ORIGINAL ARTICLE 
Annals of Nuclear Medicine Vol. 13, No. 5. 337-346, 1999 

Limitations of spontaneous reperfusion and conventional medical therapy to afford myocardial protection through antecedent angina pectoris in acute myocardial infarction 

Akiyoshi HASHIMOTO, Tomoaki NAKATA, Takeru WAKABAYASHI, Satoshi YUDA, Mariko EGUCHI,
 Hisataka SASAO, Kazufumi TSUCHIHASHI and Kazuaki SHIMAMOTO 

Second Department of Internal Medicine (Cardiovascular Medicine),
 Sapporo Medical University School of Medicine 

Despite the cardioprotective effect of rapid coronary reperfusion, the effects of spontaneous recanalization on myocardial viability and metabolism are unknown. We studied whether preinfarction angina affords cardioprotection when spontaneous coronary reperfusion occurred in acute infarct patients. Myocardial tomographies with thallium and I-123-labeled-b-methyl-p-iodophenyl penta-decanoic acid (BMIPP) were performed in 27 acute myocardial infarct patients treated medically: 15 patients had preexisting angina before infarction (group A) and 12 did not (group B). Thallium and BMIPP abnormalities and regional function were quantified by a polar map and contrast ventriculography, respectively. There was no significant difference between thallium and BMIPP in the severity index in groups A and B (89 +- 97 vs. 85 +- 68, 97 +- 28 vs. 95 +-27, respectively), and no significant difference between the groups in the thallium or BMIPP severity index. The ratio of the thallium severity index to that of BMIPP and the regional wall-motion abnormality index were identical in groups A and B. Both patient groups were divided into 2 subgroups based on the presence or absence of spontaneous coronary reperfusion: subgroups A1 and A2, and subgroups B1 and B2, respectively. There were no significant differences among the 4 subgroups in severity indexes for both tracers, the thallium/BMIPP ratio, or the asynergy score. The BMIPP severity index correlated significantly with that of thallium in all subgroups, but no significant difference between the regression lines was found. It is therefore unlikely that spontaneous coronary recanalization affords beneficial effects through preservation of myocardial viability in an ischemia-related zone, suggesting that the cardioprotective effect of preinfarction angina is a limited phenomenon in patients undergoing rapid coronary reperfusion. 

Key words: fatty acid metabolism, pre-infarction angina, cardioprotection, spontaneous coronary recanalization 

INTRODUCTION 
As DEMONSTRATED in animal models,1-4 brief ischemia prior to more prolonged ischemia may have cardioprotective effects in humans. Such cardioprotective effects 

 Received May 10, 1999, revision accepted July 28, 1999.
 For reprint contact: Tomoaki Nakata, M.D., Ph.D., Assistant Professor of Medicine, Second Department of Internal Medicine (Cardiovascular Medicine). Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, JAPAN. E-mail: tnakata@sapmed.ac.jp
 
are suppression of infarct size, arrhythmias, and cardiac dysfunction, as well as augmentation of ischemic tolerance 5-15 but controversy still remains as to whether preexisting angina before acute myocardial infarction has an "ischemic preconditioning effect" in clinical settings. We recently demonstrated the cardioprotective effects of preinfarction angina in patients with acute myocardial infarction undergoing primary percutaneous transluminal coronary angioplasty by quantitatively assessing myocardial perfusion, fatty acid metabolism, and regional cardiac function. 15 The results also suggested that complete reperfusion is very important for the manifestation of cardioprotection afforded by preinfarction angina in clinical settings as well as in animal models. Another type of coronary reperfusion-spontaneous coronary reperfusion-has also been observed.17-21 It is, however, not clear whether preexisting ischemia affords beneficial effects in medically treated patients in this case. Little is also known about the effect of spontaneous coronary reperfusion and preinfarction angina on myocardial perfusion and fatty acid metabolism, postischemic cardiac function, and their correlates. Our previous studiesl5,22-24 and other clinical investigations25-30 have demonstrated that derangement of myocardial fatty acid metabolism reflects ischemia-related injury in viable and non-viable myocardium better than myocardial perfusion abnormality. Dysfunctioning but viable myocardium in an ischemia-related zone can therefore be precisely evaluated by correlating myocardial perfusion with fatty acid metabolism by means of quantitative tomographic imaging. This technique is useful for identifying the extent of salvaged myocardium as well as infarcted myocardium in an infarct-related risk area.15
 We studied patients who experienced spontaneous reperfusion after their first myocardial infarction to determine if preinfarction angina affected myocardial perfusion, ischemia-related metabolic impairment, or functional abnormality.
 
SUBJECTS AND METHODS 
Patient population
Twenty-seven patients, 24 men and 3 women with a mean age of 61 years (range 22 to 86 years) and admitted within 2 days after the onset of acute myocardial infarction, were recruited according to the following criteria: 1) it was the first acute myocardial infarction for each patient, 2) the onset of infarction was determined by typical clinical symptoms, signs, and electrocardiographic changes, 3) both myocardial perfusion and fatty acid metabolism imaging were performed within a 3-day interval within 3 weeks after the onset of infarction, 4) the presence or absence of antecedent angina pectoris within 7 days before acute myocardial infarction was determined, and 5) informed consent was obtained for the present protocol. Patients could be excluded on the basis of the following criteria but none was: 1) successful percutaneous transluminal coronary angioplasty (PTCA) or bypass grafting following acute myocardial infarction, 2) evidence of previous myocardial infarction or coronary revascularization, 3) a critical condition, such as cardiogenic shock or uncontrollable heart failure during admission, 4) the presence of complicating cardiac conditions such as valvular heart disease or cardiomyopathy, and 5) the presence of hormonal disturbances, renal failure, or malignancies. None of the patients had vasospasm-related angina or myocardial infarction documented during the clinical course observations.
 Based on the presence or absence of preinfarction angina, the 27 patients were divided into 2 groups: 15 patients with preinfarction angina (group A) and 12 without (group B) (Table 1). The definition of preinfarction angina in the present study was chest pain suggestive of angina pectoris lasting less than 30 minutes and documented within the 7 days before the onset of acute myocardial infarction. When the following diagnostic findings were documented, the diagnosis of acute myocardial infarction was established15,22,23; severe chest pain lasting for 3O minutes or more. ST-segment increase of > 2mm in 2 or more leads of the standard 12-lead electrocardiogram for more than 30 minutes, and a definite rise in serum creatine kinase levels in serial measurements during the first 2 days after the onset of infarction. In 4 patients in group A, coronary reperfusion with primary PTCA was tried but was not successful because of technical limitations due to complex lesions. Predischarge coronary angiography was performed in all patients to identify the infarct related coronary artery, its patency status, and other coronary lesions. Cardiac function analyses were performed by radionuclide ventriculography and contrast left ventriculography as pre-discharge tests. These study protocols conformed to the regulations of the hospital ethics committee.
Study protocol
 Single-photon emission computed tomography (SPECT) with thallium and iodinated beta-methyl-p-iodophenyl pentadecanoic acid (BMIPP) was performed under resting and overnight fasting conditions at mean intervals of 11 to 15 days after the onset of infarction (Table 1). Thallium, 111 MBq, and iodine-123-1abeled BMIPP, 111 MBq (Nihon MediPhysics, Osaka, Japan), were injected simultaneously. Thirty minutes later, tomographic data were acquired at 5-degree increments for 30 seconds per increment during a 180-degree rotation from the 45-degree left posterior oblique to the 45-degree right anterior oblique view by means of a gamma camera with a high-resolution collimator. Data were stored in a 64 x 64 word matrix nuclear medicine computer (Shimadzu SNC 5 100R, Tokyo, or GE 4000XC/T, Milwaukee, Wisconsin). Based on the results of cardiac phantom experiments for dual-energy SPECT imaging in our nuclear medicine laboratory, a 159 keV photopeak of 123I with a 20% window and a 75 keV photopeak of 201T1 with a 20% window were selected. 15,22.23 After reconstruction with a back-projection algorithm and a Shepp & Logan or Hanning and Ramp filter, circumferential profile analysis was performed on short-axis slices to create a polar map display for quantification of thallium and BMIPP abnormalities,15,23 Regional wall motion was quantified by contrast left ventriculography with mean onset-to-examination intervals of about 3 weeks (Table 1). No attenuation or cross-talk correction was performed.
Quantification of scintigraphic and cardiac function data
 Reduced myocardial uptakes of thallium and BMIPP were quantified by means of a polar map method as a severity index with the following formula15,23,31:
 Severity index = D count (normal count - abnormal count *)/Total points[60x(number of slices)]
The abnormality count (*) for thallium or BMIPP in 60 data points per short-axis slice was defined as that less than the mean count minus 2 standard deviations of normal files which were produced in 4 male and 4 female control subjects in our laboratory. The severity index therefore quantitatively indicates the extension and grade of thallium or BMIPP abnormality normalized to each heart size.
 Global left ventricular function was assessed by radionuclide ventriculography with an intravenous injection of technetium-99m labeled human serum albumin (740 MBq) at rest to calculate the left ventricular ejection fraction. The data were acquired in a multiple-gated mode of 500 cardiac cycles from a left anterior oblique view with a large-field-of-view gamma camera and a low energy, general-purpose parallel-hole collimator with a framing rate of 24 frames per cycle 15,22,23 Regional wall motion of the left ventricle was assessed by quantitative contrast left ventriculography with a modified centerline method.15,23 Briefly, cine-ventriculograms were from the right anterior oblique projection of 30 degrees on 35-mm cinefilm at 50 frames per second and end-diastolic and end-systolic silhouettes at sinus beats were manually traced by 2 experienced cardiologists blinded to clinical and scintigraphic data to superimpose the silhouettes by means of a modified centerline method assisted by a computer program (CAMAC 300, Goodman, Tokyo, Japan).23 Regional wall-motion abnormality was quantified as the index (SD/chord) of sigmaSD in areas showing an SD-chord below -1.5SD of a normal file derived from 50 control subjects in our laboratory.
Statistics
 Statistical values are shown as the mean value +- SD. The difference between 2 groups in mean values was determined by an unpaired t-test. To compare the mean values for 4 subgroups, one-way analysis of variance (ANOVA) was used and when a significant difference was revealed, the Bonferroni approach was used for individual comparisons. The prevalence of clinical parameters (Table 1) was analyzed by means of 2 x 2x2 tests. Correlations between the severity indexes of thallium and BMIPP were analyzed by linear regression analysis and the difference in regression lines was tested by analysis of covariance. A probability (p) value of less than 0.05 was considered significant. 
RESULTS 
Clinical characteristics and angiographic data
The clinical backgrounds and variables for the 27 patients in groups A and B are summarized in Table 1. There were no significant differences between the groups in age, gender, the prevalence of anterior infarction, intervals between the onset of infarction and examinations, medications or the incidence of coronary risk factors. There was no significant difference in peak serum creatine kinase levels or in the prevalence of anterior infarction, although higher enzyme levels and more frequent anterior infarction were more likely to occur in group B. Coronary angiography revealed no significant differences between groups A and B in coronary luminal narrowing in the infarct-related coronary arteries, the grade of TIMI coronary flow or the collateral grade (Table 2).
Perfusion and metabolic abnormalities and their correlations
Severity indexes for both thallium and BMIPP in group A showed a tendency to lower values than those in group B : thallium, 89 +- 97 vs. 126 +- 97 and BMIPP, 85 +- 68 vs. 130 +- 95, respectively (Fig. 1A), but the differences were not statistically significant. Furthermore, there was no significant difference between thallium and BMIPP in the severity index in the groups and there was no significant difference in the ratio of the thallium severity index to that of BMIPP (that is, perfusion-metabolism mismatch index) between groups A and B (0.91 +- O.62 vs. 1.06 +- O.66, respectively). Groups A and B were divided into 4 subgroups according to the presence or absence of spontaneous recanalization without a luminal narrowing of more than 90%: subgroups A1 and A2 and subgroups B1 and B2, respectively. The BMIPP severity index showed a significant positive correlation with that of thallium in all subgroups (Fig. 2). The regression lines in the 4 subgroups were comparable with the line of identity and there was no significant difference in the regression lines among the 4 groups, despite a slight upward shift in the line for subgroup A1.
 Figure 3 shows 2 patients with acute posterolateral infarction and preinfarction angina. One patient (Fig. 3A) who was treated medically and had spontaneous recanalization of the infarct-related artery showed nearly comparable abnormalities of perfusion and fatty acid uptake, that is, there was no dominant mismatch. The other patient (Fig. 3B), who was treated with coronary reperfusion therapy, is presented as an example of less marked thallium perfusion abnormality relative to that of BMIPP, indicating a perfusion-metabolism mismatch.
Cardiac function at convalescence
There was no significant difference between groups A and B in left ventricular ejection fraction: 48 +- 9 vs. 51 +- 5%, respectively (Fig. 4A). Regional wall-motion abnormality was also comparable in groups A and B: 110 +- 42 to 140 +- 81 SD/Chord, respectively (Fig. 4B).
Effects of collaterals on perfusion, fatty acid metabolism, and cardiac function
The 27 patients in groups A and B were divided into 3 subgroups based on the Rentrop collateral grades: no visible collaterals, grade 0; definite but not sufficient collaterals, grades 1 and 2; rich collaterals, grade 3. No significant differences were found among the groups in the peak creatine kinase level, severity indexes of thallium and BMIPP, the ratio of severity indexes, or regional wall-motion abnormality (Table 3). When 13 patients without spontaneous recanalization (Groups A2 and B2) were divided into 2 subgroups, that is, 8 patients with poor collaterals (Rentrop grade 0/1) and 5 with relatively rich collaterals (Rentrop grade 2/3) based upon collateral development; there was no significant difference in the severity indexes of thallium and BMIPP and the ratio: 116 +- 120 vs. 128 +- 88, 115 +- 68 vs. 136 +- 94, and 1.0 +- 0.6 vs. 0.9 +- 0.5, respectively.
Effects of spontaneous recanalization on perfusion, fatty acid metabolism, and cardiac function
 Table 4 compares collaterals, severity indexes of thallium and BMIPP, the ratio of severity indexes, and regional wall-motion abnormality among the 4 subgroups. Group B2 had a greater tendency to have rich collaterals and Group A1 had lower severity indexes for thallium and BMIPP, a lower ratio of indexes, and smaller regional wall-motion abnormality than those in the other 3 subgroups, but these values did not reach statistical significance. 

DISCUSSION 
Correlations of myocardial perfusion, fatty acid metabolism, and left ventricular function quantitatively assessed in the present study demonstrated that preinfarction angina might have limitations in affording the cardioprotective effects (preserved myocardial viability relative to metabolic derangement and cardiac function) in acute myocardial infarct patients if rapid coronary recanalization was not achieved, even if the infarct-related coronary artery was recanalized spontaneously.
Preinfarction angina and coronary reperfusion for cardioprotection
In experimental settings, timely and complete coronary reperfusion is performed to induce ischemic preconditioning. This suggests that reperfusion after coronary occlusion is necessary to limit infarct size. We have recently demonstrated the beneficial effects of preinfarction angina on preserving myocardial viability and on functional recovery in patients undergoing primary coronary 
angioplasty.15 Our previous study15 showed significant correlations between severity indexes of thallium and BMIPP in 2 groups with and without preinfarction angina both of which underwent acute coronary reperfusion as seen in Figure 2, but what is more important in the analysis is that the slope of the regression line of the preinfarction angina group significantly (p < 0.05) shifted downwards compared to that in the non-preinfarction angina group, indicating less thallium abnormality relative to BMIPP abnormality (that is, more preserved myocardial viability relative to a metabolically damaged infarct-related zone).15 On the other hand, myocardial perfusion-fatty acid metabolism correlation assessed by thallium and BMIPP tomographies did not demonstrate less thallium perfusion abnormality relative to metabolic derangement in the present study (Fig. 2, Table 4), that is, the perfusion-metabolism mismatch observed in patients undergoing rapid coronary reperfusion therapy15 was not seen in patients who received medical treatment and had spontaneously recanalized infarct-related coronary artery (Figs. 2 and 3A). The present and our previous results15 therefore strongly suggest that rapid reperfusion is essential but spontaneous reperfusion is not sufficient to afford cardioprotection in patients with preinfarction angina. The slight, but not significant, upward shift of the regression line between severity indexes of thallium and BMIPP in Group A1 (Fig. 2) may originate in thallium attenuation artifacts in inferior regions.16 
Spontaneous recanalization, myocardial viability and cardiac function
The prevalence of spontaneous recanalization of infarct-related coronary arteries varies from 20% to 59%.17-21 It occurs gradually over time from several hours to several months and, ultimately, spontaneous recanalization is observed in more than half of all patients, suggesting a delayed process of this phenomenon.17 The timing and mechanism of spontaneous recanalization are not fully understood. There may be several factors involved for example, endogenous activities of thrombolysis and coagulability, such as platelet activity, fibrinogen, tissue plasminogen activator and its inhibitor 1,33 atherosclerotic conditions, and coronary vasomotor tone in the coronary artery. The beneficial effects of a patent infarct-related coronary artery are better prognosis, better cardiac function and ventricular remodeling suppression. In our study, however, the patency status of the infarct-related vessel at the acute stage, the timing of spontaneous reperfusion, and the coronary flow grade soon after that were not fully determined. If autothrombolysis occurs immediately after the onset of infarction so that the myocardium in an infarct-related zone could be sufficiently reperfused in patients with preinfarction angina, spontaneous recanalization may have more beneficial effects. This possibility is suggested by the findings indicating that Group A1 who had preinfraction angina and spontaneous recanalization showed a lower tendency to a thallium-BMIPP severity index ratio compared to other groups (Table 4), and that rapid spontaneous coronary reperfusion has been demonstrated in some patients with acute myocardial infarction. Although it is well known that collaterals show cardioprotective effects when antegrade coronary flow is limited, a preconditioning phenomenon is observed not only in poor collateral animals, such as the rat and rabbit, but also in a rich collateral animal, the dog. In the present study, collateral development is unlikely to have any definite effect on the thallium-BMIPP correlation. Our previous results 15 and these findings suggest that collateral per se is not an influential factor in terms of preconditioning effect manifestation. It is still not clear whether preinfarction angina closer to the onset of infarction 32 is more effective, even if coronary reperfusion occurs in a delayed fashion caused by spontaneous reperfusion. 
Rationale for myocardial fatty acid metabolism assessment
More extended and profound impairment of myocardial fatty acid metabolism relative to perfusion abnormality has been demonstrated by thallium and BMIPP imagings in patients with angina pectoris, vasospastic angina, or acute myocardial infarction.15,22-30 Myocardium which survived acute myocardial infarction and coronary reperfusion has a larger perfusion-fatty acid metabolism mismatch, as shown in Figure 3B. Myocardial BMIPP uptake is impaired in damaged but viable myocardium when the intracellular ATP level is reduced,34 as seen in infarcted myocardium. BMIPP uptake is therefore a sensitive indicator of ischemia-related myocardial injury in an ischemia-related coronary territory. Therefore, infarct size normalized to its risk (infarct-related) zone size can be assessed quantitatively by a perfusion-metabolism correlation with thallium and BMIPP imaging. 15,22,23 The quantification of the infarct-risk ratio is essential for assessing the cardioprotective effect of any interventional therapy.3,4,35,36 Except for the studies of Ottani 10 (who, however, used an angiogram from one direction for evaluating the area at risk) and of our group,15,22,23 this kind of infarct sizing relative to the risk zone size has not been performed in other clinical investigations on preinfarction angina and cardioprotection. 9,11-14,32 SPECT imaging with thallium and BMIPP can also contribute to the precise quantifying of myocyte viability and metabolic derangement. The comparable values for thallium and BMIPP abnormalities did not indicate any definite mismatch between perfusion and metabolism, and myocardium survival is less likely in an infarct-related zone. As previously demonstrated,15,22,23 the extent of perfusion metabolism mismatch relates positively to functional improvement in acute infarct patients treated with primary coronary angioplasty. Therefore, lack of a dominant perfusion-metabolism mismatch suggests lower probability of better preservation of viability and functional improvement in the ischemia-related area despite the spontaneous coronary reperfusion achieved.

STUDY LIMITATIONS 
Variations in the spontaneous coronary reperfusion process,17-21 the infarct-related risk size, location of infarction, residual coronary lesions and myocardial viability might affect the possible cardioprotective effects of preinfarction angina in clinical settings, indicating that the present results are inconclusive and thereby a large patient population is necessary, In particular, a clinical study of many patients with rapid to delayed processes of spontaneous coronary reperfusion documented angiographically can more clearly reveal the beneficial or limited effects of preinfraction angina in acute myocardial infraction. The present and our previous studies,15 however, stressed the importance of precise identification of infarct size and risk zone size as well as difficulties in assessing the effect of preinfarction angina in clinical situations. In addition to metabolic (BMIPP) imaging, more precise clinical tools are desired to assess myocardial viability and ischemic zone size in clinical practice and to evaluate collateral flow grade more easily in an emergency situation. The present study aimed to evaluate the effect of antecedent angina, which is a clinically identifiable marker for transient ischemia, but not myocardial ischemia per se, as done in earlier studies 9,11-14,32 It is still unclear whether transient silent ischemia prior to acute myocardial infarction is cardioprotective as well as antecedent angina, because it is clinically very difficult to identify a silent and brief episode of myocardial ischemia prior to the onset of acute myocardial infarction. A longer follow-up interval may be necessary for ultimate assessment of myocardial viability and functional status, as slow reperfusion may delay the manifestation of cardioprotective effects of preinfarction angina and spontaneous coronary reperfusion compared to rapid coronary reperfusion. 

CONCLUSIONS 
Perfusion-metabolism correlation assessed by thallium and BMIPP imagings shows neither a definite mismatched appearance nor better preservation of myocardial perfusion or function in medically treated patients with preinfarction angina even when the infarct-related coronary artery is spontaneously recanalized. Spontaneous coronary reperfusion due to autothrombolysis may be insufficient for manifesting the cardioprotective effects of preinfarction angina in acute myocardial infarction. 

ACKNOWLEDGMENTS 
We are greatly indebted to the staff of the Division of Nuclear Medicine, Sapporo Medical University Hospital, and K. Ichikawa, RT, Hokkaido Circulation Hospital, for their technical cooperation. We are also grateful to Dr. Naomi M. Anderson, Calgary for editorial assistance. 

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