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Background: Recent studies suggest that granulocyte colony-stimulating factor (G-CSF) may be beneficial in the treatment of myocardial infarction (MI). However, the effects of G-CSF on MI are still controversial and the molecular mechanism of G-CSF treatment for repair of the infarcted heart is not fully understood., Methods: Mice were divided into three groups: Control, MI and MI treated with G-CSF. Four weeks after MI, we examined cardiac function by Doppler echocardiography and measured non-infarcted myocardial mRNA expression by northern blot analysis., Results: Cardiac function decreased significantly in the MI groups compared with the sham-operated groups. Additionally, the ratios of E wave to A wave peak velocity (E/A) in the MI groups were higher than in the control group. E/A in G-CSF MI mice was significantly lower than in control MI mice (p<0.01). Matrix metalloproteinase-2 (MMP-2) mRNA expression was significantly increased in the MI groups compared with the control group (p<0.01). Furthermore, mRNA expression in the G-CSF MI group was significantly higher than in the Control MI group (p<0.05)., Conclusions: G-CSF can prevent the LV remodeling process after MI that accompanies progressive cardiac dysfunction. One of the mechanisms of G-CSF treatment for cardiac remodeling after MI may be overexpression of MMP-2 in non-infarcted myocardium.

Objective: To examine the effects of eplerenone, a selective aldosterone blocker, on cardiac function after myocardial infarction (MI) and myocardial remodelling related transcriptional factors and mRNA expression in non-infarcted myocardium., Methods: MI was induced by ligation of the coronary artery in Wistar rats. Rats were randomly assigned to a vehicle treated group or an eplerenone treated group (100 mg/kg/day)., Results: At four weeks after MI, left ventricular (LV) end diastolic pressure, LV weight, and LV end diastolic dimension were increased in MI rats. Eplerenone significantly reduced the increase in LV end diastolic pressure, LV weight, and LV end diastolic dimension. In the MI rats the decreased ejection fraction indicated systolic dysfunction and the increased E wave to A wave ratio and E deceleration rate indicated diastolic dysfunction. Eplerenone significantly attenuated this systolic and diastolic dysfunction. Myocardial interstitial fibrosis, transcriptional activities of activator protein 1 and nuclear factor kappaB, and mRNA expression of monocyte chemoattractant protein 1, plasminogen activator inhibitor 1, atrial natriuretic peptide, brain natriuretic peptide, and collagen types I and III were significantly increased at four weeks after MI. Eplerenone significantly attenuated interstitial fibrosis and suppressed transcriptional activity and mRNA expression of these genes., Conclusions: When administered after MI, eplerenone prevents cardiac remodelling accompanied by systolic and diastolic dysfunction and inhibits abnormal myocardial transcriptional activities and gene expression.

Osteopontin has been reported to have an important role in cardiac fibrosis. However, little is known about the effects of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin type 1 receptor blockers (ARB) on osteopontin expression in infarcted myocardium. The purpose of this study was to elucidate the effects of an ACEI (perindpril) and an ARB (candesartan cilexitil) on cardiac function as assessed by Doppler echocardiography and cardiac osteopontin expression associated with cardiac remodeling in myocardial infarcted rats. ACEI or ARB was administered after myocardial infarction (MI). At 4 weeks after MI, cardiac function, and mRNAs in non-infarcted myocardium were analyzed. ACEI and ARB equally prevented left ventricular dilatation, reduction of ejection fraction, and the increase in E/A wave velocity ratio and the rate of E wave deceleration by MI. ACEI and ARB significantly suppressed increased mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, osteopontin, and collagen I and III in the non-infarcted ventricle at 4 weeks. Immunohistochemically stained osteopontin was increased in interstitial fibrosis of non-infarcted myocardium. Both ACEI and ARB significantly prevented cardiac fibrosis and osteopontin expression. In conclusion, angiotensin blockade inhibits osteopontin expression in non-infarcted myocardium and prevents cardiac remodeling after MI.

Objective: Vascular endothelial growth factor (VEGF) plays an important role in inducing angiogenesis. Mesenchymal stem cells (MSCs) may have potential for differentiation to several types of cells, including myocytes. We hypothesized that transplantation of VEGF-expressing MSCs could effectively treat acute myocardial infarction (MI) by providing enhanced cardioprotection, followed by angiogenic effects in salvaging ischemic myocardium., Methods and Results: The human VEGF165 gene was transfected to cultured MSCs of Lewis rats using an adenoviral vector. Six million VEGF-transfected and LacZ-transfected MSCs (VEGF group), LacZ-transfected MSCs (control group), or serum-free medium only (medium group) were injected into syngeneic rat hearts 1 hour after left coronary artery occlusion. At 1 week after MI, MSCs were detected by X-gal staining in infarcted region. High expression of VEGF was immunostained in the VEGF group. At 28 days after MI, infarct size, left ventricular dimensions, ejection fraction, E wave/A wave ratio and capillary density of the infarcted region were most improved in the VEGF group, compared with the medium group. Immunohistochemically, alpha-smooth muscle actin-positive cells were most increased in the VEGF group., Conclusions: This combined strategy of cell transplantation with gene therapy could be a useful therapy for the treatment of acute MI.

Background: Several studies have demonstrated the benefit of the patency of infarct-related artery (IRA) in acute myocardial infarction (AMI). However those studies have not been concerned with myocardial viability in the region-at-risk. In the present study the effect of the patency of IRA was investigated in the setting of anterior AMI with poor viable myocardium in the risk region., Methods and Results: From 1993 to 1996 patients with a first time anterior AMI and poor viable myocardium in the region-at-risk at 1 month after onset were identified and enrolled. Patients with a totally occluded IRA were included in the Non-Open group (n=44), and patients with a reperfused IRA were included in the Open group (n=49). At 5 years after onset, left ventricular function was better preserved in the Open group than in the Non-Open group (p<0.05). Kaplan-Meier survival curves for cardiac mortality and event-free survival curves revealed poor prognoses in the Non-Open group over a 5-year period (p<0.05, respectively). The advantages of a patent IRA were further seen in health-related quality-of-life outcomes (p<0.05)., Conclusions: Even in patients with poor myocardial viability after an anterior AMI, the patency of the IRA is strongly associated with improved long-term survival, independent of residual myocardium viability.

Background: Because the effects of an aldosterone receptor antagonist on transcriptional factors and mRNA expression have not been fully examined in myocardial infarction (MI), the present study examined the effects of spironolactone (SPIRO) and candesartan cilexitil (CAN) on activation of activator protein-1 (AP-1), nuclear factor-kappaB (NF-kappaB) and mRNA expression in the non-ischemic myocardium after MI., Methods and Results: MI was induced by ligation of the coronary artery in Wistar rats, which were separated into (1) vehicle-treated group, (2) CAN-treated group (10 mg/kg per day), (3) SPIRO-treated group (100 mg/kg per day) and (4) CAN + SPIRO-treated group. The activity of both AP-1 and NF-kappaB was significantly increased at 4 weeks after MI. CAN or SPIRO significantly prevented the cardiac remodeling and activity of AP-1 and NF-kappaB. Furthermore, CAN + SPIRO prevented the cardiac remodeling and activation of AP-1 and NF-kappaB, compared with CAN or SPIRO alone. Myocardial atrial natriuretic peptide, brain natriuretic peptide, collagen I and III mRNAs were enhanced by MI, and CAN or SPIRO alone significantly reduced the mRNAs. CAN + SPIRO significantly prevented these mRNAs, compared with CAN or SPIRO alone., Conclusions: Both aldosterone and angiotensin II are involved in the myocardial transcriptional activation of AP-1, NF-kappaB and the cardiac remodeling-related mRNAs. The combination of CAN and SPIRO may be a potent therapeutic strategy for preventing cardiac remodeling after MI.

Many reports have demonstrated that smokers who have suffered an acute myocardial infarction (AMI) have a better prognosis than nonsmokers. The present study investigated the effects of current smoking on myocardial injury with resting 123I-15-iodophenyl 3-methyl pentadecanoic acid (BMIPP)/201Tl myocardial single photon emission computed tomography in 103 patients with conservatively treated AMI. The left ventricular myocardium was divided into 9 segments and BMIPP and 201Tl defects were scored using a 5-point grading system (0 = normal and 4 = no uptake). The sum of the defect scores was defined as the total defect score. There was no significant difference in either the baseline severity of the coronary artery disease or the total defect scores for BMIPP and 201Tl between the current smoker and nonsmoker groups. The difference between the total defect scores for BMIPP and 201Tl tended to be larger in the current smoker group than in the nonsmoker group (2.0 +/- 1.9 vs 1.3 +/- 1.6, p = 0.056). Forty-one (53%) of 77 patients in the current smoker group exhibited a BMIPP/201Tl mismatch, whereas only 8 (31%) of 26 patients in the nonsmoker group did (p = 0.047). In conclusion, current smokers had more likelihood of salvageable myocardium in areas at risk, as demonstrated by BMIPP/201Tl mismatch, in AMI than nonsmokers.

Inhibition of the renin-angiotensin system has been shown to prevent left ventricular remodeling after myocardial infarction. However, the effect of angiotensin on the signal transduction pathway of left ventricular remodeling after myocardial infarction is as yet unknown. The purpose of this study was to measure myocardial MAPKs and AP-1, NF- kappa B, and Sp-1 DNA-binding activities after myocardial infarction. Moreover, we evaluated the effects of angiotensin converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) on signal transduction pathway. Myocardial infarction was produced by ligation of the coronary artery in Wistar rats. Temocapril (ACE inhibitor) (3 and 30 mg/kg/day) and candesartan cilexitil (ARB) (1 and 10 mg/kg/day) were orally administered once a day. After ligation of the left descending coronary artery, JNKs (p46JNK and p55JNK) increased to 2.0- (P<0.01) and 2.8-fold (P<0.01) at 7 days, respectively. ERKs (p44ERK and p42ERK) and p38 activities did not increase significantly. AP-1 and NF- kappa B binding activities increased at 5 days, reached their peak 2.2- and 2.0-fold at 7 days. Sp-1 did not change. ACE inhibitor and ARB inhibited JNKs, NF- kappa B and AP-1 activities. Increased JNKs, AP-1, NF- kappa B, and Sp-1 DNA-binding activities were suppressed by both drugs in the infarcted region. Doppler-echocardiography showed that ACE inhibitor and ARB prevented the dilatation of left ventricular cavity at 14 days and improved diastolic filling pattern. JNKs, AP-1 and NF- kappa B activation in myocardial infarcted rats could be responsible for left ventricular remodeling after myocardial infarction and angiotensin may be related to the activation of these signals.

The present study investigated the agreement between low-dose dobutamine stress echocardiography (LDDSE) and fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and compared each technique's ability to detect myocardial viability and predict functional recovery in 30 patients. All patients underwent revascularization, followed by echocardiography 5+/-3 months. Of the 390 segments analyzed by echocardiography before revascularization, 110 (28%) had abnormal wall motion. LDDSE showed viability in 66 sites of the 110 dyssynergic segments and 58 of these viable segments recovered their wall motion. With FDG-PET, 78 of the 110 dyssynergic segments were diagnosed as viable and 62 of these showed improvement of the wall motion. The sensitivities for LDDSE and FDG-PET to assess functional recovery were 84% and 90%, respectively; specificities were 80% and 64%, respectively. Positive predictive values for LDDSE and FDG-PET were 88% and 79%; negative predictive values were 75% and 78%, respectively. Both methods had good sensitivity for detecting improvement in regional function after revascularization, but LDDSE had a higher specificity for detecting viability and a better positive predictive value for left ventricular functional recovery.

Background: Technetium-99m-labeled myocardial perfusion tracers allow simultaneous assessment of myocardial perfusion and left ventricular function by electrocardiography-gated scan. This study was performed to determine whether dobutamine stress electrocardiography-gated tetrofosmin single photon emission computed tomography (SPECT) can identify viable (as defined by positron emission tomography [PET]) but dysfunctional myocardium with contractile reserve., Methods and Results: Thirty-five patients with myocardial infarction underwent resting electrocardiography-gated SPECT and fluorodeoxyglucose (FDG) PET. The relative uptakes of tetrofosmin (%tetrofosmin) and FDG (%FDG) were calculated. Wall motion in 9 left ventricular segments was assessed at rest and during dobutamine stress on a 3-dimensional cine-mode display created with automatic left ventricular function analysis software. A total of 129 dysfunctional segments were analyzed. Forty-five (48.9%) of 92 segments with %tetrofosmin of 50% or greater and only 4 (10.8%) of 37 segments with %tetrofosmin less than 50% had contractile reserves (P <.0001). The sensitivity, specificity, and predictive accuracy of %tetrofosmin of 50% or greater for detecting %FDG of 50% or greater were 85.7%, 74%, and 82.9%, respectively. The incidence of the presence of contractile reserve rose with increasing magnitude of %FDG. The sensitivity, specificity, and predictive accuracy of the presence of contractile reserve for detecting %FDG of 50% or greater were 43.9%, 80.6%, and 52.7%, respectively., Conclusions: Dobutamine stress electrocardiography-gated SPECT can identify viable (as defined by PET) but dysfunctional myocardium with contractile reserve.

In chronic Q-wave myocardial infarction, QT dispersion is closely correlated with infarct size, but this correlation has not been evaluated for acute myocardial infarction (AMI). The effects of abnormal fatty acid metabolism on QT dispersion were examined in 123 patients with AMI who underwent resting iodine-123-15-iodophenyl 3-methyl pentadecanoic acid (BMIPP)/thallium-201(201Tl) myocardial single photon emission computed tomography (SPECT) and electrocardiographic analysis in the subacute phase. The relationship between BMIPP and 201Tl was defined as match when the total defect score for BMIPP was equal to or smaller than that for 201Tl, and as mismatch when the total defect score for BMIPP was larger than that for 201Tl. Twenty-six patients (21%) demonstrated BMIPP-201Tl match and 97 (79%) demonstrated mismatch. Infarct size was closely correlated with QT dispersion (r=0.67, p<0.001) in patients with BMIPP-201Tl match, but weakly correlated (r=0.30, p<0.005) in patients with BMIPP-201Tl mismatch. For small infarctions, QT dispersion was significantly larger in patients with BMIPP-201Tl mismatch than in those with BMIPP-201Tl match (62+/-24 ms vs 41+/-18 ms, p=0.03), but did not differ between the 2 groups for large infarctions. This study shows that QT dispersion is influenced by infarct size and by the presence of metabolically ischemic but viable myocardium in patients with AMI.

Methods: Recent studies have suggested that patients with preinfarction angina have smaller infarcts and a better in-hospital outcome than those without angina. The mechanisms responsible for limitation of infarct size in the presence of preinfarction angina are unclear. We examined the effects of preinfarction angina on myocardial injury in patients with the first acute myocardial infarction with resting 123I-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) 201TI myocardial scanning performed within 1 mo of infarction., Results: Of 136 patients tested, 48 (35%) had preinfarction angina within 72 h before infarction, whereas 88 (65%) did not. BMIPP and 201TI defects were scored in 9 segments of the left ventricle (0 = normal, 1 = mild defect, 2 = moderate defect, 3 = severe defect, and 4 = no uptake). The total defect score was defined as the sum of the defect scores. There was no significant difference in percentage diameters of stenoses of infarct-related arteries, collateral circulation, total defect scores for BMIPP, or 201TI between the groups with and without preinfarction angina. However, the ratio of total defect score for 201TI to that for BMIPP was significantly smaller for patients with than for those without preinfarction angina (0.64 +/- 0.21 versus 0.74 +/- 0.25, respectively; P = 0.007)., Conclusion: Preinfarction angina did not affect the areas at risk in acute myocardial infarction, as shown by BMIPP defect, but decreased necrotic myocardium in the areas at risk, as shown by 201TI defect, and increased metabolically damaged but viable myocardium, as shown by BMIPP and 201TI mismatch through unidentified mechanisms other than collateral circulation (e.g., ischemic preconditioning).

The in vivo activation of transcription factors, which is important for cell regulation by gene expression, has not been well examined in myocardial infarcted heart. The purpose of this study was to determine whether myocardial signal transducer and activator of transcription (STAT) pathway is activated as sis-inducing factor (SIF) in infarcted heart, and to assess the angiotensin blockade on SIF activity in ischemic and non-ischemic myocardium of rat. Myocardial infarction was made by ligation of the coronary artery in Wistar rats. In electrophoretic mobility shift assay, myocardial SIF DNA binding activities gradually increased and reached to peak at 1 week in infarcted and non-infarcted regions after myocardial infarction. Imidapril and candesartan cilexitil significantly prevented the increase in SIF DNA binding activity in infarcted and non-infarcted regions. This increased SIF DNA complex was supershifted by specific anti-STAT3 antibody, indicating that increased SIF complex at least contained activated STAT3 proteins in myocardial infarcted heart. Furthermore, immunoprecipitation-Western blot analysis revealed that STAT3 of infarcted and non-infarcted regions were tyrosine-phosphorylated at 1 week after myocardial infarction. Imidapril and candesartan cilexitil prevented the increase in phosphorylated STAT3. Thus, the transcriptional activation of STAT3 through AT1 receptor may be partially involved in cardiac remodeling after myocardial infarction., (Copyright 2000 Academic Press.)

Purpose: This study was performed to determine whether low-dose dobutamine stress electrocardiography (ECG)-gated fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) can assess wall motion and identify myocardium without contractile reserve despite preserved FDG uptake., Methods: Fifty-three patients with myocardial infarction and normal sinus rhythm underwent ECG-gated FDG-PET and transthoracic echocardiography. Wall motion of 10 segments of the left ventricle was graded as normal, hypokinetic, or akinetic/dyskinetic., Results: In 365 (76%) of 480 segments, assessment of wall motion was concordant between the 2 modalities. In 30 patients dobutamine-stress ECG-gated FDG-PET was performed. In 13 (50%) of 26 dysfunctional segments with normal FDG uptake, 16 (36%) of 44 dysfunctional segments with mildly reduced FDG uptake and 12 (25%) of 48 dysfunctional segments with moderately reduced FDG uptake, wall motion was improved by dobutamine infusion., Conclusion: Assessment of left ventricular wall motion with ECG-gated FDG-PET is feasible, and dobutamine stress ECG-gated FDG-PET can simultaneously identify metabolic viability and contractile reserve.

Unlabelled: Hypoperfused myocardium with increased uptake of 18F-fluorodeoxyglucose (FDG) is considered to be ischemic but viable myocardium. However, the significance of a more severe defect of FDG than of 13N ammonia (NH3) (i.e., reverse flow-metabolism mismatch) is not well understood., Methods: To study a reverse flow-metabolism mismatch pattern, PET with NH3 and FDG under glucose loading was performed in 35 patients within 2 wk after onset of first acute myocardial infarction (AMI) and in 29 patients with old myocardial infarction (OMI). The left ventricle was divided into nine segments on a bull's eye polar map, and the mean counts of NH3 (%NH3) and FDG (%FDG) were compared for the segment with the least %NH3., Results: Ten patients in the AMI group demonstrated a marked reverse flow-metabolism mismatch pattern (greater than 10% difference between %NH3 and %FDG), whereas only 2 patients in the OMI group demonstrated the mismatch pattern (P < 0.05). Sixteen patients with AMI demonstrated %FDG > %NH3 (group 1), and 19 patients with AMI demonstrated %FDG < %NH3 (group 2). There were no significant differences in age, sex, location of infarction, diameter of stenosis of infarct-related artery or left ventricular ejection fraction between groups 1 and 2. Eleven patients in group 2 and only 3 in group 1 had multivessel disease (P < 0.02). There was no significant relationship between the number of diseased vessels and the flow-metabolism pattern in patients with OMI., Conclusion: The finding of a reverse flow-metabolism mismatch on PET in the subacute phase of myocardial infarction was closely related to multivessel disease.

The purpose of this study was to compare the angiotensin II type 1 receptor antagonist candesartan cilexitil (candesartan) and the angiotensin-converting enzyme inhibitor cilazapril on cardiac function, assessed by Doppler echocardiography and cardiac gene expression associated with cardiac remodeling, in rats with myocardial infarction. Candesartan or cilazapril was administered after myocardial infarction. At 1 and 4 weeks after myocardial infarction, cardiac function and mRNA expression in noninfarcted myocardium were analyzed. Candesartan and cilazapril equally prevented increases in hypertrophy in noninfarcted myocardium, left ventricular dilatation, and ejection fraction at 4 weeks. The E-wave/A-wave velocity ratio and the rate of E-wave deceleration, measures of diastolic function, increased to 9.2+/-0.6 and 26.3+/-2. 6 m/s2 at 1 week after myocardial infarction. Candesartan and cilazapril, administered at a dose of 1 mg/kg per day, prevented increases in E-wave/A-wave velocity ratio and E-wave deceleration at 1 and 4 weeks. Candesartan and cilazapril significantly suppressed increased mRNA expression of beta-myosin heavy chain, alpha-skeletal actin, and atrial natriuretic peptide in noninfarcted ventricle at 1 and 4 weeks and expression of collagen I and III at 4 weeks to a similar extent. When given at a dose of 10 mg/kg per day, both candesartan and cilazapril prevented cardiac dysfunction and gene expression to the same extent as when given at 1 mg/kg per day. In conclusion, Doppler echocardiography showed that candesartan and cilazapril equally improved systolic and diastolic function and that ventricular remodeling accompanied modulation of cardiac gene expression.

Objective: To investigate the specificity and sensitivity of the combination of redistribution in exercise thallium-201 single photon emission computed tomography (SPECT) and exercise induced ST elevation for detecting the viable myocardium in patients with acute myocardial infarction., Design: 37 patients were studied within seven weeks of onset of Q wave myocardial infarction (anterior in 22, inferior in 15). All patients underwent exercise four hour redistribution thallium-201 SPECT and positron emission tomography using fluorine-18-fluorodeoxyglucose (FDG) and nitrogen-13 ammonia under fasting conditions., Results: Sixteen patients showed exercise induced ST elevation >/= 1.5 mm, and 15 of these had increased FDG uptake in the infarct region. Eleven of 16 patients (10 of 11 patients with anterior infarctions) with irreversible thallium-201 defects and increased FDG uptake showed exercise induced ST elevation. The sensitivity, specificity, and predictive accuracy of redistribution, exercise induced ST segment elevation, or both for detecting increased FDG uptake were 82%, 75%, and 67% (94%, 75%, and 91% for anterior infarctions), respectively., Conclusions: In patients with acute Q wave myocardial infarction, the combination of redistribution in exercise thallium-201 SPECT and exercise induced ST elevation can detect the viable myocardium in the infarct region with high sensitivity and specificity, especially in patients with anterior infarctions.

Objective: To investigate the relations between myocardial metabolism and the kinetics of thallium-201 in myocardial scintigraphy., Methods: 46 patients within six weeks after the onset of acute myocardial infarction underwent resting myocardial dual isotope, single acquisition, single photon emission computed tomography (SPECT) using radioiodinated 15-iodophenyl 3-methyl pentadecaenoic acid (BMIPP) and thallium-201, exercise thallium-201 SPECT, and positron emission tomography (PET) using nitrogen-13 ammonia (NH3) and [F18]fluorodeoxyglucose (FDG) under fasting conditions. The left ventricle was divided into nine segments, and the severity of defects was assessed visually., Results: In the resting SPECT, less BMIPP uptake than thallium-201 uptake was observed in all of 40 segments with reverse redistribution of thallium-201, and in 21 of 88 segments with a fixed defect of thallium-201 (p < 0.0001); and more FDG uptake than NH3 uptake (NH3-FDG mismatch) was observed in 35 of 40 segments with reverse redistribution and in 38 of 88 segments with fixed defect (p < 0.0001). Less BMIPP uptake in the resting SPECT was observed in 49 of 54 segments with slow stress redistribution in exercise SPECT, and in nine of 17 segments with rapid stress redistribution (p < 0.0005); NH3-FDG mismatch was observed in 42 of 54 segments with slow stress redistribution and in five of 17 segments with rapid stress redistribution (p < 0.0005)., Conclusions: Thallium-201 myocardial scintigraphy provides information about not only myocardial perfusion and viability but also about myocardial metabolism in patients with acute myocardial infarction.

The purpose of this study was to examine the cardiac phenotype and remodeling after myocardial infarction and the effect of the angiotensin II type 1 (AT1) receptor antagonist (TCV-116) on the gene expression. Myocardial infarction in rats was produced by ligation of the coronary artery. TCV-116 (10 mg/kg/day) was administered orally to rats from 1 day after myocardial infarction. At 1, 2 and 3 weeks after myocardial infarction, blood pressure and heart rate were measured, and the heart was removed. The left ventricle was measured for infarct size and weight, and then the total RNA from the non-ischemic left ventricle was extracted. mRNAs in the non-ischemic left ventricle were measured by Northern blot analysis. The weight of the non-ischemic left ventricle was significantly increased 3 weeks after infarction. This was completely prevented by TCV-116 treatment. mRNA levels for beta-myosin heavy chain (beta-MHC), atrial natriuretic polypeptide (ANP), collagen types I and III and transforming growth factor-beta 1 (TGF-beta 1) in the non-ischemic left ventricle were increased by a factor of 3.0, 6.7, 7.9, 4.0 and 1.4 (P < 0.01), respectively, 1 week after infarction. There was no increase in alpha-skeletal actin mRNA at 1 and 2 weeks, but it was increased by a factor of 2.9 (P < 0.05) at 3 weeks. On the other hand, there was no change in alpha-MHC mRNA during the 3 weeks. TCV-116 significantly suppressed the increased gene expression of beta-MHC and alpha-skeletal actin in the non-ischemic myocardium at all time points, and also suppressed the expression of ANP at 2 and 3 weeks. However, TCV-116 failed to inhibit the expression of collagen I and III mRNAs at 1 and 3 weeks. These results show that myocardial infarction causes a rapid shift of myocytes to fetal phenotype and a rapid activation of collagen genes in the non-ischemic myocardium. AT1 receptor may be responsible for the phenotypic modulation of myocytes following myocardial infarction.

It is widely accepted that perfusion defects in 3 to 4-h delayed images in exercise thallium-201 (201Tl) myocardial scintigraphy underestimate the viability of myocardium in the infarct region. In the present study, to examine the contribution of the condition of myocardium which demonstrates reverse redistribution in resting scintigraphy to the insufficiency of redistribution in the 4-h delayed image in exercise scintigraphy, we performed exercise and resting 201Tl myocardial single-photon emission computed tomography in 58 patients with acute myocardial infarction and a single diseased coronary artery. Twenty eight patients demonstrated reverse redistribution (group RR) and 28 showed a fixed defect (group FD) in resting scintigraphy. Redistribution in the 4-h delayed image in exercise scintigraphy was significantly more insufficient in group RR than in group FD (p < 0.01), and the degree of the insufficiency of redistribution in exercise scintigraphy closely correlated with the degree of reverse redistribution in resting scintigraphy (r = 0.79, p < 0.001). We conclude that in patients with acute myocardial infarction, the condition of myocardium which demonstrates reverse redistribution in resting myocardial scintigraphy is related to the insufficiency of redistribution in the delayed image in exercise scintigraphy.

To estimate the size of myocardial infarction, serum troponin T concentration was measured in 34 patients with acute myocardial infarction. Left ventriculography, 2-dimensional echocardiography and resting 201thallium myocardial single photon emission computed tomography (SPECT) were performed about 4 weeks after the onset of myocardial infarction and used for correlation with the late serum troponin T peak concentration which occurred on the 3rd to 5th day after onset. Both left ventricular ejection fraction (LVEF) obtained from left ventriculography and wall motion index (WMI) obtained from 2-dimensional echocardiography were inversely related to late troponin T peak value (LVEF: r = 0.68, p < 0.001, WMI: r = 0.70, p < 0.001). Extent score (ES) and severity score (SS), which were estimated from the initial resting 201thallium SPECT image, showed excellent linear correlations with late troponin T peak concentrations (ES: r = 0.77, p < 0.001, SS: r = 0.66, p < 0.001). This correlation was present both in patients with an early troponin T peak on day 1 (group A-16 patients) and in those without an early peak (group B-10 patients). Thus, late troponin T peak concentration can be used to predict infarct size regardless of the kinetics of its appearance in serum.

To determine the clinical significance of reverse redistribution (RR), resting thallium-201 myocardial single-photon emission computed tomography was performed once or twice in 80 patients in subacute phase (1 week to 2 months) of myocardial infarction. Thirty eight patients demonstrated RR on at least one study (group RR) and 32 a fixed defect only (group FD). Group RR had significantly smaller defects than group FD. Standardizing the relation of the severity of wall motion abnormality of left ventricle on echocardiogram with that of perfusion defect, in group RR wall motion abnormality in the acute and subacute phase reflected the defect of delayed image, while that in chronic phase, which was thought to reflect the viability of myocardium in the infarct region, reflected the defect of initial image. In serial thallium-201 studies, only the defect of delayed image of group RR improved on the second study, while the defect of initial image of group RR and defect of group FD did not improve. Wall motion of group RR improved with the disappearance of RR, and when RR remained, wall motion did not improve so much. We concluded that RR was thought to be demonstrated in viable myocardium with severe wall motion abnormality.

The mechanism and prognostic implications of Q wave regression following transmural acute myocardial infarction (AMI) were assessed in 54 patients. Of these subjects, 14 lost their Q waves. Exercise myocardial thallium-201 (201Tl) scintigraphy and two-dimensional echocardiography were performed before the patients were discharged from hospital. Two-dimensional echocardiography and electrocardiography were simultaneously repeated about 18 months after AMI. Both the relative 201Tl activity in the infarcted area and the improvement of echocardiographic wall motion index were higher in patients who had lost their Q waves than in those with retained Q waves (70 +/- 14% vs 58 +/- 13%, p less than 0.01; 5.2 +/- 3.0 vs 2.0 +/- 3.4, p less than 0.01, respectively). The prevalence of post-infarction angina pectoris was significantly higher in the former (29% vs 0%, p less than 0.01). We concluded that remnants of viable myocardial muscle might be responsible for Q wave regression following transmural acute myocardial infarction, and the prevalence of post-infarction angina pectoris was high among these patients.

Circulating immunoreactive endothelin (ir-ET) was measured in nine patients with acute myocardial infarction (AMI), 10 patients with stable angina pectoris (SAP), and 25 normal control subjects. In patients with AMI, the plasma ir-ET level was elevated in the acute phase and was highest on the day of onset (AMI: 3.8 +/- 1.7 pg/ml, normal control value: 0.5 +/- 0.2 pg/ml). The plasma ir-ET level showed a positive correlation with the wall motion abnormality index (rs = 0.56, p less than 0.01), thrombin-antithrombin III complex (rs = 0.55, p less than 0.01), and beta thromboglobulin (rs = 0.39, p less than 0.05). An especially high plasma ir-ET level was detected in patients in whom the Killip subset was IV. The plasma ir-ET level was not increased in patients with SAP (0.8 +/- 0.3 pg/ml). The plasma ir-ET level is increased in the acute phase of AMI. A pathophysiologic state characterized by cardiac dysfunction, an activated coagulation system, and platelet hyperactivity may be associated with this increase in plasma ir-ET.

The mechanisms by which tissue injury after acute myocardial infarction (AMI) occurs has not been fully elucidated. Recent evidence in experimental models has suggested involvement of the complement system in microvascular and macrovascular injury subsequent to AMI. With respect to angina pectoris, whether or not the complement system is activated is not clear. The present study assessed the role of complement as a mediator of myocardial inflammation by quantifying products of complement activation, including C3d, C4d, Bb, and SC5b-9 complexes, in 31 patients with AMI, 17 patients with unstable angina pectoris, 19 patients with stable angina pectoris, and 20 normal volunteers. The plasma C3d levels increased in patients with AMI and in those with unstable angina pectoris (p less than 0.01). The plasma levels of C4d, Bb, and SC5b-9 increased only in patients with AMI (p less than 0.01). The plasma SC5b-9 level was related to peak creatine phosphokinase (r = 0.71) and inversely related to the ejection fraction (r = -0.71). The plasma SC5b-9 level of patients with congestive heart failure was higher than that of patients without congestive heart failure in AMI. These results show that activation of complement system occurs after AMI and show an association of myocardial damage with complement activation. With respect to angina pectoris, the complement system is mildly activated in patients with unstable angina pectoris; however, the cardiac function of patients with unstable angina pectoris is not damaged. The complement system of patients with stable angina pectoris is not activated.

Although some studies suggest that complement activation is involved in the development of acute myocardial infarction, there has been little convincing evidence of a change in the complement system in patients suffering from myocardial infarction. In this study circulating levels of C3a, C3, C4 and the total hemolytic complement titer (CH50) were serially measured in 12 patients with acute myocardial infarction up to 10 days after an attack. The plasma C3a level was greatly elevated throughout the post-attack observation period. The C3, C4 and CH50 levels were significantly increased above those controls on days 8, 9 and 10 after infarction. These findings indicate that there is complement activation in patients with acute myocardial infarction, and suggest a pathogenetic role for complement activation in the development of myocardial damage after infarction.

The influence of dynamic exercise on plasma atrial natriuretic factor (ANF) levels was studied in a group of 10 patients with myocardial infarction (MI) and five patients with atypical chest pain (control group). Exercise protocol consisted of three fixed workloads (25, 50, and 75 watts) every 4 minutes with the use of a supine bicycle ergometer. Plasma ANF levels and hemodynamic indices were measured before, during, and 10 minutes after exercise. In the MI group, plasma ANF levels significantly increased at the 75-watt workload and significantly decreased at 10 minutes after exercise, whereas in the control group, the increase in plasma ANP levels after a 75-watt workload, compared with those at rest, was not significant. Significant correlations of pulmonary artery wedge pressure, right atrial pressure, mean arterial pressure, and heart rate to plasma ANF levels were observed at four points obtained before and during each stage of exercise in the MI group. Furthermore, a significant correlation between maximal creatine kinase levels and plasma ANF levels at a 75-watt workload and a significant inverse correlation between left ventricular ejection fraction and plasma ANF levels at a 75-watt workload were observed. These results suggest that the increase in the circulating ANF level during exercise in MI is associated with elevated atrial pressure resulting from left ventricular dysfunction and that measurement of ANF during exercise may be an indication of the severity of MI and associated left ventricular dysfunction.

Ga-67-DFO-DAS-fibrinogen (Ga-fbg) scintigraphy, a new radiopharmaceutical method, was performed for detecting intraventricular thrombi following acute myocardial infarction in five patients. The thrombi in four of them were detected by two-dimensional echocardiography (2DE) and that in the fifth patient was suspected during magnetic resonance imaging. Imaging of the heart was performed using a scinticamera with a medium energy collimator and multiple views (anterior, LAO 30 degrees, LAO 45 degrees, and lateral) three and four days after the intravenous administration of Ga-fbg. By Ga-fbg scintigraphy, intraventricular thrombi were detected in four patients. The size of the thrombi visualized by Ga-fbg appeared larger than those by 2DE. In one patient examined again after anticoagulant therapy, a thrombus was missed by 2-DE, but it was detected by Ga-fbg, though the radioactivity of the thrombus decreased. We concluded that Ga-fbg scintigraphy is a very simple method and sufficiently useful for detecting active left ventricular thrombi and for monitoring the effect of anticoagulant therapy. It could be more sensitive than 2DE for determining the extent of an active intraventricular thrombus.