Published online before print May 15, 2009, doi: 10.1161/CIRCIMAGING.108.846253
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Original Articles |
Integration of Infarct Size, Tissue Perfusion, and Metabolism by Hybrid Cardiac Positron Emission Tomography/Computed Tomography
Evaluation in a Porcine Model of Myocardial Infarction
From the Department of Radiology (R.L. M.S.J., J.M., F.M.B.), Division of Nuclear Medicine, the Department of Medicine (K.H.S., T.S., A.Y., R.A., A.C.L.), Division of Cardiology, and the Department of Biomedical Engineering (A.C.L.), Johns Hopkins Medical Institutions, Baltimore, Md, and Nuklearmedizinische Klinik und Poliklinik (S.G.N.), Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Correspondence to Frank M. Bengel, MD, Division of Nuclear Medicine, Johns Hopkins University, 601 N Caroline St, JHOC 3225, Baltimore, MD 21210. E-mail fbengel1{at}jhmi.edu
Received December 30, 2008; accepted April 13, 2009.
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Abstract |
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Background— Hybrid positron emission tomography/computed tomography (PET-CT) allows for combination of PET perfusion/metabolism imaging with infarct detection by CT delayed contrast enhancement. We used this technique to obtain biomorphological insights into the interrelation between tissue damage, inflammation, and microvascular obstruction early after myocardial infarction.
Methods and Results— A porcine model of left anterior descending coronary artery occlusion/reperfusion was studied. Seven animals underwent PET-CT within 3 days of infarction, and a control group of 3 animals was scanned at >4 weeks. Perfusion and glucose uptake were assessed by [13N]-ammonia/[18F]-deoxyglucose (FDG), and 64-slice CT delayed contrast enhancement was measured. In the acute infarct model, CT revealed a no-reflow phenomenon suggesting microvascular obstruction in 80% of all infarct segments. PET showed increased FDG uptake in 68% of the CT-defined infarct segments. Ex vivo staining and histology showed active inflammation in the acute infarct area as an explanation for increased glucose uptake. In chronic infarction, CT showed no microvascular obstruction and agreed well with matched perfusion/metabolism defects on PET.
Conclusions— Perfusion/metabolism PET and delayed enhancement CT can be combined within a single hybrid PET-CT session. Increased regional FDG uptake in the acute infarct area is frequently observed. In contrast to the chronic infarct setting, this indicates tissue inflammation that is commonly associated with microvascular obstruction as identified by no reflow on CT. The consequences of these pathophysiological findings for subsequent ventricular remodeling should be explored in further studies.
Key Words: myocardial infarction • hybrid imaging • PET • CT
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Introduction |
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Infarct size and tissue viability are related to outcome after myocardial infarction, and noninvasive imaging is being used for risk stratification in this setting.1 Contrast-enhanced MRI (ceMRI) has been successfully used to identify location, extent, and transmurality of myocardial infarction via delayed enhancement.2 It has also been used to detect microvascular obstruction by a no-reflow pattern of absent enhancement.3 Results of ceMRI have been linked to patient prognosis,4 and they are used to predict functional recovery after revascularization.5,6 More recently, multidetector CT has been used to measure delayed contrast enhancement in a manner similar to ceMRI. This technique has been validated against MRI and against ex vivo measurements of infarct size.7–11 Although there is less clinical experience with multidetector CT than with ceMRI, it is a technique that can be used in the hybrid PET-CT environment, where it can be combined with PET-derived biological information.12
Clinical Perspective on p 299
PET is still considered a gold standard for clinical evaluation of myocardial viability.13,14 In chronic ischemic heart disease, the metabolic tracer [18F]-deoxyglucose (FDG) distinguishes ischemically compromised but viable "hibernating myocardium," which shows increased myocardial glucose uptake in a hypoperfused region from nonviable scar that shows a matched reduction of perfusion and metabolism.15 The situation, however, is less clear in the setting of acute infarction. Early after reperfusion, tissue inflammation may occur. This may result in increased regional glucose uptake, and a pattern similar to hibernating myocardium may be observed,16,17 although it represents a different pathophysiological state that may also have different clinical implications.
We hypothesized that postinfarction inflammation occurs frequently early after ischemia and reperfusion and that it can be detected by increased FDG uptake on PET images. Also, we hypothesized that inflammation is associated with microvascular obstruction, as identified by a no-reflow phenomenon on delayed contrast enhancement imaging. To test both hypotheses, we made use of the potential of integrated PET-CT to measure perfusion, metabolism, and contrast enhancement pattern in a large animal model of acute and chronic myocardial infarction.
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Methods |
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Animal Model
Myocardial infarction was induced in 3 young farm pigs and 7 adult female Göttingen mini swine (weight, 21 to 42 kg). Under general anesthesia (induction with ketamine/xylazine/telazol, maintenance with 1.2 to 2.0% isoflurane), balloon occlusion of the mid left anterior descending coronary artery, immediately distal to the second diagonal branch, was performed for 120 to 150 minutes under fluoroscopic guidance. Postoperative treatment included narcotics and nonsteroidal anti-inflammatory drugs (ketorolac tromethamine). Hybrid PET-CT imaging was performed either 24 to 72 hours (acute phase, n=7) or >4 weeks (chronic phase, n=3, control group) after the procedure, under general anesthesia. The experimental protocol was approved by the Institutional Animal Care and Use Committee. Animals were maintained in accordance with the guiding principles of the American Physiological Society.
PET-CT Protocol
PET-CT imaging was performed with a GE Discovery Rx VCT scanner (GE Medical Systems), equipped with a LYSO PET component and a 64-slice CT component. After a minimum of 12 hours of fasting, animals were positioned supine in a cradle and a CT scout scan followed by a low-dose CT scan (120 kV, 80 mA) for attenuation correction were obtained. CT scans were followed by intravenous [13N]-ammonia infusion (30 seconds, 370 to 555 MBq) and list-mode perfusion PET data acquisition (VIP, GE Healthcare, Waukesha, Wis) was continued for 20 minutes.
Immediately after perfusion PET, diagnostic CT was started. Ventilation was stopped for each acquisition, for breath-hold simulation. Contrast agent (120 mL; Iodixanol 320 g/mL, Visipaque, GE Healthcare, Princeton, NJ) was injected at a rate of 5 mL/s through a femoral vein, and a first CT acquisition was conducted with a fixed delay of 25 seconds for coronary angiography. The same CT acquisition was then repeated at 10 minutes after contrast injection for delayed enhancement imaging. Scan parameters were the same for both acquisitions and were standard parameters used for a high-resolution coronary angiography (retrospective ECG gating, helical acquisition; pitch, 0.24; slice thickness, 0.65 mm; rotation time, 350 ms; 120 kV, 600 mA).
After CT, myocardial glucose uptake was studied with [18F]FDG. In the first 2 animals, preparation was performed using simplified glucose/insulin loading (20 g of dextrose intravenously with simultaneous intravenous and subcutaneous insulin to adjust blood glucose to 5 mmol/L; [18F]FDG injection after 60 minutes; 20 minutes list-mode PET acquisition after 60 minutes of uptake). In the remaining 8 animals, euglycemic hyperinsulinemic clamping was performed according to a standard protocol,18 and at 90 minutes, 185 MBq [18F]FDG was injected and list-mode PET data acquisition(VIP, GE Healthcare) was started for 40 minutes.
List-mode PET data were resampled to attenuation corrected, iteratively reconstructed, static, ECG-gated (8 bins for the cardiac cycle), and dynamic images (21 frames for [13N]-ammonia: 12x10 seconds, 6x30 seconds, 3x300 seconds, and 19 frames for [18F]FDG: 8x15 seconds, 2x30 seconds, 2x120 seconds, 1x180 seconds, 6x300 seconds). Because misalignment of CT and PET affects tracer uptake, alignment for attenuation correction was checked using fusion software in all studies. It was excellent in all cases (due to lack of motion in the anesthetized animals); thus, no realignment was necessary.19
PET Data Analysis
PET data were volumetrically sampled, and polar maps of left ventricular myocardial activity were generated by using previously validated software.20 Static tomographic images and polar maps were normalized to their maximum and used for visual analysis of regional perfusion/metabolism patterns using the American Heart Association 17-segment model. Visual classification was done by 2 independent observers blinded to CT data as normal, matched defect, or mismatch segments. Discrepancies were resolved by consensus. A threshold of 60% of the individual maximal ammonia uptake was used to define perfusion defect.21 Normal segments had no perfusion defect in the [13N]-ammonia polar maps. Segments with a perfusion defect were visually defined as matched defect segments if [18F]FDG uptake was concordantly reduced and as mismatch segments if [18F]FDG uptake was higher than perfusion tracer uptake.
From gated [13N]-ammonia datasets, resting left ventricular ejection fraction was measured as previously reported.22
Additionally, from dynamic imaging sequences, absolute myocardial blood flow at rest was quantified from myocardial and arterial blood time activity curves using a validated 3-compartment model for [13N]-ammonia,23 and Patlak graphical analysis for [18F]FDG, assuming a lumped constant of 1.0.24–26 To determine whole-body insulin resistance, glucose deposition was measured from plasma samples in the animals receiving hyperinsulinemic euglycemic clamp, using a previously described method.18
CT Data Analysis
All CT datasets were reformatted to short-axis images with a thickness of 3.3 mm. Short-axis slices were divided into 17 segments to match PET data analysis. Segments were visually classified by 2 independent observers, blinded to PET results, as remote with no enhancement pattern, nontransmural, or transmural infarct. Infarct segments were further analyzed for the no-reflow phenomenon, with a signal void as a sign for microvascular obstruction (Figure 1).7
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Pathology and Histology for Ex Vivo Analysis
Five pigs of the acute myocardial infarction group were immediately euthanized after the imaging study. Hearts were arrested in diastole by slow retrograde infusion of an ice-cold solution of 4 mmol/L potassium chloride (KCl) in phosphate-buffered saline, and hearts were excised for ex vivo tissue analysis. The other animals were kept alive for the purpose of other scientific projects. In those 5 animals, 12.5 mL/kg 2% triphenyltetrazolium-chloride (TTC)-containing saline was infused immediately before the animals were euthanized. After fixation of excised hearts in 10% formaldehyde, gross macroscopic left ventricular (LV) short-axis slices were created. Three midventricular/apical rings were analyzed for presence of TTC-stained infarct tissue in segments that were matched with in vivo PET-CT images. Additionally, 1 representative short-axis slice was embedded in paraffin; 5-µm sections were cut and stained for hematoxylin and eosin staining. Light microscopy images were obtained on a Zeiss Axiophot microscope (Carl Zeiss NTS GmbH, Oberkochen, Germany).
Infarct and remote regions were semiquantitatively analyzed for the amount of inflammatory cells. Similar sizes of regions of interest (rectangle of 0.040 mm2) were placed on the mid infarct region and on the mid remote region on the histological sample with x64 magnification, and the amount of inflammatory cells were calculated per millimeter squared.
Statistical Analysis
Kappa statistics were used for calculation of interobserver agreement and agreement in segmental characteristics between PET, CT, and ex vivo results. The Kruskall-Wallis test with the exact test was used to compare continuous variables between chronic and acute-phase animals. To compare quantitative PET data between scar and remote regions, the Wilcoxon signed-rank test was used. Correlation between the amount of inflammatory cells and quantitative PET data are reported with Spearman correlation coefficients. A probability value of <0.05 was considered statistically significant. Statistical analyses were performed with SAS 8.2 (SAS Institute, Cary, NC) and MedCalc version 9.3.0.0 (Medcalc Software, Mariakerke, Belgium).
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Results |
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Animal Characteristics
In the acute and chronic infarct models, resting left ventricular ejection fraction was 48±12% and 41±9% (P=0.31), and PET perfusion defect size was 36±9% and 31±9% of the LV (P=0.43), respectively. In all animals, PET perfusion defect and CT hyperenhanced region were located in the anteroseptal area supplied by the left anterior descending coronary artery. Whole-body glucose uptake as a measure of insulin resistance was significantly lower in the acute model compared with chronic infarction (25.6±13.5 versus 91.6±0.6 µmol/kg/min, P=0.046, respectively).
Gross Segmental PET and CT Analysis
Overall, the 2 independent observers were in good agreement for segmental analysis of PET (
=0.74) and CT (=0.81) data. When analyzed separately, interobserver agreement was still good for animals with chronic (=0.62 and =0.87 for PET and CT, respectively) and acute infarction (=0.78 and =0.78).
Segmental results for PET and CT in both groups are shown in Tables 1 and 2
. In the chronic infarct model, PET and CT were in good agreement for distinguishing normal segments from abnormal segments (=0.76). Of the 51 segments, 32 (63%) were normal on PET. Of these normal PET segments, 30 of 32 (94%) were also normal on CT. Conversely, of the 19 segments with a PET perfusion defect, 16 (84%) showed delayed enhancement on CT. An example of integrated PET-CT image patterns in the chronic infarct model is shown in Figure 2.
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In the acute infarct model, 69 of 119 segments (58%) were normal on PET. Of these, 66 of 69 (96%) were also normal on CT. Among the abnormal segments, a variety of combinations of CT and PET patterns was observed (Table 1). Of note, the combination of transmural infarct with no-reflow pattern and PET mismatch was most frequent. An example of integrated PET-CT image patterns in the acute infarct model is shown in Figure 2.
PET and CT Patterns in the Acute Infarct Area
In the group of animals imaged early after infarction, 37 of 119 segments (31%) showed evidence of infarction on CT (Table 1). Of those, 28 (76%) showed a no-reflow phenomenon, indicating microvascular obstruction. On PET, 50 of 119 segments (42%) were abnormal. Of those, 36 (72%) showed a mismatch with reduced perfusion but increased FDG uptake. Eighteen segments (50% of all mismatch segments and 64% of all segment with no reflow) showed both a PET mismatch as well as a CT no-reflow phenomenon. This combination was the most frequent pattern of abnormality in acute infarct animals.
Quantitative PET Data
Global myocardial blood flow at rest (0.69±0.35 for chronic versus 0.58±0.39 mL/g/min for acute infarction, P=0.52) and global myocardial glucose uptake (6.8±2.2 versus 4.7±0.9 µmol/100 g/min, P=0.25) were not different between both animal models. Regional analysis expectedly showed a significant flow reduction in the CT-defined infarct area versus remote myocardium in acute infarcts (Figure 3A). In chronic animals, there was a similar trend which fell short of significance, probably due to the low number of animals (Figure 3A). Glucose uptake tended to be higher in the acute infarct area compared with the remote region, whereas such a trend was not observed in chronic animals.
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Postmortem Analysis
Fifty midventricular segments of acute infarct animals were available for ex vivo TTC staining analysis. Overall, there was a good agreement of TTC staining with abnormal PET (
=0.64) and CT (=0.75) for infarct detection (Figure 4; Tables 3 and 4). On histology, hematoxylin and eosin staining consistently confirmed myocyte damage and revealed a high content of inflammatory cells in all acute infarct segments (3535±1880 cells/mm2; Figure 5). Semiquantitatively, the amount of inflammatory cells correlated significantly with myocardial glucose uptake in the infarct region (r=0.90, P=0.037) but not in the remote region (r=0.56, P=0.32).
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Discussion |
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In summary, this is the first study to our knowledge to use a hybrid PET-CT approach for integrated assessment of infarct pathophysiology. In our porcine model, PET frequently revealed increased regional glucose uptake in the hypoperfused infarct area early after reperfusion. Correlation with histology showed inflammation as the underlying cause. Inflammation was frequently but not always associated with microvascular obstruction, as identified by no reflow on CT, suggesting a pathophysiological interrelation. Finally, in chronic infarcts, PET and CT agreed well and showed hypoperfusion, reduced glucose uptake, and delayed enhancement without signs of no reflow.
From multiple clinical studies in chronic ischemic heart disease with LV dysfunction, it is well known that decreased FDG uptake in combination with a perfusion defect represents nonviable scar tissue. Preserved or increased FDG uptake in the region of a perfusion defect, the so-called perfusion/metabolism mismatch, is thought to represent hibernating myocardium in this setting, which benefits from the restoration of blood flow.27 On the contrary, in our model of acute myocardial infarction induced by ischemia and reperfusion, perfusion/metabolism mismatch indicates inflammation in otherwise nonviable scar regions as identified by CT and postmortem TTC staining. This is important to recognize because it may complicate the use of FDG for clinical viability assessment early after infarct reperfusion therapy.
It has previously been suggested that ischemia/reperfusion is followed by an increased inflammatory response, which improves tissue repair and wound healing.28 Cellular necrosis and reperfusion damage attract inflammatory cells29 that contribute to regionally increased glucose uptake. Of note, many of the acute infarct segments with a PET mismatch in our study also showed a no-reflow pattern on CT. This is thought to reflect microvascular obstruction, which may be a consequence of multiple mechanisms. Free radical formation after ischemia-reperfusion may damage endothelial and microvascular structure, and microthrombi may contribute to occlusion. Compression by tissue swelling as a consequence of inflammation has been discussed as another potential contributor to microvascular obstruction,30 which is supported by our hybrid imaging data.
Importantly, the no-reflow phenomenon has been related to worse outcome in the clinical setting.30 It is known to be more prevalent in the acute infarct phase,9 and its presence appears to predict myocardial wall thinning and remodeling later after infarction.31 Speculatively, the different PET/CT patterns observed in our study (infarct with/without inflammation and with/without microvascular obstruction) may have different implications for the subsequent course of LV function, geometry, and remodeling. This hypothesis would need to be tested in future studies that include follow-up observations.
Importantly, for the purpose of detecting pathophysiological mechanisms that precede adverse ventricular remodeling, other more specific radiotracers targeting inflammation or other key processes such as MMP activity32 or neurohumoral activation33 may be preferable over the less specific FDG. Combination with CT as a morphological technique in the PET-CT environment may be even more attractive for these compounds, which are expected to show a weaker albeit more specific molecular signal that would require additional information for accurate localization.
In conclusion, our observations suggest that CT and PET yield information that can be combined into a single hybrid imaging session for a comprehensive assessment of postischemic tissue damage. Acute inflammation and microvascular obstruction may coexist early after acute myocardial infarction, and they can be detected by increased FDG uptake on PET and no reflow on delayed enhancement CT, respectively. The implications for subsequent changes of ventricular structure and transition to heart failure should be determined.
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Acknowledgments |
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We thank the staff of the PET-CT center of Johns Hopkins Hospital for their excellent technical assistance. We also thank Norman J. Barker, MS, MA, RBP, for his expertise and helpful suggestions obtaining pathology and histology images.
Sources of Funding
Dr Lautamäki is supported by grants from the Finnish Cardiac Research Foundation, the Finnish Medical Foundation, the Instrumentarium Foundation for Science, and the Paavo Nurmi Foundation and by the Bracco/SNM Research Fellowship in Cardiovascular Molecular Imaging kindly provided by the Cardiovascular and Radiopharmaceutical Sciences Councils, the Society of Nuclear Medicine, and Bracco.
Disclosures
None.
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