Embozene™ microspheres induced nonreperfused myocardial infarction in an experimental swine model.

OBJECTIVES: To develop a magnetic resonance imaging (MRI) compatible, percutaneous technique for the generation of nonreperfused myocardial infarct (MI). BACKGROUND: Modeling nontreated MI has major importance in the development and preclinical testing of new therapeutic strategies for patients missing the time window suitable for revascularization following MI. METHODS: In 31 male swine, nonreperfused MI was generated by permanent occlusion of either the LAD or LCX coronary artery using 900 µm Embozene™ microspheres. Animals were monitored for 90 min postocclusion. Surviving animals were followed up for 2 (n = 6), 4 (n = 6), 14 (n = 6), or 56 (n = 6) days. At the end of the planned study session, contrast enhanced MRI, triphenyl-tetrazolium-chloride staining, and microscopic histopathology were carried out. RESULTS: The mortality rate in this study was 22.6%. Intraoperative arrhythmias occurred in 14 cases: premature ventricular complexes with (5) or without (3) ventricular tachycardia, 2nd degree atrio-ventricular block (1), and ventricular fibrillation (6). MRI, TTC, and histology confirmed the existence of MI in every case. Macroscopic pathology showed that the microspheres caused a practically total occlusion at the epicardial level of the coronary artery. Multiple infarcts were detected in one case, probably due to unintentional reflux of the microspheres. Microspheres retained in the coronary arteries did not cause any MRI artifact. CONCLUSIONS: The generation of nonreperfused MI is feasible by percutaneous injection of Embozene into the coronary artery system. The MI model thus obtained is suitable for the purposes of MRI experiments.

Percent infarct mapping for delayed contrast enhancement magnetic resonance imaging to quantify myocardial viability by Gd(DTPA).

PURPOSE: To demonstrate the advantages of signal intensity percent-infarct-mapping (SI-PIM) using the standard delayed enhancement (DE) acquisition in assessing viability following myocardial infarction (MI). SI-PIM quantifies MI density with a voxel-by-voxel resolution in clinically used DE images. MATERIALS AND METHODS: In canines (n= 6), 96 hours after reperfused MI and administration of 0.2 mmol/kg Gd(DTPA), ex vivo DE images were acquired and SI-PIMs calculated. SI-PIM data were compared with data from DE images analyzed with several thresholding levels using SI(remote+2SD), SI(remote+6SD), SI full width half maximum (SI(FWHM)), and with triphenyl-tetrazolium-chloride (TTC) staining. SI-PIM was also compared to R1 percent infarct mapping (R1-PIM). RESULTS: Left ventricular infarct volumes (IV) in DE images, IV(SIremote+2SD) and IV(SIremote+6SD), overestimated (P < 0.05) TTC by medians of 13.21 mL [10.2; 15.2] and 6.2 mL [3.79; 8.23], respectively. SI(FWHM), SI-PIM, and R1-PIM, however, only nonsignificantly underestimated TTC, by medians of -0.10 mL [-0.12, -0.06], -0.86 mL [-1.04; 1.54], and -1.30 mL [-4.99; -0.29], respectively. The infarct-involved voxel volume (IIVV) of SI-PIM, 32.4 mL [21.2, 46.3] is higher (P < 0.01) than IIVVs of SI(FWHM) 8.3 mL [3.79, 19.0]. SI-PIM(FWHM), however, underestimates TTC (-5.74 mL [-11.89; -2.52] (P < 0.01)). Thus, SI-PIM outperforms SI(FWHM) because larger IIVVs are obtained, and thus PIs both in the rim and the core of the infarcted tissue are characterized, in contradistinction from DE-SI(FWHM), which shows mainly the infarct core. CONCLUSION: We have shown here, ex vivo, that SI-PIM has the same advantages as R1-PIM, but it is based on the scanning sequences of DE imaging, and thus it is obtainable within the same short scanning time as DE. This makes it a practical method for clinical studies.

Differentiation of acute and four-week old myocardial infarct with Gd(ABE-DTTA)-enhanced CMR.

BACKGROUND: Standard extracellular cardiovascular magnetic resonance (CMR) contrast agents (CA) do not provide differentiation between acute and older myocardial infarcts (MI). The purpose of this study was to develop a method for differentiation between acute and older myocardial infarct using myocardial late-enhancement (LE) CMR by a new, low molecular weight contrast agent.Dogs (n = 6) were studied in a closed-chest, reperfused, double myocardial infarct model. Myocardial infarcts were generated by occluding the Left Anterior Descending (LAD) coronary artery with an angioplasty balloon for 180 min, and four weeks later occluding the Left Circumflex (LCx) coronary artery for 180 min. LE images were obtained on day 3 and day 4 after second myocardial infarct, using Gd(DTPA) (standard extracellular contrast agent) and Gd(ABE-DTTA) (new, low molecular weight contrast agent), respectively. Triphenyltetrazolium chloride (TTC) histomorphometry validated existence and location of infarcts. Hematoxylin-eosin and Masson's trichrome staining provided histologic evaluation of infarcts. RESULTS: Gd(ABE-DTTA) or Gd(DTPA) highlighted the acute infarct, whereas the four-week old infarct was visualized by Gd(DTPA), but not by Gd(ABE-DTTA). With Gd(ABE-DTTA), the mean +/- SD signal intensity enhancement (SIE) was 366 +/- 166% and 24 +/- 59% in the acute infarct and the four-week old infarct, respectively (P < 0.05). The latter did not differ significantly from signal intensity in healthy myocardium (P = NS). Gd(DTPA) produced signal intensity enhancements which were similar in acute (431 +/- 124%) and four-week old infarcts (400 +/- 124%, P = NS), and not statistically different from the Gd(ABE-DTTA)-induced SIE in acute infarct. The existence and localization of both infarcts were confirmed by triphenyltetrazolium chloride (TTC). Histologic evaluation demonstrated coagulation necrosis, inflammation, and multiple foci of calcification in the four day old infarct, while the late subacute infarct showed granulation tissue and early collagen deposition. CONCLUSIONS: Late enhancement CMR with separate administrations of standard extracellular contrast agent, Gd(DTPA), and the new low molecular weight contrast agent, Gd(ABE-DTTA), differentiates between acute and late subacute infarct in a reperfused, double infarct, canine model.

Virtual in vivo biopsy map of early prostate neoplasm in TRAMP mice by MRI.

BACKGROUND: The noninvasive, early detection of Prostate Intraepithelial Neoplasia (PIN), a precancerous neoplasia of the prostate, would be highly desirable. In our experiments, we used TRAMP mice to model PIN in the range of grade 1 through grade 4. METHODS: Contrast enhanced pixel-by-pixel R1 mapping of the prostate was used to detect areas with the different prostate neoplasia grades. After anesthesia, Gd(ABE-DTTA) was injected I.V. A series of MRI images with varying TI were then acquired to create R1 maps in a 2 mm transversal tomographic slice that included the prostate. After euthanasia and the excision of the prostate, a 2 mm slice, corresponding to the tomographic slice, was selected and prepared for histological analysis. The microscopic sections of this slice were scanned and analyzed along with the R1 maps. The R1 values were normalized to that measured in muscle tissue in each individual mouse to account for possible variations among the mice in contrast agent uptake (R1(norm)). The R1(norm) values and the histological grades in the corresponding areas were correlated. RESULTS: A significant difference was found between the R1(norm) values measured in areas with grade 1-2 versus those observed in areas with grades 3-4. Also, a significant correlation was found between the area size of the ROIs differentiated by MRI, and those determined by histology. CONCLUSION: This method has the potential for early noninvasive detection of developing prostate cancer.

Myocardial tissue characterization by combining late gadolinium enhancement imaging and percent edema mapping: a novel T2 map-based MRI method in canine myocardial infarction.

BACKGROUND: Assessing the extent of ischemic and reperfusion-associated myocardial injuries remains challenging with current magnetic resonance imaging (MRI) techniques. Our aim was to develop a tissue characterization mapping (TCM) technique by combining late gadolinium enhancement (LGE) with our novel percent edema mapping (PEM) approach to enable the classification of tissue represented by MRI voxels as healthy, myocardial edema (ME), necrosis, myocardial hemorrhage (MH), or scar. METHODS: Six dogs underwent closed-chest myocardial infarct (MI) generation. Serial MRI scans were performed post-MI on days 3, 4, 6, 14, and 56, including T2 mapping and LGE. Dogs were sacrificed on day 4 (n = 4, acute MI) or day 56 (n = 2, chronic MI). TCMs were generated based on a voxel classification algorithm taking into account signal intensity from LGE and T2-based estimation of ME. TCM-based MI and MH were validated with post mortem triphenyl tetrazolium chloride (TTC) staining. Pearson's correlation and Bland-Altman analyses were performed. RESULTS: The MI, ME, and MH measured by TCM were 13.4% [25th-75th percentile 1.6-28.8], 28.1% [2.1-37.5] and 4.3% [1.0-11.3], respectively. TCM measured higher MH and MI compared to TTC (p = 0.0033 and p = 0.0007, respectively). MH size was linearly correlated with MI size by both MRI (r = 0.9528, p < 0.0001) and TTC (r = 0.9625, p < 0.0001). MH quantification demonstrated good agreement between TCM and TTC (r = 0.8766, p < 0.0001, 2.4% overestimation by TCM). A similar correlation was observed for MI size (r = 0.9429, p < 0.0001, 6.1% overestimation by TCM). CONCLUSIONS: Preliminary results suggest that the TCM method is feasible for the in vivo localization and quantification of various MI-related tissue components.

Equilibrium signal intensity mapping, an MRI method for fast mapping of longitudinal relaxation rates and for image enhancement.

INTRODUCTION: Inhomogeneity of magnetic fields, both B(0) and B(1), has been a major challenge in magnetic resonance imaging (MRI). Field inhomogeneity leads to image artifacts and unreliability of signal intensity (SI) measurements. This work proposes and shows the feasibility of generating equilibrium signal intensity (SI(Eq)) maps that can be utilized either to speed up relaxation-rate measurement or to enhance image quality and relaxation-rate-based weighting in various applications. METHODS: A 1.5-T MRI scanner was used. In canines (n=4), myocardial infarction was induced, and 48 h after the administration of 0.05 mmol kg(-1) Gd(ABE-DTTA), a contrast agent with slow tissue kinetics, in vivo R(1) mapping was carried out using an inversion recovery (IR)-prepared, fast gradient-echo sequence with varying inversion times (TIs). To test the SI(Eq) mapping method without the confounding effects of motion and blood flow, we carried out ex vivo R(1) mapping after the administration of 0.2 mmol kg(-1) Gd(DTPA) using an IR-prepared, fast spin-echo sequence in another group of dogs (n=2). R(1,full) maps and SI(Eq) maps were generated from the data from both sequences by three-parameter nonlinear curve fitting of the SI versus TI dependence. R(1,full) maps served as the reference standard. Raw IR images were then divided by the SI(Eq) maps, yielding corrected SI maps (COSIMs). Additionally, R(1) values were calculated from each single-TI image separately, using the SI(Eq) value and a one-parameter curve-fitting procedure (R(1,single)). Voxelwise correlation analysis was carried out for the COSIMs and the R(1,single) maps, both versus the standard R(1,full) maps. Deviations of R(1,single) from R(1,full) were statistically evaluated. RESULTS: In vivo, COSIM versus R(1,full) showed significantly (P<.05) better correlation [correlation coefficient (CC)=0.95] than SI versus R(1,full) with a TI=700-800 ms, which is 200-300 ms longer than the tau(null) (500 ms) of viable myocardium. With such TIs, SI versus R(1,full) yielded CCs of 0.86-0.88. R(1,single) versus R(1,full) yielded a peak CC of 0.96 at TI=700-900 ms. Mean deviations of R(1,single) from R(1,full) were below 5% for TIs between 500 and 1000 ms. Ex vivo, where tau(null) was 300 ms, the advantage of correction with SI(Eq) was not in the improvement of linear correlation but more in the reduction of scatter. Peak CCs for SI versus R(1,full) and COSIM versus R(1,full) at TI=500 ms were 0.96 for both. The ex vivo CC for R(1,single) versus R(1,full) at TI=500 ms was 0.98. Mean deviations of R(1,single) from R(1,full) were below 5% for TIs between 400 and 700 ms. CONCLUSIONS: Once the corresponding SI(Eq) map is obtained from a control stack, R(1) can be obtained accurately, using only a single IR image and without the need for a stack of TI-varied images. This approach could be applied in various dynamic MRI studies where short measurement time, once the dynamics has started, is of essence. When using this method with IR-prepared T(1)-weighted images, it is essential that the single TI be chosen such that the longitudinal relaxation in all voxels of interest would have passed tau(null). SI(Eq) maps are also useful in eliminating confounders from MR images to allow obtaining SI values that reflect more faithfully the relaxation parameter (R(1)) sought.

The MRI characteristics of the no-flow region are similar in reperfused and non-reperfused myocardial infarcts: an MRI and histopathology study in swine.

BACKGROUND: The no-flow region (NF) visualised by magnetic resonance imaging (MRI) in myocardial infarction (MI) has been explained as the product of reperfusion-injury-induced microvascular obstruction. However, a similar MRI phenomenon occurs in non-reperfused MI. Accordingly, our purpose was to compare the MRI and histopathologic characteristics of the NF in reperfused and non-reperfused MIs. METHODS: Reperfused (n = 7) and non-reperfused MIs (n = 7) were generated in swine by percutaneous balloon occlusion and microsphere embolisation techniques. Four days post-MI, animals underwent myocardial T2-mapping, early and serial late gadolinium enhancement MRI. MI and NF were compared between the models using the independent samples t test. Serial measurements were analysed using repeated measures analysis of variance. Triphenyltetrazolium chloride (TTC) macroscopic and microscopic histopathologic assessment was also performed. RESULTS: The MI size in the reperfused and non-reperfused groups was 17.1 ± 3.4 ml and 19.4 ± 8.1 ml, respectively (p = 0.090), in agreement with TTC assessment (p = 0.216; p = 0.484), and the NF size was 7.7 ± 2.4 ml and 8.1 ± 1.9 ml, respectively (P = 0.211). Compared to the reference 2-min post-contrast measurement, the NF size was significantly reduced at 20 min in the reperfused group and at 25 min in the non-reperfused group (both p < 0.001). Nevertheless, the NF was still detectable at 45 min after injection. No significant T2 difference was observed between the groups (p > 0.326). Histopathologic assessment revealed extensive calcification and hemosiderin deposition in the NF of the reperfused MI, but not in the non-reperfused MI. CONCLUSIONS: The NF in non-reperfused and reperfused MIs have similar characteristics on MRI despite the different pathophysiologic and underlying histopathologic conditions, indicating that the presence of the NF alone cannot differentiate between these two types of MI.

In Vitro Longitudinal Relaxivity Profile of Gd(ABE-DTTA), an Investigational Magnetic Resonance Imaging Contrast Agent.

PURPOSE: MRI contrast agents (CA) whose contrast enhancement remains relatively high even at the higher end of the magnetic field strength range would be desirable. The purpose of this work was to demonstrate such a desired magnetic field dependency of the longitudinal relaxivity for an experimental MRI CA, Gd(ABE-DTTA). MATERIALS AND METHODS: The relaxivity of 0.5mM and 1mM Gd(ABE-DTTA) was measured by Nuclear Magnetic Relaxation Dispersion (NMRD) in the range of 0.0002 to 1T. Two MRI and five NMR instruments were used to cover the range between 1.5 to 20T. Parallel measurement of a Gd-DTPA sample was performed throughout as reference. All measurements were carried out at 37°C and pH 7.4. RESULTS: The relaxivity values of 0.5mM and 1mM Gd(ABE-DTTA) measured at 1.5, 3, and 7T, within the presently clinically relevant magnetic field range, were 15.3, 11.8, 12.4 s-1mM-1 and 18.1, 16.7, and 13.5 s-1mM-1, respectively. The control 4 mM Gd-DTPA relaxivities at the same magnetic fields were 3.6, 3.3, and 3.0 s-1mM-1, respectively. CONCLUSIONS: The longitudinal relaxivity of Gd(ABE-DTTA) measured within the presently clinically relevant field range is three to five times higher than that of most commercially available agents. Thus, Gd(ABE-DTTA) could be a practical choice at any field strength currently used in clinical imaging including those at the higher end.

Acute infarct selective MRI contrast agent.

To determine the infarct affinity of a low molecular weight contrast agent, Gd(ABE-DTTA), during the subacute phase of myocardial infarct (MI). Dogs (n = 7) were examined, using a closed-chest, reperfused MI model. MI was generated by occluding for 180 min the left anterior descending (LAD) coronary artery with an angioplasty balloon. DE-MRI images with Gd(ABE-DTTA) were obtained on days 4, 14, and 28 after MI. Control DE-MRI by Gd(DTPA) was carried out on day 27. T2-TSE images were acquired on day 3, 13 and 27. Triphenyltetrazolium chloride (TTC) histomorphometry validated postmortem the existence of infarct. Gd(ABE-DTTA) highlighted the infarct on day 4, but not at all on day 14 or on day 28, following MI. On day 4, the mean ± SD signal intensity (SI) of infarcted myocardium in the presence of Gd(ABE-DTTA) significantly differed from that of healthy myocardium (45 ± 6.0 vs. 10 ± 5.0, P < 0.05), but it did not on day 14 (11 ± 9.4 vs. 10 ± 5.7, P = NS), nor on day 28 (7 ± 1.5 vs. 7 ± 2.4, P = NS). The mean ± SD signal intensity enhancement (SIE) induced by Gd(ABE-DTTA) was 386 ± 165% on day 4, significantly different from mean SIE on day 14 (9 ± 20%), and from mean SIE on day 28 (12 ± 18%), following MI (P < 0.05). The last two mean values did not differ significantly (P = NS) from each other. As control, Gd(DTPA) was used and it did highlight the infarct on day 27, inducing a mean SIE value of 312 ± 40%. The mean SIE on day 3, 13, or 27 did not vary significantly (P = NS) on the T2-TSE images (114 ± 41%, 123 ± 41%, and 150 ± 79%, respectively). Post mortem, the existence of infarcts was confirmed by TTC staining. The infarct affinity of Gd(ABE-DTTA) vanishes in the subacute phase of scar healing, allowing its use for infarct age differentiation early on, immediately following the acute phase.

Determination of infarct size in ex vivo swine hearts by multidetector computed tomography using gadolinium as contrast medium.

OBJECTIVE: To demonstrate the feasibility of using multidetector computed tomography with gadolinium contrast (Gd-MDCT) for the quantification of myocardial infarct (MI). MATERIALS AND METHODS: MI was induced in male swine (n = 6). One week later, the animals received 0.2-mmol/kg gadopentetate dimeglumine and were sacrificed. On the excised hearts, Gd-MDCT with several tube voltages (80, 120, and 140 kV), late gadolinium enhancement MRI (LGE-MRI), and triphenyl-tetrazolium-chloride staining were then conducted. We used a 2-SD threshold for the CT images and several threshold limits (2, 3, 4, 5, 6 SD, and full width at half-maximum [FWHM]) for the LGE-MRI images to delineate the infarct area. Total infarct volume and infarct fraction of each heart were calculated. RESULTS: MI size measured by MDCT at 140 kV showed good correlation with the reference triphenyl-tetrazolium-chloride value. Applying an 80-kV tube voltage, however, significantly underestimated MI size. In our study, the LGE-MRI method, using the 6-SD threshold, provided the most accurate determination of MI size. LGE-MRI, using the 2- and 3-SD threshold limits, significantly overestimated infarct size. CONCLUSIONS: The Gd-MDCT technique has been found suitable for the evaluation of MI in an ex vivo experimental setting. Gd-MDCT has the ability to detect MI even at low kV settings, but accuracy is limited by a high image noise because of reduced photon flux.