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Long-acting Ca2+-channel blockers have been reported to be effective in treating ischemic heart disease. However, their effects on cardiac remodeling after myocardial infarction (MI) are still unclear. We performed this study to examine the effect of azelnidipine on left ventricular (LV) remodeling, including systolic and diastolic dysfunction, in rats with MI. MI was induced by ligation of the left anterior descending artery. The rats were then separated into 3 groups: a sham-operated group (n = 9), untreated MI group (n = 10), and azelnidipine-treated MI group (n = 10). Four weeks after MI, hemodynamic measurements and Doppler echocardiographic assessment were performed. LV weight and LV end-diastolic dimension were significantly higher in the untreated MI group than in the sham-operated group. Azelnidipine significantly prevented the increases in these parameters. Azelnidipine also improved the ejection fraction (42 ± 3%, P

Erythropoietin (EPO) has been suggested to have a cardioprotective effect against ischemia. The purpose of this study was to examine the effects of EPO on cardiac remodeling after myocardial infarction (MI). MI was induced by ligation of the coronary artery in Wistar rats. The rats with MI were randomly divided into untreated MI and two EPO-treated MI groups. EPO was administered subcutaneously by injection once a day for 4 days after MI at 5000 U/kg or 3 times a week for 4 weeks at 1000 U/kg. Five days after MI, EPO prevented the increase in activated caspase 3, matrix metalloproteinase-2, and transcriptional activation of activator protein-1 in non-infarcted myocardium. Four weeks after MI, left ventricular weight, left ventricular end-diastolic pressure, and left ventricular dimension were increased, and ejection fraction and E wave deceleration time were decreased. EPO significantly attenuated this ventricular remodeling and systolic and diastolic dysfunction. In addition, EPO significantly attenuated the interstitial fibrosis and remodeling-related gene expression in non-infarcted myocardium. Furthermore, EPO significantly enhanced angiogenesis and reduced apoptotic cell death in peri-infarcted myocardium. In conclusion, when administered after MI, EPO prevents cardiac remodeling and improves ventricular function with enhanced angiogenesis and reduced apoptosis. Keywords:: myocardial infarction, cardiac remodeling, erythropoietin, angiogenesis, apoptosis

The circulating endothelial progenitor cells (EPCs) have an important role in angiogenesis, and the smooth muscle progenitor cells (SMPCs) participate in atherosclerosis. However, little is known about the effects of treatment of diabetes mellitus (DM) on EPCs and SMPCs. Therefore, we investigated the relations between the number of circulating vasucular progenitor cells before and after the treatment for DM. Ten previously untreated DM patients were enrolled in this study. Blood samples were collected before and after treatment. The peripheral mononuclear cells were purified and cultured to differentiate them into EPCs and SMPCs. After two weeks, the number of EPCs was determined by Dil-labeled acetylated low density lipoprotein and lectin binding. The number of SMPCs was evaluated by immunocytochemical staining of α-smooth muscle actin. Before treatment, the number of EPCs and SMPCs was significantly related to hemoglobin A1c and blood sugar. Serial examination revealed that improvement of glycemic control significantly increased the number of both EPCs and SMPCs. DM reduces the number of circulating EPCs and SMPCs according to its severity, and treatment of DM significantly increases the number of EPCs and SMPCs, which may be involved in angiogenesis and atherosclerosis in diabetes. Keywords:: diabetes mellitus, endothelial progenitor cell, smooth muscle progenitor cell, glycemic control

Circulating bone marrow-derived vascular progenitor cells contribute to angiogenesis, atherosclerosis, and the response to vascular injury. These vascular progenitor cells consist of two cell groups, endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs). Although HMG-CoA reductase inhibitors (statins) have been reported to inhibit atherosclerosis partially by increased EPCs, the effects of statins on SMPCs are unclear. Therefore, we investigated the relationship between EPCs and SMPCs and whether pravastatin has atheroprotective effects on SMPCs. Peripheral mononuclear cells (MNCs) were isolated and cultured on fibronectin-coated dishes in SMPC medium. MNCs were stained with acetylated low density lipoprotein and lectin, or α-smooth muscle actin, and cell numbers were counted. mRNA expression and vascular endothelial growth factor (VEGF) protein synthesis of MNCs were evaluated. Pravastatin significantly increased the number of EPC and decreased the number of SMPC. mRNA expression of VEGF, endothelial nitric oxide synthase, VEGF receptor-2 (KDR), and Akt were up-regulated, and VEGF secretion was increased by pravastatin. The present study demonstrated that pravastatin has promotive effects on the differentiation from MNCs to EPC cells, while inhibitory effects to SMPC cells. Our findings suggest a previously unreported mechanism of the effect of statin therapy on vascular progenitor cells. Keywords:: endothelial progenitor cell, smooth muscle progenitor cell, statin, atherosclerosis

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 κB, 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.

Objective: Rapamycin-coated stents in coronary artery lesions have recently been shown to be effective in inhibiting neointimal formation. However, little is known about the effects of rapamycin on mitogen-activated protein kinase (MAPK), which is an important signal for neointimal formation. Therefore, we examined the effects of rapamycin on MAPK and transcriptional factors in cultured human coronary artery smooth muscle cells (CASMC) and in balloon-injured rat carotid arteries. Methods and Results: Activation of ERK, JNK, p38MAPK, AP-1, and NF-kB in coronary artery smooth muscle cells was increased by 2% fetal bovine serum. Ten nmol/L of rapamycin prevented the activation of JNK, p38MAPK, AP-1, and NF-kB (65%, 65%, 67%, and 26% respectively, P < 0.01). In an in vivo study, remarkable neointimal formation was observed 14 days after injury. Coating Pluronic gel with 20 and 50 μg rapamycin around the injured artery significantly decreased the intimal area/medial area ratio, compared with vehicle (0.75 vs. 1.2, P < 0.01). Rapamycin prevented the increase in activation of JNK, p38MAPK, AP-1, and NF-kB in injured artery (42%, 70%, 75%, and 60% respectively, P < 0.05). Conclusions: Neointimal formation after balloon injury is inhibited by rapamycin, which is partially mediated by inhibition of JNK and p38MAPK, followed by AP-1 and NF-kB.

Background Hypertension is one of the risk factors for coronary artery disease. However, because most coronary blood flow to the left ventricle occurs during diastole, high diastolic blood pressure during exercise may have a protective effect against exercise-induced myocardial ischemia. The aim of the present study was to test this hypothesis. Methods and Results We identified 469 patients with sinus rhythm and known or suspected coronary artery disease who underwent exercise thallium-201 myocardial single-photon emission computed tomography and coronary arteriography. High diastolic blood pressure during exercise was defined as diastolic blood pressure at peak exercise ≥90 mm Hg. There was no significant difference in medications, number of diseased vessels, or Gensini score between patients with high (n = 228) and normal (n = 241) diastolic blood pressure during exercise, whereas patients with high diastolic blood pressure during exercise exhibited a higher pressure-rate product during exercise than patients with normal diastolic blood pressure during exercise. The reversibility score on thallium-201 myocardial scan was significantly smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise ( P = .021). Conclusions High diastolic blood pressure during exercise has a potential protective effect against exercise-induced ischemia, although the mechanism of such effects remains to be determined.

Background: It is well known that angiotensin converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor blockers (ARBs) prevent left ventricular (LV) remodelling after myocardial infarction (MI). However, it is still not clear whether inhibition of the AT1 receptor is enough to prevent LV remodelling after MI. Objective: To elucidate the effects of ACE inhibitors that are not mediated by the AT1 receptor on LV remodelling, MI was experimentally induced in wild-type (WT-MI) mice and AT1 receptor knockout (KO-MI) mice. Methods: Mice were divided into six groups: WT-control, KO-control, WT-MI, KO-MI, WT-MI treated with an ACE inhibitor, and KO-MI treated with an ACE inhibitor. Four weeks after MI, cardiac function was assessed by Doppler echocardiography and 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, in the MI groups end diastolic dimension, E wave velocity, the ratio of peak velocity of E wave to A wave, deceleration rate of E wave, and mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, and collagens I and III increased significantly compared with the sham groups. LV remodelling after MI was prevented in KO-MI mice compared with WT-MI mice. ACE inhibitor administration significantly attenuated progressive LV remodelling in both WT and KO-MI groups. Conclusion: ACE inhibitors can prevent the LV remodelling process that accompanies cardiac dysfunction after MI, even in AT1 KO mice. These findings suggest that ACE inhibitors prevent LV remodelling after MI by mechanisms other than inhibition of angiotensin AT1 receptor mediated effects.

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 VEGF 165 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, α-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.

Plasminogen activator inhibitor-1 (PAI-1) has been implicated as a contributing risk factor for cardiovascular disease. However, little is known about molecular mechanisms of cardiac PAI-1 gene expression. To elucidate these mechanisms, dominant negative mutants of c-Jun NH(2)-terminal kinase (JNK), p38MAPK, apoptosis signal-regulating kinase-1 (ASK-1) and c-Jun were overexpressed in rat neonatal ventricular cardiac myocytes and fibroblasts by adenovirus vector to abrogate the activation of the corresponding endogenous proteins. One hundred nmol/l of angiotensin II significantly enhanced the JNK and p38MAPK activities of cardiomyocytes (2.3-fold and 1.9-fold, P0.05) and fibroblasts (3.2-fold and 2.5-fold, P0.05). At 3 h after stimulation, angiotensin II was found to have significantly increased PAI-1 mRNA, by 5.2-fold in cardiomyocytes and by 9.7-fold in fibroblasts. Dominant negative mutants of JNK, ASK-1 and c-Jun significantly inhibited PAI-1 mRNA expression and protein synthesis in both cardiomyocytes and fibroblasts, whereas a dominant negative mutant of p38MAPK did not change this expression. Moreover, a dominant negative mutant of JNK also significantly prevented the induction of PAI-1 mRNA expression by 100 nmol/l endothelin-1 and 10 micromol/l phenylephrine. In conclusion, G-protein-coupled receptor agonist-induced PAI-1 expression is partially mediated through JNK activation.

BACKGROUND Measurement of left ventricular (LV) volumes and ejection fraction (EF) is important in managing patients with coronary artery disease (CAD). Introduction of free-hand three-dimensional echocardiography (3DE) system which is equipped with small magnetic tracking system and average rotational geometry for LV volumes may provide easy and accurate quantification of LV systolic function in CAD patients. PURPOSE To evaluate the feasibility and accuracy of LV volumes and EF measurement by free-hand 3DE with rotational geometry in patients with CAD. METHODS AND RESULTS The study subjects consisted of consecutive 25 patients with CAD who were scheduled for quantitative gated single-photon emission computed tomography (QGS). LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were determined by conventional two-dimensional echocardiography (2DE), 3DE, and QGS. Three-dimensional echocardiography data acquisition and analysis were possible in 22 of 25 subjects (feasibility 88%). In this 3DE system, image acquisition time was 2 minutes, and 5 minutes were needed for off-line analysis of LV volumes and EF. Correlations and the limits of agreement between 3DE and QGS (r = 0.97, 0.0 +/- 9.1 ml for EDV, r = 0.99, 0.0 +/- 5.0 ml for ESV, and r = 0.97, 0.5 +/- 3.3% for EF, respectively) were superior to those between 2DE and QGS (r = 0.85, 12.6 +/- 26.8 ml for EDV, r = 0.85, 9.7 +/- 26.1 ml for ESV, and r = 0.90, -1.3 +/- 6.9% for EF, respectively). Inter- and intra-observer variabilities of 3DE were smaller than that of 2DE (5% vs 10%, 5% vs 10% for EDV, 6% vs 13%, 5% vs 9% for ESV, and 4% vs 11%, 4% vs 6% for EF, respectively). CONCLUSION Three-dimensional echocardiography using magnetic tracking system and average rotational geometry offered a feasible and accurate method for quantification of LV volumes and EF in patients with CAD.

Because granulocyte-colony stimulating factor (G-CSF) mobilizes bone marrow cells including endothelial progenitor cells, we examined whether G-CSF augments angiogenesis and collateral vessel formation induced by bone marrow-mononuclear cells transplantation (BMT). Unilateral hindlimb ischemia was surgically induced in Lewis rats. One week after surgery, administration of 100 mg/kg per day G-CSF significantly increased the laser Doppler blood perfusion index (LDBPI), number of angiographically detectable collateral vessels (angiographic score), and capillary density determined by alkaline phosphatase staining. In the BMT group (1 × 107 cells/rat) and the group with combined G-CSF treatment and BMT, LDBPI was significantly increased compared with that in the vehicle-treated group. In the BMT group, neovascularization was significantly increased as evidenced by the angiographic score and capillary density compared with the vehicle-treated group. Furthermore, the combination of G-CSF treatment and BMT augmented neovascularization compared with BMT alone, as evidenced by the angiographic score and capillary density. Moreover, G-CSF significantly increased vascular endothelial growth factor mRNA and fibroblast growth factor-2 mRNA in hindlimb muscle. In conclusion, G-CSF was found to augment neovascularization in rat hindlimb ischemia. Combined use of G-CSF treatment and BMT may be a useful strategy for therapeutic neovascularization in ischemic tissues. Keywords:: granulocyte-colony stimulating factor, bone marrow-mononuclear cell transplantation, angiogenesis, hindlimb ischemia, endothelial progenitor cell

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. Keywords:: osteopontin, renin-angiotensin system, cardiac remodeling, myocardial infarction

This study examined the effect of azithromycin therapy on the coronary microcirculation using measurement of coronary flow velocity reserve (CFVR) by transthoracic Doppler echocardiography in 35 patients with coronary artery disease. CFVR increased significantly after azithromycin therapy (3.0 +/- 0.7 vs 3.5 +/- 0.7, p0.001). The changes in CFVR were negatively correlated with changes in high-sensitivity C-reactive protein levels in patients receiving azithromycin.

Objectives: To clarify the value of cycle dependent variation of myocardial integrated backscatter (CV-IB) analysis, which non-invasively measures acoustic properties of the myocardium, for early detection of cardiac involvement in patients with sarcoidosis. Methods: The study population consisted of 22 consecutive patients with biopsy proven sarcoidosis who did not have any abnormal findings on conventional two dimensional echocardiogram. Cardiac sarcoidosis was diagnosed by radionuclide testing including thallium-201 scintigraphy, gallium-67 scintigraphy, and cardiac fluorine-18-deoxyglucose positron emission tomography. The magnitude and delay of the CV-IB were analysed in the basal mid septum and the basal mid posterior wall of the left ventricle of all patients. Results: The patients were divided into two groups: 8 patients with cardiac involvement and 14 patients without cardiac involvement. In the basal septum, a major reduction in the magnitude (mean (SD) 1.8 (4.4) v 6.6 (1.3), p = 0.012) and an increase in the time delay (1.3 (0.5) v 1.0 (0.1), p = 0.038) of CV-IB were observed in patients with cardiac sarcoidosis even in the absence of two dimensional echocardiographic abnormalities. The sensitivity for detecting cardiac involvement was such that the magnitude of CV-IB in the basal septum discriminated 75% of patients with cardiac sarcoidosis from those with non-cardiac sarcoidosis, whereas two dimensional echocardiographic parameters did not discriminate between these two groups. Conclusions: The CV-IB is decreased in the basal septum in patients with cardiac sarcoidosis even in the absence of two dimensional echocardiographic abnormalities. Analysis of CV-IB may be a useful method to detect early myocardial involvement in patients with sarcoidosis.

Oolong tea has been studied for its effect on cardiovascular disease and obesity. Plasma adiponectin levels are reduced in obesity, in patients with type 2 diabetes mellitus and in coronary artery disease (CAD).To investigate prospectively, whether intake of Oolong tea influences plasma adiponectin levels, low-density lipoprotein (LDL) particle size, total cholesterol, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, serum triglyceride and plasma glucose levels in patients with CAD.Twenty two patients in our study consumed Oolong tea (1000 ml) or water for 1 month in our randomized cross-over study design.There was a significant difference in plasma adiponectin levels before and after 1 month intake of Oolong tea (6.26 +/- 3.26 microg/ml versus 6.88 +/- 3.28 microg/ml, P0.05), and in plasma level LDL particle size (25.02+/-0.67 nm versus 25.31+/-0.60 nm, P0.01). The water-consuming control group showed no changes (6.28+/-3.28 microg/ml versus 6.23+/-3.21 microg/ml) in adiponectin levels or LDL particle sizes (25.03+/-0.70 nm versus 25.02+/-0.72 nm). We also observed a significant difference in hemoglobin A1c levels (7.23 +/- 4.45% versus 6.99 +/- 4.30%, P0.05) before and after intake of Oolong tea.Oolong tea may have beneficial effects on the progression of atherosclerosis in patients with CAD.

To investigate whether concentrations of plasma adiponectin constitute a significant coronary risk factor, with particular focus on the relation between plasma concentrations of adiponectin and the development of acute coronary syndrome (ACS).Plasma concentrations of adiponectin were measured in 123 patients with coronary artery disease (CAD) and in 17 control participants. Patients were divided into three groups according to condition type: acute myocardial infarction (AMI) group (n = 59), unstable angina pectoris (UAP) group (n = 28), and stable angina pectoris (SAP) group (n = 36).Plasma concentrations of adiponectin correlated negatively with body mass index (r = -0.18, p0.05), serum triglyceride (r = -0.25, p0.01), and fasting glucose concentrations (r = -0.21, p0.05), but correlated positively with age (r = 0.26, p0.01), high density lipoprotein cholesterol concentrations (r = 0.35, p0.01), and low density lipoprotein particle size (r = 0.37, p0.01). Plasma concentrations of adiponectin in patients with ACS, in both the AMI and UAP groups, were significantly lower than those in patients with SAP and in the control group (ACS, 6.5 (3.0) microg/ml; SAP, 11.3 (5.9) micro g/ml; control 12.8 (4.3) microg/ml; p0.01). Additionally, plasma concentrations of adiponectin in patients with CAD (7.9 (4.6) microg/ml, p0.01) were significantly lower than in the control group. There were, however, no significant differences between patients with SAP and the control group (p = 0.36). Multiple logistic regression analysis showed that smoking, fasting glucose concentration, and low log adiponectin concentration correlated independently with the development of an ACS.The findings suggest that measurement of plasma concentrations of adiponectin may be of use for assessing the risk of CAD and may be related to the development of ACS.

Objective: To evaluate the acute effects on haemodynamic variables of biatrial pacing in comparison with high right atrial (HRA) pacing and left lateral atrial pacing. Patients and design: 23 patients were paced from the HRA site, the lateral site of the coronary sinus (CS), and both sites on two fixed atrioventricular delays (100 and 150 ms) during atrioventricular sequential pacing at 80 and 100 beats/min in random order. Main outcome measures: After five minute pacing, the maximum P wave duration on a 12 lead ECG, cardiac output, pulmonary capillary wedge pressure, and the transmitral flow pattern by transthoracic echocardiography were measured. Results: Biatrial pacing delivered the shortest P wave duration (133 (25) ms, 133 (27) ms, and 96 (15) ms during HRA, CS, and biatrial pacing, respectively; p < 0.001), and the most improvement in cardiac output and pulmonary capillary wedge pressure (3.71 (0.93) l/min and 15 (7) mm Hg, 3.79 (0.97) l/min, and 14 (6) mm Hg, and 4.09 (1.01) l/min and 13(6) mm Hg during HRA, CS, and biatrial pacing, respectively; p < 0.01). Biatrial pacing most significantly decreased the intervals between the atrial pacing spike and the peak and end of the atrial filling wave (186 (16) ms and 250 (22) ms, 172 (19) ms and 242 (24) ms, and 153 (15) ms and 227 (23) ms during HRA, CS, and biatrial pacing, respectively; p < 0.001). It also significantly increased the mitral flow time velocity integral and peak atrial filling wave velocity (7.5 (3.4) cm and 63.8 (17.6) cm/s, 7.8 (3.0) cm and 62.4 (16.6) cm/s, and 8.3 (3.4) cm and 67.8 (19.3) cm/s during HRA, CS, and biatrial pacing, respectively; p < 0.05). The improvements in haemodynamic variables were especially remarkable in patients who had a longer interatrial conduction delay. Conclusions: Biatrial pacing yielded the most significant improvements in haemodynamic variables. These haemodynamic benefits may play a part in reducing intra-atrial pressure and preventing atrial fibrillation.

Background: Coronary flow velocity reserve (CFVR) measurement by transthoracic Doppler echocardiography (TTDE) has been found to be useful for assessing left anterior descending coronary artery (LAD) stenosis. However, this method has been restricted only for the LAD. The purpose of this study was to detect severe right coronary artery (RCA) stenosis by CFVR measurement using contrast-enhanced TTDE. Methods: In 60 consecutive patients with angina pectoris (mean (SD) age: 60 (11), 18 women), coronary flow velocities in the RCA were recorded in the postero-descending coronary artery by contrast-enhanced TTDE at rest and during hyperemia induced by intravenous infusion of adenosine triphosphate (140 mcg/ml/kg). CFVR was calculated as the ratio of hyperemic to basal peak and mean diastolic flow velocity. CFVR measurements by TTDE were compared with the results of coronary angiography performed within 1 week. Results: Coronary flow velocity was successfully recorded in 49 (82%) of the 60 patients with contrast agent. CFVR (mean (SD)) was 1.4 (0.4) in patients with, and 2.6 (0.6) in patients without significant stenosis in the RCA (%diameter stenosis > 75%, P < 0.001). Using the cutoff value 2.0 for CFVR in the RCA, its sensitivity and specificity in detecting significant stenosis in the RCA were 88% and 91%, respectively. Conclusion: CFVR measurement in the postero-descending coronary artery by contrast enhanced TTDE is a new, noninvasive method to detect significant stenosis in the RCA. (ECHOCARDIOGRAPHY, Volume 21, April 2004)

Objective— Monocyte chemoattractant protein 1 (MCP-1) could contribute to enhanced leukocyte recruitment and activation resulting in chronic tissue damage. However, little is known about the molecular mechanisms of cardiac MCP-1 expression. To elucidate these molecular mechanisms, angiotensin II-induced expression of MCP-1 was examined in cultured rat neonatal ventricular cardiomyocytes and fibroblasts by adenovirus gene transfer. Methods and Results— MCP-1 mRNA increased 3.6-fold in cardiac fibroblasts at 3 hours after 100 nmol/L angiotensin-II stimulation ( P Conclusion— Angiotensin II induced MCP-1 gene expression in cardiac fibroblasts. The angiotensin II-induced activation of ASK-1 followed by p38MAPK and NF-κB signaling in cardiac fibroblasts is partially involved in myocardial MCP-1 expression.

Background Myocardial infarction (MI) promotes deleterious remodeling of the myocardium, resulting in ventricular dilation and pump dysfunction. Supplementing infarcted myocardium with neonatal myocyte would attenuate deleterious remodeling and so the present study used Doppler echocardiography and histology to analyze the cardiac function and histological regeneration of the damaged myocardium after cellular cardiomyoplasty. Methods and Results Experimental MI was induced by 24-h coronary ligation followed by reperfusion in adult male Lewis rats and neonatal myocytes were injected directly into the infarct and peri-infarct regions. Three groups of animals were studied at 4 weeks after cellular cardiomyoplasty: noninfarcted control (control), MI plus sham injection (MI), and MI plus cell injection (MI + cell). Ventricular remodeling and cardiac performance were assessed by Doppler echocardiography or contrast echocardiography. At 4 weeks after cellular cardiomyoplasty, MI + cell hearts exhibited attenuation of global ventricular dilation and cardiac function compared with MI hearts not receiving cellular cardiomyoplasty. Immunohistochemically, connexin-43-positive small cells were observed in the vicinity of the infarction in MI + cell heart. By electron microscopy, these cells contained myofilaments with Z-bands and poorly developed intercalated disks, suggesting neonatal myocardial cells. Furthermore, the myocardial cells were often making close contact with interstitial cells. Conclusions Implanted neonatal myocytes form viable grafts after MI, resulting in attenuated ventricular dilation and enhanced contractile function. Echocardiography, electron microscopy, and immunohistochemistry are useful methods for assessing the functional and histological regeneration of the damaged myocardium. (Circ J 2004; 68: 580 - 586)

In this study, we investigated whether the Na+/Ca2+ exchanger (NCX) inhibitor SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy-5-ethoxyaniline) might have a protective effect against myocardial ischemia-reperfusion injury in rats. In particular, we focused on cardiac function using Doppler echocardiography and cardiac gene expression. We intravenously administered either SEA0400 and delivery vehicle or only the vehicle (as a control) to Wistar rats 5 min before ischemia was induced. Reperfusion was performed after 30 min of ischemia. At 1 week after ischemia-reperfusion injury, we assessed hemodynamics by inserting a polyethylene-tubing catheter, cardiac function by Doppler echocardiography, and myocardial mRNA expression was determined by Northern blot analysis. Left ventricular (LV) end-diastolic dimensions (LVDd) and LV end-diastolic volume (LVEDV) were significantly increased in the ischemia-reperfusion rat model group compared to the control group. The SEA0400-treated group had a significantly attenuated LVDd (P

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

Background. Intravenous myocardial contrast echocardiography (MCE) has emerged as a novel method for assessment of myocardial blood volume (MBV), which changes in proportion to coronary stenosis severity at rest. The purpose of this study was to clarify the relation between phasic changes in MBV and the severity of coronary artery stenosis in humans.Methods. We studied 58 patients with suspected coronary artery disease who underwent MCE with harmonic power Doppler imaging and continuous infusion of Levovist. Both end-systolic and end-diastolic images were obtained separately at every cardiac cycle. Regions of interest were placed at the mid-septum, and phasic changes in myocardial signal intensity (SI) were calculated as (SI at end-diastole)-(SI at end-systole).Results. Twenty-four patients had significant coronary stenosis in the left anterior descending coronary artery (LAD), and 34 did not. The phasic changes in patients with LAD stenosis were significantly lower than that in patients without LAD stenosis (−0.5±1.2dB vs. 1.3±1.4dB, p 70% stenosis in LAD, the phasic changes

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-κB (NF-κB) 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-κB was significantly increased at 4 weeks after MI. CAN or SPIRO significantly prevented the cardiac remodeling and activity of AP-1 and NF-κB. Furthermore, CAN + SPIRO prevented the cardiac remodeling and activation of AP-1 and NF-κB, 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-κB and the cardiac remodeling-related mRNAs. The combination of CAN and SPIRO may be a potent therapeutic strategy for preventing cardiac remodeling after MI. (Circ J 2004; 68: 376 - 382)

Background Low-dose dobutamine stress echocardiography (LDDE) has become a useful and safe method for identifying hibernating or stunned myocardium and for predicting improvement in wall motion after coronary revascularization. Methods and Results In the present study, fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), rest-redistribution thallium-201 (201Tl) single-photon emission computed tomography (RR-Tl SPECT), 123I-15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid (BMIPP) and LDDE were performed in 30 patients with acute myocardial infarction (AMI) at 10±3 days after the onset of AMI. Also, exercise 201Tl reinjection SPECT (RI-Tl SPECT) was performed at 14±2 days. Follow-up echocardiography was performed 5±3 months later in all patients after interventional therapy for the assessment of functional recovery. Of the 390 segments analyzed by echocardiography, 110 (28%) had abnormal wall motion. There were no significant differences between RR-Tl SPECT and LDDE in sensitivity, specificity, positive predictive value and negative predictive value using the χ2-test; however, in akinetic segments, there was a significant difference in sensitivity. Among FDG-PET, RI-Tl SPECT, BMIPP and LDDE, there were significant differences in 3 variables. In akinetic segments, LDDE is superior to RR-Tl SPECT in sensitivity and to FDG-PET in specificity. In hypokinetic segments, LDDE is superior to RI-Tl SPECT and BMIPP in sensitivity, and to FDG-PET and BMIPP in specificity. Conclusions LDDE could detect functional recovery of viable myocardium in the early period of AMI and can be performed easily and safely. (Circ J 2004; 68: 950 - 957)

Hypertrophic cardiomyopathy (HCM) is defined as inappropriate ventricular hypertrophy without a cardiac or systemic cause. On the other hand, hepatitis C virus (HCV) causes extrahepatic manifestations as well as chronic persistent infection in hepatocytes. We studied the association of HCV infection with HCM, comparing the prevalence of HCV antibodies between HCM patients and age- and gender-matched controls with other cardiovascular diseases at a single institution, for reasons of exclusion of bias. We then described the clinical features and genotype analysis of HCV RNA in HCM. The diagnosis of HCM was established by echocardiographic demonstration of a hypertrophied (or =15 mm), nondilated left ventricle in the absence of another systemic or cardiovascular disease capable of producing the magnitude of hypertrophy observed. The study population consisted of 80 patients with HCM, in whom HCV antibody was examined (55 men and 25 women; mean age 56.6 +/- 12.4 years; ranging from 19 to 80 years), compared with a total of 80 age- and gender-matched controls without HCM. The prevalence of HCV infection in patients with HCM (18/80) was significantly higher than in control subjects (5/80) (Chi(2) = 7.312, P = 0.007). Of the 12 patients in whom the genotype of HCV was analyzed, 7 had type 1b and 5 had type 2a. The prevalence of HCV infection was higher in patients with HCM than in age- and gender-matched control subjects with other cardiovascular diseases. The result suggests that HCV may play an important role in these HCV-positive HCM patients.

Objective: To evaluate the feasibility of quantifying low temperature radiofrequency catheter ablation (RFCA) lesions using a phased array intracardiac echocardiography (ICE) catheter—with better tissue penetration and in a deflectable device—in the canine model. Intervention: Low temperature radiofrequency (RF) energy (50–60°C at up to 40 W) was delivered to the left ventricle in 11 beagles for 60 seconds, using an 8 French catheter with a deflectable tip and a 4 mm distal electrode. Main outcome measures: Comparison of the width and depth of RFCA lesions measured by ICE with pathological findings. Results: 33 RF energies were delivered in 11 dogs. 31 lesions (94%) were confirmed at necropsy. 27 of 31 ablation lesions (87%) were detected by ICE. The mean (SD) width and depth of the ICE detected lesions were 10.4 (2.6) mm and 5.7 (1.9) mm, respectively. Pathological findings showed that RFCA lesions consisted of inner and outer layers. Macroscopically, the mean (SD) width and depth of the inner layers were 7.6 (2.3) mm and 3.6 (1.2) mm and those for the whole layers were 10.0 (2.8) mm and 5.3 (1.5) mm, respectively. Microscopically, the inner and outer layers corresponded to necrotic and oedematous areas, respectively. The ICE detected lesion size had better correlation with the pathological measurements of the whole layers in width (r = 0.911) and in depth (r = 0.756). Conclusion: The real time evaluation of RFCA lesion size using the phased array ICE is feasible, even with a low temperature RF application. However, ICE slightly overestimates RFCA lesion size compared with pathological necrotic lesion size.

The automated contour tracking (ACT) method has been developed for the automated measurement of area volume using the energy minimization method without tracing a region of interest. The purpose of this study was to compare the ACT method and left ventriculography (LVG) for the measurement of left ventricular (LV) function in the clinical setting. An apical four-chamber view was visualized by two-dimensional echocardiography and recorded for off-line analysis in 14 patients with high-quality images who underwent LVG. The ACT method automatically traces the endocardial border from the recorded images and calculates LV volumes (end-diastole and end-systole) and ejection fraction (EF). Both ACT and LVG were compared by linear regression analysis for the measurement of EF. EF determined by the ACT method agreed well with that by LVG (r = 0.96, y = 0.94x + 4.6, standard error of the estimate = 3.9%). The mean difference between the ACT and LVG was –1.4%± 7.3%.In conclusion, the ACT method is reliable for noninvasive estimation of EF in high-quality images. This suggests that this new technique may be useful in the automated quantification of LV function. (ECHOCARDIOGRAPHY, Volume 20, May 2003)

It remains uncertain whether factors other than the severity of coronary artery disease (CAD) are associated with the worsening of the left ventricular ejection fraction (LVEF) by exercise. In the present study the impact of coronary risk factors on the worsening of LVEF by exercise was investigated in 391 patients with known or suspected CAD using exercise-gated 201Tl scanning to calculate the LVEF. Significant worsening of the LVEF by exercise was defined as >4.7% (mean plus 1 SD of the value in 116 patients without CAD). Multivariate analysis revealed that diabetes mellitus (DM) was an independent risk factor for the worsening of LVEF by exercise in patients with multivessel (2- or 3-vessel) CAD with an odds ratio (95% confidence interval) of 2.2 (1.1-4.5, p=0.037). In 157 patients with 2- or 3-vessel CAD, 20 (23.5%) of 85 nondiabetic patients and 31 (43.1%, p=0.009 vs nondiabetic patients) of 72 diabetic patients showed significant worsening of LVEF by exercise. In patients with 2- or 3-vessel CAD, there was no significant difference in Gensini score or reversibility of perfusion defects between nondiabetic and diabetic patients. Thus, DM is a risk factor for worsening LVEF by exercise in addition to the severity of CAD. (Circ J 2003; 67: 839 - 845)

Experimental studies have postulated the ischemic cascade and the present study was designed to elucidate whether it can be observed in the clinical setting. Fifty-three patients suspected of having coronary artery disease were studied. Myocardial perfusion abnormalities (MPA) and wall motion abnormalities (WMA) were assessed simultaneously by infusion of Levovist during dobutamine stress echocardiography. Time - intensity data of myocardial opacification were fitted for Y=A (1-e-β t) from which the rate of increase (β) of intensity were derived both at rest and during stress. Wall motion was also given a score. Bright opacification was observed in 50 patients: 25 showed significant stenosis (>50%) in the left anterior descending artery (group II) on coronary angiography and 25 did not (group I). Significant differences were found in the β ratio (stress/rest) between the 2 groups at a low-dose (2.0±0.3 vs 1.5±0.5, p

The Multi-Link stent is superior to other stents in terms of low rates of restenosis and target vessel revascularization. However, few data exist regarding short- and long-term outcomes for side branches after stenting. We evaluated short and long clinical outcomes and angiographic predictors of side-branch occlusion after the deployment of 137 Multi-Link stents. Thirty-four (25%) of the 137 side branches occluded immediately after stenting. We attempted reangioplasty for the side branches and our success rate was 85%. The incidence of side branches with intrinsic ostial disease was more than 50% before stenting and origination from the stented midsegment was a powerful angiographic predictor of side-branch occlusion. Side-branch patency is well maintained long-term. The incidence of restenosis within and near the stented segment of the parent vessel was 19%, and the incidence of target vessel revascularization was 15%. We recommend the use of Multi-Link stents regardless of the presence of side branches in the vicinity of the stenosis.

Aneurysm of the membranous ventricular septum (AMS) is a congenital cardiac anomaly often associated with ventricular septal defect. This aneurysm usually pouches into the right side of the heart and remains intracardiac. An AMS that extends outside of the heart is rare. We report an unusual case of a giant extracardiac AMS diagnosed by transthoracic color flow Doppler echocardiography.

Oxidized low-density lipoprotein (ox-LDL) is considered to play a key role in the genesis of inflammatory processes in atherosclerotic lesions. It has also been shown that LDL isolated from patients with diabetes mellitus (DM) has an enhanced susceptibility to oxidation. Recently, a sandwich ELISA method for measurement of plasma ox-LDL levels has been developed. To elucidate the role of ox-LDL in plaque instability in coronary artery disease, we measured the plasma ox-LDL levels in patients with acute myocardial infarction (AMI), unstable angina pectoris (UAP), and stable angina pectoris (SAP), and moreover assessed whether a relationship is present between plasma ox-LDL levels and DM. We also measured the plasma ox-LDL level in a patient who died of AMI, thus enabling us to study the presence of ox-LDL and CD 36, which is one of the ox-LDL receptors, in the culprit lesion. Plasma ox-LDL levels were measured in 210 patients (AMI: 70, UAP: 70, SAP: 70), and in 55 control subjects. Plasma ox-LDL levels in AMI patients were significantly higher than in UAP patients (P

The activator protein 1 (AP-1) transcriptional complex, containing Jun and Fos proteins, is involved in regulating many cellular processes such as proliferation and differentiation. However, little is known about a direct relationship between AP-1 activities and cardiomyocyte hypertrophy. To elucidate the roles of myocardial AP-1 activities, dominant negative mutant of c-Jun (DNJun) was overexpressed in cultured rat neonatal ventricular myocytes by adenovirus vector to abrogate endogenous AP-1 activation. Cardiomyocytes were treated with 100 nmol/L endothelin 1 (ET) and 10 μmol/L phenylephrine (PE) to induce myocardial cell hypertrophy. Both ET and PE significantly enhanced AP-1 DNA binding activities (3.4-fold by ET and 4.8-fold by PE at 3 hours, P 3 H-phenylalanine (1.4-fold by ET and 1.5-fold by PE, P P P P 3 H-phenylalanine, cell size, and the mRNA expression of ANP and BNP by ET and PE. In conclusion, we provide the first evidence that DNJun inhibits cardiomyocyte hypertrophy through inhibition of AP-1 transcriptional activity.

Hepatocyte growth factor (HGF) is a well-known powerful proliferative factor of vascular endothelial cells and it has been reported that plasma HGF concentrations are increased in acute myocardial infarction (AMI), although the mechanisms are not yet well delineated. Serum HGF levels and C-reactive protein (CRP) were measured in 22 patients with unstable angina pectoris (UAP) (15 males, 7 females; class IIb or IIIb of the Braunwald classification), 60 patients with AMI (37 males, 23 females; average time from the onset of symptoms to admission 4.6±0.7 h, range, 0.5-12 h), and 20 normal subjects. Immediate angioplasties were performed in 51 patients with AMI, and the time course of the HGF levels were measured in 31 patients among them. Heparin dramatically increased the HGF level and it declined to the normal range 18 h after heparin injection. Blood samples were taken before heparin treatment, or at least 24 h after. Serum HGF levels on admission was significantly increased in UAP (mean ± SE: 0.30±0.03 ng/ml, p

OBJECTIVESThe purpose of this study was twofold: 1) to examine the relationship between menstrual cycle and coronary flow velocity reserve (CFVR) in young healthy women, and 2) to evaluate the effect of hormone replacement therapy by estrogen on CFVR in postmenopausal women, using transthoracic color Doppler echocardiography (TTCDE).BACKGROUNDAlthough the incidence of cardiovascular disease is lower in women before menopause compared with men, postmenopausal women have an incidence of coronary artery disease similar to that of men of the same age. This is mainly dependent upon estrogen deficiency. However, no clinical report has yet examined the effect of estrogen on CFVR, which is one index of coronary microcirculation.METHODSWe examined 15 male and both 15 premenopausal and 10 postmenopausal female healthy volunteers. We measured coronary flow velocity of the left anterior descending coronary artery at baseline and hyperemic conditions during adenosine triphosphate infusion by TTCDE and determined CFVR. Each premenopausal woman was studied two times (menstrual [M] and follicular [F] phases) in one menstrual cycle. Fifteen men were also studied at a time corresponding to women’s menstrual cycle. The postmenopausal women were studied before and two hours after oral administration of conjugated estrogen (CE).RESULTSSerum 17β-estradiol level in premenopausal women increased in the F phase and decreased to the same levels as in men, as in the M phase and as in postmenopausal women (123 ± 9 pg/ml vs. 28 ± 6 pg/ml, 25 ± 9 pg/ml and 19 ± 11 pg/ml; p < 0.0001, respectively). The CFVR increased in the F phase compared with that in the M phase (4.8 ± 0.4 vs. 3.7 ± 0.8, p < 0.0001). We found that CFVR in men remained unchanged (3.7 ± 0.6 vs. 3.8 ± 0.5). After CE administration, CFVR increased compared with baseline in postmenopausal women (4.1 ± 0.8 vs. 3.4 ± 0.8, p < 0.005).CONCLUSIONSIn premenopausal women, CFVR determined by TTCDE varied during the menstrual cycle, and in postmenopausal women, CFVR increased after acute estrogen replacement.

Coronary flow velocity can be measured by transthoracic Doppler echocardiography (TTDE). The purpose of this study was to detect severe coronary stenosis using the diastolic-to-systolic flow velocity ratio (DSVR) determined by TTDE at rest. We prospectively examined 190 consecutive patients with angina pectoris for whom coronary angiography was planned. Doppler spectral tracings of flow velocity in the distal left anterior descending artery were recorded by TTDE at rest. The mean and peak DSVR values were computed using mean and peak coronary flow velocities. DSVR measurement by TTDE at rest was performed within 24 hours before angiography, and in patients who underwent coronary intervention it was performed again within 48 hours after the intervention. The success rate for DSVR measurement by TTDE was 83.7%. There were significant differences in peak DSVR and mean DSVR between the patients with severe stenosis (percent diameter stenosis85%) and those without severe stenosis (1.3 +/- 0.4 vs 1.9 +/- 0.50 and 1.2 +/- 0.4 vs 1.8 +/- 0.5, respectively; p0.0001). In the 17 patients with successful intervention, DSVR was significantly increased after the procedure (mean 1.2 +/- 0.1 vs 2.0 +/- 0.2; peak 1.2 +/- 0.2 vs 2.0 +/- 0.3, respectively; p0.0001). For percent diameter stenosis85%, the best cut-off points were 1.6 for peak DSVR (sensitivity 79.0%, specificity 75.7%) and 1.5 for mean DSVR (sensitivity 77.0%, specificity 77.9%). Thus, DSVR measurement by TTDE is a simple, noninvasive method for detection of severe coronary stenosis at rest.

OBJECTIVES We evaluated the value of coronary flow reserve (CFR), as determined by transthoracic Doppler echocardiography (TTDE), for physiologic assessment of coronary artery stenosis severity, and we compared TTDE measurements with those obtained by exercise thallium-201 (Tl-201) single-photon emission computed tomography (SPECT). BACKGROUND Coronary flow reserve measurements by TTDE have been reported to be useful for assessing angiographic left anterior descending coronary artery (LAD) stenosis. However, discrepancies exist between angiographic and physiologic estimates of coronary lesion severity. METHODS We studied 36 patients suspected of having coronary artery disease. The flow velocity in the distal LAD was measured by TTDE both at rest and during intravenous infusion of adenosine. Coronary flow reserve was calculated as the ratio of hyperemic to basal peak (peak CFR) and mean (mean CFR) diastolic flow velocities. The CFR measurements by TTDE were compared with the results of Tl-201–SPECT. RESULTS Complete TTDE data were acquired for 33 of 36 study patients. Of these 33 patients, Tl-201–SPECT confirmed reversible perfusion defects in the LAD territories in 12 patients (group A). Twenty-one patients had normal perfusion in the LAD territories (group B). Peak CFR and mean CFR (mean value ± SD) were 1.5 ± 0.6 and 1.5 ± 0.7 in group A and 2.8 ± 0.8 and 2.7 ± 0.7 in group B, respectively. Both peak and mean CFR ≤2.0 predicted reversible perfusion defects, with a sensitivity and specificity of 92% and 90%, respectively. CONCLUSIONS Noninvasive measurement of CFR by TTDE provides data equivalent to those obtained by Tl-201–SPECT for physiologic estimation of the severity of LAD stenosis.

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