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DOI: 10.1148/radiol.2243011372
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(Radiology 2002;224:830-837.)
© RSNA, 2002

Experimental Studies

Left Ventricular Remodeling after Infarction: Sequential MR Imaging with Oral Nicorandil Therapy in Rat Model1

Maythem Saeed, DVM, PhD, Norbert Watzinger, MD, Gabriele A. Krombach, MD, Gunnar K. Lund, MD, Michael F. Wendland, PhD, Mitsuaki Chujo, PhD and Charles B. Higgins, MD

1 From the Department of Radiology, University of California, San Francisco, 505 Parnassus Ave, Rm L-308, San Francisco, CA 94143-0628 (M.S., N.W., G.A.K., G.K.L., M.F.W., C.B.H.); and Chugai Pharmaceutical, Tokyo, Japan (M.C.). Received August 13, 2001; revision requested October 9; final revision received March 4, 2002; accepted March 25. Supported by Chugai Pharmaceutical. Address correspondence to M.S. (e-mail: maythem.saeed@radiology.ucsf.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To use magnetic resonance (MR) imaging in quantification of the short- and long-term effects of therapy with orally administered nicorandil on left ventricular (LV) geometry and function independent of infarction size.

MATERIALS AND METHODS: Forty-six rats were subjected to reperfused infarction and randomly divided into two groups. Group 1 rats (n = 21) were treated with nicorandil (3 mg/kg/day in drinking water) for 4 days before infarction and 8 weeks after infarction (hereafter, the nicorandil group). Group 2 rats (n = 25) received tap water for the same period and served as the control group. Mesoporphyrin- (as a necrosis-specific agent) enhanced MR imaging was used to define necrotic myocardium on day 2 after infarction in all 46 animals. Contrast material–enhanced MR images showed large but identical infarction size in 11 control and 11 nicorandil rats. Only these 22 rats underwent repeat MR imaging at 8 weeks after infarction. The following variables were measured: LV volumes, ejection fraction, mass, wall thickness, and infarction size. Student t test and analysis of variance for repeated measurements were used for statistical analysis.

RESULTS: The size of the necrotic region on mesoporphyrin-enhanced MR images was 39% ± 3 of the size of the left ventricle in the control group and 41% ± 2 in the nicorandil group (difference not significant, unpaired Student t test). Pretreatment with nicorandil for 6 days before imaging did not reduce LV dilation or improve function compared with those in control animals with identical infarction size. Eight weeks after infarction, control animals showed deterioration in LV function, wall thinning, and gradient in regional dysfunction (analysis of variance test). Nicorandil produced significant salutary effects on LV ejection fraction (37% ± 3 in the nicorandil group vs 24% ± 3 in the control group), end-diastolic volume (0.53 mL ± 0.03 vs 0.65 mL ± 0.04), end-systolic volume (0.36 mL ± 0.03 vs 0.49 mL ± 0.05), LV wall thickening in remote noninfarcted myocardium (28% ± 2 vs 19% ± 1), and a rim of infarction (16% ± 2 vs 8% ± 1) (P < .05 for all parameters). The increase in LV mass was reduced in the nicorandil group (0.73 g ± 0.03) compared with that in the control group (0.89 g ± 0.04) (P < .05).

CONCLUSION: In animals studied longitudinally, MR imaging demonstrated the deleterious changes in LV geometry and function in the period after infarction and the salutary effects of medical therapy.

© RSNA, 2002

Index terms: Animals • Heart, experimental studies, 511.12143 • Heart, MR, 511.121411, 511.121416, 511.12143 • Myocardium, infarction, 511.771 • Myocardium, ischemia, 511.1939 • Myocardium, MR, 511.121411, 511.121416, 511.12143


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Chronic progressive left ventricular (LV) dysfunction is a major sequela of large acute myocardial infarction. Myocardial infarction promotes acute and chronic transformation of both infarcted and noninfarcted regions, which leads to global LV dilation, which is referred to as "ventricular remodeling" (1–3). Pharmacologic therapies, such as angiotensin-converting enzyme inhibitors and ß-blockers, have been used to improve cardiac function and to decrease subsequent LV remodeling (4). Findings in a recent study demonstrated that nicorandil preserves microvascular integrity and myocardial viability in patients with reperfused infarction (5). Although the beneficial effects of intravenous infusion of nicorandil on acute infarction size and LV function are well documented (5–7), the short- and long-term effects of pretreatment with orally administered nicorandil on LV geometry and function after infarction have not been demonstrated at magnetic resonance (MR) imaging, to our knowledge. Nicorandil has been marketed since 1984 in Japan and later in 24 European and Asian countries but not in the United States. Currently, it is used for the prevention and long-term treatment of angina pectoris. According to United Kingdom guidelines, the recommended initial oral dose of nicorandil is 10 mg twice daily upgraded to as much as 30 mg twice daily. Different strategies of therapy have been used to determine the salutary effects of nicorandil in patients with ischemic heart disease. Nicorandil has been used in patients before, during, and after pharmacologic and surgical interventions (5–9).

The low interobserver variability and the high interstudy reproducibility of MR imaging for quantifying LV volume, wall thickening, and mass make it an attractive noninvasive imaging technique for follow-up studies in patients with ischemic coronary artery disease and LV remodeling after infarction (10–12). Furthermore, contrast material–enhanced MR imaging has been shown to be accurate for measuring acute and chronic infarction size and for predicting chronic myocardial contractile dysfunction in patients and experimental animals (13–18).

In the current study, a necrosis-specific MR contrast medium was used to determine the size of acute myocardial infarction. Marchal et al (16) found that this agent accumulates in necrotic myocardium and provides prolonged (~24 hours) delineation of infarction. Findings in several subsequent studies have confirmed that this agent provides an accurate quantification of necrotic myocardium (17,18). An established rat model of coronary occlusion or reperfusion to produce LV remodeling (19) was used in the current study. In this model, the process of LV remodeling starts in the 1st day after infarction (20). The purposes of this longitudinal MR study were (a) to perform MR imaging on day 2 and at 8 weeks after infarction for defining the infarction size and for monitoring the progression of LV remodeling and (b) to evaluate the effect of pretreatment with nicorandil on acute and chronic LV remodeling and function.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Experimental Protocol
All experimental procedures received approval from the institutional committee on animal research and were performed in accordance with the National Institutes of Health guidelines for care and use of laboratory animals. Commercially obtained female Sprague Dawley rats (Simonsen Laboratories, Gilroy, Calif) (n = 46; age range, 10–12 weeks; body weight range, 230–245 g) were housed in our animal facility. All animals were allowed free access to food and water (with or without the potassium channel opener, nicorandil (Chugai Pharmaceutical, Tokyo, Japan). The room was controlled for temperature and humidity and had a 12-hour light-dark cycle.

The most important criterion in this experimental protocol was the use of animals with large but identical infarction size (~40% of LV volume) in control and nicorandil groups (a) to eliminate the effect of infarction size on the magnitude of LV remodeling (20), (b) to eliminate the effect of nicorandil on the size of acute myocardial infarction (21), and (c) to determine the effect of pretreatment with nicorandil on LV function and anatomy. The model of large infarction in rats, as used in the present study, has been used previously in the discovery of the effect of the angiotensin-converting enzyme inhibitor, captopril, on LV remodeling (22,23). Currently, this is the therapy of choice for preventing LV remodeling in patients with coronary artery disease (24). Furthermore, pretreatment with nicorandil was not intended as an intervention for patients with acute infarction but rather potentially for patients with chronic coronary artery disease who undergo coronary intervention or cardiac surgery. The animals were randomly assigned to two groups.

Group 1, nicorandil rats (n = 21).—Twenty-one rats received nicorandil in drinking water 4 days before coronary artery occlusion. The average volume of water ingested was 10 mL per 100 g of body weight per day; this finding was in agreement with those in our previous experiments in rats (25). On day 4 after treatment, the rats were subjected to 60 minutes of coronary artery occlusion followed by reperfusion to produce transmural infarction and LV dilation (20,26,27). On day 6 of treatment (2 days after coronary occlusion or reperfusion), the size of the infarction was determined in all 21 rats with MR imaging with the necrosis-specific MR contrast medium mesoporphyrin (Gadophyrin II; Schering, Berlin, Germany). Eleven of the 21 rats showed large infarction and met the size criteria of this study for large infarction (~40% of LV volume). The 11 rats with large infarction were the only rats that were used in the current study, and nicorandil treatment continued with them for 8 weeks. The other 10 rats were eliminated from this study because the infarction was small (6%–25% of LV volume). Findings at postmortem histochemical examination supported the presence of small infarction seen at MR imaging in the 10 rats.

Group 2, control rats (n = 25).—The rats in the control group received only tap water before and after occlusion of the coronary artery. On day 4, all rats in this group were also subjected to 60 minutes of coronary artery occlusion followed by reperfusion. On day 6, the size of the infarction was determined in all 25 rats by using mesoporphyrin. Eleven of the 25 rats showed large infarction (~40% of LV volume). The 11 rats with large but matched infarction size served as controls for the rest of the study. The other 14 rats were excluded from this study for the same reason (ie, small infarction, 10%–30% of LV volume). Findings at postmortem histochemical examination supported the presence of small infarctions seen at MR imaging in the 14 rats. Similar to findings in the current study, Pfeffer et al found large myocardial infarction in 46.7% of the rats subjected to coronary occlusion (23). The percentage of the animals with large infarction in the current study is in agreement with that in the Pfeffer et al study (23).

It should be emphasized that the number of animals per group (n = 11) was dictated by the results of contrast-enhanced MR imaging on day 2 after infarction. This number of animals per group is sufficient to allow determination of the requisite outcomes with the desired power. For example, the power of 80% requires a sample size of nine to produce a P value of less than .05 (28).

Orally administered nicorandil is rapidly absorbed with peak plasma concentration occurring 30–60 minutes after a single dose. During repeated oral doses of 20 mg twice daily, a steady-state plasma concentration of 250–300 µg/L occurs within 4 days of the first dose in humans (9). For this reason, the rats were treated for 4 days before infarction in the current study. In the blood, nicorandil diffuses rapidly from the intravascular space into the extracellular space. Because it has a low molecular weight of 211, it may enter into the ischemic region by means of diffusion or convection. At the myocardial level, nicorandil is preferentially distributed into mitochondria (29).

MR Contrast Medium
Mesoporphyrin is a gadolinium porphyrin chelate. It provides persistent enhancement (>24 hours) and a long imaging window of infarcted myocardium that can be used as a landmark for measurements of regional wall thickening (17,18). The T1 and T2 relaxivities of mesoporphyrin are relatively higher (8.9 and 12 L · mmol-1 · sec-1, respectively) than those of gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ; 3.7 and 5.6 L · mmol-1 · sec-1, respectively). The molecular weight of this agent is 1,697. This agent has relatively high affinity (50%–70%) for binding plasma proteins. Mesoporphyrin (0.05 mmol/kg) was administered intravenously 12 hours before MR imaging to be accumulated in necrotic myocardium (16). At this stage, this MR contrast agent is not approved for clinical use.

MR Imaging
Copper needles were placed into a forelimb and the abdomen of each rat and connected to a patient electrocardiographic monitor (Accusyn-6L; Advanced Medical Research, Milford, Conn) to provide an R wave signal for triggering of the MR pulse sequence, R-R intervals for calculation of the end-systolic phase, and heart rate (30). The animals were placed inside a 5.5-cm-diameter bridge imaging coil. Electrocardiographically gated MR images were acquired at 85.6 MHz with a 2.0-T imager (Omega CSI; Bruker Instruments, Fremont, Calif). MR images were acquired on day 2 and at 8 weeks after infarction (N.W., G.K.L., M.S., M.F.W.). The respiratory rate was constant during MR imaging (60 strokes per minute). With T1-weighted spin-echo MR imaging (repetition time, two R-R intervals; echo time, 12 msec; section thickness, 2 mm; four signals acquired; field of view, 50 x 50 mm; raw data matrix, 256 x 128 zero filled to 256 x 256; pixel dimensions, 0.195 x 0.195 mm; acquisition time, 2.5 minutes [depending on heart rate]), multisection short-axis views were acquired to encompass the entire heart at end diastole and at end systole. End-diastolic images were acquired at the peak of the QRS wave, and end-systolic images were acquired at 45% of the R-R interval (18).

Postmortem Evaluation
After completion of MR imaging, the animals were euthanized by injecting 200 mg/kg of pentobarbital. Then, the heart was excised, and the left ventricle was separated and weighed. The left ventricle was transversely cut into 2-mm-thick sections that corresponded to the MR images. The sections were imaged with a flatbed imager (Silverscan IV; LaCie, Hillsboro, Ore). The methods for staining and measuring of acute and chronic infarction and measuring of myocardial water content have been described previously (18,30) (N.W., M.S.).

Image Analysis
Software (Image, version 1.59; National Institutes of Health, Bethesda, Md) was used to measure LV mass, LV chamber volumes during systole and diastole, regional signal intensity, and the size of the infarction on MR images and at postmortem examination. Two observers (N.W., M.S.) measured the signal intensity and extent of the mesoporphyrin-enhanced region. Double oblique short-axis views were used in the measurement of LV wall thickness. By delineating endocardial and epicardial contours on end-diastolic and end-systolic images and adding them together, LV volumes and masses were determined (10–12). Absolute wall thickness and percentage thickening on day 2 and at 8 weeks after infarction were determined on three contiguous midventricular sections (M.S., G.A.K.). Regional spoke lengths were obtained from regions that contained no papillary muscles. Spoke lengths at end systole (ES) and end diastole (ED) were acquired, and the percentage of wall thickening (WT) was calculated with the following equation: WT = (WTES - WTED) x 100/WTED. Measurements of wall thickness were obtained from the infarcted region, rim of the infarcted region, and normal remote myocardium (18,21).

Statistical Analysis
Data are expressed as the mean plus or minus standard error of the mean. The paired and unpaired Student t tests were used to compare normally distributed variables in the group and between control and nicorandil animals. The significance of differences in sizes of LV volume and wall thickness were determined by means of analysis of variance for repeated measurements. If the analysis showed an overall P value of less than .05, the Scheffé F test was implemented to determine the difference between measurements on day 2 and at 8 weeks after infarction (31). Linear regression analysis {kappa} values were used to determine interobserver correlation coefficients and agreement coefficients between the observers (12,28). Differences with a P value of less than .05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Contrast-enhanced MR Imaging
Short-axis mesoporphyrin-enhanced MR images of the entire heart (five to six sections per heart) were successfully obtained in all rats on day 2 after infarction. The necrotic tissue after coronary artery occlusion or reperfusion was noninvasively characterized with mesoporphyrin. The infarcted region, which appeared as a homogeneously bright region compared with remote noninfarcted myocardium, was located in the anterolateral wall of the left ventricle (Fig 1). The signal intensity ratio between the infarcted myocardium and the remote noninfarcted myocardium was 1.65 ± 0.05 (mean ± standard error of the mean). The size of the enhanced necrotic region varied widely from animal to animal, but such a large variability has been previously reported in rats (23). Of the 46 rats, 22 showed almost identical infarction size. The infarction size in the control animals was 39% ± 3 of LV volume and 41% ± 2 of LV volume in nicorandil animals (difference not significant). Findings with triphenyltetrazolium chloride, or TTC, staining at postmortem examination confirmed the small size of the infarction in the 24 rats. The percentage of animals with large infarctions was 44% in the control group and 52% in the nicorandil group. This percentage of large infarctions is in agreement with that in a previous study of rats (23). Pfeffer et al found large infarctions (~40% of LV volume) in 47% of the rats subjected to ischemia (23).



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  		Figure 1. Representative multisection mesoporphyrin-enhanced short-axis MR images (300/12 [repetition time msec/echo time msec]) during (top row) end diastole and (bottom row) end systole in a control animal. The sharply delineated areas shown during diastole and systole represent infarcted myocardium (arrows). These images were acquired on day 2 at 12 hours after administration of 0.05 mmol/kg of mesoporphyrin.

 
Similarity in infarction size permitted determination of the acute and chronic effects of nicorandil pretreatment on LV geometry and function in the same set of animals. Eight weeks after infarction, MR and postmortem infarction sizes were 41% of LV volume ± 3 in control rates and 42% of LV volume ± 3 in nicorandil rats (difference not significant, analysis of variance text). Excellent agreement was found between MR imaging and postmortem infarction sizes (r = 0.98, P = .001).

Hemodynamic Parameters
Table 1 displays the hemodynamic parameters on day 2 and at 8 weeks after infarction for control and nicorandil rats. In the acute phase (on day 2 after infarction), there were no significant differences (unpaired Student t test) between control and nicorandil groups for the following parameters: LV volume, ejection fraction, or mass. Similarly, there were no significant differences between the two groups in the acute phase with respect to regional (remote normal, rim of the infarction, and core of infarction) wall thickness and systolic thickening (Table 2).


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  		TABLE 1. Noninvasive Measurement of Changes in LV Findings at MR Imaging

 

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  		TABLE 2. Regional Wall Thickening Seen at MR Imaging after Infarction

 
Figures 2 and 3 display the differences in end-diastolic and end-systolic volumes between control and nicorandil rats in the chronic phase (at 8 weeks after infarction) at MR imaging. End-systolic LV volume (0.49 mL ± 0.05 in the control group vs 0.36 mL ± 0.03 in the nicorandil group, P < .05) and end-diastolic LV volume (0.65 mL ± 0.04 in the control group vs 0.53 mL ± 0.03 in the nicorandil group, P < .05) were significantly smaller in nicorandil animals (Table 1). In the chronic phase, the reductions in end-systolic and end-diastolic LV volumes were associated with significant (P < .05) improvement in the ejection fraction (37% ± 3 in nicorandil rats vs 24% ± 3 in control rats, Table 1).



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  		Figure 2. Representative short-axis functional MR images (300/12) during (top row) end diastole and (bottom row) end systole in a control animal. LV enlargement and global (remodeling) and regional wall thinning (arrows = site of infarction) are pronounced at 8 weeks after infarction. Note the difference between findings on day 2 (Fig 1) and at 8 weeks after infarction. EDV = end-diastolic LV volume, ESV = end-systolic LV volume.

 


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  		Figure 3. Representative functional short-axis MR images (300/12) during (top row) end diastole and (bottom row) end systole in a nicorandil animal. Arrows show the extent of infarction at 8 weeks after coronary occlusion or reperfusion. Note the differences in LV volumes, particularly end-systolic LV volume (ESV), between this nicorandil rat and the control rat (Fig 2). EDV = end-diastolic LV volume.

 
There was a significant decrease in heart rate in both groups over the course of 8 weeks. The decrease in heart rate cannot be attributed to nicorandil therapy because both groups showed a decline in heart rate (from 283 heartbeats per minute ± 15 to 233 heartbeats per minute ± 10 in the control group and from 256 heartbeats per minute ± 5 to 221 heartbeats per minute ± 10 in the nicorandil group, differences not significant). There was no significant difference in heart rate between the two groups on day 2 or at 8 weeks.

Wall Thickening and Myocardial Mass
At day 2 after infarction, the LV wall thicknesses in the remote noninfarcted myocardium, rim of infarction, and core of infarction were similar in both experimental groups; these findings suggest that nicorandil pretreatment had no protective preconditioning effect on wall thickness. At 8 weeks after infarction, functional MR images showed deterioration in LV function, LV dilation, and the gradient in regional wall thickening compared with findings on day 2 after infarction in the control group (compare Figs 1, 2).

At 8 weeks after infarction, however, the major morphologic change seen at MR imaging was LV wall thinning in the control group (Fig 2). In control rats, diastolic and systolic wall thickness in remote noninfarcted and infarcted myocardium were significantly (P < .05) decreased compared with findings on day 2 after infarction (Table 2). On MR images, the rim of the infarcted region appeared hypertrophied due to the wall thinning in the adjacent regions, namely remote noninfarcted and infarcted myocardium. In the rim, there was no change in absolute wall thickness during systole and diastole over the course of time. However, the percentage changes in wall thickening in the remote noninfarcted myocardium and rim of infarction were significantly reduced at 8 weeks after infarction, and the infarcted region showed persistent dysfunction (Table 2).

In nicorandil rats, there were no significant changes in diastolic and systolic wall thicknesses between day 2 and 8 weeks after infarction. Unlike in control rats, nicorandil prevented LV wall thinning in the remote noninfarcted myocardium and rim of infarction in the treated rats (Fig 3, Table 2). Furthermore, there was no significant change in the percentage of systolic wall thickening of the remote noninfarcted myocardium and rim of the infarction over the course of 8 weeks (Table 2); these findings suggest that nicorandil preserved LV wall thickening.

On day 2 after infarction, there was no significant difference in LV mass between control and nicorandil animals at MR imaging (Table 1). At 8 weeks after infarction, LV mass measured with MR imaging was significantly greater in control animals (0.89 g ± 0.04) compared with nicorandil animals (0.73 g ± 0.03) (P < .05). There was no significant difference in LV mass measured with MR imaging and at autopsy (0.91 g ± 0.03 in control vs 0.75 g ± 0.02 in treated animals, difference not significant). Interestingly, the increase in LV mass in the control group was associated with global LV wall thinning, a sign of heart failure after large infarction. The increase in LV mass was not attributed to differences in (a) body weight (289 g ± 12 in the control group vs 276 g ± 6 in the nicorandil group, difference not significant) and (b) myocardial water content (ratio of wet weight mass to dry weight mass, 4.61 ± 0.09 in the control group vs 4.70 ± 0.16 in the nicorandil group; difference not significant). The ratio of LV mass to body weight (as an index) was 2.52 mg/g ± 0.1 in the control group and 3.01 mg/g ± 0.13 in the nicorandil group (P < .05). The interobserver variation {kappa} values were 0.93 for infarction sizes (N.W., M.S.), 0.91 for regional wall thicknesses (M.S., G.A.K.), and 0.91 for LV volumes (M.S., G.A.K.). We did not determine interobserver variability for parameters for each group separately because the same observers measured identical parameters in both groups.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Major findings in our study are the following:

1. MR imaging can be used as a noninvasive method for sequential (acute and chronic) assessment of myocardial infarction, geometry (LV remodeling and mass), and function (ejection fraction and wall thickening) after infarction.

2. Findings at MR imaging demonstrated the salutary effects of a pharmacologic intervention (nicorandil) on LV remodeling.

3. Nicorandil attenuated LV remodeling and improved global LV function at 8 weeks, but not on day 2, after infarction, independent of initial infarction size.

MR Imaging for Measurement of LV Mass and Infarction Size
The first relevant sign of LV remodeling after infarction is the increase in LV mass (32). In the current study, the control group showed greater increase in LV mass (0.18 g ± 0.03) than did the treated group (0.03 g ± 0.03) (P < .05) on MR images. There was no significant difference in LV mass measured with MR imaging and at autopsy at 8 weeks after infarction. The increase in LV mass was associated with global LV wall thinning, a sign of a failing heart after large infarction. In contrast to echocardiography, MR imaging measurements of LV volume and mass can be performed by applying the Simpson rule to short-axis images without the need for geometric assumption (10–12,33). Reproducibility and interstudy variability for measurements of LV parameters with MR imaging have been found to be less than 5%–10% for end-diastolic volume, ejection fraction, and mass in healthy subjects and in patients with dilated cardiomyopathy and hypertrophy (12).

Findings at mesoporphyrin-enhanced MR imaging permitted the noninvasive study of the short-term effect of orally administered nicorandil independent of the infarction size and the follow up of the effect of this therapy in the same animals. Contrast-enhanced MR imaging provides a systematic and high-resolution method for determining function in nontransmural infarction and the periinfarction zone (17,18,26). Persistent enhancement of acutely infarcted myocardium with mesoporphyrin can also be used as a landmark for determining the extent of stunning or of hibernating myocardium adjacent to reperfused infarctions (18,26). Infarction sizes measured on mesoporphyrin-enhanced MR images obtained on day 2 and at 8 weeks after infarction were identical (analysis of variance); these findings suggest that mesoporphyrin-enhanced MR imaging may be useful for predicting LV remodeling. At this stage, the use of mesoporphyrin is limited to animal studies, and it is not approved for human use.

MR Imaging for LV Remodeling
Adaptive responses that occur after infarction are seen in LV volumes, in remote noninfarcted myocardium, and at the rim of infarction. Wall thinning was evident along the anterior and lateral infarcted walls in both control and treated animals. Results in control rats showed a gradient in contractile dysfunction, with the most severe dysfunction in the infarcted region and less dysfunction in the rim of infarction and remote noninfarcted myocardium at 8 weeks after infarction. Findings in MR tagging studies have demonstrated similar gradient dysfunction in humans (34,35), dogs (36), and sheep (37). Although the mechanism for severe dysfunction in the infarcted region is well understood, the mechanisms that underlie dysfunction in the rim of infarction (periinfarction zone) are not well defined. Possible mechanisms include changes in mechanical load that lead to cellular hypertrophy and dysfunction (37), reduced coronary reserve (38), increased systolic wall stress (39), and oxidative stress and inflammation (40).

The decrease in wall thickness of remote noninfarcted myocardium, however, is a clear sign of a failing heart. An increasing workload and mechanical tethering (41) in the compensating (42) remote noninfarcted myocardium have been suggested to cause wall thinning in remote noninfarcted myocardium. Impaired microvascular function of the remote noninfarcted myocardium that supplies an adjacent periinfarction zone may also cause a reduction in perfusion of this region (43).

Findings in previous studies have indicated that the effect of a given medical therapy can be examined with sequential MR imaging to evaluate changes in end-diastolic LV volume, end-systolic LV volume, ejection fraction, mass, and regional thickness and thickening (10,11,30). In the current study, MR images depicted the effect of a medical therapy on the typical structural (necrotic myocardium), geometric (LV volume and wall thickness), and functional (wall thickening and ejection fraction) changes associated with myocardial infarction. Almost all of these parameters serve as predictors of late LV remodeling (4). Furthermore, an indication for use of the potassium channel opener, nicorandil, in LV remodeling has been demonstrated in the current study with contrast-enhanced and functional MR imaging. More studies in larger animals are needed to confirm these findings.

Mechanisms Involved in the Salutary Actions of Nicorandil
Pretreatment with nicorandil appears not to precondition the heart during coronary occlusion or reperfusion. Thus, the acute effects of pretreatment with orally administered nicorandil (6 days before imaging) on LV geometry and function were not pronounced, possibly owing to the short duration of pretreatment, the low dose of nicorandil, or the presence of a large infarction (~40% of LV volume). In contrast, nicorandil treatment for 8 weeks after infarction resulted in significantly decreased LV volume and wall thinning compared with those in the control group. The resulting changes in LV volumes and ejection fractions resemble those shown after administration of the angiotensin II receptor antagonist, losartan potassium, and the angiotensin-converting enzyme inhibitor, ramipril, for 8 weeks after infarction (44). Contributions of opening the potassium–adenosine triphosphate channels, including reduced preload and afterload and reduced free radical formation and neutrophil-modulating properties, have been postulated after nicorandil therapy (45–47). Opening of the potassium channel with nicorandil helps suppress mitochondrial calcium overload and prevent increased cytosolic calcium during ischemia and reperfusion (37). Increased cytosolic calcium during ischemia and reperfusion impairs generation of adenosine triphosphate (9). Preservation of adenosine triphosphate and reduced passive and receptor-mediated passage of calcium across the sarcolemma are important mechanisms for maintaining calcium homeostasis in animals treated with nicorandil (48).

Practical application: MR imaging provides an effective technique for sequential assessment of LV remodeling and cardioprotective therapies. Mesoporphyrin-enhanced MR imaging is a sensitive technique for accurate measurement of acute infarction size, and it may be useful for predicting LV remodeling. Pretreatment with nicorandil is effective in attenuating LV remodeling in a large myocardial infarction model. It should be noted that our results refer to only the rat model described in this study.


   FOOTNOTES
 
Abbreviation: LV = left ventricular

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


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

  1. Garg R, Packer M, Pitt B, et al. Heart failure in the 1990s: evolution of a major public health problem in cardiovascular medicine. J Am Coll Cardiol 1993; 22(4 suppl A):3A-5A.
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