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Aims Although distinct DNA methylation patterns have been reported, its localization and roles remain to be defined in heart failure. We investigated the cellular and subcellular localization of DNA methylation and its pathophysiological significance in human failing hearts. Methods and results Using left ventricular (LV) endomyocardial biopsy specimens from 75 patients with dilated cardiomyopathy (DCM; age: 58 ± 14 years old, %female: 32%) and 20 patients without heart failure (controls; age: 56 ± 17 years old, %female: 45%), we performed immunohistochemistry and immunoelectron microscopy for methylated DNA, 5‐methylcytosine (5‐mC). We next investigated possible relations of the incidence of 5‐mC‐positive (%5‐mC+) cardiomyocytes with clinicopathological parameters. Immunopositivity for 5‐mC was detected in the cardiomyocytes and other cell types. The %5‐mC+ cardiomyocytes was significantly greater in DCM hearts than in controls (57 ± 13% in DCM vs. 25 ± 12% in controls, P < 0.0001). The localization of 5‐mC immunopositivity in cardiomyocyte nuclei coincided well with that of heterochromatin, as confirmed by immunoelectron microscopy. Substantial DNA methylation was also observed in interstitial non‐cardiomyocytes, but the incidences did not differ between control and DCM hearts (39 ± 7.9% in DCM vs. 41 ± 10% in controls, P = 0.4099). In DCM patients, the %5‐mC+ cardiomyocytes showed a significant inverse correlation with LV functional parameters such as heart rate (r = 0.2391, P = 0.0388), end‐diastolic pressure (r = 0.2397, P = 0.0397), and ejection fraction (r = −0.2917, P = 0.0111) and a positive correlation with LV dilatation (volume index at diastole; r = 0.2442, P = 0.0347; and volume index at systole; r = 0.3136, P = 0.0062) and LV hypertrophy (mass index; r = 0.2287, P = 0.0484)—that is, LV remodelling parameters. No significant correlations between DNA methylation and the histological parameters of the biopsies, including cardiomyocyte hypertrophy, fibrosis, and inflammatory cell infiltration, were noted. Conclusions The present study revealed increased nuclear DNA methylation in cardiomyocytes, but not other cell types, from DCM hearts, with predominant localization in the heterochromatin. Its significant relations with LV functional and remodelling parameters imply a pathophysiological significance of DNA methylation in heart failure.

We encountered an unfamiliar finding during electron microscopic examination of an endomyocardial biopsy obtained from a 55-year-old woman suffering from heart failure due to dilated phase hypertrophic cardiomyopathy. Many cardiomyocytes contained large vacuoles that were mainly empty except for small amounts of amorphous substrate. These were not autophagic vacuoles, as they lacked limiting membranes. Six years later, we encountered similar histological findings in three successive biopsies sourced from another hospital. They were obtained from a 77-year-old man with hypertrophic cardiomyopathy, a 28-year-old woman with endocardial fibrosis, and a 33-year-old man with dilated cardiomyopathy. This biopsy was the second for the endocardial fibrosis patient, and her first biopsy showed no vacuoles within cardiomyocytes. Close inspection of the procedures revealed that in all of these cases the fixed biopsy specimens were carried to the hospital from other institutes using a refrigerated courier service. We then fixed rat heart tissues, froze them once, and processed them for electron microscopy. In that experiment, we were able to reproduce the vacuolar cardiomyocytes, thereby demonstrating it to be a laboratory artifact. We therefore want to emphasize to physicians not to freeze biopsy specimens and not to use a refrigerated courier service for their transport.

Background: Decreased skeletal muscle mass index (SMI) is a major complication of severe chronic heart failure (HF), but no appropriate indices have been developed to predict decreased SMI. Methods and Results: We enrolled patients with a structural heart disease or history of HF and collected body composition and blood sample data, including serum amino acid concentration. On multivariate logistic regression analysis and receiver operating characteristic curve analysis, serum branched-chain amino acid (BCAA) concentration was a significant predictor of decreased SMI at 1-year follow-up. Conclusions: Serum BCAA concentration at baseline was significantly associated with decreased SMI at 1-year follow-up.

The index case was a 51-year-old woman suffering from doxorubicin cardiomyopathy. In her endomyocardial biopsy specimen, we observed under electron microscopy six scenes in which degenerative cardiomyocytes were engulfed by neighbouring cardiomyocytes. The enclosed cardiomyocytes appeared more degenerative than the enclosing ones in every pair: the myofibrils were more severely damaged. At more degenerative stages, some desmosomes of the intercalated discs on the enclosed cardiomyocyte had disappeared. The membranes between the cardiomyocytes were occasionally disrupted, and there appeared to be sharing of cellular contents between the cells. One pair of such a phagocytosis-like figure was observed in one case with 5-fluorouracil cardiomyopathy (a 68-year-old man) among eight other chemotherapy-induced cardiomyopathies but none among 30 non-drug-induced dilated cardiomyopathies. The findings suggest a mechanism for disposal of degenerative cardiomyocytes in human failing hearts: phagocytosis by a neighbour, although alternative interpretations remain (e.g. giant autophagic vacuoles or two cardiomyocytes with degenerative intercalated discs).

Anti-apoptotic therapy for cardiomyocytes could be an effective strategy for preventing or treating heart failure. Notably, however, morphological evidence definitively demonstrating cardiomyocyte apoptosis has been very rare in actual heart diseases such as acute myocardial infarction and heart failure. By contrast, within the postinfarction heart, interstitial noncardiomyocytes such as granulation tissue cells do die via apoptosis to form scar tissue. Blockade of this apoptosis improves survival and mitigates ventricular remodeling and dysfunction during the chronic stage. Possible mechanisms to explain this benefit might be preservation of infarcted wall thickness and preservation of myofibroblasts, which could promote infarct shrinkage; both would reduce wall stress through Laplace's law. On the other hand, autophagy is an intracellular degradation mechanism that compensates for energy insufficiency by digesting and recycling intracellular components, and is often observed in cardiomyocytes within failing hearts with various origins including postinfarction. Starvation strongly induces and activates autophagic degeneration within cardiomyocytes. When that activation is inhibited, the starved animals suffer from heart failure. Promoting autophagy through caloric restriction or several reagents not only reduces the acute infarct size but also mitigates postinfarction cardiac remodeling and dysfunction during chronic stages. Moreover, augmenting autophagy by the treatment with resveratrol or exercise can bring about reverse remodeling in failing hearts with a large old myocardial infarction. In conclusion, we propose two strategies for managing postinfarction heart failure through control of cell death/degeneration: (1) anti-apoptosis in granulation tissue noncardiomyocytes; and (2) pro-autophagy in salvaged cardiomyocytes.

Background Hyogo Prefecture is the 2nd prefecture in Japan, after Kanagawa, to enact a ban with penal code on smoking in public places, although the restriction is partial.Methods and Results:This study included consecutive patients with acute coronary syndrome (ACS) who were admitted to 33 major hospitals in the Hyogo District during the 12 months before implementation of the legislation and during the 24 months thereafter. Consecutive patients with ACS from Gifu Prefecture who were admitted to 20 major hospitals were enrolled as geographical controls. The number of ACS admissions did not change from the years 2012-2015 in both Hyogo District (1,774 in the pre-year, 1,784 in the 1st year, and 1,720 in the 2nd year) and Gifu Prefecture (1,226 in the pre-year, 1,174 in the 1st year, and 1,206 in the 2nd year). However, a clear reduction was observed in the subanalysis for Kobe City (895 in the preceding year, 830 (-7.3%) in the 1st year, and 792 (-11.5%) in the 2nd year), where adherence to the smoking ban was higher than in other Hyogo districts. Conclusions The primary endpoint did not show a significant change. However, the subanalysis showed a significant decrease in ACS admissions in Kobe City. These results suggest that ACS reduction may depend on the degree of adherence to a smoking ban. (Circ J 2016; 80: 2528-2532).

Background The purpose of the present study was to evaluate the tissue characteristics of plaques with moderate or mild stenosis in the inner and outer curvature of the left anterior descending artery (LAD) using integrated backscatter intravascular ultrasound. Methods We evaluated 66 plaques with moderate stenosis (plaque burden >50% but ≤75%) and 49 plaques with mild stenosis (plaque burden >30% but ≤50%) in 66 patients undergoing percutaneous intervention to the LAD. All plaques were >10 mm away from any side branch or previously implanted stents. We divided vessel cross-sections into four quadrants (inner curvature, outer curvature, clockwise lateral side, and counterclockwise lateral side) using the septal branch as a landmark for the inner curvature. We averaged relative lipid area, relative fibrous area, and relative calcified area in minimal lumen area (MLA), three cross-sections proximal to the site of MLA, and three cross-sections distal to the site of MLA. Results In plaques with moderate stenosis, the relative lipid area in the inner curvature was significantly greater than in the outer curvature and lateral sides, whereas there was no significant difference in plaques with mild stenosis. Conclusion The present study provides new findings that lipid pool is clustered in the inner curvature and fibrous tissue is clustered in the outer curvature of plaques with moderate stenosis in non-branching LAD lesions.

Although OPC-28326, 4-( N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl) piperidine hydrochloride monohydrate, was developed as a selective peripheral vasodilator with α2-adrenergic antagonist properties, it also reportedly exhibits angiogenic activity in an ischemic leg model. The purpose of this study was to examine the effect of OPC-28326 on the architectural dynamics and function of the infarcted left ventricle during the chronic stage of myocardial infarction. Myocardial infarction was induced in male C3H/He mice, after which the mice were randomly assigned into two groups: a control group receiving a normal diet and an OPC group whose diet contained 0.05% OPC-28326. The survival rate among the mice ( n = 18 in each group) 4 wk postinfarction was significantly greater in the OPC than control group (83 vs. 44%; P < 0.05), and left ventricular remodeling and dysfunction were significantly mitigated. Histologically, infarct wall thickness was significantly greater in the OPC group, due in part to an abundance of nonmyocyte components, including blood vessels and myofibroblasts. Five days postinfarction, Ki-67-positive proliferating cells were more abundant in the granulation tissue in the OPC group, and there were fewer apoptotic cells. These effects were accompanied by activation of myocardial Akt and endothelial nitric oxide synthase. Hypoxia within the infarct issue, assessed using pimonidazole staining, was markedly attenuated in the OPC group. In summary, OPC-28326 increased the nonmyocyte population in infarct tissue by increasing proliferation and reducing apoptosis, thereby altering the tissue dynamics such that wall stress was reduced, which might have contributed to a mitigation of postinfarction cardiac remodeling and dysfunction.

Loss of skeletal muscle mass and low nutritional status are major complications of severe chronic heart failure (CHF) and have been associated with poor prognosis. This study aimed to identify the nutritional status of outpatients with CHF based on their body composition, such as skeletal muscle index (SMI) and serum amino acid concentration.We compared the body composition data and results of blood samples, including the serum amino acid concentration, of patients with CHF and those of controls.No significant difference was found in total amino acid concentration between 105 patients with CHF (62% men, mean age: 71.0±11.0 years) and 106 controls (67% men, mean age: 69.1±9.4 years) (CHF: 3459.1±504.9nmol/ml, control: 3575.8±513.1nmol/ml; p=0.072). However, the concentration of essential amino acids (EAA) (CHF: 949.5±197.9nmol/ml, control: 1034.1±207.3nmol/ml; p=0.002) and branched-chain amino acid (BCAA) (CHF: 449.3±114.3nmol/ml, control: 503.9±118.2nmol/ml; p0.001) and Fischer's ratio (CHF: 2.86±0.62, control: 3.17±0.50; p0.001) were significantly lower in patients with CHF. Integrated analysis of these data revealed that SMI was negatively correlated with age [correlation coefficient (R), -0.313; 95% confidence interval (CI), -0.514 to -0.079; p=0.010], but positively correlated with EAA concentration (R, 0.256; 95% CI, 0.017-0.467; p=0.037), BCAA concentration (R, 0.362; 95% CI, 0.134-0.554; p=0.003), and Fischer's ratio (R, 0.573; 95% CI, 0.386-0.715; p0.001).Serum concentrations of EAA and BCAA and Fischer's ratio were lower in patients with CHF than in controls, while SMI correlated with EAA, BCAA, and Fischer's ratio.

BACKGROUND The results of previous clinical trials on the effects of ezetimibe-statin combination therapy on atherosclerosis are inconsistent, and the anti-atherosclerotic effect of ezetimibe remains controversial.Methods and Results:We conducted a prospective, randomized open-label study at 10 centers. One hundred and twenty-eight statin-naive patients with acute coronary syndrome (ACS) undergoing intravascular ultrasound (IVUS)-guided percutaneous coronary intervention were randomized to receive either 2 mg/day pitavastatin plus 10 mg/day ezetimibe, or 2 mg/day pitavastatin. One hundred and 3 patients had evaluable IVUS of non-culprit coronary lesions at baseline and at follow-up. The primary endpoint was the percentage change in non-culprit coronary plaque volume (PV) and lipid PV on integrated backscatter IVUS. Mean low-density lipoprotein cholesterol was reduced from 123 mg/dL to 64 mg/dL in the combination therapy group (n=50) and 126 mg/dL to 87 mg/dL in the statin alone group (n=53; between-group difference, 16.9%, P

Recently, a new generation of multi-detector row computed tomography (CT) with 320-detector rows (DR) has become available in the clinical settings. The purpose of the present study was to determine the cutoff values of Hounsfield unit (HU) for discrimination of plaque components by comparing HU of coronary plaques with integrated backscatter intravascular ultrasound (IB-IVUS) serving as a gold standard. Seventy-seven coronary atherosclerotic lesions in 77 patients with angina were visualized by both 320-DR CT (Aquilion One, Toshiba, Japan) and IB-IVUS at the same site. To determine the thresholds for discrimination of plaque components, we compared HU with IB values as a gold standard. Optimal thresholds were determined from receiver operating characteristic (ROC) curves analysis. The HU values of lipid pool (n = 115), fibrosis (n = 93), vessel lumen and calcification (n = 73) were 28 ± 19 HU (range −18 to 69 HU), 98 ± 31 HU (44 to 195 HU), 357 ± 65 HU (227 to 534 HU) and 998 ± 236 HU (366 to 1,489 HU), respectively. The thresholds of 56 HU, 210 HU and 490 HU were the most reliable predictors of lipid pool, fibrosis, vessel lumen and calcification, respectively. Lipid volume measured by 320-DR CT was correlated with that measured by IB-IVUS (r = 0.63, p

Inflammatory bowel disease (IBD) severely affects the quality of life of patients. At present, there is no clinical solution for this condition; therefore, there is a need for innovative therapies for IBD. Hepatocyte growth factor (HGF) exerts various biological activities in various organs. However, a clinically applicable and effective HGF-based therapy for IBD has yet to be developed. In this study, we examined the therapeutic effect of injecting an adenoviral vector encoding the human HGF gene (Ad.HGF) into the hindlimbs of mice with dextran sodium sulfate (DSS)-induced colitis. Plasma levels of circulating human HGF (hHGF) were measured in injected mice. The results showed that weight loss and colon shortening were significantly lower in Ad.HGF-infected mice as compared to control (Ad.LacZ-infected) colitic mice. Additionally, inflammation and crypt scores were significantly reduced in the entire length of the colon, particularly in the distal section. This therapeutic effect was associated with increased cell proliferation and an antiapoptotic effect, as well as a reduction in the number of CD4+ cells and a decreased CD4/CD8 ratio. The levels of inflammatory, as well as Th1 and Th2 cytokines were higher in Ad.HGF-infected mice as compared to the control colitic mice. Thus, systemically circulating hHGF protein, produced by an adenovirally transduced hHGF gene introduced at distal sites in the limbs, significantly ameliorated DSS-induced colitis by promoting cell proliferation (i.e., regeneration), preventing apoptosis, and immunomodulation. Owing to its clinical feasibility and potent therapeutic effects, this method may be developed into a clinical therapy for treating IBD.

Background Hyogo is the second prefecture, after Kanagawa, to enact a smoking ban in public places in Japan. The effect of this smoking ban on acute coronary syndrome (ACS) has not been evaluated. Purpose Changes in the annual number of ACS hospital cases in Hyogo Prefecture, before and after the enactment of the prefectural legislative ban on smoking in public places, are to be compared with those in Gifu Prefecture, where there is no smoking-ban legislation. Methods Consecutive Hyogo residents with ACS, admitted to 33 major hospitals in the Hanshin-Awaji-Kobe district, which covers 56% of the population, during the 12 months before implementation of the legislation (April 2012 through March 2013) and during the same 24 months thereafter (April 2013 through March 2015) will be enrolled. Consecutive patients with ACS, who are Gifu residents, treated at the 20 major hospitals in Gifu Prefecture will be enrolled as geographical controls. The primary endpoint is the change in number of ACS admissions from April 2012 through March 2015, considering the periods before and after the smoking-ban legislation in Hyogo prefecture. Conclusion Our study has certain strengths: (1) This is the first large Japanese study of ACS registry with smoking-ban legislation. (2) Major hospitals in the Hanshin-Awaji-Kobe district are included. (3) The data will cover 3 years including 1 year before legislation enactment. (4) The data will be compared with those of Gifu Prefecture, where smoking-ban legislation will not be enacted. (5) The very large database makes possible analysis of subgroups based on age and gender.

Background:In hypertensive patients, left ventricular hypertrophy (LVH) may persist despite satisfactory blood pressure (BP) control. The efficacy of thiazide diuretics in Western countries has been reported, but whether this applies to hypertensive Japanese patients is uncertain.Methods and Results:We randomly assigned 94 patients whose BP was poorly controlled with usual doses of angiotensin-II receptor blockers (ARB), to losartan/hydrochlorothiazide (HCTZ) fixed-dose combination vs. maximum doses of ARB. After 6 months follow-up, decrease in BP, regression of electrocardiographic LVH, and changes in laboratory measurements were examined. Although a similar decrease in BP was observed in both groups, the decrease in LV Sokolow-Lyon voltage, from 34.4±9.2 to 29.4±8.8 mm in the losartan/HCTZ vs. from 29.9±10.2 to 29.1±8.4 mm in the ARB group (P=0.0003), and the decrease in serum B-type natriuretic peptide (BNP) level, from 30.1±28.5 to 26.8±28.0 pg/ml vs. from 23.7±14.8 to 29.8±29.3 pg/ml (P=0.045) were greater in the losartan/HCTZ group. By single variable logistic regression analysis, ∆BNP (P=0.012) and treatment with losartan/HCTZ (P

We investigated the effect of cardiac-targeting erythropoietin (EPO)-encapsulated liposomes with sialyl LewisX (SLX) on myocardial infarct (MI) size, left ventricular (LV) remodeling and function, and its molecular mechanism for repairing infarcted myocardium. In rabbits, MI was induced by 30 min of coronary occlusion followed by reperfusion. EPO-encapsulated liposomes with SLX (L-EPO group), EPO-encapsulated liposomes without SLX (L-EPO without SLX group), liposomes with SLX without EPO (L group), or saline (saline group) were intravenously administered immediately after MI. MI sizes and numbers of microvessels were assessed 14 days after MI. Prosurvival proteins and signals were assessed by Western blot analysis 2 and 14 days after MI. Confocal microscopy and electron microscopy showed the specific accumulation of liposomes with SLX in the infarcted myocardium. MI and cardiac fibrosis areas were significantly smaller in the L-EPO group than in the other groups. LV function and remodeling were improved in the L-EPO group. The number of CD31-positive microvessels was significantly greater in the L-EPO group than in the other groups. Higher expressions of EPO receptors, phosphorylated (p)Akt, pERK, pStat3, VEGF, Bcl-2, and promatrix metalloproteinase-1 were observed in the infarct area in the L-EPO group than in the other groups. EPO-encapsulated liposomes with SLX selectively accumulated in the infarct area, reduced MI size, and improved LV remodeling and function through activation of prosurvival signals and by exerting antifibrotic and angiogenic effects. EPO-encapsulated liposomes with SLX may be a promising strategy for active targeting treatment of acute MI.

We investigated the effect of resveratrol, a popular natural polyphenolic compound with antioxidant and proautophagic actions, on postinfarction heart failure. Myocardial infarction was induced in mice by left coronary artery ligation. Four weeks postinfarction, when heart failure was established, the surviving mice were started on 2-week treatments with one of the following: vehicle, low- or high-dose resveratrol (5 or 50 mg/kg/day, respectively), chloroquine (an autophagy inhibitor), or high-dose resveratrol plus chloroquine. High-dose resveratrol partially reversed left ventricular dilation (reverse remodeling) and significantly improved cardiac function. Autophagy was augmented in those hearts, as indicated by up-regulation of myocardial microtubule-associated protein-1 light chain 3-II, ATP content, and autophagic vacuoles. The activities of AMP-activated protein kinase and silent information regulator-1 were enhanced in hearts treated with resveratrol, whereas Akt activity and manganese superoxide dismutase expression were unchanged, and the activities of mammalian target of rapamycin and p70 S6 kinase were suppressed. Chloroquine elicited opposite results, including exacerbation of cardiac remodeling associated with a reduction in autophagic activity. When resveratrol and chloroquine were administered together, the effects offset one another. In vitro , compound C (AMP-activated protein kinase inhibitor) suppressed resveratrol-induced autophagy in cardiomyocytes, but did not affect the events evoked by chloroquine. In conclusion, resveratrol is a beneficial pharmacological tool that augments autophagy to bring about reverse remodeling in the postinfarction heart.

The effect of β-blockers in ST-elevation myocardial infarction (STEMI) patients who have undergone primary percutaneous coronary intervention (PCI) has not been adequately evaluated. Using a large multi-center registry in Japan, we identified 3,692 patients who underwent PCI within 24 h from onset of STEMI and were discharged alive from 2005 to 2007. Three-year cardiovascular outcomes were compared between the 2 groups of patients with (N = 1,614) or without (N = 2,078) β-blocker prescription at discharge. Compared with patients in the no-β group, patients in the β group were younger, more frequently male, more often had hypertension and atrial fibrillation but less often had chronic obstructive pulmonary disease than in the no-β group. Statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers were more frequently prescribed in the β group. Crude incidence of cardiac death and/or recurrent myocardial infarction (cardiac death/MI) tended to be higher in the β group (7.6 vs. 6.2 %, log-rank p = 0.1). After adjusting for potential confounders, β-blockers were associated with significantly higher risk for cardiac death/MI (hazard ratio 1.43, 95 % CI: 1.06–1.94, p = 0.01). β-Blocker prescription at discharge was not associated with better cardiovascular outcomes in patients who underwent PCI after STEMI. Large-scale randomized controlled trials are needed to evaluate the role of β-blocker therapy in these patients.

The Joint European Society of Cardiology-American College of Cardiology Foundation-American Heart Association-World Heart Federation Task Force for the Redefinition of Myocardial Infarction recommends cardiac troponin (cTn)-T as a first-line biomarker, and suggests the use of the 99th percentile of a reference population with acceptable precision (i.e. a coefficient of variance ≤10%) as a cut-off for the diagnosis of acute myocardial infarction. Recently developed troponin assays fulfill this analytical precision. While conventional cTnT assays have often been used as a positive or negative categorical variable, stepwise rises in high sensitivity (Hs)-cTnT in patients presenting with chronic heart failure (HF) have been associated with a progressive increase in the incidence of cardiovascular events. Similar observations have been made in the general population. Hs-cTnT at baseline and during follow-up is a powerful predictor of cardiac events in patients with HF and in the general population. Whether it is the ideal biomarker remains to be confirmed, however. We review the potential contributions of TnT assays in the assessment of risk of HF, in HF, and in myocardial diseases that cause HF.

Summary Background The ambulatory treatment of advanced heart failure (HF) with intermittent infusions of inotropes or natriuretic peptide chosen immediately before each infusion has not been described. Methods Between May 2005 and July 2009, we treated 11 patients presenting with advanced HF, who received a total of 369 infusions of carperitide, olprinone, dopamine, or dobutamine, once or twice weekly. The pharmaceutical was selected before each infusion based on the systolic blood pressure (BP). Results Carperitide, olprinone, and catecholamines were administered to 8 (73 infusions of 0.030 ± 0.004 μg/kg/min for 3.3 ± 0.8 h), 4 (18 infusions of 0.070 ± 0.017 μg/kg/min for 3.3 ± 0.5 h), and 6 patients (278 infusions of 3.6 ± 1.9 μg/kg/min for 2.8 ± 1.0 h), respectively. No adverse effect requiring cessation of infusion was observed. Over a mean follow-up of 29.3 ± 28.8 months (range 2–104), 4 patients died, all from cardiac causes. The Kaplan–Meier cumulative survival rate was 69.3% at 20 months (median follow-up). Compared with the pre-infusion period, the duration and number of hospitalizations for management of HF were decreased by 73.9% ( p = 0.017), and 51.9% ( p = 0.007), respectively, during the treatment period, and the overall medical costs by 56.9% ( p = 0.021). Conclusions In this study population, intermittent drug infusions selected from inotropes or natriuretic peptide based on the baseline systolic BP significantly decreased the length and number of hospitalizations and costs, without increasing mortality. These results indicate that intermittent infusions might be one of the therapeutic options in advanced HF.

Background— There still remain safety concerns on surgical procedures after coronary drug-eluting stents (DES) implantation, and optimal management of perioperative antiplatelet therapy (APT) has not been yet established. Methods and Results— During 3-year follow-up of 12 207 patients (DES=6802 patients and bare-metal stent [BMS] only=5405 patients) who underwent coronary stent implantation in the CREDO-Kyoto registry cohort-2, surgical procedures were performed in 2398 patients (DES=1295 patients and BMS=1103 patients). Surgical procedures (early surgery in particular) were more frequently performed in the BMS group than in the DES group (4.4% versus 1.9% at 42-day and 23% versus 21% at 3-year, log-rank P =0.0007). Cumulative incidences of death/myocardial infarction (MI)/stent thrombosis (ST) and bleeding at 30 days after surgery were low, without differences between BMS and DES (3.5% versus 2.9%, P =0.4 and 3.2% versus 2.1%, P =0.2, respectively). The adjusted risks of DES use relative to BMS use for death/MI/ST and bleeding were not significant (hazard ratio: 1.63, 95% confidence interval: 0.93 to 2.87, P =0.09 and hazard ratio: 0.6, 95% confidence interval: 0.34 to 1.06, P =0.08, respectively). The risks of perioperative single- and no-APT relative to dual-APT for both death/MI/ST and bleeding were not significant; single-APT as compared with dual-APT tended to be associated with lower risk for death/MI/ST (hazard ratio: 0.4, 95% confidence interval: 0.13 to 1.01, P =0.053). Conclusions— Surgical procedures were commonly performed after coronary stent implantation, and the risk of ischemic and bleeding complications in surgical procedures was low. In patients selected to receive DES or BMS, there were no differences in outcomes. Perioperative administration of dual-APT was not associated with lower risk for ischemic events.

SummaryIn industrialized countries, chronic heart failure (HF) is a major illness and cause of death. However, because of the paucity of specific clinical manifestations of HF, its early diagnosis and management might be challenging. Therefore, biochemical markers of HF are now being closely scrutinized. An ideal biochemical marker should be a prognostic indicator, should assist in the early diagnosis, reflect the therapeutic response, and help grading the risk associated with each stage of HF. This review summarizes our current understanding of biochemical markers of HF.

Tetomilast was originally identified as a potent inhibitor of superoxide production in human neutrophils, and is of interest because it may relieve oxidative stress related to chronic obstructive pulmonary disease (COPD). Our objective was to determine whether tetomilast effectively protects against the development of porcine pancreatic elastase (PPE)-induced emphysema in rabbits. Rabbits were divided into three groups (sham n=19, PPE n=19, PPE/Tetomilast n=18). The rabbits were once daily orally administered vehicle solution or tetomilast 5 d/week for 4 weeks before the PPE instillation. We compared pulmonary function, inflammatory cell infiltration, oxidative stress, and the incidences of apoptosis among the three groups. Tetomilast suppressed PPE-induced increases in the incidence of apoptosis and the production of 8-hydroxy-deoxyguanosine (8-OHdG) in lung tissues. PPE-instilled rabbits treated with tetomilast showed significantly less mean linear intercept and significantly better pulmonary function than rabbits administered PPE alone. Tetomilast may inhibit the development of emphysema by attenuating pulmonary inflammation and apoptosis caused by PPE-induced oxidative stress.

Background: It has been reported that the morbidity rate of vasospastic angina is higher in Japan compared to western countries, and its prognosis has already been reported. However, the prognosis of vasospastic angina in relation to coronary angiographic findings, prognostic risk factors and treatment has not yet been fully investigated. Methods and results: From January 2000 to October 2005, 1047 patients with va-sospastic angina diagnosed by coronary angiography at Gifu University Hospital and related hospitals were registered in a cohort study (follow-up rate: 91.4 %, median follow-up duration: 3.8 years). The presence of coronary artery stenosis, diabetes mellitus, total spasm, and age of more than 65 years had a negative prognostic impact on cardiovascular events. Patients were treated with calcium channel blockers such as diltiazem (CAS 33286-22-5, CAS 42399-41-7), am-lodipine (CAS 111470-99-6), nifedipine (CAS 21829-25-4), and benidipine (CAS 91599-74-5). Among these calcium channel blockers, when patient background was matched by the propensity score in patients treated with calcium channel blockers only, the cardiovascular event rate was significantly lower in the benid-ipine group than in the diltiazem group. Conclusion: The study demonstrated for the first time that total spasm is a risk factor, independent of other factors, for cardiovascular events in patients with va-sospastic angina. Treatment with benid-ipine showed a better prognosis than that with diltiazem.

BACKGROUND AND PURPOSE We previously reported that pre-ischaemic i.v. miglitol reduces myocardial infarct size through the inhibition of glycogenolysis during ischaemia. Oral administration of miglitol has been reported to produce glucagon-like peptide 1 (GLP-1). We hypothesized that p.o. administration of miglitol, an absorbable antidiabetic drug, reduces myocardial infarct size by stimulating GLP-1 receptors and inhibiting glycogenolysis in the myocardium. EXPERIMENTAL APPROACH The effects of p.o. and i.v. administration of miglitol on myocardial infarct size were compared in a rabbit model of ischaemia induced by 30 min of coronary occlusion and 48 h of reperfusion. The levels of phospho(p)-PI3kinase and p-Akt were measured in cardiac tissue by use of Western blot analysis. RESULTS Both p.o. and i.v. administration of miglitol reduced the infarct size, and this effect was greater after p.o. than after i.v. administration under similar plasma miglitol concentrations. The reduction in infarct size induced by p.o. miglitol but not that induced by i.v. miglitol was partially inhibited by treatment with exendin(9-39), a GLP-1 receptor blocker. Both p.o. and i.v. miglitol improved ejection fraction and ±dP/dt after myocardial infarction. Miglitol administered p.o. but not i.v. up-regulated the myocardial expression of phospho(p)-PI3kinase and p-Akt following myocardial infarction; an effect that was inhibited by exendin(9-39). CONCLUSIONS AND IMPLICATIONS Administration of miglitol p.o. reduces myocardial infarct size through stimulation of GLP-1 receptors and activation of PI3kinase-Akt pathway in addition to the inhibition of glycogenolysis. These findings may have clinical implications for the p.o. administration of miglitol for the treatment of patients with diabetes mellitus combined with coronary artery disease.

Long-term safety and efficacy of drug-eluting stents remains controversial. The CREDO-Kyoto registry cohort-2 is a physician-initiated non-company sponsored multi-center registry enrolling consecutive patients undergoing first coronary revascularization in 26 centers in Japan. We compared 3-year outcome between patients treated with sirolimus-eluting stent (SES) only (5092 patients) and bare-metal stent (BMS) only (5405 patients). SES-use as compared with BMS-use was associated with significantly lower adjusted risk for all-cause death [hazard ratio (HR) [95% confidence interval (CI)] 0.72 (0.59–0.87), P = 0.0007], which was mainly driven by the reduction in non-cardiac death [HR (95% CI) 0.64 (0.48–0.85), P = 0.002]. The risk of cardiac death [HR (95% CI) 0.82 (0.63–1.07), P = 0.15], myocardial infarction [HR (95% CI) 0.73 (0.51–1.03), P = 0.07] and definite stent thrombosis [HR (95% CI) 0.62 (0.35–1.09), P = 0.1] was not different between the two groups. Despite longer duration of thienopyridine administration, SES-use was associated with significantly lower risk for bleeding [HR (95% CI) 0.75 (0.6–0.95), P = 0.02] and similar risk for stroke [HR (95% CI) 1.0 (0.75–1.34), P = 1.0]. The risk for target-lesion revascularization (TLR) was markedly lower in the SES group [HR (95% CI) 0.42 (0.36–0.48), P < 0.0001]. The direction and magnitude of the effect of SES relative to BMS in patients presenting acute myocardial infarction (AMI) were similar to those in patients presenting otherwise. In conclusion, SES-use as compared with BMS-use was associated with marked reduction of TLR without any increases in death, myocardial infarction, stent thrombosis, stroke and bleeding in real world clinical practice regardless of clinical presentation including AMI.

Previous studies have shown inconsistent results regarding the effects of concomitant use of clopidogrel and proton pump inhibitors (PPI) on cardiovascular outcomes. We sought to evaluate the clinical impact of PPI-use in patients treated with thienopyridines after percutaneous coronary intervention (PCI) in a large Japanese observational database. Among 12446 patients discharged alive on thienopyridines (ticlopidine 90.4% and clopidogrel 9.6%), 3223 patients were treated with PPIs and 9223 patients without PPI at the time of hospital discharge. The PPI group included more patients with co-morbidities than the non-PPI group. The adjusted hazard ratio (HR) of PPI-use for a composite of cardiovascular death, myocardial infarction, and stroke was 1.26 (95% confidence interval (CI) 1.09-1.47, p = 0.002). The adjusted HR of PPI-use for bleeding was 1.26 (95% CI 1.05-1.52, p = 0.013). Cardiovascular and bleeding outcomes were not different among the three groups receiving three different types of PPI. The negative effect of PPI on cardiovascular outcome was consistently seen in both drug-eluting stent (DES) [HR 1.31 (95% CI 1.07-1.6, p = 0.0097)] and non-DES strata [HR 1.25 (95% CI: 0.99-1.57, p = 0.057)] (Interaction p = 0.79) despite the fact that the duration of thienopyridine administration was significantly longer in patients receiving DES. In conclusion, cardiovascular outcomes after PCI were significantly worse in patients with PPI than in patients without PPI in the Japanese real clinical practice. However, the observed poorer cardiovascular outcome in patients receiving PPI was most likely to be related to residual confounding and seemed not causally related to attenuation of antiplatelet effect of thienopyridine through interaction with PPI.

Granulocyte colony-stimulating factor (G-CSF) is a potent angiogenic factor. We hypothesized that G-CSF-immersed gelatin hydrogel microspheres (G-CSF-GHMs) injected into the ischemic legs might continuously release a small amount of G-CSF to locally stimulate angiogenesis without unfavorable systemic effects. Just after ligation of the right femoral artery of BALB/c mice, recombinant human G-CSF (100-μg/kg)-immersed GHM was injected into the right hindlimb muscles; the controls included a saline-injected group, an intramuscularly injected G-CSF group, a subcutaneously injected G-CSG group, and an empty GHM-injected group. Eight weeks later, improvement of blood perfusion to the ischemic limb was significantly augmented in the G-CSF-GHM group compared with any of the control groups. Despite there being no increase in the serum concentration of G-CSF, in peripheral granulocytes, or in circulating endothelial progenitor cells, not only capillary but also arteriolar density was significantly increased in this group. Next, we started treatment with G-CSF-GHM 4 weeks after ligation to examine whether the treatment is effective if performed during the chronic stage of ischemia. The late treatment was also found to effectively improve blood flow in the ischemic leg. In conclusion, G-CSF-GHM administration is suggested to be a promising and readily usable approach to treating peripheral artery disease, applicable even during the chronic stage.

Aims Autophagy is activated in cardiomyocytes in ischaemic heart disease, but its dynamics and functional roles remain unclear after myocardial infarction. We observed the dynamics of cardiomyocyte autophagy and examined its role during postinfarction cardiac remodelling. Methods and results Myocardial infarction was induced in mice by ligating the left coronary artery. During both the subacute and chronic stages (1 and 3 weeks postinfarction, respectively), autophagy was found to be activated in surviving cardiomyocytes, as demonstrated by the up-regulated expression of microtubule-associated protein-1 light chain 3-II (LC3-II), p62 and cathepsin D, and by electron microscopic findings. Activation of autophagy, specifically the digestion step, was prominent in cardiomyocytes 1 week postinfarction, especially in those bordering the infarct area, while the formation of autophagosomes was prominent 3 weeks postinfarction. Bafilomycin A1 (an autophagy inhibitor) significantly aggravated postinfarction cardiac dysfunction and remodelling. Cardiac hypertrophy was exacerbated in this group and was accompanied by augmented ventricular expression of atrial natriuretic peptide. In these hearts, autophagic findings (i.e. expression of LC3-II and the presence of autophagosomes) were diminished, and activation of AMP-activated protein kinase was enhanced. Treatment with rapamycin (an autophagy enhancer) brought about opposite outcomes, including mitigation of cardiac dysfunction and adverse remodelling. A combined treatment with bafilomycin A1 and rapamycin offset each effect on cardiomyocyte autophagy and cardiac remodelling in the postinfarction heart. Conclusion These findings suggest that cardiomyocyte autophagy is an innate mechanism that protects against progression of postinfarction cardiac remodelling, implying that augmenting autophagy could be a therapeutic strategy.

The GIFU substudy of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was conducted to compare the long-term effects of candesartan and amlodipine on office- and home-measured blood pressure (BP), QTc dispersion and left ventricular mass index (LVMI) in high-risk Japanese patients with hypertension. We used a prospective, randomized, open-label design with blinded assessment of endpoints. Patients were assigned to candesartan-based therapy up to 12 mg/day (n = 100) or amlodipine-based therapy up to 10 mg/day (n = 101) and followed for 3 years. LVMI was assessed by echocardiography and QTc dispersion was obtained from electrocardiograms. Both candesartan and amlodipine lowered and controlled office- and home-measured BP levels with no significant between-treatment differences. In patients diagnosed with left ventricular hypertrophy (LVH) at baseline, both candesartan and amlodipine significantly regressed LVMI after 3 years. However, candesartan (41.7 ± 15.1 ms at baseline vs 32.9 ± 16.6 ms after 3 years, p < 0.01), but not amlodipine (41.4 ± 13.5 ms at baseline vs 41.5 ± 16.1 ms after 3 years), produced a significant reduction in QTc dispersion. Larger studies in patients treated for longer periods are needed to determine whether this candesartan effect will translate into improved prognosis in terms of cardiovascular mortality and morbidity.

Objectives We examined the effect of asialoerythropoietin (asialoEPO), a nonerythrogenic derivative of erythropoietin (EPO), on renal dysfunction-associated heart failure. Background Although EPO is known to exert beneficial effects on cardiac function, the clinical benefits in patients with chronic kidney disease are controversial. It remains to be addressed whether previously reported outcomes were the result of relief of the anemia, adverse effects of EPO, or direct cardiovascular effects. Methods Mice underwent 5/6 nephrectomy to cause renal dysfunction. Eight weeks later, when renal dysfunction was established, anemia and cardiac dysfunction and remodeling were apparent. Mice were then assigned to receive saline (control), recombinant human erythropoietin (rhEPO) at 5,000 IU (714 pmol)/kg, or asialoEPO at 714 pmol/kg, twice/week for 4 weeks. Results Although only rhEPO relieved the nephrectomy-induced anemia, both rhEPO and asialoEPO significantly and similarly mitigated left ventricular dilation and dysfunction. The hearts of rhEPO- or asialoEPO-treated mice showed less hypertrophy, reflecting decreases in cardiomyocyte hypertrophy and degenerative subcellular changes, as well as significant attenuation of fibrosis, leukocyte infiltration, and oxidative deoxyribonucleic acid damage. These phenotypes were accompanied by restored expression of GATA-4, sarcomeric proteins, and vascular endothelial growth factor and decreased inflammatory cytokines and lipid peroxidation. Finally, myocardial activation was observed of extracellular signal-regulated protein kinase and signal transducer and activator of transcription pathways in the treated mice. Conclusions EPO receptor signaling exerts direct cardioprotection in an animal model of renal dysfunction-associated heart failure, probably by mitigating degenerative, pro-fibrosis, inflammatory, and oxidative processes but not through relief of anemia.

Anemia may accelerate angiogenesis in ischemic organs through its ability to augment tissue hypoxia-induced generation of several known angiogenic factors and to increase erythropoietin levels, which are also potently angiogenic. We examined the effect of controlled phlebotomy (bloodletting) on blood flow in a mouse ischemic leg model. We ligated the right femoral artery of BALB/c mice. In the phlebotomy group, 200 μl of blood were drawn from the tail vein once a week. After 4 wk, blood flow in the ischemic leg was significantly better in the phlebotomy group (flow ratio of the ischemic to nonischemic leg, 0.87 ± 0.04) than the control group (0.59 ± 0.05, P < 0.05), and capillary density was significantly higher. Repeated phlebotomy increased serum erythropoietin levels as well as the expression of hypoxia-inducible transcription factor-1α and vascular endothelial growth factor and both the expression and activity of Akt and endothelial nitric oxide synthase (eNOS) in ischemic legs. Treatment with wortmannin or Nω-nitro-l-arginine methyl ester significantly attenuated the phlebotomy-induced improvement of blood flow. In addition, fluorescence-activated cell sorting analysis revealed an increase in circulating peripheral endothelial progenitor cells in the phlebotomy group, and treatment with AMD3100, a specific inhibitor of the chemokine receptor CXCR4, blocked the beneficial effect of phlebotomy. These findings suggest that repeated phlebotomy improves blood flow in ischemic legs through an angiogenic action that involves the Akt/eNOS pathway, endothelial progenitor cell mobilization, and their complicated cross talk. An adequately controlled phlebotomy might be one method by which to induce therapeutic angiogenesis.

Objective: The comparative effect of telmisartan and valsartan upon insulin resistance and adipocytokines in nondiabetic patients with mild hypertension is unclear. Methods: Fifty nondiabetic patients with untreated mild hypertension were randomly assigned to telmisartan (40 mg/day) and valsartan (80 mg/day) groups and were switched in a crossover manner at 3-month intervals. Serum leptin, adiponectin, hsCRP and the HOMA-R were measured before and at 3 months during each treatment period. Results: The HOMA-R significantly improved over the 3 months in the high insulin resistance group (HOMA-R>/=2.5) during the telmisartan treatment period (p=0.042), but not during the valsartan period. Both telmisartan and valsartan significantly decreased serum leptin levels in each female group during each treatment period (p/=0.1) of both treatment groups (p=0.044 and p=0.015, respectively). Conclusions: Telmisartan significantly improved insulin resistance, possibly through the effect on PPAR-gamma, while both telmisartan and valsartan significantly decreased serum leptin levels in female groups and hsCRP in both genders, suggesting no significantly different effects on adipocytokines by either drug in nondiabetic patients with mild hypertension.

Lindera strychnifolia (Tendai-Uyaku), a medicinal plant, has long been used for the treatment of cardiac, renal and rheumatic diseases in Japan. We investigated the effect of Lindera strychnifolia on systolic blood pressure, cardiac function, and plasma noradrenaline levels in rats. Spontaneously hypertensive rats (SHR) were given free access to water or extract solution of Lindera strychnifolia, which was extracted with a ratio of 10 g Lindera strychnifolia roots/20 ml water. Systolic blood pressure was measured by using a tail-cuf sphygmomanometer twice a week from 10 to 30 weeks of age, and compared to the age-matched Wistar Kyoto rats (WKY) as a control group. At 30 weeks of age, heart function was measured by echocardiography and blood samples were taken for detection of plasma noradrenaline levels, and rats were then sacrificed. Systolic blood pressure gradually increased from 10 to 30 weeks of age in the SHR group, while it did not change in the WKY group. In the Lindera-treated SHR group, the increase in systolic blood pressure was significantly attenuated from 21 to 30 weeks of age. Echocardiography showed a significant increase in ejection fraction in the Lindera-treated SHR group (60.4 ± 7.8%) as compared to the SHR group (39.7 ± 23.4%). Plasma noradrenaline levels were significantly decreased in Lindera-treated SHR group compared to the SHR group. These results suggest that Lindera strychnifolia has an anti-hypertensive effect and improves cardiac function in spontaneous hypertensive rats. These effects may be related to the decrease in plasma noradrenaline levels by Lindera strychnifolia.

We investigated whether postinfarct treatment with oxytocin (OT) improves left ventricular (LV) function and remodeling via cardiac repair of myocardial ischemia-reperfusion injury.Experiments were performed with 30 minutes of coronary occlusion and 2 or 14 days of reperfusion rabbit model of myocardial infarction. LV function and remodeling were significantly improved in the OT group. The infarct size was significantly reduced in the OT group. The number of CD31-positive microvessels was increased significantly in the OT group. There were no Ki67-positive myocytes in either group. The expression of the OT receptor, phosphorylated (p)-Akt protein kinase, p-extracellular signal-regulated protein kinase, p-enodthelial NO synthase, p-signal transducer and activator of transcription 3, vascular endothelial growth factor, B-cell lymphoma 2, and matrix metalloproteinase-1 (MMP-1) were markedly increased in the OT group days 2 and 14 post myocardial infarction.Postinfarct treatment with OT reduces myocardial infarct size and improves LV function and remodeling by activating OT receptors and prosurvival signals and by exerting antifibrotic and angiogenic effects through activation of MMP-1, endothelial NO synthase, and vascular endothelial growth factor. These findings provide new insight into therapeutic strategies for ischemic heart disease.

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 Acarbose, an antidiabetic drug, is an alpha-glucosidase inhibitor that can inhibit glucose absorption in the intestine. A recent large-scale clinical trial, STOP-NIDDM, showed that acarbose reduces the risk of myocardial infarction. We examined whether acarbose reduces myocardial infarct size and investigated its mechanisms. METHODS AND RESULTS Rabbits were fed with 1 of 2 diets in this study: normal chow, 30 mg acarbose per 100 g chow for 7 days. Rabbits were assigned randomly to 1 of 4 groups: control (n = 10), acarbose (n = 10), acarbose + 5HD (n = 10, intravenous 5 mg/kg of 5-hydroxydecanoate), and 5HD (n = 10, intravenous 5 mg/kg of 5HD). Rabbits then underwent 30 minutes of coronary occlusion followed by 48-hour reperfusion. Postprandial blood glucose levels were higher in the control group than in the acarbose group. The infarct size as a percentage of the left ventricular area at risk was reduced significantly in the acarbose (19.4% +/- 2.3%) compared with the control groups (42.8% +/- 5.4%). The infarct size-reducing effect of acarbose was abolished by 5HD (43.4% +/- 4.7%). Myocardial interstitial 2,5-dihydroxybenzoic acid levels, an indicator of hydroxyl radicals, increased during reperfusion after 30 minutes of ischemia, but this increase was inhibited in the acarbose group. This was reversed by 5HD. CONCLUSION Acarbose reduces myocardial infarct size by opening mitochondrial KATP channels, which may be related to the prevention of postprandial hyperglycemia and hydroxyl radical production.

Objectives We hypothesized that erythropoietin (EPO)-immersed gelatin hydrogel microspheres (GHM) injected into ischemic legs might continuously release a small amount of EPO to locally stimulate angiogenesis without unfavorable systemic effects. Background EPO is a potent angiogenic factor, but its use for relieving ischemic organs is limited because of the untoward systemic erythrogenic effect and its short half-life in plasma. Methods The right femoral arteries of BALB/c mice were ligated. Recombinant human EPO (5,000 IU/kg)-immersed GHM was injected into the right hind limb muscles (n = 12); the control groups included a saline-injected group (n = 12), an EPO-injected group (n = 8), and an empty GHM-injected group (n = 8). Results Eight weeks later, improvement of blood perfusion to the ischemic limb was significantly augmented in the EPO-GHM group compared with any of the control groups. There was no increase in the hemoglobin level, nor was there any increase in endothelial progenitor cells. However, capillary and arteriolar densities were significantly increased in this group. Although the treatment did not affect the levels of vascular endothelial growth factor or interleukin-1 beta, it up-regulated the EPO receptor and matrix metalloproteinase-2 and activated the downstream signaling of Akt and also endothelial nitric oxide synthase in ischemic limbs, which might have been associated with the evident angiogenic and arteriogenic effects in the present system. Conclusions The present drug delivery system is suggested to have potential as a novel noninvasive therapy for ischemic peripheral artery disease.

We hypothesized that therapy, composed of antiapoptotic soluble Fas (sFas) gene transfer, combined with administration of the cardioprotective cytokine granulocyte colony-stimulating factor (G-CSF), would markedly mitigate cardiac remodeling and dysfunction following myocardial infarction (MI). On the 3rd day after MI induced by ligating the left coronary artery in mice, four different treatments were initiated: saline injection (Group C, n = 26); G-CSF administration (Group G, n = 27); adenoviral transfer of sFas gene (Group F, n = 26); and the latter two together (Group G+F, n = 26). Four weeks post-MI, Group G+F showed better survival than Group C (96 vs. 65%, P < 0.05) and the best cardiac function among the four groups. In Group G, the infarct scar was smaller and less fibrotic, whereas in Group F the scar was thicker, without a reduction in area, and contained abundant myofibroblasts and vascular cells; Group G+F showed both phenotypes. G-CSF exerted a beneficial effect on infarct tissue dynamics through antifibrotic and proliferative effects on granulation tissue; however, it also exerts an adverse proapoptotic effect that leads to thinning of the infarct scar. sFas appeared to offset the latter drawback. In vitro study using cultured myofibroblasts derived from the infarct tissue revealed that G-CSF increased proliferating activity of those cells accompanying activation of Akt and signal transducer and activator of transcription 3, while accelerating Fas-mediated apoptosis with increasing Bax-to-Bcl-2 ratio. The results suggest that combined use of G-CSF administration and sFas gene therapy is a potentially powerful tool against post-MI heart failure.

【目的】内科入院患者の鍼灸治療の利用状況に関する詳細な報告はない。 今回、 当院循環・呼吸・腎臓内科病棟 (以下、 当科) における鍼灸治療の現状について、 鍼灸治療の依頼状況を中心に報告する。 【方法】2004年6月から2007年3月に当科入院中に鍼灸治療が依頼された患者を対象に、 鍼灸依頼愁訴 (主訴)、 入院基礎疾患、 依頼愁訴と基礎疾患との関連の有無を調べた。 【結果】鍼灸依頼件数は266 件であった。 依頼愁訴の最多は、 嘔気・食欲不振・しびれなどの肺癌化学療法副作用であり、 息切れ・呼吸困難、 癌性疼痛、 筋骨格系の疼痛、 食欲不振、 倦怠感などが続き、 少数例では便通異常や意識障害などが挙げられた。 また、 総依頼件数の86.4％が、 依頼愁訴と入院治療に関連を認めた。 1日の平均治療人数の推定値は約10人であり、 当科病床53床の約2割に相当した。 【考察・結語】鍼灸依頼愁訴の多くが入院治療に関係していたことから、 当科における鍼灸治療の依頼に際して、 鍼灸治療が入院治療の一つとしての役割を期待されていたことが推察された。

To define the pathological features of Kawasaki disease (KD) in the healed stage (over 40 days of illness), 69 autopsied infants with clinically typical KD (25 in the healed stage and 38 in the acute stage) and atypical KD (four in the healed stage and two in the acute stage) were examined. In the medium-sized arteries with coronary aneurysm in KD, panvasculitis was evident in the acute stages, while scar formation was noted in the healed stage. Thrombi, marked intimal thickening, marked stenosis, and recanalization were seen in the coronary arteries. In KD without aneurysm, acute inflammation was localized in the intima and the perivascular area of the coronary arteries in the acute stages, but was absent in the healed stage. Although intimal thickening was noted, marked stenosis and thrombi were not evident in KD without aneurysm. In KD with and without aneurysm, acute angiitis in small arteries and micro-vessels and acute inflammation of various organs were noted in the acute stages, but disappeared in the healed stage. Fibrinoid necrosis of the artery was rare in the acute stages and was not noted in the healed stage. Atypical cases of KD showed the same pathological features as those in cases with clinically typical KD. The common cause of death in the healed stage was ischemic heart disease. Old myocardial infarction was noted in 80% of the cases, and acute myocardial infarction was seen in 35%. KD is an acute systemic inflammatory disease and KD without aneurysm is a disease with mild angiitis.

1. In the present study, we examined the effects of inhibiting transforming growth factor (TGF)-beta in a mouse model of diabetic nephropathy. 2. An adenovirus harbouring the gene encoding soluble TGF-beta type II receptor (Ad.CAG-sTbetaRII), a competitive inhibitor of TGF-beta, was injected into hindlimb muscles (systemic delivery) of mice 5 weeks after the induction of diabetes with streptozotocin. The control group was injected with an adenovirus encoding the LacZ gene (Ad-LacZ). 3. Five weeks after administration, anti-TGF-beta gene therapy was found to have had no effect on renal function, albuminuria or glucose metabolism in mice with diabetic nephropathy. Nonetheless, this gene therapy did significantly reduce fibrosis in both glomeruli and renal tubules. These effects were accompanied by attenuation of the increased expression of alpha-smooth muscle actin normally seen in kidneys of diabetic mice and better preservation of glomerular cell numbers, although the thickness of the glomerular capillary basement membrane was unchanged. The plasma concentration of soluble TGF-beta type II receptor peaked on Day 7 after treatment, but was undetectable by Day 14. Moreover, a second treatment with Ad.CAG-sTbetaRII failed to prolong the interval of gene product expression in the blood. 4. The present anti-TGF-beta gene therapy showed a significant antifibrotic effect in a model of diabetic nephropathy, but failed to improve renal function. The inadequacy of the observed effect is likely due to the relatively short interval of gene product expression. This problem will have to be overcome if gene therapies for slowly progressing diseases, like diabetic nephropathy, are to be realised.

Many claims have been made regarding the therapeutic efficacy of acupuncture. However, most controlled clinical studies have been limited to treatment of pain-related disorders and do not provide objective, quantifiable data for analysis. Traditional acupuncture has been applied to chronic obstructive pulmonary disease (COPD). However, only a few studies have been performed to determine the efficacy of this treatment. This study was conducted to determine whether a combination of traditional acupuncture treatment and conservative treatment for COPD improves dyspnea on exercise.This was a prospective trial with matched-pair parallel groups of patients from the departments of respiratory internal medicine of Gifu University of Medicine, Meiji University of Oriental Medicine, and Gifu Red Cross Hospital, Japan. Thirty patients were divided into the acupuncture group (n = 15) and the control group (n = 15). The control group received conservative treatment with medication only. The acupuncture group received acupuncture treatments once a week for 10 weeks, in addition to conservative treatment with medication. The main outcome measure was the Modified Borg dyspnea scale after the 6-minute walk test.The acupuncture group had significantly better results on the Borg scale than the control group after 10 weeks (2.2 +/- 2.7 versus 6.4 +/- 3.4, p = 0.0001, 95% confidence interval, -5.10 to -2.35, paired t-test). The 6-minute walk distance and oxygen saturation at the minimum rate improved significantly in the acupuncture group compared with the control group.This study demonstrated that acupuncture contributed to the reduction of COPD-related dyspnea on exercise in 15 matched-pair parallel subjects.

Objectives This study sought to determine whether initial medical therapy (MT) only or percutaneous coronary intervention plus medical therapy (PCI+MT) is better for patients with low-risk stable coronary artery disease (CAD) indicated for intervention in Japan. Background Several multicenter studies have suggested that in the above patients, an initial management strategy of PCI+MT does not reduce the long-term risk of cardiovascular events more effectively than initial MT only. Methods We conducted a randomized comparative study (JSAP [Japanese Stable Angina Pectoris] study) in the previously mentioned patients. Results The patients were randomized to PCI+MT (n = 192) or initial MT only group (n = 192), and the patient characteristics were very similar in the 2 groups. During the 3.3-year follow-up, there was no significant difference in the cumulative death rate between PCI+MT (2.9%) and MT (3.9%). However, the cumulative risk of death plus acute coronary syndrome was significantly smaller in PCI+MT. Conclusions In stable low-risk CAD, PCI+MT may improve long-term prognosis more effectively than MT.

During the progression of heart failure (HF), phases of chronic compensation and acute decompensation alternate and the clinical status worsens during the acute phase. At the present time, few studies have focused their attention on the cycles of compensated and decompensated phases from the perspective of myocyte injury. We hypothesize that persistently increased serum cTn concentrations during chronic compensated HF identify patients likely to need multiple admissions to the hospital for management of acute cardiac decompensation, worsening their long-term prognosis by causing further myocyte injury during the acute phase. In patients with acute cardiac decompensation, myocyte injury observed within hours or days has a long-term predictive value, and the acute surge of myocyte injury occurring in the acutely decompensated phase might be an important therapeutic target from the perspective of myocyte preservation. Clinical trials that limit myocyte injury during acutely decompensated as well as during chronic compensated HF are warranted.

Tissue characterization of plaques of coronary arteries is important to clarify the process of acute coronary syndrome and prevent it. The purpose of this study is to develop an online integrated backscatter intravascular ultrasound (IB-IVUS) system and validate the diagnostic accuracy for the characterization of coronary plaques. A personal computer equipped with custom software was connected to an IVUS imaging system. Images were acquired from 242 segments of 46 coronary arteries from 25 cadavers obtained at autopsy. In the training study, a total of 724 regions-of-interests on color-coded maps were compared with histologic images. In the validation study, a total of 192 cross-sections of coronary arteries were evaluated. Receiver operating characteristic curve analysis showed that the cut-off points of −49 dB (area under curve = 0.98) and −29 dB (area under curve = 0.99) were the most reliable predictors of lipid pools, fibrosis and calcification. In the validation study, the analysis using IB values classified fibrous, lipid-rich and fibrocalcific plaque components with a high accuracy of 93%, 90% and 96%, respectively. The overall agreement between histologic and IB-IVUS diagnoses (n = 175) was high (Cohen’s κ = 0.81). The IB-IVUS system provides high diagnostic accuracy for analysis of tissue characteristics of coronary plaques. (E-mail: masanori@ya2.so-net.ne.jp )

SummaryObjectivesTreatment of mitral valve stenosis with catheter balloon commissurotomy (CBC) yields acceptable immediate results even when one commissure shows calcification. However, the long-term outcomes in such cases remain unclear.MethodsWe examined the immediate and long-term (mean: 11±5 years) outcomes of 57 patients who underwent 58 CBC procedures. Patients were classified into group A (no commissural calcification, n=44) or group B (unilateral commissural calcification, n=13). From the appearance of the mitral valve just after CBC, commissurotomy was judged to be bilateral, incomplete, or excessive. End points were death, recurrence of congestive heart failure necessitating hospitalization, embolism, repeat CBC, or mitral valve replacement.ResultsThere were significant numbers of unfavorable mitral valve morphologies evaluated according to Sellors classification, estimated by echocardiograms; Sellors class I: 20 patients in group A vs. none in group B (p

Proteinuria and hypertension are predictors of poor renal outcome in chronic glomerulonephritis (CGN). At the same level of blood pressure (BP) control, we evaluated which is superior, dual blockade of the rennin–angiotensin system (RAS) with both angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 (AT-1) receptor blockade (ARB) or single blockade of ARB to reduce proteinuria and to preserve renal function in patients with CGN. In this prospective, parallel, open study of 86 patients with CGN, we compared the effects on proteinuria and renal functions of 36 months with comparable blood pressure (BP) control achieved by candesartan cilexetil (candesartan, 4–12 mg/day) or benazepril hydrochrolide (benazepril, 2.5–10 mg/day) with candesartan (4 mg/day). Aiming at BP 125/75 mmHg or less, the dose of candesartan (single blockade) or benazepril (dual blockade) was increased. Dual blockade decreased proteinuria more than single blockade with ARB (−42.3 vs. −60.5%, P

Background Integrated backscatter (IB) intravascular ultrasound (IVUS) and IVUS Virtual Histology (VH) have been developed for tissue characterization, but have never been compared directly. The purpose of this study was to compare the overall agreement between IB-IVUS and IVUS-VH in the tissue characterization of plaques from the same coronary arterial cross-section. Methods and Results Images were acquired from 46 coronary arteries from 25 cadavers. Of a total of 392 histology/IVUS image pairs, 152 pairs were diagnosed as Stary's type III, IV, Va, Vb and Vc, and compared for IB-IVUS, IVUS-VH and histology. In the qualitative comparison, the overall agreement between histological and IB-IVUS diagnoses was higher (κ=0.81, 95% confidence interval (CI): 0.74-0.89) than that of the IVUS-VH diagnoses (κ=0.66, 95%CI: 0.56-0.75). The % fibrosis area determined by IB-IVUS was significantly correlated with the relative area of fibrosis based on histology (r=0.67, p

小半夏加茯苓湯の方意を含む漢方薬治療で症状の著明改善が図れたパニック障害の3例を経験した。症例1：47歳男性，運転士，血圧上昇を伴う一過性脳虚血発作を引き金に発症。身体疾患の発症がストレスを増強させ心下の気水が鬱して痰熱となりパニック発作になったと考えられる。小半夏加茯苓湯に黄連湯の方意をあわせて症状は消失した。症例2：49歳女性，主婦，家庭内のストレスをきっかけに発症。肝血不足，疎泄不良と脾虚が重なり心下の飲を起こしたと考え，小半夏加茯苓湯を含む茯苓飲合半夏厚朴湯エキスに加味逍遙散エキスを合わせて奏効した。症例3：32歳女性，主婦，子育ての疲労をきっかけに発症。疲れによって脾虚から心下の飲がおこるとともに血虚に陥ったと考え，小半夏加茯苓湯と十全大補湯合方を用い奏効した。『金匱要略』の方剤小半夏加茯苓湯は，中焦の飲と気の上逆を引き降ろすことで「心下痞」「眩悸，」を全例で改善し，症例毎に随証治療をあわせおこなうことでパニック発作が消失した。