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DOI: 10.1148/radiol.2362030847
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(Radiology 2005;236:510-518.)
© RSNA, 2005

Experimental Studies

Gadomer-enhanced MR Imaging in the Detection of Microvascular Obstruction: Alleviation with Nicorandil Therapy1

Gabriele A. Krombach, MD2, Charles B. Higgins, MD, Mitsuaki Chujo, PhD and Maythem Saeed, DVM, PhD

1 From the Department of Radiology, University of California, San Francisco, 505 Parnassus Ave, HSW 207B, San Francisco, CA 94143-0628 (G.A.K., C.B.H., M.S.); and Chugai Pharmaceutical, Tokyo, Japan (M.C.). From the 2002 RSNA Annual Meeting. Received June 20, 2003; revision requested August 29; final revision received October 3, 2004; accepted October 28. Partial financial support was provided by Chugai Pharmaceutical, Tokyo, Japan. Address correspondence to M.S. (e-mail: Maythem.Saeed{at}radiology.ucsf.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To evaluate Gadomer-enhanced magnetic resonance (MR) imaging in the quantification of small microvascular obstruction regions and determine if nicroandil alleviates the formation of microvascular obstruction.

MATERIALS AND METHODS: Approval of the institutional committee on animal research was obtained, and this study complied with guidelines for care and use of animals. Rats underwent coronary artery occlusion and reperfusion. After 24 hours, Gadomer-enhanced T1-weighted spin-echo MR imaging was used to define microvascular obstruction in animals in control and nicorandil groups. Sequential MR images obtained at two midventricular levels were acquired to measure microvascular obstruction and ischemically injured regions and monitor diffusive and/or convective transport of Gadomer in microvascular obstruction regions. Two investigators working in consensus and using threshold signal intensity measured differentially enhanced regions. Left-ventricular (LV) end-systolic and end-diastolic MR images obtained at the same two midventricular levels were used to measure regional wall thickening and systolic reduction in LV relative volumes. Agreement and correlation between MR imaging and postmortem data were determined with Bland-Altman and linear regression analyses. Animals were sacrificed 3 minutes after intravenous injection of blue dye.

RESULTS: On Gadomer-enhanced MR images, two differentially enhanced regions were observed in ischemically injured myocardium, namely, the hypoenhanced region and the surrounding hyperenhanced region. Hypoenhanced regions at MR imaging and unstained regions at blue dye administration were identical 3 minutes after administration (17% ± 1 and 17% ± 2; P = .6; r = 0.98). In the control group, Gadomer provided a prolonged imaging window (eg, 6 minutes) for accurately quantifying small microvascular obstruction regions. Microvascular obstruction was observed in all animals in the control group and 27% of animals in the nicorandil group. Microvascular obstruction regions were smaller in the nicorandil group (eg, 3% ± 1) than in the control group (eg, 17% ± 2) (P < .001). Hyper- and hypoenhanced regions were also smaller (eg, 20% ± 2) in rats in the nicorandil group than in those in the control group (37% ± 4, P < .001). Improvement in LV function in the nicorandil group is likely related to alleviation and reduction in infarct size.

CONCLUSION: Gadomer-enhanced MR imaging can be used to quantify small microvascular obstruction regions 24 hours after reperfusion. Intravenous therapy with nicorandil reduces formation of microvascular obstruction regions.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Microvascular obstruction has been observed after reperfusion of acute myocardial infarction (1–3) and atherosclerotic plaque rupture (4,5). Patients with a large region of microvascular obstruction have profound myocardial dysfunction and poor clinical outcome. The clinical frequency and importance of small microvascular obstruction regions has been recognized (6,7). The most effective methods in the detection of microvascular obstruction are contrast material–enhanced echocardiography (1,2), positron emission tomography (8), and contrast-enhanced magnetic resonance (MR) imaging (9–13).

Extracellular MR contrast media have been used successfully in patients with acute myocardial infarction for delineation of regions of microvascular obstruction (9). Regions of microvascular obstruction can briefly be depicted as hypoenhanced regions after administration of gadopentetate dimeglumine in acutely infarcted hearts in humans (11) and large animals (12–14). On the other hand, small regions of microvascular obstruction cannot be depicted with this technique (9). Unlike extracellular MR contrast media, blood pool contrast media have the potential to delineate small microvascular obstruction regions in small animals with T1-weighted spin-echo MR imaging (9,15,16). Gadomer is a new gadolinium-based blood pool contrast medium for use with MR imaging (17). Studies have shown that Gadomer enables delineation of ischemic myocardium with T1-weighted spin-echo MR imaging (17) and hypoperfused myocardium with fast low-angle shot MR imaging over a longer time period after intravenous injection than does the extracellular contrast agent gadopentetate dimeglumine (18). In addition, Gadomer has been used in experimental coronary MR angiography (19) and assessment of microvascular permeability with a two-compartment kinetic model (17); to our knowledge, however, it has not been used in the delineation of microvascular obstruction regions. Gadomer is in phase II clinical trials (20,21).

Several agents have been used to preserve microvascular integrity, including calcium blockers, nitrates, adenosine, monoclonal antileukocyte antibodies, and glycoprotein IIb/IIIa receptor inhibitors (22–26). Investigators demonstrated that adjunctive treatment with nicorandil, which is a hybrid of an ATP-sensitive potassium channel opener and a nitrate, improves myocardial perfusion and enhances left-ventricular (LV) function in patients with acute myocardial infarction when compared with reperfusion alone (25,27–29). A unique pharmacologic characteristic of nicorandil is that it activates the ATP-sensitive potassium channel opener on the mitochondrial membrane, thus acting as an end effector of the preconditioning pathway (30).

Clinical research on cell protection currently targets ischemia, reperfusion, prevention in high-risk situations, or reversible dysfunction. In previous studies (31–34), it was found that oral or intravenous nicorandil therapy preserves myocardial viability, suppresses microvascular permeability, improves LV function, and attenuates LV remodeling. Unlike previous studies, the present study was designed to test the hypothesis that Gadomer–enhanced MR imaging has the potential to enable physicians to not only quantify microvascular obstruction regions by using T1-weighted spin-echo MR imaging but also assess the intravenous effect of nicorandil on the formation of microvascular obstruction after 24 hours of reperfusion.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Gadomer: A Blood Pool Contrast Medium
Gadomer is a water-soluble polymeric dendrimeric complex chelating agent with 24 gadolinium atoms (Schering, Berlin, Germany). It has higher R1 relaxivity (eg, 18.7 [L · mmol–1]/sec) than gadolpentetate dimeglumine (eg, 5.2 [L · mmol–1]/sec) (20). Gadomer is distributed exclusively within the blood pool, without substantial distribution into the interstitial space. The volume of distribution ranges from 0.04 L per kilogram of body weight in rats and rabbits to 0.06 L/kg in monkeys and 0.07 L/kg in dogs, which reflects plasma volume (20). The efficacy and safety of Gadomer, when administered at a dose of 0.1 mmol/kg, has been evaluated recently in humans (21). The study showed that Gadomer was well tolerated in all patients (n = 12).

Nicorandil: A Hybrid of ATP-Sensitive Potassium Channel Opener and Nitrate
Nicorandil (Chugai Pharmaceutical, Tokyo, Japan) is clinically approved as an antianginal therapy in Japan and Europe (35,36). Pharmacologic studies have indicated that the protective effects of nicorandil are related to activation of ATP-sensitive potassium channels and cyclic guanylate monophosphate (36,37). It has been shown by using echocardiography that intravenous administration of nicorandil preserves microvascular integrity and myocardial viability in patients with acute infarction (28,29). Thus, in the current study, nicorandil was administered intravenously.

Experimental Protocol
All experimental protocols received previous approval from the institutional committee on animal research, and our study was performed in accordance with National Institutes of Health guidelines for care and use of laboratory animals.

Twenty-two rats were included in the current study. Anesthetized rats underwent intraperitoneal injection of 50 mg/kg ketamine and 1.4 mg/kg xylazine. These rats then underwent left thoracotomy, and the anterior branch of the left coronary artery was occluded for 45 minutes and followed by 24 hours of reperfusion (M.S.) (38). A 5-0 silk suture (Ethicon, Somerville, NJ) was used to temporally occlude the left anterior descending coronary artery at its origin beneath the left appendage by using a snare ligature. The presence of occlusion was confirmed by the development of regional myocardial cyanosis and inversion of the T wave from the two echocardiographic leads attached in the arms (G.A.K., M.S.). The reperfusion was initiated by loosening the snare ligature and confirmed by the absence of regional cyanosis (G.A.K., M.S.). After the ligature was loosened, small echocardiographic changes, such as an increase in the amplitude, could be observed; however, inversion of the T wave remained visible. The rat model used in this study was shown to produce microvascular obstruction in situ (9,10,15) and in isolated heart preparation (39). In animals with low collateral flow, such as pigs and rats, intramyocardial hemorrhage and microvascular obstruction occur in myocardial infarcts reperfused after 45 minutes or more of coronary artery occlusion and reperfusion (40,41).

The rats were randomly assigned to undergo either intravenous nicorandil therapy (n = 11) or intravenous injection of 5 mL of saline solution 15 minutes after occlusion and infused for 3.5 hours (n = 11). Rats in the nicorandil group received an intravenous injection of 100 µg/kg nicorandil at 15 minutes of coronary occlusion followed by intravenous infusion of 25 (µg · kg–1)/min for 3.5 hours (32). In humans, the plasma half-life of nicorandil is 1 hour, and all metabolites are excreted within 24 hours (42).

MR Imaging
MR images were obtained with a 2-T MR imager (Omega CSI; Bruker Instruments, Fremont, Calif) (G.A.K., M.S.) by using echocardiographic gating. T1-weighted spin-echo MR images were acquired before and after intravenous injection of Gadomer. A spin-echo sequence was used without inversion prepulse, since R1 of Gadomer is high, and imaging time could be saved by not using an inversion pulse. Acquisition parameters were as follows: repetition time, 200 msec ± 30 depending on heart rate; echo time, 12 msec; matrix size, 256 x 128 interpolated to 256 x 256; field of view, 50 x 50 mm; section thickness, 2 mm; four signals acquired; imaging time, 2.5 minutes. The pixel size was 0.195 mm2 (32,43). The small difference in repetition time between rats may have an effect on the degree of contrast observed on unenhanced MR images. Administration of MR contrast media reduces the small contrast differences that are due to variations in repetition time.

At 24 hours of reperfusion, all animals were imaged before and 1, 3, 6, 9, 12, 15, 18, 21, 24, and 27 minutes after administration of 0.05 mmol/kg Gadomer. Two images obtained at contiguous LV locations (eg, equidistant 2 mm at midventricular level) were acquired to determine the microvascular obstruction region, ischemically injured myocardium, end-systolic and end-diastolic LV relative volumes (measured in cubic millimeters), regional wall thickness, and signal intensity (32). To obtain images shortly after injection of Gadomer, injection of the contrast medium began 1 minute after the imaging sequence began. Thus, the central lines of k-space, which account for image contrast, were acquired shortly after injection of contrast medium. The sequence was finished 1 minute after injection of the contrast medium. At the rise of the QRS complex, end-diastolic images were obtained, while end-systolic images were obtained by using a delay of 45% of the R-R interval after the rise of the QRS complex (43). The heart rate was 280–300 beats per minute (R-R interval = 200–215 msec) (43). Nicorandil has no important effect on heart rate (31). A previous report (44) showed high correlation between infarction size, as measured in all anatomic slices of the heart, and measurements derived from only two midventricular MR sections in rats, when the coronary artery occlusion site is at the origin of the left anterior descending coronary artery. Thus, we used this occlusion site and two midventricular sections in the current study. Lower occlusion sites in rats provide variable infarction sizes, as in humans. All measurements were obtained from these two midventricular sections.

The sizes of the true microvascular obstruction regions (eg, unstained regions) were determined 3 minutes after intravenous injection of phthalocyanine blue dye (Engelhard, Louisville, Ky), which served as the blood pool contrast medium. To delineate microvascular obstruction regions, the left anterior descending coronary artery was not reoccluded. The 3-minute time point was chosen for excision of the heart to obtain optimum mixing of the radiotracers in the blood, and it is in line with our previous study in this animal model (9). This time point was chosen to enable measurement of the microvascular obstruction region on MR images and allow comparison with findings at postmortem tissue staining (9).

Image Analysis
Two investigators performed all measurements in this study in consensus (M.S., G.A.K.). All images were transferred via Ethernet to a computer and analyzed with the public domain image program, which was developed by the National Institutes of Health and is available on the Internet at rsb.info.nih.gov/nih-image/. LV end-diastolic volume, end-systolic volume, systolic volume reduction, regional wall thickness (eg, two or three measurements from each region), and wall thickening were measured in the control and nicorandil groups. Systolic wall thickening was calculated as the difference between systolic and diastolic mean wall thickness, multiplied by 100, and divided by the diastolic wall thickness.

The mapping tool (NIH Image, version 1.59; National Institutes of Health, Bethesda, Maryland) was used to null the signal of remote myocardium (eg, septal wall), thus accentuating the differentially enhanced region (16). The hypoenhanced region was defined as an area with a signal intensity that was less than 2 standard deviations from that of the remote myocardium, while the hyperenhanced region was defined as an area with a signal intensity that was more than 2 standard deviations from that of the remote myocardium (9). Sizes of the hypo- and of the hyperenhanced regions were measured 1 minute after administration of contrast material; measurements were obtained at 3-minute intervals thereafter until the cutoff point of 27 minutes was reached. Signal intensity of the hypoenhanced region, hyperenhanced region, and remote myocardium were measured in all images obtained before and after the administration of contrast medium. To measure signal intensity in the remote myocardium and the two zones of ischemically injured myocardium before administration of the contrast medium, the location of the regions of interest was copied from the images obtained after administration of the contrast medium.

At postmortem analysis, the left ventricle was transversely cut into 2-mm slices after removal of the atria and right ventricle and measurement of the LV length. The two midventricular slices corresponding to the in vivo MR image were imaged, and these images were compared with the in vivo MR images. MR images were visually aligned with stained postmortem slices according to anatomic landmarks, such as insertion of the right ventricle with the left ventricle and papillary muscle. The differentially enhanced regions on MR images were expressed as a percentage of the total LV size from the two slices. Absolute wall thickness and systolic wall thickening were also measured on two contiguous midventricular slices.

Statistical Analysis
Descriptive statistical calculations were performed by using Statview 5.0 (SAS Institute, Cary, NC), while repeated-measures analysis of variance was performed by using SAS 8.2 (SAS Institute). The data are presented as mean ± standard error of the mean. We assessed regional signal intensity of ischemically injured myocardium, microvascular obstruction region, and remote noninjured myocardium of the different groups at each time point. LV relative volume, wall thickness, and wall thickening have been measured once in each animal.

The size of the microvascular obstruction regions and the signal intensity of microvascular obstruction regions, hyperenhanced regions, and remote myocardium were measured repeatedly in the same animals and compared by using analysis of variance. The Bland-Altman method was used to determine the agreement between microvascular obstruction size measured at postmortem analysis and on MR images. Unpaired t tests were also used to determine the significance of the difference between the size of hyperenhanced regions in control animals and the size in those that received nicorandil. Linear regression analysis was used to determine the correlation between LV end-diastolic midventricular cavity size and microvascular obstruction regions.

Mean differences in signal intensity were compared by using repeated-measures analysis of variance. In the fitted model, the repeated variables (eg, time and region) and the nonrepeated variable (eg, group) were used as independent group factors. In addition to the three main effects (eg, time, region, and group), all two- and three-way interaction terms between the three factors were included in the model. For the variable of time, a linear trend was assumed. In case of significant global effects, post hoc pairwise comparisons of the mean differences between groups (separately for every region at each time point) and between regions (separately for the nicorandil group and the control group) were performed. Statistical analysis was conducted in an explorative manner; thus, multiple comparison adjustment of the significance level was not needed. Thus, at a prespecified significance level (ie, {alpha} = 5%), significant mean differences in signal intensities are indicated by P values of .05 or less.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Microvascular obstruction regions were indistinguishable from remote normal myocardium prior to the administration of Gadomer. The signal intensity ratio between injured and remote normal myocardium was 0.99 ± 0.01. After Gadomer administration, three distinct regions with differential enhancement patterns were observed; namely, moderate enhancement was observed in remote myocardium, a hyperenhanced region was observed in the rim of ischemically injured myocardium, and a hypoenhanced area was observed in the center of the ischemically injured area. Repeated-measures analysis of variance showed that signal intensity of the remote normal myocardium significantly increased by 100% ± 12 at 6 minutes after administration of contrast media and gradually decreased to 66% ± 6 at 27 minutes after administration of contrast media (Figs 1, 2) (F = 5.32, df = 20, P < .001). At the rim of the ischemically injured region, signal intensity rapidly increased by 183% ± 9, without a significant decline over the course of 27 minutes. It should be noted that the hyperenhanced rim may be composed of viable and nonviable myocardium (43). The rim of the ischemically injured region was hyperenhanced when compared with either the remote normal myocardium or the microvascular obstruction region. In the first 6 minutes after administration of Gadomer, there was no significant increase in the signal intensity of the center of the ischemically injured myocardium when compared with the MR image acquired before administration of Gadomer (Fig 2), which suggests that the rate of delivery of the contrast agent is very slow in this region. After 6 minutes, signal intensity of the center of the ischemically injured myocardium slowly increased when compared with signal intensity of the rest of the heart. This pattern resulted in the appearance of a hypoenhanced region in the center of the ischemically injured myocardium when compared with the signal intensity of the normal remote myocardium. At 21 minutes, the hypoenhanced tissue became almost isointense (signal intensity = 107 arbitrary units ± 4) with the rim (117 arbitrary units ± 4) (P > .05, as calculated with analysis of variance).



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  		Figure 1a. (a) Sequential Gadomer-enhanced MR images of the heart (repetition time msec/echo time msec, 200/12; single section) obtained in a control rat. The top left image is a short-axis view of the left and right ventricles prior to administration of Gadomer. The top right image shows the microvascular obstruction region (arrows) 3 minutes after administration of 0.05 mmol/kg Gadomer. The bottom left image shows the enhanced rim of the injured region (arrows) and the smaller microvascular obstruction 15 minutes after Gadomer administration. The bottom right image shows complete filling of the injured myocardium with Gadomer 27 minutes after administration. The hyperenhancement of the microvascular obstruction region on the delayed image (27 minutes) is most likely caused by the entrance of contrast medium into the interstitium and intracellular compartments of infarcted myocytes (ie, increase in fractional distribution volume of Gadomer compared with that of remote myocardium). High signal intensity in the LV chamber represents sluggish blood flow that is adjacent to the dysfunctional wall. (b) Gadomer–enhanced MR images (200/12) obtained in two rats treated with nicorandil. Top and bottom left images show short-axis view of the left and right ventricles prior to Gadomer administration. The remaining images were acquired 3, 9, and 15 minutes after Gadomer administration. The pattern of contrast enhancement in these rats is different. Images in the top row represent the eight (73%) animals that do not show microvascular obstruction region. Images in the bottom row represent the patchy microvascular obstruction region (arrows) seen in three (27%) animals. Note that the size of the enhanced region (arrowheads in the far right images) in both rats is substantially smaller than that seen in control rats.

 


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  		Figure 1b. (a) Sequential Gadomer-enhanced MR images of the heart (repetition time msec/echo time msec, 200/12; single section) obtained in a control rat. The top left image is a short-axis view of the left and right ventricles prior to administration of Gadomer. The top right image shows the microvascular obstruction region (arrows) 3 minutes after administration of 0.05 mmol/kg Gadomer. The bottom left image shows the enhanced rim of the injured region (arrows) and the smaller microvascular obstruction 15 minutes after Gadomer administration. The bottom right image shows complete filling of the injured myocardium with Gadomer 27 minutes after administration. The hyperenhancement of the microvascular obstruction region on the delayed image (27 minutes) is most likely caused by the entrance of contrast medium into the interstitium and intracellular compartments of infarcted myocytes (ie, increase in fractional distribution volume of Gadomer compared with that of remote myocardium). High signal intensity in the LV chamber represents sluggish blood flow that is adjacent to the dysfunctional wall. (b) Gadomer–enhanced MR images (200/12) obtained in two rats treated with nicorandil. Top and bottom left images show short-axis view of the left and right ventricles prior to Gadomer administration. The remaining images were acquired 3, 9, and 15 minutes after Gadomer administration. The pattern of contrast enhancement in these rats is different. Images in the top row represent the eight (73%) animals that do not show microvascular obstruction region. Images in the bottom row represent the patchy microvascular obstruction region (arrows) seen in three (27%) animals. Note that the size of the enhanced region (arrowheads in the far right images) in both rats is substantially smaller than that seen in control rats.

 


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  		Figure 2. Graph shows changes over time in signal intensity (a.u. = arbitrary units) of the microvascular obstruction (MO) region, rim of ischemically injured myocardium, and remote normal myocardium in the control group (n = 11). Signal intensity curves were derived from sequential images obtained before and after administration of Gadomer. Enhancement of microvascular obstruction region on delayed images indicates that Gadomer is delivered into the injured region either by plasma flow in microvessels, convection transport, or both.

 
Gadomer was used to delineate very small microvascular obstruction regions (number of pixels, five; pixel size, 0.39 mm3). At 3 minutes after injection of contrast medium or blue dye, the size of the hypoenhanced myocardium on the MR image was identical to that of the unstained blue region at postmortem analysis. Regression analysis revealed excellent correlation between the MR image and postmortem measurements of the microvascular obstruction regions 3 minutes after administration (y = –1.01 + 1.10x) (r = 0.98). The hypoenhanced region was 17% ± 1 of LV of midventricular sections at Gadomer-enhanced MR imaging and 17% ± 2 of LV of midventricular sections at phthalocyanine blue dye staining (Fig 3). Bland-Altman analysis showed good agreement between data obtained with MR imaging and data obtained at postmortem analysis with blue dye staining. The mean difference between the two measurements was 0.4% ± 2, as calculated with the Bland-Altman test (Fig 4).



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  		Figure 3. MR images (200/12) of the microvascular obstruction region. MR image obtained 3 minutes after contrast medium injection (top left image, arrowheads) was compared with an MR image of the true microvascular obstruction region obtained 3 minutes after blue dye injection (top right image, arrowheads) in control rat. Note the high signal intensity from slow-flowing blood in the LV chamber, which is caused by dyskinesia of the adjacent wall (arrows). In animals treated with nicorandil, there was no evidence of microvascular obstruction 3 minutes after contrast medium injection (bottom left image) or blue dye injection (bottom right image).

 


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  		Figure 4. Bland-Altman plot shows the limit of agreement between MR images and blue dye true microvascular obstruction regions. Measurements were obtained 3 minutes after radiotracer injection, and the agreement is very close (mean ± standard deviation, 0.4% ± 2).

 
The hypoenhanced regions became smaller as a function of time (17% ± 1 at 3 and 6 minutes after administration of contrast medium, 12% ± 1 at 9 minutes, 9% ± 1 at 15 minutes, and 6% ± 1 at 21 minutes). On the other hand, the size of hyper- and hypoenhanced regions did not significantly change between 15 (37% ± 4) and 27 (34% ± 4) minutes after administration. The size of the rim of enhancement could be determined by measuring the border of the hyperenhanced region and subtracting the size of the hypoenhanced region from this value.

Nicorandil abolished the incidence of microvascular obstruction in eight (73%) animals. In the nicorandil group, the hypoenhanced region had a patchy appearance in three of 11 rats. Figure 1 shows two examples of rats in the nicorandil group; one rat had a hypoenhanced region, and one did not. In the nicorandil group, the hypoenhanced regions were 2.0% ± 1.0 at contrast-enhanced MR imaging and 3.0% ± 1.0 at administration of phthalocyanine blue dye (P > .05, as calculated with the two-sample t test). Regression analysis revealed excellent correlation between the hypoenhanced regions on MR images and the true microvascular obstruction after injection of phthalocyanine blue dye (y = 0.119 + 1.028x) (r = 0.98). Because of the size of the hypoenhanced regions in the nicorandil group, microvascular obstruction could be depicted briefly after Gadomer injection. Figures 2 and 5 demonstrate the changes in the hypoenhanced region and regional signal intensity.



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  		Figure 5. Graph shows time course changes in signal intensity of the microvascular obstruction (MO) region, ischemically injured myocardium, and remote normal myocardium in the nicorandil group (n = 11). Curves were derived from sequential MR images obtained before and after administration of 0.05 mmol/kg Gadomer. This graph shows the fast increase in signal intensity of the injured region.

 
The hyperenhanced regions were smaller (20% ± 2 of the left ventricle) in animals in the nicorandil group than in animals in the control group (37% ± 4; P < .001, as calculated with the two-sample t test). Figure 6 shows significant differences in the hypo- and hyperenhanced regions between the control and nicorandil groups. The ratio between the hypo- and hyperenhanced regions was 0.46 ± 0.11 in the control group and 0.10 ± 0.05 in the nicorandil group. This difference was statistically significant (P < .001, as calculated with the unpaired t test).



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  		Figure 6. Bar graph shows the extent of the Gadomer-enhanced region and the true microvascular obstruction (MO) region in the control (n = 11) and nicorandil (n = 11) groups. All measurements were obtained 3 minutes after administration of Gadomer and blue dye. Rats in the nicorandil group showed significantly smaller microvascular obstruction region than did rats in the control group. * = P value of less than .01.

 
Tables 1 and 2 show the LV relative volumes and wall thickness data of control and nicorandil groups. Wall thickening in all regions was significantly improved in the nicorandil group, as compared with that of the control group. End-diastolic and end-systolic LV relative volumes were significantly (P < .01, as calculated with the unpaired t test) different in the nicorandil group compared with those of the control group (Table 2). LV end-diastolic relative volume was significantly decreased in the nicorandil group. Close correlation was found between the hypoenhanced region and LV end-diastolic relative volume (y = 31.58 + 1.08x) (r = 0.79; P < .001, as calculated with the unpaired t test) (Fig 7). Figure 7 also shows the shift to the left of LV end-diastolic relative volume in the nicorandil group.


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  		TABLE 1. Diastolic and Systolic Wall Thickness and Systolic Wall Thickening

 

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  		TABLE 2. LV End-Diastolic and End-Systolic Midventricular Relative Volume and Systolic Reduction

 


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  		Figure 7. Graph shows correlation between the microvascular obstruction (MO) region and LV end-diastolic midventricular cavity size in rats in the control and rats in the nicorandil group. Note the shift to the left in the rats treated with nicorandil. The perpendicular line separates the two groups.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
There are three major findings of this study: Gadomer–enhanced T1-weighted spin-echo MR imaging has the capability to quantify small microvascular obstruction regions in ischemically injured myocardium, and it demonstrates the benefits of pharmacologic intervention on microvascular obstruction and ischemic myocardial injury. The alleviation of microvascular obstruction with nicorandil was associated with improvement of diastolic and systolic wall thickness, LV systolic wall thickening, LV end-diastolic and end-systolic midventricular relative volume, and percentage of systolic reduction. Close correlation was found between the microvascular obstruction regions and end-diastolic LV midventricular relative volume on two sections of the middle left ventricle. Thus, early nicorandil treatment during ischemia and reperfusion improves diastolic and systolic wall thickness and LV systolic wall thickening. It also reduces LV end-diastolic and end-systolic midventricular relative volume and increases the percentage of systolic reduction in midventricular cavity size.

Unlike MR imaging with extracellular contrast media (9), Gadomer-enhanced MR imaging has the potential to delineate very small (eg, a few pixels in size) microvascular obstruction regions, as measured in two sections (section thickness, 2 mm). After administration of extracellular contrast medium, Schwitter et al (9) were unable to define microvascular obstruction regions on gadopentetate dimeglumine–enhanced MR images in excised rat hearts subjected to different durations of ischemia and reperfusion. In large animals, extracellular MR contrast media provided accurate but brief (eg, 1-2 minutes) delineation of microvascular obstruction regions (12–14). Thus, blood pool contrast media may be useful in the detection of small microvascular obstruction (microembolized) regions for a relatively long time period (eg, 6 minutes). Furthermore, slow diffusive and/or convective transport of blood pool contrast media in microvascular obstruction regions may prove useful in lessening the technical demands for central bolus injection of extracellular MR contrast media and the high gradients needed for fast MR imaging. The hyperenhancement of microvascular obstruction regions on delayed images is most likely caused by the delivery of the contrast medium into the intracellular spaces of infarcted myocytes (ie, increase in fractional distribution volume of Gadomer) (15). These time course signal intensity MR imaging data also suggest that microvascular obstruction may experience blood cell exclusion but not plasma exclusion.

Microvascular Obstruction and Pharmacologic Intervention
Atherosclerotic plaque rupture is a key event in the pathogenesis of acute coronary syndromes and during coronary interventions. Much effort has been expended to elucidate the role of therapeutic drugs in the treatment of microvascular obstruction (22–26). Taniyama et al (25) found that after percutaneous transluminal coronary angioplasty, intracoronary nicorandil or verapamil administration reduces the formation of microvascular obstruction, augments myocardial blood flow, and improves functional outcome compared with percutaneous transluminal coronary angioplasty alone. Hillegass et al (23) also found that nitroprusside is an effective therapy for prevention of microvascular obstruction formation with percutaneous transluminal coronary angioplasty. The complex role played by nicorandil may reflect actions on diverse cell types.

There is mounting evidence (31–34) that nicorandil preserves myocardial viability by reducing ischemically injured areas. Results of the current MR study confirm this finding. Intravenous infusion of nicorandil before intervention (eg, contrast medium bolus followed by infusion prior to coronary reperfusion) improved delivery of the blood pool contrast medium into the microvascular obstruction region (Figs 3, 5), which may be used as a marker of tissue perfusion. Preintervention treatment is particularly important because it can be used in patients who arrive in the emergency department with myocardial infarction but do not necessarily require cardiac catheterization (28,29). Intravenous infusion of nicorandil before intervention has been used in 272 patients with acute myocardial infarction. Sugimoto et al (29) routinely used nicorandil infusion to reperfuse microvessels in all patients with acute myocardial infarction.

The current study showed a close correlation between microvascular obstruction regions, and LV end-diastolic midventricular relative volume in the two middle LV sections was found. It also showed a shift to the left in LV end-diastolic midventricular relative volume in the nicorandil group. Regional wall thickening was impaired in rats in the control group. LV changes were coupled with less systolic relative volume reduction in rats in the control group than in rats that received nicorandil. Such adaptive LV changes have been described after acute infarction (45,46). Our findings are in line with those of previous clinical studies, in which nicorandil increased cardiac index by 55% in patients with congestive heart failure (42), by 19% in patients with myocardial infarction (35), and by 16% in patients with coronary artery disease (47). It remains to be seen whether the correlation between microvascular obstruction and clinical outcome simply reflects the infarction size or whether this correlation is directly related to microvascular damage that might impede infarct healing, promote LV dilation, or potentially reduce collateral formation.

MR Imaging
Fast MR imaging with bolus injection of extracellular MR contrast medium (represented by gadopentetate dimeglumine) has been used in the detection of microvascular obstruction in dogs (12,13) and patients (11). However, extracellular MR contrast media were not useful in the detection of small microvascular obstruction regions (9). The lack of success in the detection of small microvascular obstruction regions may be attributed to the small area of microvascular obstruction (eg, few pixels) and fast diffusion rate of the low-molecular-weight contrast agents. Our results show that Gadomer can be used to delineate small microvascular obstruction regions (eg, more than 5 pixels; pixel size = 0.39 mm2), and the technique may be useful in the detection of microembolized regions in patients.

Unlike in previous MR imaging studies (12,13), we used conventional T1-weighted spin-echo MR imaging in the detection of microvascular obstruction regions. We used T1-weighted spin-echo MR imaging because images obtained with this sequence have better spatial resolution than images obtained with the fast low-angle shot sequence and because it is available in all MR imagers (12,13). Furthermore, the delineation of microvascular obstruction regions with Gadomer-enhanced T1-weighted spin-echo MR imaging is useful in lessening the technical demands for high-field-strength gradients and rapid bolus injection of extracellular agents.

In the control group, the pattern of enhancement in the ischemically injured myocardium after administration of Gadomer suggests that there is a gradient in the severity of microvascular injury, namely, obstructed microvessels in the core surrounded by patent nonobstructed microvessels in the rim. It should be noted that the patent nonobstructed microvessels in the rim are permeable to Gadomer. It is known from previous studies (48,49) that hyperpermeability of capillaries is the first sign of ischemic injury. Electron microscopy revealed that microvascular obstruction is due to endothelial cell bleeding, white cell infiltration, red blood cell stagnation, and extravascular edema (50). Microvascular obstruction can increase after reperfusion (51). We have previously depicted these two differentially enhanced regions after administration of the blood pool contrast medium gadopentetate dimeglumine–albumin-biotin (15).

In the nicorandil group, the fast increase in signal intensity in the center of ischemically injured myocardium reflects delivery of Gadomer to the reperfused region and high permeability of microvessels. Discrimination of the effect of perfusion from permeability or blood volume is not possible with current MR imaging capabilities. Although the mechanism of nicorandil alleviation of microvascular obstruction is still speculative (2), several hypotheses regarding the protective mechanism of myocardial viability have been advanced: (a) It increases coronary blood flow (52); (b) the nitrate moiety in it acts as a free radical scavenger, thereby preventing microvascular damage and platelet aggregation (16); and (c) it inhibits calcium overload (30,53,54). Horn et al (55) used MR spectroscopy and found that nicorandil prevents deterioration of ATP in rats.

Gadomer–enhanced MR imaging provides an opportunity to measure small microvascular obstruction regions with conventional MR imaging systems and assess the effects of pharmacologic intervention on microvascular obstruction and ischemically injured myocardium. Nicorandil significantly reduced the frequency of microvascular obstruction in reperfused infarction. The findings of this investigation parallel clinical observations, which suggest a close relationship between microvascular obstruction and recovery of function.

There are some limitations of the current study. First, we did not assess the true size of infarction with histochemical staining. This was not possible in the current study, since the application of tissue dye for delineation of microvascular obstruction excludes delineation of infarction. Second, a small 2-T animal MR imager as opposed to a clinical MR imager was used in the evaluation of microvascular obstruction and therapy. However, similar sequences can be used on clinical MR systems. It should be noted that the data were derived from two middle LV slices and not from the entire heart. A previous study (44) showed high correlation between infarction size derived from all slices of the heart compared with that derived from only two middle ventricular slices in rats when the occlusion is at the origin of the left anterior descending coronary artery.

Practical application: The delineation of microvascular obstruction and assessment of size of microvascular obstruction in patients with reperfused myocardial infarction is important in assessing the prognosis and possible clinical outcome of patients. Gadomer is currently in phase II clinical trials (21,22), and it can be used in patients after it is fully approved by the U.S. Food and Drug Administration. According to the results of the current study, the time window for delineation of microvascular obstruction is relatively wide, namely, in the range of minutes. This allows for repeated imaging after administration of Gadomer if a patient has difficulty holding his or her breath. Furthermore, the left ventricle can be covered within this time, and fast MR sequences are not necessarily required. This allows the use of standard MR imaging systems and application of the protocol on a broad base. The beneficial effect of nicorandil has already been proved in patients with acute myocardial infarction. The findings of the current study suggest an additional beneficial effect of nicorandil, which can be attributed to reduction of microvascular obstruction. After additional clinical studies, this drug may be applied as an adjunct in patients with myocardial infarction and microvascular obstruction.


   FOOTNOTES
 

Abbreviations: LV = left ventricular

2 Department of Radiology, University of Technology, Aachen, Germany Back

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


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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