Search

Technetium-99m-sestamibi (

Pathological studies have suggested the different process of in-stent restenosis (ISR) of bare-metal stents (BMS) and drug-eluting stents (DES). Here, we evaluated the components of neointimal tissue using integrated backscatter intravascular ultrasound (IB-IVUS) and focused on the time course after stent implantation and tissue signal distribution. We evaluated 125 lesions of 125 patients who underwent target lesion revascularization for ISR (BMS: n = 73, DES: n = 52). Volume analysis of a 4-mm length centered on a minimum lumen area in every 1-mm cross-sectional area was performed. For IB-IVUS analysis, color-coded maps were constructed from the default setting based on the integrated backscatter (IB) values (middle-IB value, green: fibrous and low-IB value, blue: lipid pool). For the neointimal tissue volume, we evaluated the ratios of the green (%G) and blue (%B) areas. Tissue signal distribution (TD) was also obtained from the default setting based on IB values in each pixel of IB-IVUS imaging. We compared values of neointimal tissues measured by IB-IVUS between the DES and BMS and time course. The observed period was longer after BMS implantation than after DES implantation (BMS: 2545 days, DES: 1233 days, p

Remote sensing is a desirable method for measuring ocean currents on various spatial and temporal scales. Coastal acoustic tomography (CAT) can measure current velocity in coastal and shallow seas, but the application of this method in stratified shallow estuaries has not been sufficiently tested. This study revisits the acoustic transmission data obtained from the 2013 Hiroshima Bay CAT experiment and investigates what information could be obtained from acoustic data when a relatively strong southward wind blew in the bay. We determined path-averaged currents of the first arrival rays and compared the temporal variations in this path-averaged current with those in the wind, water temperature, and detided sea level. When the southward wind was intensifying, the sea level at the northern coast of the bay decreased and then recovered when the southward wind subsided. These sea level variations must be accompanied by net volume transport variations. When sea level was recovering, the path-averaged current exhibited a positive bias, reflecting an increase of volume transport toward the inner part of the bay. In contrast, the path-averaged current did not show a noticeable variation when the sea level was decreasing although the surface layer current was expected to be intensified southward. This is because the first arrival ray did not propagate through the surface layer during the period, and therefore, the path-averaged current from the first arrival rays did not contain surface current velocity information. CAT is promising method for measuring variations in current velocity fields associated with winds; however, in the application to stratified and shallow estuaries such as Hiroshima Bay, it is crucial to consider acoustic ray-path variations when analyzing and interpreting travel time data time series.

Although genetic variants, which regulate lipid metabolism, have been extensively investigated in Caucasian populations, the genes, which confer susceptibility to dyslipidemia in Japanese individuals, remain to be elucidated. The aim of the present study was to examine a possible association among hypertriglyceridemia, hypo‑high density lipoprotein (HDL)‑cholesterolemia or hyper‑low density lipoprotein (LDL)‑cholesterolemia in Japanese individuals with 29 polymorphisms observed to confer susceptibility for coronary heart disease. This was performed through meta‑analyses of genome‑wide association studies in Caucasian populations. The study population comprised 2,354 individuals with dyslipidemia (hypertriglyceridemia, hypo‑HDL‑cholesterolemia or hyper‑LDL‑cholesterolemia) and 3,106 control individuals. To compensate for multiple comparisons of genotypes, a false discovery rate (FDR) of

Recent genome-wide association studies (GWASs) and their meta-analyses have identified various genes and loci underlying the predisposition to ischemic stroke or coronary artery disease in Caucasian populations. Given that ischemic stroke and coronary artery disease may have a shared genetic architecture, certain polymorphisms may confer genetic susceptibility to these two diseases. The aim of the present study was to examine the possible association of ischemic stroke with 29 single-nucleotide polymorphisms (SNPs) previously identified by the meta-analyses of GWASs as susceptibility loci for coronary artery disease. The study population comprised 3,187 Japanese individuals, including 894 subjects with ischemic stroke and 2,293 controls. The genotypes for the 29 SNPs of the 28 genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons of the allele frequencies by the χ2 test between subjects with ischemic stroke and controls revealed that rs9319428 (G→A) of the fms-related tyrosine kinase 1 gene (P=0.0471), rs2075650 (G→A) of the translocase of outer mitochondrial membrane 40 homolog gene (TOMM40, P=0.0102) and rs273909 (T→C) of the solute carrier family 22, member 4 gene (SLC22A4, P=0.0097) were significantly (P

Aim Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified in Caucasian populations by genome-wide association studies (GWASs). The aim of the present study was to examine a possible association of chronic kidney disease (CKD) with 29 polymorphisms previously identified as susceptibility loci for CAD by meta-analyses of GWASs. Methods The study population comprised 2247 Japanese individuals, including 1588 subjects with CKD [estimated glomerular filtration rate (eGFR) of

Various loci and genes that confer susceptibility to coronary heart disease (CHD) have been identified in Caucasian populations by genome-wide association studies (GWASs). As type 2 diabetes mellitus (DM) is an important risk factor for CHD, we hypothesized that certain polymorphisms may contribute to the genetic susceptibility to CHD through affecting the susceptibility to type 2 DM. The purpose of the present study was to examine a possible association of type 2 DM in Japanese individuals with 29 polymorphisms identified as susceptibility loci for CHD by meta-analyses of the GWASs. The study subjects comprised of 3,757 individuals (1,444 subjects with type 2 DM and 2,313 controls). The polymorphism genotypes were determined by the multiplex bead-based Luminex assay, which combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. To compensate for multiple comparisons of genotypes, the criterion of a false discovery rate (FDR) ≤0.05 was adopted for testing the statistical significance of the association. The comparisons of allele frequencies by the χ2 test revealed that the rs964184 (C→G) of the ZPR1 zinc finger gene (ZPR1) was significantly associated (P=0.0017; FDR=0.050) with type 2 DM. Multivariable logistic regression analysis with adjustment for age, gender and body mass index revealed that rs964184 of ZPR1 was significantly associated (P=0.0012; odds ratio, 1.25; dominant model) with type 2 DM with the minor G allele representing a risk factor for this condition. Fasting plasma glucose levels (P=0.0076) and blood glycosylated hemoglobin contents (P=0.0132) significantly differed among ZPR1 genotypes with the G allele associated with increases in these parameters. ZPR1 may thus be a susceptibility locus for type 2 DM in Japanese individuals.

Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified mainly in Caucasian populations by genome-wide association studies (GWASs). As hypertension is a major risk factor for CAD, certain polymorphisms may contribute to the genetic susceptibility to CAD through affecting the predisposition to hypertension. The aim of the present study was to examine a possible association of hypertension with 29 single-nucleotide polymorphisms (SNPs) previously identified by meta-analyses of GWASs as susceptibility loci for CAD. Study subjects comprised of 5,460 individuals (3,348 subjects with hypertension and 2,112 controls). The genotypes of SNPs were determined by the multiplex bead-based Luminex assay. The χ2 test revealed that genotype distributions and allele frequencies for rs12190287 of the transcription factor 21 gene (TCF21) and rs1122608 of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 gene (SMARCA4) were significantly (P

We assessed the hypothesis that blood pressure (BP)-lowering therapy has a beneficial effect on left atrial (LA) structure and function and may decrease the incidence of new-onset atrial fibrillation (AF) in elderly patients with hypertension (HTN). We divided 234 subjects ≥65 years old into four groups based on mean office BP achieved: a normotensive group (n=71), a HTN group with good BP control (n=72), a HTN group with poor BP control (n=41) and a HTN group with moderate BP control (n=50). LA volume, emptying function (EF), strain and strain rate (SR) were measured by speckle tracking echocardiography. LA volume, EF, strain and SR in the HTN group with good BP control were better preserved than those parameters in the HTN group with poor BP control. The incidence of new-onset AF during 2 years was significantly higher in the HTN group with poor BP control (hazard ratio: 7.015; 95% confidence interval: 2.433-20.22; P

Objectives The purpose of this study was to elucidate the usefulness of integrated backscatter (IBS) transesophageal echocardiography (TEE) for the evaluation of atrial degeneration and clarify whether atrial degeneration predicts the occurrence of atrial fibrillation (AF). Background One of the causes of AF is pathological degeneration of the left atrium (LA). However, there is no appropriate method to evaluate degeneration of the LA in the clinical setting. Methods The IBS images were acquired with TEE with a 4- to 7-MHz transducer. The IBS values were calculated as the average power of the backscattered signal from regions of interest (ROI). In the pathological study, we measured IBS values of 21 left atrial specimens obtained from 10 autopsied hearts. Relative interstitial area in the ROI was automatically calculated by a personal computer. In the clinical study, we measured IBS values of the entire LA wall at 5-mm intervals (except the posterior wall) in 42 patients (18 non-AF patients, 14 paroxysmal AF patients, and 10 chronic AF patients). Each IBS value was color-coded to construct 3-dimensional maps. Results There was a weak correlation between the relative interstitial area and IBS values (r = 0.45, p = 0.038). Average corrected IBS values of total voxels in color-coded maps in the AF group (24.4 ± 6.4 dB) and the paroxysmal AF group (23.9 ± 9.6 dB) were significantly greater than those in the non-AF group (15.6 ± 7.4 dB, p = 0.007), whereas there was no significant difference in LA diameter between the paroxysmal AF group (39.4 ± 6.5 mm) and the non-AF group (36.7 ± 5.5 mm). Conclusions With IBS-TEE, we can identify an increase in atrial degeneration that might predict the occurrence of AF before LA dilation.

Background It is still unclear whether celiprolol, a β1-selective blocker, reduces myocardial infarct size. This study will examine whether celiprolol reduces myocardial infarct size, as well as investigate the mechanisms for its infarct size-reducing effect in rabbits. Methods and Results Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Celiprolol (1 or 10 mg · kg -1 · h-1 for 60 min, iv) was administered 20 min before ischemia with or without pretreatment with Nω-nitro-L-arginine methylester (L-NAME, 10 mg/kg, iv, a nitric oxide synthase inhibitor) or 5-hydroxydecanoic acid sodium salt (5-HD, 5 mg/kg, iv, a mitochondrial KATP channel blocker). The area at risk as a percentage of the left ventricle was determined by using Evens blue dye, and the infarct size was determined as a percentage of the area at risk by triphenyl tetrazolium chloride staining. Celiprolol 1 and 10 mg · kg-1 · h-1 significantly reduced the infarct size in a dose-dependent manner (36.4±1.7%, n=7 and 25.4±2.9%, n=7, respectively) compared with the control (46.2±3.1%, n=8). The infarct size-reducing effect of celiprolol was completely blocked by L-NAME (40.4 ±2.8%, n=8) but not by 5-HD (27.3±1.0%, n=8). Celiprolol 1 mg · kg-1 · h -1 increased the myocardial interstitial levels of NOx, an indicator of nitric oxide, and reduced the intensity of dihydroetidium staining of myocardium, an indicator of superoxide, during reperfusion after 30 min of ischemia. Conclusion Celiprolol reduces myocardial infarct size and also increases nitric oxide production and reduces superoxide levels but not mitochondrial KATP channels in rabbits. (Circ J 2007; 71: 574 - 579)

Recent genome-wide association studies (GWASs) identified various genes and loci that confer susceptibility to coronary artery disease or myocardial infarction among Caucasian populations. As myocardial ischemia is an important risk factor for atrial fibrillation, we hypothesized that certain polymorphisms may contribute to the genetic susceptibility to atrial fibrillation through affecting the susceptibility to coronary artery disease. The aim of the present study was to examine the possible association of atrial fibrillation in Japanese individuals with 29 polymorphisms identified as susceptibility loci for coronary artery disease or myocardial infarction in the meta-analyses of GWASs in Caucasian populations. The study subjects comprised 5,470 Japanese individuals (305 subjects with atrial fibrillation and 5,165 controls). Genotypes for 29 polymorphisms were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons of the allele frequencies by the χ2 test revealed that rs599839 (G→A) of the proline/serine-rich coiled-coil 1 gene (PSRC1, P=0.0084) and rs11556924 (C→T, Arg363His) of the zinc finger, C3HC-type containing 1 gene (ZC3HC1, P=0.0076) were significantly (P

Although genome-wide association studies (GWASs) have identified various genes and loci in predisposition to metabolic syndrome (MetS) or each component of this condition, the genetic basis of MetS in individuals remains to be identified definitively. The aim of the present study was to examine the possible association of MetS in individuals with 29 polymorphisms that were previously identified as susceptibility loci for coronary artery disease or myocardial infarction by meta-analyses of GWASs. The study population comprised 1,822 subjects with MetS and 1,096 controls. Subjects with MetS had ≥3 of the 5 components of the diagnostic criteria for MetS, whereas control individuals had 0–1 of the 5 components. The genotypes for the 29 polymorphisms were determined by the multiplex bead-based Luminex assay. Comparisons of allele frequencies by the χ2 test revealed that rs17514846 (A→C) of the furin (paired basic amino acid-cleaving enzyme) gene (FURIN; P=0.0006), rs964184 (C→G) of the ZPR1 zinc finger gene (ZPR1; P=0.0078) and rs599839 (G→A) of the proline/serine-rich coiled-coil 1 gene (P=0.0486) were significantly (P

Risk stratification in heart failure (HF) among patients and healthy subjects using pulmonary capillary wedge pressure (PCWP) is important for understanding when and why HF develops. The aim of the present study was to evaluate the impact of gender and healthy aging on estimated PCWP using a kinetics-tracking index in patients and in healthy subjects without hypertension. The study population consisted of 198 healthy subjects without cardiovascular or other systemic diseases and who were not taking any medications. Echocardiographic studies were performed using an ACUSON Sequoia 512 ultrasound system. Active left atrial (LA) emptying function (EF) was defined as (pre-atrial contraction LA volume-minimum LA volume)/pre-atrial contraction LA volume × 100%. With an increase in age, the E/A and E/e' ratios (markers of left ventricular (LV) diastolic dysfunction (DD)) showed a similar decrease in males and females. PCWP was maintained at 8.3±1.8 mm Hg in males and 8.2±2.3 mm Hg in females because of compensation by an increase in active LA EF. In contrast, the compensation for LV DD with an increase in active LA EF in females tended to be more gradual (slope=0.11) than in males (slope=0.18, P=0.060 vs. female). The parameters that indicated LV DD deteriorated with advancing age. PCWP might be maintained because of compensation, namely an increase in active LA EF in both males and females. The compensation in female septuagenarians and octogenarians was weaker than in male septuagenarians and octogenarians. This difference in compensation may explain why HF with preserved LV ejection fraction occurs more frequently in females than in males.

Background We sought to evaluate the effects of a strong lipophilic statin (pitavastatin) on plaque components and morphology assessed by transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE), as well as plaque inflammation assessed by 18 F-fluorodeoxyglucose (FDG) PET/CT in the thoracic aorta and the carotid artery. Furthermore, we compared the effects of pitavastatin with those of mild hydrophilic statin (pravastatin). Methods We examined atherosclerotic plaques in the thoracic aorta by TEE and those in the carotid artery by integrated backscatter (IBS)-TTE and PET/CT. We identified the target plaque, where there was macrophage infiltration and inflammation, by strong FDG uptake in the thoracic aorta and carotid arteries and measured maximum standard uptake values (max SUV) by PET/CT. We measured the intima-media thickness (IMT) and the corrected IBS (cIBS) values in the intima-media complex by TEE and TTE at the same site of FDG accumulation by PET/CT. Results Patients were randomly divided into two treatment groups: a pitavastatin group (PI group: n =10, 68.4 ± 5.1 years) and a pravastatin group (PR group: n =10, 63.9 ± 11.2 years). The same examinations were performed after six months at the same site in each patient. We used calculated target-to-background ratio (TBR) to measure max SUV of plaques and evaluated percent change of TBR. There was no significant difference in low density lipoprotein-cholesterol, TBR, IMT and cIBS values in plaques at baseline between the PI and PR groups. After treatment, there was greater improvement in TBR, cIBS values and IMT in the PI group than the PR group. Conclusions The pravastatin treatment was less effective on plaque inflammation than pitavastatin treatment. This trend was the same in the carotid arteries and the thoracic aorta. Pitavastatin not only improved the atherosis as measured by IMT and cIBS values but also attenuated inflammation of plaques as measured by max SUV at the same site. The present study indicated that pitavastatin has stronger effects on the regression and stabilization of plaques in the thoracic aorta and carotid arteries compared with pravastatin.

Recent genome-wide association studies (GWASs) and their meta-analyses have identified various genes and loci underlying the predisposition to ischemic stroke or coronary artery disease in Caucasian populations. Given that ischemic stroke and coronary artery disease may have a shared genetic architecture, certain polymorphisms may confer genetic susceptibility to these two diseases. The aim of the present study was to examine the possible association of ischemic stroke with 29 single-nucleotide polymorphisms (SNPs) previously identified by the meta-analyses of GWASs as susceptibility loci for coronary artery disease. The study population comprised 3,187 Japanese individuals, including 894 subjects with ischemic stroke and 2,293 controls. The genotypes for the 29 SNPs of the 28 genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons of the allele frequencies by the χ2 test between subjects with ischemic stroke and controls revealed that rs9319428 (G→A) of the fms-related tyrosine kinase 1 gene (P=0.0471), rs2075650 (G→A) of the translocase of outer mitochondrial membrane 40 homolog gene (TOMM40, P=0.0102) and rs273909 (T→C) of the solute carrier family 22, member 4 gene (SLC22A4, P=0.0097) were significantly (P

1. In the present study, we investigated the effect of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), a free radical scavenger, on myocardial infarct (MI) size and cardiac function in an in vivo model of MI in rabbits. We further investigated the contribution of hydroxyl radicals, superoxide and nitric oxide (NO) to its effects. 2. Anaesthetized open-chest Japanese white male rabbits were subjected to 30 min coronary occlusion and 48 h reperfusion. The control group (n = 10) was injected with saline 10 min before reperfusion. The edaravone group (n = 10) was injected with a bolus of 3 mg/kg edaravone 10 min before reperfusion. The edaravone + N(G)-nitro-L-arginine methyl ester (L-NAME) group (n = 5) was given 10 mg/kg, i.v., L-NAME 10 min before the administration of 3 mg/kg edaravone. The L-NAME group (n = 5) was given 10 mg/kg, i.v., L-NAME 20 min before reperfusion. Infarct size was measured using the triphenyl tetrazolium chloride method and is expressed as a percentage of area at risk. Cardiac function was assessed by echocardiography 14 days after infarction. 3. In another series of experiments, rabbits were subjected to 30 min coronary occlusion and 30 min reperfusion and myocardial interstitial 2,3-dihydroxybenzoic acid (DHBA) and 2,5-DHBA levels, indicators of hydroxyl radical, were measured using a microdialysis technique. 4. Infarct size in the edaravone group was significantly reduced compared with that in the control group (27.4 +/- 6.8 vs 43.4 +/- 6.8%, respectively; P < 0.05). The edaravone-induced reduction of infarct size was abolished by pretreatment with L-NAME. Myocardial interstitial levels of 2,3-DHBA and 2,5-DHBA increased 20 and 30 min after ischaemia and peaked at 10 min reperfusion in the control group. Edaravone significantly inhibited the increase in 2,3-DHBA and 2,5-DHBA levels seen during reperfusion. Dihydroethidium staining showing in situ detection of superoxide was less intense in ischaemic myocardium in the edaravone-treated group compared with the control group. Edaravone improved cardiac function and left ventricular remodelling 14 days after infarction. 5. In conclusion, edaravone significantly reduces MI size and improves cardiac function and LV remodelling by decreasing hydroxyl radicals and superoxide in the myocardium and increasing the production of NO during reperfusion in rabbits.

Recent studies suggest transplanted bone marrow cells (BMCs) can be used to reconstitute coronary vessels and myocardium following acute myocardial infarction, thereby improving cardiac function. We sought to investigate the therapeutic potential of BMC transplantation in the treatment of nonischemic cardiomyopathy. Experimental cardiomyopathy was produced by treating rabbits for 8 weeks with doxorubicin (2 mg/kg per week). Two weeks after the treatment was finished, freshly aspirated BMCs or an equivalent volume of phosphate-buffered saline was injected directly into the left ventricular free wall. Four weeks later, heart function was examined during perfusion on a Langendorff apparatus. Left ventricular developed pressure and +/-dp/dt were significantly better in the transplantation group, among which echocardiography also showed significantly better ejection fractions. In addition, left ventricular weights as a fraction of body weight and left ventricular wall thicknesses were both lower in rabbits transplanted with BMCs than in controls. Immunohistochemical analyses carried out 2 weeks after transplantation showed no new myocardium and a very small number of endothelial cells originating from BMCs. On the other hand, immunoblotting revealed upregulated expression of transforming growth factor-beta1 and downregulated expression of matrix metalloproteinase-1 and tumor necrosis factor-alpha following BMC transplantation. In conclusion, autologous BMC transplantation into cardiomyopathic rabbit hearts ameliorates the decline in ventricular function without regenerating cardiomyocytes, most likely by altering expression of various cytokines.

Background The purpose of this study was to determine whether treatment with granulocyte colony-stimulating factor (G-CSF), which mobilizes endothelial progenitor cells from bone marrow, can safely improve the clinical outcomes of patients with atherosclerotic peripheral artery disease (PAD). Methods and Results Thirty-nine patients with intractable PAD were randomly assigned to 3 groups: a negative control group (n=12) treated with conventional drug therapy; a positive control group (n=13) treated with conventional drug therapy plus bone marrow transplantation (BMT); and a G-CSF group (n=14) treated with conventional therapy plus subcutaneous injection of 2-5 μg/kg of recombinant human G-CSF once daily for 10 days. One month after treatment, subjective symptoms improved significantly in the G-CSF and BMT groups. Ankle-brachial pressure index and transcutaneous oxygen pressure increased significantly in the BMT and G-CSF groups, but no such improvements were seen in the group receiving conventional therapy alone. Conclusions G-CSF improves the clinical signs and symptoms of patients with intractable PAD to the same degree as BMT does. This noninvasive treatment may thus represent a useful new approach to managing the disease. (Circ J 2006; 70: 1093 - 1098)

Background In animal models, granulocyte colony-stimulating factor (G-CSF) improves post-infarct cardiac function. However, in pilot studies involving patients with angina and acute myocardial infarction (AMI), G-CSF at a high dose frequently induced coronary occlusion or restenosis, but those at a low dose showed no significant beneficial effect. We hypothesized that a low dose but long duration of G-CSF will have a beneficial effect without serious complications to patients with coronary heart disease. Methods and Results Forty-six patients with angina or AMI were randomly assigned into G-CSF and non-G-CSF control groups, respectively. Recombinant G-CSF was subcutaneously injected once a day for 10 days. The leukocyte counts in the peripheral blood were controlled at approximately 30,000 /μl. One month later, a Thallium-201 single photon emission computed tomography revealed the increased percentage uptake and the reduced extent and severity scores in the G-CSF angina group. In the G-CSF AMI group, the curve between the ejection fraction and peak creatine kinase shifted significantly upward, compared with that of the non-G-CSF AMI group. Serious complications were not observed during the 6 months of observation. Conclusions A low dose but long duration of G-CSF treatment may have a beneficial effect without any serious complications in patients with coronary heart disease. (Circ J 2006; 70: 430 - 437)

Background Nicorandil has been reported to induce cardioprotection by opening the mitochondrial KATP channels. However, whether nicorandil affects reactive oxygen species is unclear. Methods and Results The hearts of male Sprague-Dawley rats were excised and perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O2 and 5% CO2. 1 mmol/L of nicorandil was given 10 min before ischemia. Left ventricular developed pressure (LVDP, mmHg), ±dP/dt (mmHg/s) and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 min consisting of a 30 min pre-ischemic period, followed by a 30 min global ischemia and 60 min reperfusion with and without 5-hydroxydecanoic acid sodium salt (5-HD), a mitochondrial KATP channel blocker. The concentrations of 2,3-dihydroxybenzoic acid (2,3-DHBA), an indicator of hydroxyl radicals, in the perfusate during reperfusion period were also measured. Nicorandil significantly improved LVDP and ±dP/dt, and increased coronary flow during reperfusion. Pretreatment with 5-HD abolished the improvement of LVDP and ±dP/dt, and the increase in coronary flow induced by nicorandil. Nicorandil significantly attenuated the concentrations of 2,3-DHBA during reperfusion, which were restored by 5-HD. Conclusion Nicorandil is protective against post-ischemic left ventricular dysfunction in association with opening the mitochondrial KATP channels, decreasing hydroxyl radicals and increasing coronary flow in the isolated rat heart. (Circ J 2006; 70: 1650 - 1654)

Recently, ultrasound tissue characterization of the carotid arteries with an integrated backscatter (IB) analysis was shown to identify a high-risk group of atherosclerosis. To clarify whether IB ultrasound is useful in assessing arterial sclerosis as well as stiffness beta and whether IB values reflect the histological structure, we measured IB values of common carotid media in 52 subjects without coronary risk factors and in 10 patients with systemic sclerosis (SSc) in the clinical studies and 12 patients in the histological studies with a Philips Medical Systems Sonos 5500. IB values were correlated with age (r=0.69, P0.0001), intima-media thickness (r=0.72, P0.0001) and stiffness beta (r=0.80, P0.0001) in the control subjects. IB values and stiffness beta in the SSc group were greater than in an age- and sex-matched control group (IB values: 9.6+/-2.7dB versus 16.1+/-1.8dB; stiffness beta: 11.5+/-4.5 versus 20.6+/-5.6, P0.01). IB values of the media were correlated with the elastic fragmentation index (r=0.63, P=0.029) and the collagen fiber index (r=0.59, P=0.046). Measurements of IB values of carotid media are useful for non-invasively evaluating arterial sclerosis.

1 We examined whether antidiabetic drug miglitol could reduce ischaemia/reperfusion-induced myocardial apoptosis by attenuating production. 2 Japanese white rabbits were subjected to 30-min coronary occlusion followed by 4-h reperfusion with miglitol (10 mg kg(-1), i.v., n=20) or saline (n=20). The infarct area was determined by myoglobin staining, and the infarct size (IS) was expressed as a percentage of the area at risk. DNA fragmentation was assessed by TUNEL method and DNA ladder formation. The expression of Bcl-XL and Bax was detected by immunohistochemical analysis and Western blot analysis. Myocardial interstitial 2,5-DHBA levels, an indicator of hydroxyl radicals, were measured during 30-min ischaemia and 30-min reperfusion in the absence (n=10) or presence of miglitol (10 mg kg(-1), i.v., n=10) using a microdialysis technique. 3 The IS was significantly reduced in the miglitol group (22.4+/-3.4%, n=10) compared to the control group (52.8+/-3.5%, n=10). Miglitol significantly decreased the 2,5-DHBA level during ischaemia and reperfusion and suppressed the incidence of TUNEL-positive myocytes in the ischaemic region (from 10.7+/-3.4 to 4.1+/-3.0%) and the intensity of DNA ladder formation. Miglitol significantly decreased the incidence of Bax-positive myocytes in the ischaemic region (7.4+/-1.7 vs 13.7+/-1.9% of the control) and significantly attenuated the upregulation of Bax protein in the ischaemic regions (from 179+/-17 to 90+/-12% of sham). There was no difference in the expression of Bcl-XL between the two groups. 4 These data suggest that miglitol reduces myocardial apoptosis by attenuating production of hydroxyl radicals and suppressing the upregulation of the expression of Bax protein.

Background— We investigated whether the improvement of cardiac function and remodeling after myocardial infarction (MI) by granulocyte colony–stimulating factor (G-CSF) relates to acceleration of the healing process, in addition to myocardial regeneration. Methods and Results— In a 30-minute coronary occlusion and reperfusion rabbit model, saline (S) or 10 μg · kg −1 · d −1 of human recombinant G-CSF (G) was injected subcutaneously from 1 to 5 days after MI. Smaller left ventricular (LV) dimension, increased LV ejection fraction, and thicker infarct-LV wall were seen in G at 3 months after MI. At 2, 7, and 14 days and 3 months after MI, necrotic tissue areas were 14.2±1.5/13.4±1.1, 0.4±0.1/1.8±0.5*, 0/0, and 0/0 mm 2 · slice −1 · kg −1 , granulation areas 0/0, 4.0±0.7/8.5±1.0*, 3.9±0.8/5.7±0.7,* and 0/0 mm 2 · slice −1 · kg −1 , and scar areas 0/0, 0/0, 0/0, and 4.2±0.5/7.9±0.9* mm 2 · slice −1 · kg −1 in G and S, respectively (* P Conclusions— The acceleration of the healing process and myocardial regeneration may play an important role for the beneficial effect of post-MI G-CSF treatment.

Lindera strychnifolia (Tendai-Uyaku), a medicinal plant, has long been used for the treatment of cardiac, renal and rheumatic diseases in Japan. We aim to clarify (1) whether L. strychnifolia is protective against post-ischemic myocardial dysfunction, and (2) whether its effect is related to scavenging hydroxyl radicals and opening the mitochondrial K ATP channels in isolated rat hearts. Male Sprague-Dawley rats were orally given 1 ml/day of L. strychnifolia, which was extracted from 0.75 and 1.5 g/kg of roots of L. strychnifolia for 4 days. The rat hearts were excised and perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O 2 and 5% CO 2. The hearts were paced at 320 beats/min except during ischemia. Left ventricular developed pressure (LVDP, mmHg), ± dP/dt (mmHg/sec) and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 minutes consisting of a 30-minute pre-ischemic period followed by 30 minutes of global ischemia and 60 minutes of reperfusion with or without 5-HD, a mitochondrial K ATP channel blocker. The levels of lactate, LDH and 2,5-DHBA, an indicator of hydroxyl radicals, in the perfusate during reperfusion period were also measured. Treatment with L. strychnifolia significantly improved LVDP and ± dP/dt without altering coronary flow during reperfusion. The 100 μM of 5-HD in Krebs-Henseleit solution was perfused during the 10 minutes of pre-ischemic periods. Pretreatment with 5-HD abolished the improvement of LVDP and ± dP/dt by L. strychnifolia. L. strychnifolia significantly attenuated the levels of lactate, LDH and 2,5-DHBA during reperfusion, and which were restored by pretreatment with 5-HD. In conclusion, L. strychnifolia is protective against post-ischemic left ventricular dysfunction through scavenging hydroxyl radicals and opening the K ATP channels in the isolated rat heart.

For studying coastal ocean processes, a new ocean model has been developed based on the semi-spectral method using three-dimensional primitive equations. The basic idea is that the vertical mode is used as a basis. As a first step in the development of the model, the Fourier cosine series is used as a basis by assuming that the reference density is homogeneous. To test the performance of the model, it has been applied to the regional model of the Neko Seto Sea in the Seto Inland Sea. The model result has been compared intensively with the observational result of acoustic Doppler current profiler (ADCP) on the eastern side of the Meneko Seto Strait. The model reproduced the realistic horizontal and vertical structure of the tidal current and vortices. The tidal current in Nigata Bay has been compared with a previous observational study. The generation process of the clockwise vortex at eastward flow is found to be different from the previous observational description. By using the vorticity analysis, it was found that the vortex stretching associated with the sloping bottom topography is essential to the generation of the counterclockwise vortex during eastward flow and the clockwise vortex during westward flow in Nigata Bay. On the other hand, the advection of vorticity from the edge-like coastal geometry is essential for the generation of the vortices on the eastern side of the Strait. However, the positive vorticity supply from tilting enhances the growth of the counterclockwise vortex, and is indispensable for reproducing its realistic position.

We describe an operational ocean data assimilation system for the Kuroshio and its validation using a nine-year reanalysis (historical run from 1993 to 2001) dataset of upper-ocean state estimation in the North Pacific. The horizontal structure of volume transport of the Ryukyu Current System (RCS) is shown from the reanalysis: The RCS is connected to the flow of the subtropical gyre, and its volume transport gradually increases from south-east of Okinawa (5–10 Sv) to the east of Amami-Ohshima Island (20 Sv). Comparing the reanalysis with independent observations on the southeast slope of the Amami-Ohshima Island indicates that the root mean square differences (RMSDs) are 0.076 (0.037) m/s in the period of December 1998 to November 1999 (November 1999 to November 2000) respectively. The reanalysis field has a bias (3.1 Sv) of the volume transport of the RCS and the RMSD (3.5 Sv) which is larger than the observed variability (2.81 Sv). Surface velocity and the Kuroshio axis south of Japan are also examined. Comparison of the reanalysis and ADCP data gave maximum RMSD of 0.749 (0.271) m/s in the strong (weak) current regions, respectively. The annual mean value of the axis error is 19 km in 1998. The RMSD of the error is at most 50 km, in 294 cases in the observation period, which is smaller than the observed root mean square variability of the axis (64 km).

A method has been developed to monitor the surface velocity field by combining repeated acoustic Doppler current profiler (ADCP) observations and satellite altimetry data. The geostrophic velocity anomaly is calculated from the sea surface height anomaly field estimated from the altimetry data by an optimal interpolation. It has been confirmed that this accurately observes the smoothed velocity anomaly field when the interpolation scales are set according to the spatio-temporal sampling pattern of the altimeter used. The velocity anomaly obtained from the altimetry data is subtracted from the repeated ADCP observations to estimate temporal mean velocity along the ship tracks. Regularly sampled, nine-year time series of surface velocity can then be obtained by adding the computed mean velocity and the altimetry anomaly components. This clearly illustrates surface velocity fluctuations such as the movement of the Kuroshio axis due to its meandering and an increase of the interannual variability of the Subtropical Countercurrent toward its downstream region.

Objectives We aimed to clarify the relation between sarpogrelate (SG), a 5-hydroxytryptamine (5-HT)-2 receptor blocker, and myocardial interstitial serotonin or infarct size during ischemia and reperfusion. Background In cardiac tissues serotonin is rich in vascular platelets, mast cells, sympathetic nerve endings, and the receptors are present in platelets and cardiomyocytes. Methods The myocardial interstitial serotonin levels were measured using a microdialysis technique during 30-min ischemia with and without SG in in vivo as well as isolated rabbit hearts. Other rabbits underwent 30 min of ischemia and 48 h of reperfusion, and the effect of SG on the infarct size was investigated in the absence and presence of a selective protein kinase C (PKC) inhibitor, chelerythrine (5 mg/kg, intravenously), or a mitochondrial adenosine triphosphate sensitive potassium (KATP) channel blocker, 5-hydroxydecanoate (5-HD) (5 mg/kg, intravenously). In another series, the effect of SG on PKC isoforms in cytosol and membrane fraction was assessed after a 20-min global ischemia in isolated rabbit hearts. Results Interstitial serotonin levels were markedly increased during 30-min ischemia in in vivo and isolated hearts, and the increases were inhibited by SG in each. The infarct size was reduced by SG (27 ± 2% vs. 40 ± 3% of control). This effect was blocked by chelerythrine and 5-HD, respectively. Sarpogrelate further enhanced the ischemia-induced translocation of PKC-ϵ to the membrane fraction. Conclusions Sarpogrelate reduces the myocardial infarct size by inhibiting the serotonin release followed by enhancement of PKC-ϵ translocation and opening of the mitochondrial KATP channel in ischemic myocytes.

Background — The purpose of the present study was to define whether integrated backscatter (IB) combined with conventional intravascular ultrasound (IVUS) makes tissue characterization of coronary arterial plaques possible. Methods and Results — IB-IVUS was performed in coronary arteries (total 18 segments) of 9 patients at autopsy, and the findings were compared with the histology. RF signals, which were digitized at 2 GHz in 8-bit resolution, were obtained with an IVUS system with a 40-MHz catheter. IB values of the RF signal from the region of interest (ROI) (100-μm depth, 1.4° per line) were calculated by use of a personal computer. IB values on the ROIs were divided into 5 categories, compared with each of the plaque histologies: category 1 (thrombus), −88 < IB ≤ −80; category 2 (intimal hyperplasia or lipid core), −73 < IB ≤ −63; category 3 (fibrous tissue), −63 < IB ≤ −55; category 4 (mixed lesions), −55 < IB ≤ −30; and category 5 (calcification), −30 < IB ≤ −23. On the basis of these categories, we analyzed 5120 ROIs per segment in each ring-like arterial specimen. Color-coded maps of plaques were constructed by use of these IB data and conventional IVUS data, which reflected the plaque histology of autopsied coronary arteries well. Then, the same method was undertaken in 24 segments with plaque from 12 patients in vivo with angina pectoris. Comparisons between coronary angioscopy and IB-IVUS revealed that the surface color of plaques in angioscopy reflected the thickness of the fibrous cap rather than the size of the lipid core. Conclusions — IB-IVUS represents a new and useful tool for evaluating the tissue structure of human coronary arterial plaques.

The present study used isolated rat hearts to investigate whether (1) Sheng-Mei-San (SMS), a traditional Chinese formulation comprising Radix Ginseng, Radix Ophiopogonis and Fructus Schisandrae, is protective against post-ischemic myocardial dysfunction, and (2) whether the cardioprotective effect of SMS is related to scavenging of hydroxyl radicals and opening the mitochondrial KATP channels. The excised hearts of male Sprague-Dawley rats were perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O2 and 5% CO2. Left ventricular end-diastolic pressure (LVEDP, mmHg), left ventricular developed pressure (LVDP, mmHg), ±dP/dt (mmHg/s) and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 min consisting of a 30-min pre-ischemic period followed by a 30-min global ischemia and 60-min reperfusion. Lactate, lactate dehydrogenase (LDH) and 2,5-dihydroxybenzoic acid (2,5-DHBA) concentrations in the effluent were measured during reperfusion. Three days' treatment with SMS (1.67 ml/kg per day) inhibited the rise in LVEDP and improved the post-ischemic LVDP and ±dP/dt significantly better than in the untreated control hearts during reperfusion. SMS increased the coronary flow at baseline, and during reperfusion. Pretreatment with 5-hydroxydecanoic acid (5-HD), a mitochondrial KATP channel blocker, abolished the inhibition of the rise in LVEDP, the increase in coronary flow and the improvement in LVDP and ±dP/dt induced by SMS. SMS significantly attenuated the concentrations of lactate, LDH and 2,5-DHBA during reperfusion, but the pretreatment with 5-HD restored them; 5-HD alone did not affect the concentrations. SMS improved the post-ischemic myocardial dysfunction through opening the mitochondrial KATP channels. (Circ J 2002; 66: 763 - 768)

Chronic congestive heart failure (CHF) causes structural remodeling of the liver, generally leading to nutmeg liver. Male UM-X7.1 hamsters, a strain developing cardiomyopathy, had no CHF and decompensated CHF (n = 6 each) at the age of 10 and 30 weeks, respectively. We used age-matched, male Syrian hamsters without CHF (n = 6 each) as controls. All the 30-week-old UM-X7.1 hamsters had a typical nutmeg liver in which the population of hepatocytes was decreased. Positive in situ nick end labeling (TUNEL) was found in 2.2 +/- 0.74% of hepatocytes in congestive livers, being significantly higher compared with the other groups without CHF (< 0.5%). DNA ladder pattern was also evident in the congestive livers. Electron microscopy revealed a typical apoptotic ultrastructure in the hepatocytes of the 30-week-old UM-X7.1 hamsters. However, many showed secondary necrotic changes. Although hepatocytes undergoing oncosis (primary necrosis) are rare, they were also found. The level of soluble Fas ligand in the plasma was increased, and Fas receptor in the liver was overexpressed in the CHF animals. In addition, both the Bax/Bcl-2 ratio and the Bad/Bcl-xL ratio were increased, and caspase-3 was activated in them. Our findings suggest that hepatocyte apoptosis contributes to hepatic remodeling under conditions of CHF.

Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified in Caucasian populations by genome-wide association studies (GWASs). The aim of the present study was to examine a possible association of chronic kidney disease (CKD) with 29 polymorphisms previously identified as susceptibility loci for CAD by meta-analyses of GWASs.The study population comprised 2247 Japanese individuals, including 1588 subjects with CKD [estimated glomerular filtration rate (eGFR) of60 mL min(-1) 1.73 m(-2) ] and 659 controls (eGFR of ≥90 mL min(-1) 1.73 m(-2) ). The genotypes for 29 polymorphisms of 28 candidate genes were determined.The χ(2) test revealed that rs4845625 (T→C) of IL6R, rs4773144 (A→G) of COL4A1, rs9319428 (G→A) of FLT1, and rs46522 (T→C) of UBE2Z were significantly (P 0.05) related to CKD. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and dyslipidaemia revealed that rs4845625 of IL6R (P = 0.0008; dominant model; odds ratio, 1.49), rs4773144 of COL4A1 (P = 0.0252; dominant model; odds ratio, 1.28), and rs9319428 of FLT1 (P = 0.0260: additive model; odds ratio, 0.77) were significantly associated with CKD. The serum concentration of creatinine was significantly (P = 0.0065) greater and eGFR was significantly (P = 0.0009) lower in individuals with the TC or CC genotype of IL6R than in those with the TT genotype.The rs4845625 of IL6R may be a susceptibility locus for CKD in Japanese individuals.

Background: Hypertension (HTN) is one of the major causes of atrial fibrillation (AF), since it is usually accompanied by left atrial (LA) remodeling due to pressure and/or volume (LAV) overload. We examined the relationship between ventricular (LV) geometry or LV properties in HTN and the incidence of paroxysmal AF (PAF) using novel, one-beat, automated, 3-dimensional speckle tacking echocardiography (3D-STE) with high volume rates. Methods: Patients with HTN (n=107, age 69±7) and controls (n=60, age 69±9) were prospectively enrolled. HTN patients were divided into 5 groups according to LV geometry and the presence of hypertensive heat failure (HHF) {normal geometry (n=25), concentric remodeling (n=20), concentric hypertrophy (LVH) (n=24), eccentric LVH (n=21) and HHF (n=17)}. Isovolumic relaxation time (IVRT) was measured by Doppler echo. We evaluated LV ejection fraction (EF), E/e’, pulmonary capillary wedge pressure (PCWP), Tau, LV diastolic stress, LV strain and LV myocardial stiffness in sinus rhythm. PCWP was estimated as 10.7- 12.4 x log (LA active emptying function / minimum LAV) as we reported. Tau was calculated as IVRT / (ln 0.9 x systolic blood pressure - ln PCWP). LV diastolic stress was calculated as LV radius at end diastole x PCWP / thickness. LV strain rate (SR) during IVR, as an index of relaxation, and LV strain were measured by the 3D-STE with volume rates of 50-80vps. LV myocardial stiffness was estimated as LV stress / LV strain. Results: LVEF was reduced only in HHF compared with controls (56±7 vs. 67±6%). Conclusion: LVEF in HHF was decreased but still remained within the normal range, whereas diastolic properties in eccentric LVH and HHF were reduced compared with control. The incidence of PAF significantly increased in eccentric LVH and HHF associated with the impairment of LV relaxation and stiffness and increased LV stress. This suggests that the target of treatment to reduce the incidence of PAF in HTN must be diastolic function.

Background: The incidence of new-onset atrial fibrillation (AF) is increasing with the prevalence of diastolic dysfunction. Diastolic dysfunction is thought to be responsible for heart failure with preserved ejection fraction (HFPEF). Effective medication for the treatment of HFPEF has been controversial, although angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) and beta-blockers (BBs) have been proven to be effective in heart failure with reduced EF. We recently reported that pulmonary capillary wedge pressure (ePCWP) estimated by the combination of left atrial (LA) volume (V) and emptying function (EF) evaluated by speckle tracking echocardiography (STE) had a strong correlation with PCWP measured by cardiac catheterization (r=0.86-0.92). Methods: We screened 663 elderly (>65 years old) patients and identified 228 who had no AF history and met the criteria for diastolic dysfunction according to the Echocardiography Association of the European Society of Cardiology. These patients were prospectively followed for 4 years to identify new-onset AF. We measured echocardiographic parameters such as left ventricular (LV) mass index, LV ejection fraction, E/A, E/e’ and ePCWP at baseline. Concomitant medication was left to the discretion of the physicians in charge. Results: During a mean follow-up of 43 months, 63 elderly patients (age 73±6, 39 men) developed electrocardiographically-confirmed AF. There was no significant difference in the development of new-onset AF between the groups treated with and without BBs (hazard ratio (HR): 0.615, p=0.15). There was also no significant difference in new-onset AF between the groups with and without ACEIs or ARBs (HR: 0.796, p=0.46). However, in multivariate analysis that included ePCWP, LVM index, E/e’ and E/A, ePCWP at baseline independently predicted the risk of new-onset AF (HR: 1.42, 95% confidence interval: 1.29-1.57, p Conclusions: ACEIs, ARBs or BBs had no beneficial effects on the prevention of new-onset AF as a marker of diastolic dysfunction in the patients with HFPEF. Estimation of ePCWP by STE had incremental value for the risk stratification of new-onset AF.

Although various genes that confer susceptibility to myocardial infarction (MI) have been identified for Caucasian populations in genome-wide association studies (GWAS), genetic variants related to this condition in Japanese individuals have not been identified definitively. The aim of the present study was to examine an association of MI in Japanese individuals with 29 polymorphisms identified as susceptibility loci for MI or coronary artery disease in Caucasian populations by meta- analyses of GWAS. The study subjects comprised 1,824 subjects with MI and 2,329 controls. Genotypes of the polymorphisms were determined by Luminex bead-based multiplex assay. To compensate for multiple comparisons, we adopted the criterion of a false discovery rate (FDR) of

BackgroundWe hypothesized that a development of a novel index based on the combination of left atrial volume (LAV) and left atrial (LA) function evaluated by the time–LA volume curve using speckle tracking echocardiography (STE) would be accurate and useful to estimate pulmonary capillary wedge pressure (PCWP). Our goal was to develop a novel index of PCWP based on a combination of LAV and LA function using STE.MethodsA cross-validation study was performed with the patients divided into a training study to define the novel index (n=50) and a testing study to validate the index (n=196). PCWP was measured by right heart catheterization, and phasic LAV and emptying function (EF) were measured by STE.ResultsSimple linear regression analysis in the training study revealed that the novel index that best estimated PCWP was the kinetics-tracking index [KT index=log10 (active LAEF/minimum LAV index)]. Multiple regression analysis revealed that the KT index was the most reliable predictor of PCWP. It had the strongest correlation with PCWP (r=−0.86, p

Left ventricular (LV) systolic properties in hypertension (HTN) may be impaired by pressure overload, resulting in heart failure (HF) with reduced ejection fraction (EF). Using tissue Doppler and 2-dimensional speckle tracking echocardiography (2D-STE), LV myocardial strain rate (SR) was reported as

During 1997 to 1998, near-surface currents in the western North Pacific subtropical gyre have been measured repeatedly by an ADCP mounted on the hull of the volunteer observing ship (VOS) operated mainly between Japan and Australia. The Kuroshio Current, the Kuroshio Recirculation and the North Equatorial Current are clearly identified as two-year mean currents in the latitude belt 10–34.5° N. Current variability was dominated by baroclinic Rossby waves or mesoscale eddies over the 10–30° N belt except in the latitude belt 13–17° N where the north-to-south shifts of the North Equatorial Current stream axis may dominate current variability. The energy of the mesoscale variability was concentrated to form large peaks around 18.5°N and 23°N.

The anti-diabetic drug miglitol, an α-glucosidase inhibitor, which is currently used clinically, reduces myocardial infarct size by reducing the glycogenolytic rate through inhibition of the α-1,6-glucosidase of glycogen-debranching enzyme in the heart. Nicorandil, a KATP channel opener with a nitrate-like effect, which is also currently used clinically, also reduces the infarct size. Therefore, we hypothesized that combination of nicorandil and submaximal dose of miglitol could markedly reduce myocardial infarct size more than miglitol or nicorandil alone, and investigated the mechanism for the infarct size-reducing effect. Japanese white rabbits without collateral circulation were subjected to 30 min coronary occlusion followed by 48 h reperfusion. Pre-ischaemic treatment with submaximal dose of miglitol (5 mg kg−1, i.v.) and nicorandil alone (100 μg kg−1 min−1 5 min) moderately reduced the infarct size as a percentage of area at risk (24±4 and 25±4%, respectively), and 10 mg kg−1 of miglitol markedly reduced the infarct size (15±2%) compared with the controls (42±2%). Combination of 5 mg kg−1 of miglitol and nicorandil (100 μg kg−1 min−1 5 min), and 10 mg kg−1 of miglitol and nicorandil (100 μg kg−1 min−1 5 min) significantly reduced the infarct size (13±4 and 12±3%, respectively) more than miglitol or nicorandil alone. Pretreatment with 5HD completely abolished the infarct size-reducing effect of 10 mg kg−1 of miglitol alone (36±7%) and that of combination of 5 mg kg−1 of miglitol and nicorandil (46±2%). Combination of nicorandil and submaximal dose of miglitol markedly reduced the myocardial infarct size more than miglitol or nicorandil alone. This effect was suggested to be related to the opening of mitochondrial KATP channels. British Journal of Pharmacology (2001) 133, 1041–1046; doi:10.1038/sj.bjp.0704166

OBJECTIVES The purpose of the present study was to define clinicopathologically whether integrated backscatter (IB) combined with conventional two-dimensional echo (2DE) can differentiate the tissue characteristics of calcification (CL), fibrosis (FI), lipid pool (LP) with fibrous cap, intimal hyperplasia (IH) and thrombus (TH) and can construct two-dimensional tissue plaque structure in vivo. BACKGROUND It is difficult to characterize the components of plaque using conventional 2DE techniques. METHODS Integrated backscatter values of plaques were measured in the right common carotid and femoral arteries (total 24 segments) both during life and after autopsy in 12 patients (age 68 to 84 years, 10 men and two women). Integrated backscatter values were determined using a 5–12 MHz multifrequency transducer, setting the region of interests (ROIs) (11 × 11 pixels) on the echo tomography of the entire arterial wall (55 ± 10 ROI/segment) and comparing it with histologic features in the autopsied arterial specimens. RESULTS Corrected IB values obtained before death and at autopsy were significantly correlated (r = 0.93, p CONCLUSIONS Integrated backscatter with 2DE represents a useful noninvasive tool for evaluating the tissue structure of human plaque.

Preischaemic treatment with N-methyl-1-deoxynojirimycin (MOR-14), an α-1,6-glucosidase inhibitor, attenuates glycogenolysis and lactate accumulation during ischaemia and markedly reduces infarct size in rabbit hearts. In the present study, we have investigated whether protein kinase C (PKC), a principal mediator of ischaemic preconditioning, is also involved in the cardioprotective effect of MOR-14. To assess the effect of PKC inhibition on infarct size in MOR-14-treated hearts, 38 rabbits were subjected to 30 min of ischaemia followed by 48 h of reperfusion. Infarct size, as a per cent of area at risk, was significantly smaller in rabbits administered 100 mg kg−1 of MOR-14 10 min before ischaemia (17±2%, n=10), than in a control group (46±5%, n=10). This beneficial effect of MOR-14 was abolished when 5 mg kg−1 of chelerythrine, a PKC inhibitor, was given 10 min prior to MOR-14 injection (39±4%, n=10), although chelerythrine alone did not alter infarct size (43±4%, n=8). Further, chelerythrine had no effect on MOR-14-induced attenuation of glycogen breakdown and lactate accumulation in hearts excised at 30 min of ischaemia. Immunoblot analysis of PKC in homogenates of Langendorff-perfused rabbit hearts revealed that MOR-14 significantly increased levels of PKC-e in the particulate fraction at 20 and 30 min of ischaemia and in the cytosolic fraction at 30 min of ischaemia. Taken as a whole, our data suggest that PKC acts downstream of the inhibition of glycogenolysis by MOR-14 to reduce infarct size. Thus, activation of PKC is a more direct mediator of the cardioprotection afforded by MOR-14 than is inhibition of glycogenolysis. British Journal of Pharmacology (2001) 133, 635–642; doi:10.1038/sj.bjp.0704107

N-methyl-1-deoxynojirimycin (NMDN), an a-glucosidase inhibitor, reduces myocardial infarct size by reducing the glycogenolytic rate through inhibition of the alpha-1,6-glucosidase of glycogen-debranching enzyme in the heart, in addition to possessing an antihyperglycemic action by blocking alpha-1,4-glucosidase in the intestine. Ischemic preconditioning (PC), which markedly reduces the size of the myocardial infarct, is known to reduce the activity of phosphorylase and reduce the glycogenolytic rate. Therefore, it was hypothesized that a combination of pharmacological inhibition of glycogenolysis by an alpha-1,6-glucosidase inhibitor, NMDN, and PC could markedly reduce myocardial infarct size more than NMDN or PC alone. Japanese white rabbits without collateral circulation were subjected to a 30-min coronary occlusion followed by 48-h reperfusion. The infarct sizes as a percentage of area at risk were significantly reduced by pre-ischemic treatment with either 100mg/kg of NMDN or PC of 5 min ischemia and 5 min reperfusion alone (15.9+/-2.0%, n=8, and 10.3+/-1.2%, n=8, respectively) as compared with the control (43.9+/-2.2%, n=8). However, the combination of 100mg/kg of NMDN and PC significantly reduced the infarct size (4.9+/-1.2, n=8) compared with NMDN or PC alone. Another 40 rabbits, also given 100mg of NMDN, PC, NMDN+PC or saline before ischemia (n=10 in each group), were killed for biochemical analysis after 30 min of ischemia. NMDN and PC preserved the glycogen content and attenuated the lactate accumulation, respectively, as compared with the control. However, the combination of NMDN and PC preserved significantly more glycogen and significantly reduced lactate accumulation than either NMDN or PC alone. The combination of NMDN and PC markedly reduced the myocardial infarct size more than either process alone. The marked preservation of glycogen and marked attenuation of lactate accumulation by the combination of NMDN and PC suggest that the mechanism for this effect of NMDN+PC is related to the inhibition of glycogenolysis.

Some infarcted myocytes undergo caspase-dependent DNA fragmentation, but serine protease-dependent DNA fragmentation may also be involved. There is controversy regarding whether caspase inhibitors can reduce infarct size, so the present study investigated whether serine protease inhibitor can reduce the DNA fragmentation of infarcted myocytes and whether serine protease or caspase inhibitors attenuates myocardial infarct size in Japanese white rabbits without collateral circulation. Rabbits were subjected to 30-min coronary occlusion followed by 48-h reperfusion. A vehicle (dimethylsulfoxide, control group, n=8) or Z-Val-Ala-Asp(Ome)-CH2F (ZVAD-fmk, a caspase inhibitor, ZVAD group, 0.8 mg/kg iv at 20 min before coronary occlusion and 0.8 mg/kg at 90 min after reperfusion, n=8) or 3,4-dichloroisocoumarin (DCI, a serine protease inhibitor, 2 mg/kg iv at 20 min before coronary occlusion, DCI group, n=8) was administered. Animals were killed at 48h after reperfusion for the detection of myocardial infarct size and at 4h after reperfusion for the detection of dUTP nick end-labeling (TUNEL)-positive myocytes, the electrophoretic pattern of DNA fragmentation and ultrastructural analysis. The left ventricle (LV) was excised and sliced. The myocardial infarct size as a percentage of the area at risk was assessed by triphenyltetrazolium chloride staining. DNA fragmentation was assessed by in situ TUNEL at the light microscopic level. ZVAD and DCI significantly reduced the mean blood pressure during reperfusion without affecting heart rate. There was no significant difference in the % area at risk (AAR) of LV among the 3 groups (control: 26.3+/-3.0%; ZVAD: 25.6+/-2.6%; DCI: 25.6+/-2.0%). The % infarct size as a percentage of the AAR in the ZVAD group (41.3+/-4.5%) and the DCI group (50.4+/-3.8%) was not significantly different from the control group (43.5+/-4.5%). However, the percent DNA fragmentation in the infarcted area in the ZVAD (3.5+/-0.8%) and DCI groups (4.2+/-0.9%) was significantly reduced compared with the control group (10.7+/-1.9%). The DNA ladder pattern observed in the control group was attenuated in both the ZVAD and DCI groups. There was no difference in electron microscopic changes among the 3 groups. Serine protease-dependent DNA fragmentation is present in infarcted myocytes, in addition to caspase-dependent DNA fragmentation, but an infarct-size reducing effect was not observed with either of these inhibitors.

We examined whether pharmacological inhibition of glycogenolysis by N-methyl-1-deoxynojirimycin (MOR-14), a new compound which reduces the glycogenolytic rate by inhibiting the alpha-1,6-glucosidase activity of the glycogen-debranching enzyme, can protect the heart against postischemic left ventricular dysfunction. The hearts of male Sprague-Dawley rats were excised, and perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O2 and 5% CO2. The hearts were paced at 320 beats/min except during the ischemia. Left ventricular developed pressure (LVDP, mmHg), +/-dP/dt (mmHg/s), and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 min including a 30-min preischemic period followed by a 30-min episode of global ischemia and 60 min reperfusion. with or without 0.5 or 2 mM of MOR-14 during the 30-min preischemic period or the first 30 min of reperfusion. In another series of experiments, the myocardial content of glycogen and lactate was measured during the 30-min episode of ischemia in groups treated with and without 2mM of MOR-14. Preischemic but not postischemic treatment with MOR-14 significantly improved LVDP and +/-dP/dt without altering coronary flow during reperfusion in a dose-dependent manner. MOR-14 significantly preserved the glycogen content and significantly attenuated the lactate accumulation during the 30-min episode of ischemia. Preischemic treatment with MOR-14 is protective against postischemic left ventricular dysfunction through the inhibition of glycogenolysis in the isolated rat heart.