 kg ± 10 [SD]) (Earle Parsons & Sons, Hadley, Mass). After intramuscular induction of anesthesia (4–6 mg per kilogram of body weight of Telazol [50 µg/µL tiletamine hydrochloride and 50 µg/µL zolazepam hydrochloride], Ford Dodge Laboratories, Ford Dodge, Iowa; and 2 mg/kg of xylazine [Mobay, Shawnee, Kan]), the animals were intubated. Anesthesia was maintained by means of a mechanical respirator (Narkovet II; Drager, Telford, Pa) with 2%–3% nitrous oxide, 1% oxygen, and 2%–3% isoflurane (Baxter Pharmaceutical, Deerfield, Ill) for both surgery and imaging. Respiration was assisted with an artificial tidal volume of 8–12 mL/kg and a frequency of 20 strokes per minute. The animals’ physiologic functions were monitored throughout the protocol by using a portable system (Propag 102 EL; Welde Allyn Technologies, Beaverton, Ore) (electrocardiography, arterial pressure, and blood oxygen saturation).

After median sternotomy was achieved, a ligature was placed around the left anterior descending coronary artery (n = 5) or the second diagonal branch (n = 2). Afterward, the pericardium and sternotomy were closed, and a drainage tube was placed through the intercostal space. During multi–detector row CT, vecuronium bromide (Nocurou; Ben Venue Laboratories, Bedford, Ohio) was given continuously at a rate of 50–100 µg/min for breath holding. At completion of the imaging protocols, the animals were euthanized with 100–200 mg/kg of pentobarbitol (Sodium Pentobarbital; Fort Dodge Animal Health, Fort Dodge, Iowa). The experiments were performed with approval of the Massachusetts General Hospital subcommittee on research animal care.

Multi–Detector Row CT
All images were acquired by using a four-section multi–detector row CT scanner (LightSpeed Plus; GE Medical Systems, Milwaukee, Wis). First, the delay between contrast material injection and acquisition of the CT scan (transit time of contrast material from injection site to the imaging volume) was determined by means of application of a bolus of 20 mL of contrast agent (at a flow rate of 2 mL/sec) prior to CT scanning (mean, 15 seconds ± 3). The cardiac CT scan was acquired during peripheral intravenous injection of contrast agent (140 mL at 2 mL/sec) in four parallel sections (1.25-mm section thickness) with a gantry rotation time of 500 msec and a pitch of 1.5 during forced inspiratory breath hold. Tube current was 270 mA at 140 kVp. By using a multisector reconstruction algorithm, nonoverlapping cross-sectional images were reconstructed by using retrospective electrocardiographic gating with a temporal resolution of 125–250 msec, depending on the animal’s heart rate (mean, 85 beats per minute ± 7) (7). End-systolic and end-diastolic data sets based on the smallest and largest intraventricular areas at a midventricular location, respectively, were reconstructed for each CT study.

Image Analysis
On the basis of the end-systolic and end-diastolic data sets, continuous 7.5-mm-thick cross-sections were rendered in short-axis orientation on an off-line workstation (Advanced Windows; GE Medical Systems). Two observers (S.G. and U.H., with >3 years of experience in cardiac CT), who were blinded to the findings of triphenyltetrazolium chloride (TTC) staining and microsphere-determined blood flow measurements, independently inspected the images for the presence of myocardial perfusion deficits (lack of contrast enhancement within the myocardium), occlusion of a coronary artery (interruption of the contrast-enhanced lumen), and systolic wall motion abnormalities.

To quantify CT attenuation and contrast enhancement, a standardized 10-mm² region of interest was placed independently by each observer within the perfusion deficit and normal areas in the interventricular septum and in the posterior and lateral walls at a single midinfarct image location. From each location, the mean value of three measurements in Hounsfield units was used for further analysis.

To quantify perfusion deficits, the endo- and epicardial contours of the left ventricle and the contours of the perfusion deficit were drawn manually in each section by each observer independently. The overall myocardial volume was calculated by subtracting the endocardial area from the epicardial area, with the remainder multiplied by the section thickness. The infarcted myocardial volume was calculated as the infarcted area multiplied by the section thickness. The fractional infarcted myocardium was determined as infarcted myocardial volume divided by the overall myocardial volume, with the quotient multiplied by 100.

The image sets that were used to measure CT attenuation were also used to analyze regional left ventricular function. Systolic and diastolic wall thickness was measured in the infarcted region that was identified visually and in a reference region in the lateral wall of the left ventricular myocardium by using dedicated software (CardIQ5.0; GE Medical Systems). The mean value of three repeat measurements of systolic wall thickening (end-systolic wall thickness minus end-diastolic wall thickness, multiplied by 100 then divided by end-diastolic wall thickness) was used for further analysis.

Microsphere Preparation
To measure regional myocardial blood flow, colored microspheres (Biophysics Assay Laboratory, Worchester, Mass) were injected into the left atrial appendage prior to coronary occlusion and at the time of CT examination (mean time after occlusion, 171.4 minutes ± 22; range, 132–199 minutes) (R.M.). The number of injected microspheres was determined by means of the following formula: Y = (1.2 · 10⁶) + (1.9 · 10⁵X), where Y is the minimum number of spheres to be injected and X is the mass of the subject in kilograms; the equation represents a linear regression of the association between weight and blood distribution volume of the animal. We injected 7.5–10 million microspheres per animal (3 or 4 mL) to ensure a statistically significant concentration of microspheres (>400 microspheres per milligram of tissue) in areas with decreased blood flow, such as in our animal model of myocardial infarction (8,9). To calculate absolute myocardial blood flow, a reference blood sample was drawn simultaneously by means of a carotid arterial catheter by using a withdrawal pump (Rabbit Plus; Rainin Instruments, Woburn, Mass).

TTC and Microsphere Measurements
The excised hearts were rinsed with saline (SansSaLine; Biophysics Assay Laboratory) and sliced 7.5-mm thick in the short-axis orientation. These slices were placed into a TTC bath for 15–20 minutes until the infarcted area became visible. They were then photographed digitally for measurements of infarct area. Images were loaded into software (Analyze 3.1; Mayo Clinic, Rochester, Minn). Normal and infarcted myocardial area and volume were calculated with a technique similar to that used with the CT data sets (R.M.).

For microsphere analysis, the tissue was divided into approximately 1 g of epicardial and endocardial specimen, and the location of each specimen was recorded on the acetate tracings. The samples were placed into assay vials, and the mass of each sample was recorded. Blood and tissue samples were sent to the Biophysics Assay Laboratory for analysis by means of neutron activation (8).

Statistical Analysis
Data are presented as mean ± SD. Regression analysis and Bland-Altman analysis were performed to compare multi–detector row CT and TTC measurements of infarction volume. Repeated-measures analysis of variance was performed to test whether CT attenuation was significantly different between infarcted and normal myocardium. The Student t test was used for comparison of microsphere-measured blood flow at baseline and at the time of scanning and for comparison of end-diastolic and end-systolic wall thickness. A P value less than .05 was considered to indicate a statistically significant difference.

	RESULTS

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Available Data
Multi–detector row CT was performed without complications in five of seven animals. One pig died because of ventricular arrhythmias before the CT examination could be performed. Another pig could not be evaluated because of severely reduced image quality. In this pig, complicated sedation together with a high heart rate of 112 beats per minute led to poor electrocardiographic gating and motion artifacts. Data were thus available for five animals.

Occlusion Sites and Myocardium
In all five animals available for evaluation, the site of coronary occlusion was detected by both observers (Fig 1). In each animal, an area of reduced CT attenuation could be identified in the anteroseptal myocardial wall. The identified areas corresponded to the location of nonstained areas in the TTC-stained tissue samples in all cases (Fig 2).

View larger version (112K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Left: Curved multiplanar reformatted multi-detector row CT image. The contrast-enhanced lumen (upper white arrow) of the left anterior descending artery is clearly visible and abruptly ends distal to the second diagonal branch (black arrow), where the left anterior descending coronary artery was occluded during open-heart surgery. The nonperfused distal left anterior descending coronary artery (lower white arrow) is still marginally visible. Right: Corresponding post mortem image of the anterior portion of excised heart. The ligature is zoomed out. The large accompanying vessel (arrow) is a cardiac vein.

View larger version (138K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Right: Three consecutive multi-detector row CT images of an acute transmural infarct in short-axis orientation. The infarct can be visually detected by means of low CT tissue attenuation due to lack of contrast enhancement (arrows). Left: Corresponding TTC-stained specimen (short-axis orientation). The infarct is displayed as a region of unstained myocardium (arrows).

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Plot of CT tissue attenuation in the area of infarct compared with normal regions in the septum and lateral and posterior myocardial walls at a midventricular level. Tissue attenuation in the infarcted area was significantly lower than that in normally perfused myocardium across all animals. ROI = region of interest, NS = not significant.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Figure 4a. Bland-Altman analysis was used to compare percentage infarct volume as calculated from multi-detector row CT (MDCT) images and TTC-stained specimens. Plots show (a) end-systolic and (b) end-diastolic CT data. CT measurements led to slight overestimation of infarct size.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 4b. Bland-Altman analysis was used to compare percentage infarct volume as calculated from multi-detector row CT (MDCT) images and TTC-stained specimens. Plots show (a) end-systolic and (b) end-diastolic CT data. CT measurements led to slight overestimation of infarct size.

	DISCUSSION

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The results of this study demonstrate that if image quality is adequate, multi–detector row CT with retrospective electrocardiographic gating permits the detection of acute myocardial infarction (five of five pigs) in a porcine model of total coronary occlusion. The improved spatial resolution in the z-axis direction (1.25-mm multi–detector row CT vs 3-mm electron beam CT) and increased signal-to-noise ratio permit accurate measurements of infarct size (mean bias, 3%). In addition, all underlying coronary occlusions could be detected in the same data set.

Infarct areas were further characterized by regional wall motion abnormalities (akinesis, no systolic wall thickening). Similar to previous studies with electron beam CT (10–13), CT tissue attenuation in infarct areas was lower than that in normal areas (32.1 HU ± 8.5 vs 75.6 HU ± 16.7) and correlated with changes in microsphere-determined blood flow. However, a threshold for tissue attenuation of normal and infarcted myocardium across animals could not be defined, which reflects different imaging conditions that may arise from differences in animal weight and body composition, cardiac output, and the presence of artifacts induced by cardiac motion or beam hardening through the contrast material bolus in the left ventricle.

In one animal, a fast heart rate (112 beats per minute) caused severe artifacts, and the data sets could not be evaluated. This limitation of multi–detector row CT is well known and has been documented in humans in the detection of coronary artery stenosis (14). The relatively long image acquisition window (125–250 msec) of multi–detector row CT leads to severe motion artifacts at high heart rates with short diastolic phases. Further shortening of the image acquisition window and an improved spatial resolution that could help to overcome this limitation have already been introduced in the latest 16-section multi–detector row CT scanner technology (15).

More general limitations of multi–detector row CT include the necessity for iodinated contrast material and radiation exposure similar to that of diagnostic coronary angiography (3.9–5.8 mSv) (16,17). While magnetic resonance imaging permits detection of myocardial infarction without radiation, visualization of coronary artery stenosis is still limited and time-consuming (18).

The encouraging results of the present investigation justify further research to evaluate multi–detector row CT in more complex situations, such as models of occlusion and reperfusion.

In conclusion, contrast-enhanced helical multi–detector row CT with retrospective electrocardiographically gated image reconstruction can accurately depict acute myocardial infarction and help quantify infarct size in a porcine model of complete coronary occlusion. Infarcts can be further characterized by means of detection of the underlying coronary occlusion and regional left ventricular dysfunction.

Practical application: Clinically, the ability to accurately measure infarct size after acute myocardial infarction may be important because it indicates mortality risk during short- and long-term follow-up (19,20). Potentially, multi–detector row CT could be used to noninvasively verify the success of attempted reperfusion therapy and to define the infarct area.

	FOOTNOTES

 
Abbreviation: TTC = triphenyltetrazolium chloride

Author contributions: Guarantors of integrity of entire study, T.J.B., U.H.; study concepts, C.E., U.H., T.J.B.; study design, R.M., J.T., D.K.; literature research, U.H., R.M.; experimental studies, U.H., R.M., C.E., J.T., D.K.; data acquisition, U.H., R.M., C.E., S.G., M.F.; data analysis/interpretation, M.F., S.A., S.G., U.H.; statistical analysis, M.F., U.H.; manuscript preparation, D.S., U.H., S.A., M.F., C.E.; manuscript definition of intellectual content, T.J.B., S.A., U.H.; manuscript editing, D.S., D.K., R.M.; manuscript revision/review, T.J.B., S.A., D.S.; manuscript final version approval, T.J.B., U.H.

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TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

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