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Published online before print October 30, 2001, 10.1148/radiol.2213010533
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(Radiology. 2001;221:676-682.)
© RSNA, 2001

Experimental Studies

Assessment of Nicorandil Therapy in Ischemic Myocardial Injury by Using Contrast-enhanced and Functional MR Imaging1

Gunnar K. Lund, MD, Charles B. Higgins, MD, Michael F. Wendland, PhD, Norbert Watzinger, MD, Hanns-Joachim Weinmann, PhD and Maythem Saeed, DVM, PhD

1 From the Department of Radiology, University of California, San Francisco, 505 Parnassus Ave, Rm L-308, San Francisco, CA 94143-0628 (G.K.L., C.B.H., M.F.W., N.W., M.S.); and Schering AG, Berlin, Germany (H.J.W.). Received February 28, 2001; revision requested April 2; revision received June 7; accepted July 5. Supported in part by a gift from Schering AG, Berlin, Germany. G.K.L. supported in part by a scholarship from the University Hospital Eppendorf, Hamburg, Germany. N.W. supported in part by a scholarship from the Max-Kade Foundation, New York, NY. Address correspondence to M.S. (e-mail: maythem.saeed@radiology.ucsf.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To determine the potential of mesoporphyrin– and gadopentetate dimeglumine–enhanced and functional magnetic resonance (MR) imaging in the assessment of the acute effect of nicorandil on ischemic injury of the myocardium.

MATERIALS AND METHODS: Spin-echo MR imaging was used to monitor changes in myocardial contrast and function in reperfused myocardial injury. Inversion-recovery echo-planar MR imaging was used to depict the injured region. Myocardial injury in rats was produced by using 30 minutes of coronary occlusion followed by 24 hours reperfusion. Nicorandil (n = 9) was infused during occlusion and early reperfusion. Control animals (n = 11) received no therapy. At 24 hours, after administration of mesoporphyrin and gadopentetate dimeglumine and histochemical staining, the function and size of the injured region of the left ventricle (LV) were determined. A t test was used to compare data between groups of animals, whereas regression and Bland-Altman analyses were used to determine correlation and agreement between MR imaging and histomorphometry, respectively.

RESULTS: Treated animals showed reduced infarction size as compared with the control group from 25.6% ± 7.9 (SD) to 7.9% ± 6.8 of LV myocardial area (P < .001), as defined with mesoporphyrin-enhanced MR imaging; while the size of the rim increased from 10.8% ± 10.0 to 16.1% ± 14.4 (P < .05). The diastolic-midventricular cavity area was smaller in treated animals (15.2 mm2 ± 4.3) compared with the control group (28.5 mm2 ± 7.9; P < .001). At functional MR imaging, nicorandil improved systolic reduction in LV cavity area (57.5% ± 17.3) compared with the control group (38.0% ± 16.0; P < .05) and preserved regional LV wall thickening at the site of injury (12.2% ± 11.1 in treated group vs 0.3% ± 8.6 in the control group; P < .05).

CONCLUSION: Contrast material–enhanced MR imaging has the potential to demonstrate reduction in size of ischemically injured myocardium, whereas functional MR imaging demonstrated the recovery of LV function 24 hours after nicorandil therapy.

Index terms: Heart, experimental studies, 511.12143 • Heart, MR, 511.121413, 511.121416, 511.12143 • Myocardium, infarction, 511.771 • Myocardium, ischemia, 511.1939 • Myocardium, MR, 511.121413, 511.121416, 511.12143


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Nicorandil is an antianginal drug, clinically approved in Europe and Japan, that has cardioprotective properties by causing vasodilation like a nitrate (1) and by opening myocardial adenosine triphosphate–sensitive potassium channels (2). Recent findings in patients, by using echocardiography, have indicated that intravenously administered nicorandil preserves microvascular integrity and function of the left ventricle (LV) after acute myocardial infarction (3) and improves ischemic tolerance during coronary angioplasty (4). Physiologic studies (4–8) in animal models have indicated that nicorandil decreases LV end-diastolic and arterial pressures. Sato et al (9) found that nicorandil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by selective activation of mitochondrial adenosine triphosphate–sensitive potassium channels. Other study findings (5–8) have demonstrated that nicorandil reduces the size of infarction. Imagawa et al (8) reported that 5-hydroxydecanoate, the selective mitochondrial adenosine triphosphate–sensitive potassium channel inhibitor, abolishes the infarct size-limiting effect of nicorandil.

Contrast material–enhanced magnetic resonance (MR) imaging techniques have been developed to measure the size of infarction (10–12). To our knowledge, Marchal et al (10) first reported that bis-gadolinium-mesoporphyrin (mesoporphyrin) is a necrosis-specific agent. Authors of recent studies (11,12) demonstrated that mesoporphyrin enhances only necrotic myocardium and provides an accurate estimation of acute (24–28 hours after) infarction. In this time frame, use of extracellular nonspecific agents, such as gadopentetate dimeglumine, results in overestimation of infarction size by inclusion of a portion of the area at risk (12,13). The overestimated hyperenhanced portion of myocardium has been recently called "periinfarction zone" (12,14). Accordingly, it was proposed that subtraction of the gadolinium-enhanced region from the mesoporphyrin-enhanced region provided an estimate of the viable periinfarction zone in the early stage of infarction (14). The purpose of this study was to determine the potential of mesoporphyrin-enhanced, gadolinium-enhanced, and functional MR imaging in the assessment of the acute effect of the cardioprotective drug nicorandil on ischemically injured myocardium.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Myocardial Injury and Experimental Protocols
All experimental protocols received previous approval from the Committee on Animal Research at our institution and were performed with the National Institutes of Health guidelines for care and the use of laboratory animals. Rats (Simonson Lab, Modesto, Calif; n = 20; weight range, 260–300 g) were anesthetized by using intraperitoneal administration of 50 mg of ketamine (Ketaset; Fort Dodge Labs, Fort Dodge, Iowa) per kilogram of body weight and 1.4 mg/kg xylazine (Anased; Lloyd Labs, Shenandoah, Iowa). A catheter was placed in the tail vein for drug and contrast material administration. A thoracotomy on the left side was performed under mechanical ventilation, and the left coronary artery was occluded for 30 minutes by placing a snare loop around the artery.

The two groups of rats were randomly assigned to receive either a saline or nicorandil solution. At 15 minutes after occlusion, the animals in the treated group (n = 9) received a bolus of 100 µg/kg followed by infusion of 25 µg/kg/min nicorandil for 60 minutes. This dose of nicorandil was chosen because it was found to produce a 15–20-mm Hg decline in mean arterial pressure in dogs for almost 1 hour after administration (5). In humans, the apparent elimination half-life (plasma half-life) of nicorandil is 1 hour, and all metabolites are excreted in 24 hours (4). The control group (n = 11) received saline infusion. At 2 hours of reperfusion, each animal received 0.05 mmol/kg mesoporphyrin, and images were obtained at 24 hours of reperfusion.

Contrast-enhanced MR Imaging
Mesoporphyrin and gadopentetate dimeglumine were synthesized and supplied by Schering AG, Berlin, Germany. Mesoporphyrin is a necrosis-specific metalloporphyrin that may bind to necrotic tissue or cellular debris and, thus, is distinguished from gadopentetate dimeglumine, which distributes in necrotic cells and in the edematous periinfarction zone (10–12). The T1 and T2 relaxivities of mesoporphyrin are two times higher (8.9 and 12 sec-1 mM-1) than those of gadopentetate dimeglumine (3.7 and 5.6 sec-1 mM-1). The dose (0.05 mmol/kg) of mesoporphyrin used in this study was one-sixth of the dose of gadopentetate dimeglumine. The 0.05 mmol/kg mesoporphyrin dose resulted in an equivalent increase in signal intensity compared with a 0.3 mmol/kg gadopentetate dimeglumine dose. Detailed physiochemical properties of both contrast materials have been previously described (15,16). Animals were again anesthetized for imaging by using 60 mg/kg sodium pentobarbital (Nembutal Sodium Solution; Abbott Laboratories, North Chicago, Ill). Copper leads were inserted into a forelimb and the lower chest wall and connected to an electrocardiographic monitor (AccuSync 6L; AMR, Milford, Conn) to provide cardiac gating. Each rat was placed supine in a custom-made birdcage radio-frequency coil (5.6-cm inner diameter and 7.6-cm length), and MR images were acquired with a 2.0-T magnet (Bruker Instruments, Fremont, Calif). The magnet was equipped with self-shielded gradient coils (Acustar S-150; Bruker Instruments) (±20 G/cm, 15-cm diameter). MR imaging was performed 24 hours after infarction by using the following sequences.

Spin-echo MR imaging.—Multisection T1-weighted transverse spin-echo images were obtained, after administration of mesoporphyrin and gadopentetate dimeglumine, to measure the size of the enhanced region. Three adjacent equidistant (2-mm) sections were acquired at the apex, center, and base of the LV. The acquisition parameters were a repetition time of 30 msec, an echo time of 12 msec, a section thickness of 2 mm, a field of view of 5 x 5 cm, an image matrix of 256 x 128 (0.20 mm per pixel), and an acquisition time of 2.5 minutes, depending on the heart rate. After acquisition of mesoporphyrin-enhanced MR images, gadopentetate dimeglumine was intravenously injected without removing the animal from the magnet. A second set of images was acquired 30 minutes after injection of gadopentetate dimeglumine with the identical MR imaging parameters and section locations as with the mesoporphyrin-enhanced images. LV function was demonstrated on a single midventricular short-axis plane with images obtained at end diastole, defined as the rise of QRS complex and end-systolic images acquired at approximately 45% of R-R interval (14).

Inversion-recovery echo-planar imaging.—Regional T1 was measured on a single midventricular section in the transverse plane 22 hours after administration of mesoporphyrin. MR imaging parameters were a repetition time of at least 6 seconds, an echo time of 10 msec, an inversion time of 20–1,000 msec, a slice thickness of 2 mm, a field of view of 5 x 5 cm, an image matrix of 64 x 64 (0.78 mm per pixel) and an acquisition time for each image of 33 msec. T1 values were obtained from a set of 20 images in which the time to inversion was incremented from 20 to 1,000 msec, to detect the time to inversion with null signal. T1 values were calculated from the time to inversion at the null point by using the relation T1 = time to inversion with null signal/ln 2 (17).

Postmortem Evaluation
After MR imaging, the left coronary artery was again occluded, and 0.2 mL of phthalocyanine blue dye (Engelhard, Louisville, Ky) was intravenously administered to define the area at risk. The LV was transversely sectioned into three 2-mm-thick sections at the apex, center, and base that corresponded to MR images. Both upper and lower surfaces of the stained slices were scanned with a flatbed scanner (Silverscanner IV; LaCie, Hillsboro, Ore). Each slice was then incubated in a 2% triphenyltetrazolium chloride (TTC) solution (Sigma Chemical, St Louis, Mo) to define infarcted myocardium. Both faces of each slice were rescanned and digitally stored for analysis.

Data Analysis
The size of mesoporphyrin- and gadolinium–enhanced regions on MR images, the true infarction size depicted with TTC staining, and the area at risk depicted with blue dye were measured by using computer-assisted planimetry and an imaging program (public domain NIH image program developed at the United States National Institutes of Health, available at rsb.info.nih.gov/nih-image/). The periinfarction zone was calculated by subtracting the size of the mesoporphyrin-enhanced region from the size of the gadolinium-enhanced region (12,14). Wall thickness was measured at end diastole and end systole in four regions, namely, the mesoporphyrin-enhanced region, the rim of gadolinium-enhanced region, and the remote posterior and septal walls. The LV cavity area was measured during end diastole and end systole to calculate the systolic reduction of cavity size. Regional T1 values were computed from the inversion-recovery null point (17).

Statistical Analysis
Data were expressed as the mean plus or minus the SD. The two-sample t test was used to compare control and nicorandil-treated animals. Measurements in each group were analyzed by using the paired t test. Linear regression and Bland-Altman analysis were used to determine correlation and agreement, respectively, between contrast-enhanced MR images and histomorphometry. The null hypothesis was rejected when the P value was less than .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Comparison between Gadolinium- and Mesoporphyrin-enhanced MR Imaging Regions
The mesoporphyrin-enhanced region was substantially smaller in animals treated with nicorandil (treated) compared with animals not treated (control animals) (Fig 1). The sizes of mesoporphyrin-enhanced regions were 25.6% ± 7.9 of the LV myocardial areas in controls and 7.9% ± 6.8 in nicorandil-treated animals (P < .001), which is consistent with a 69% reduction in infarction size (Fig 2). Gadolinium-enhanced regions (infarcted myocardium plus periinfarction zone) also were reduced, 36.4% ± 8.4 in control animals to 24.7% ± 10.3 in treated animals (-32%, P < .001). However, the size of the periinfarction zone (gadolinium-enhanced region minus mesoporphyrin-enhanced region) was larger in treated (16.1% ± 11.4) compared with control (10.8% ± 10.0) animals (P < .05) (Fig 3). The decrease in infarction size and increase in periinfarction zone size in treated animals cannot be attributed to a difference in the size of area at risk between the groups, because the size of area at risk was not different (control animals, 48.7% ± 7.8; treated animals, 50.7% ± 7.3; P > .05) (Fig 2).



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  		Figure 1. Multisection mesoporphyrin-enhanced short-axis view MR images acquired in control (top row) and treated (bottom row) rats at end diastole. The size of the mesoporphyrin-enhanced region (arrowheads) and LV dilatation is substantially reduced in treated compared with control animal. The high blood signal intensity in control animal is caused by slow blood flow in the LV due to reduced global function.

 


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  		Figure 2. Bar graph depicts the size of area at risk (black bars), true size of infarction (white bars) by using TTC staining, and mesoporphyrin-enhanced region (bars with oblique lines). The infarction size was reduced in nicorandil-treated rats as demonstrated with mesoporphyrin-enhanced MR imaging and confirmed with TTC staining. The area at risk was not significantly different between the groups, which suggests that the reduction in the size of infarction is not attributed to a difference in the size of area at risk. The P value was less than .001 (*) for control versus treated animals.

 


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  		Figure 3. Bar graph depicts the gadolinium-enhanced region (black bars) (infarcted myocardium and periinfarction zone) and the calculated periinfarction zone (white bars) (gadolinium-enhanced region minus mesoporphyrin-enhanced region). The gadolinium-enhanced region was smaller in nicorandil-treated animals. However, nicorandil treatment increased the size of the viable periinfarction zone. The P value was less than .001 (*) and less than .05 ({dagger}) for control versus treated animals.

 
Effect of Nicorandil on the Size of Infarction
TTC staining confirmed the reduction in infarction size demonstrated on mesoporphyrin-enhanced images in nicorandil-treated rats. Linear regression analysis revealed a strong correlation (Y = 1.65 + 0.95 x X, r = 0.96, P < .001; standard error of the estimate = 3.11) between TTC-depicted infarction size and mesoporphyrin-enhanced regions. Bland-Altman analysis revealed no systematic measurement bias over a wide range of sizes of infarction. The mean difference in measurements was 0.77% ± 3.1 of LV myocardial area and the limits of agreement ranged from -5.5% to +7.1%. Conversely, only a fair correlation was found between the size of gadolinium-enhanced regions and TTC staining (Y = 22.3 + 0.52 x X, r = 0.53, P < .001; standard error of the estimate = 9.39). Bland-Altman analysis revealed an overestimation of infarction size of +14.0% ± 10.8 of LV myocardial area by using gadolinium-enhanced MR imaging. Figure 4 shows the area at risk, or region of infarction demonstrated with TCC staining, and mesoporphyrin-enhanced region on the corresponding midventricular sections.



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  		Figure 4. Photographs of tissue specimens and short-axis view MR images obtained at midventricular level in control and treated animals. In both sets of animals, the location and size of the mesoporphyrin-enhanced region (right, bright regions defined with arrowheads) corresponded well to the true infarction size demonstrated with TTC staining (center, gray regions defined with arrowheads). The size of infarction was substantially smaller in the nicorandil-treated compared with control animal. The area at risk (left, unstained light regions defined with arrowheads) was comparable in size in both sets of animals, which indicates the reduction in infarction size was not attributed to a difference in area at risk.

 
Effect of Nicorandil on Regional T1 Relaxation Time
The difference in regional T1 values between control and treated animals was evident on mesoporphyrin-enhanced inversion-recovery echo-planar images. The T1 value of ischemically injured myocardium was significantly shorter in control (660 msec ± 86) than in treated (960 msec ± 53) animals (P < .001). The remote normal myocardium revealed no difference in T1 relaxation time between control (910 msec ± 14) and treated (900 msec ± 26) animals.

Effects of Nicorandil on LV Dilatation and Function
MR imaging revealed marked diastolic dilatation of the LV cavity area in control animals (Table). A positive correlation was found between end-diastolic LV cavity area and infarction size measured on identical mesoporphyrin-enhanced MR images (Fig 5). MR images acquired at 24 hours after acute myocardial infarction showed better global and regional contractile function in nicorandil-treated animals compared with control animals. The systolic reduction in LV cavity area was 57.5% ± 17.3 in nicorandil-treated animals compared with 38.0% ± 16.0 in control animals (P < .05). Regional wall thickening was depressed in control animals, with no wall thickening in the mesoporphyrin-enhanced region, and severely reduced in the rim of the gadolinium–enhanced region (Fig 6). Nicorandil improved wall thickening of ischemically injured myocardium in treated animals. There was no significant difference in regional wall thickening, in the remote posterior and septal walls (Fig 7), between the two groups.


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  		End-diastolic LV Cavity Area Measured at MR Imaging in Control and Nicorandil-treated Animals

 


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  		Figure 5. Graph shows correlation between infarction size (mesoporphyrin-enhanced region) and end-diastolic LV cavity area depicted on identical MR images (60 images from 20 rats). A direct correlation was made between infarction size and extent of LV dilatation from each single image (Y = 13.3 +0.44 x X, r = 0.5, P < .001, standard error of the estimate = 8.48). Nicorandil-treated animals (white diamonds) showed smaller infarction size and diminished LV dilatation in almost all images compared with control animals (black diamonds), underlining the beneficial effect of infarction size reduction with early LV remodeling.

 


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  		Figure 6. Functional MR images in short-axis view show the mesoporphyrin- and gadolinium-enhanced regions during diastole and systole in control and nicorandil-treated rats. Note the reduced LV dilatation and improved LV wall thickening in nicorandil-treated rat compared with the control rat. Furthermore, the gadolinium-enhanced region (arrowheads) is substantially larger than the mesoporphyrin-enhanced region (arrowheads) in the nicorandil-treated animal.

 


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  		Figure 7. Bar graph shows regional LV wall thickening in control and nicorandil-treated animals. There was no wall thickening in the mesoporphyrin-enhanced anterolateral wall (white bars) in control animals. Nicorandil significantly (P < .05) improved the function in the anterolateral wall in the treated animals. Additionally, better wall thickening was also observed in the gadolinium-enhanced rim (bars with oblique lines) of the nicorandil-treated animals (P < .05). No difference in wall thickening was observed in the remote noninfarcted posterior (gray bars) and septal (black bars) regions of the LV.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
The major findings of the current study were the following: (a) In the acute stage (24 hours) of myocardial infarction, the necrosis-specific MR imaging contrast material, mesoporphyrin demonstrated a reduction in the size of infarction. The decrease in infarction size demonstrated with mesoporphyrin was subsequently confirmed by using histochemical TTC staining. (b) Nicorandil reduced the size of the entire gadolinium-enhanced region. The salvage of ischemically injured myocardium is reflected by the expansion of the periinfarction zone defined by the difference in mesoporphyrin and gadolinium-enhanced regions. (c) Functional MR imaging revealed reduction in LV cavity area and preservation of regional wall thickening in nicorandil-treated animals. (d) Shortening in regional T1 relaxation time indicated accumulation of mesoporphyrin in ischemically injured regions of control, but not in nicorandil-treated animals.

The use of necrosis-specific radiotracers, such as technetium 99m pyrophosphate and labeled monoclonal antibodies, for the identification and determination of the size of acute myocardial infarction is well established in nuclear medicine. However, the diagnostic accuracy of these nuclear tracers is limited by difficulties in the detection of small or nonreperfused infarctions, interference with overlying rib uptake, residual blood activity, and limited spatial resolution of scintigraphic technique (18). Measurement of the size of infarction by using mesoporphyrin-enhanced MR imaging has overcome some of the limitations of scintigraphic techniques and nonspecific extracellular MR imaging contrast material.

Mesoporphyrin used with new or conventional MR imaging sequences provides for accurate sizing of reperfused and occlusive infarctions (10–12,14). Intracellular binding, or precipitation of the contrast material, demonstrates the specificity of mesoporphyrin for depicting necrotic tissues and cellular debris, such as denatured protein, nucleotide, or calcium precipitates of necrotic cells (19). Conversely, gadopentetate dimeglumine has no binding site and distributes passively into edematous and infarcted myocardium and enhances both regions (12,14,20). Its influence on signal intensity is attributed to a greater accessibility to free water in edematous and infarcted myocardium. Thus, tandem administration of mesoporphyrin and a high dose of gadopentetate dimeglumine was used to map the edematous periinfarction zone, as described in a previous report (12,14). Overestimation of the size of acute myocardial infarction (24 hours) was observed after administration of extracellular MR imaging contrast material as demonstrated in the current study and in previous reports (12–14). This overestimation cannot be attributed to the volume averaging effect of new or conventional MR imaging techniques because mesoporphyrin- and gadolinium-enhanced MR imaging was performed in one session without removing the animal from the magnet, by using a single pulse sequence and identical section position and thickness. Furthermore, the theory that a gadolinium-enhanced region encompasses viable and nonviable portions, especially, in reperfused infarctions older than a couple of days, is still controversial.

Contrast-enhanced MR Imaging in Demonstrating the Reduction in the Size of Infarction
The strategy used in the current study was to administer nicorandil in the middle of the period of coronary artery occlusion and in the 1st hour of reperfusion. With the use of this approach, nicorandil statistically reduced the size of infarction, as shown at contrast-enhanced MR imaging and histomorphometry. Furthermore, inversion-recovery echo-planar MR imaging revealed a much greater reduction in T1 in ischemically injured myocardium in control animals compared with that in nicorandil-treated rats. These findings indicate that nicorandil preserved large portions of the area at risk and subsequently reduced the accumulation of mesoporphyrin in necrotic myocardium.

Contrast-enhanced MR Imaging in Determining the Reduction in the Size of the Injured Region
Our study was performed to assess the periinfarction zone in the early stage of reperfused infarction at 24 hours after coronary occlusion by using contrast-enhanced and functional MR imaging in control and treated animals. To obtain a sizable periinfarction zone, a relatively short period of coronary artery occlusion was used. A relatively short period of coronary artery occlusion was also used to mimic the clinical setting of nontransmural infarction. This occlusion time provided a situation in which a substantial amount of edematous but salvageable myocardium existed in the area at risk (14,20). The existence of the periinfarction zone has been very recently documented in rats (by using MR imaging) (12,14), cats (by using MR imaging and electron microscopy) (21), pigs (by using MR imaging and electron microscopy) (22), and humans (by using thallium-201 single photon emission computed tomography and combined positron emission tomography with tagged MR imaging) (23,24).

The effect of therapy on the periinfarction zone by using noninvasive imaging methods, as found in this study, to our knowledge, has not been previously described. There are several possible reasons for the increase in the periinfarction zone depicted in nicorandil-treated animals. First, nicorandil increased the size of the periinfarction zone at the cost of the size of infarction, which was substantially decreased in treated animals. Second, the augmented periinfarction zone may be due to an increased tolerance to ischemia during coronary occlusion. This explanation is supported by the observation of Schultz et al (25), who found that nicorandil has a pharmacologic preconditioning effect by opening adenosine triphosphate–sensitive potassium channels. Similarly, Matsubara et al (4) found an increased ischemic tolerance in patients treated with nicorandil subjected to coronary angioplasty. Finally, nicorandil may have caused a diminution of edema in the periinfarction zone during occlusion and reperfusion in treated animals, which resulted in a smaller gadolinium-enhanced region compared with that in control animals. Results of previous reports have indicated that edema is initiated during occlusion (26) and reperfusion (27) after extravasation of plasma proteins into the extracellular space. Nicorandil may impede the accumulation of plasma proteins in the ischemically injured region by preserving microvascular function. Authors of a recent clinical study (3), using echocardiography, suggested a microvascular protection by nicorandil in reperfused acute myocardial infarction.

Functional MR Imaging in Determining the Improvement of LV Function
The adaptive cardiac responses to acute myocardial infarction are well described in the literature (28–31). The main changes include infarct expansion, regional dilatation, and thinning of the infarct zone, which occurs as early as 1 day after the ischemic event (31). Chronic infarction models have shown that the size of infarction is the main predictor of late LV remodeling (29). Results of the current study demonstrate that nicorandil effectively prevents early LV dilatation after myocardial infarction and improved regional LV function.

In conclusion, contrast-enhanced MR imaging has the potential to demonstrate reduction in size of ischemically injured myocardium, whereas functional MR imaging demonstrates the recovery of LV function 24 hours after therapy. The beneficial effect of newly developed cardioprotective agents can be noninvasively monitored by using contrast-enhanced MR imaging.

Furthermore, beside prompt restoration of coronary blood flow with thrombolysis or angioplasty, early therapy with intravenously administered nicorandil may be an ideal adjunctive therapy to reduce the size of infarction and to improve LV function. The early reduction in the size of infarction and LV dilatation depicted may attenuate late LV remodeling. Further MR imaging studies are warranted to investigate the beneficial effect of early nicorandil treatment to limit late LV remodeling and to improve the prognosis of patients.

Practical application: There are a number of potential applications pertaining to these results. If necrosis-specific MR imaging contrast material were approved for clinical use, it would provide the following advantages over nonspecific extracellular MR imaging contrast material: (a) MR images could be obtained in a wide time window after administration of this type of agent, allowing flexible scheduling for MR imaging. (b) Persistent enhancement provided with mesoporphyrin enables a correlation between the size of infarction and the extent of wall motion abnormality measured on identical MR image sections. Chronologic measurements of regional wall motion abnormality and size of infarction will provide further insight into the time course of functional recovery in ischemically injured but viable myocardium after therapy. (c) Dual contrast-enhanced imaging enables characterization of the periinfarction zone. The issue of toxicity of porphyrins has to be resolved before this new contrast material can be applied in humans. Phase I clinical trials are expected in the near future.


   ACKNOWLEDGMENTS
 
Mitsuaki Chujo, PhD (Chugai Pharmaceutical, Tokyo, Japan) and Hanns-Joachim Weinmann, PhD (Schering AG, Berlin, Germany) kindly provided nicorandil and mesoporphyrin, respectively, as gifts.


   FOOTNOTES
 
Abbreviations: LV = left ventricle, TTC = triphenyltetrazolium chloride

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


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

  1. Taira N. Nicorandil as a hybrid between nitrates and potassium channel activators. Am J Cardiol 1989; 63:18J-24J.
  2. Yoneyama F, Satoh K, Taira N. Nicorandil increases coronary blood flow predominantly by K-channel opening mechanism. Cardiovasc Drugs Ther 1990; 4:1119-1126.
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