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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. more...

BACKGROUND The Hyogo Prefectural Government has been enforcing a smoking ban ordinance since April 2013. The present survey was conducted to determine the extent to which the smoking ban has been successfully implemented in eating establishments in Kobe City and Amagasaki City.Methods and Results:The Health and Welfare Department of the Hyogo Prefectural Government provided a list of eating establishments in Kobe and Amagasaki City. From these, we chose 1,300 from each city using random number generation. Responses were obtained from 310 establishments in Kobe City (response rate: 23.8%) and 297 in Amagasaki City (22.8%). Overall, 58.1% of the establishments surveyed in Kobe City were aware of the ordinance, a recognition rate significantly higher than that of Amagasaki City, where only 45.5% of eateries were aware of the ordinance (P=0.003). Of the Kobe City eateries, 31.7% had succeeded in implementing a complete ban on smoking. In Amagasaki City, the rate was significantly lower, at just 13.4% (P more...

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. more...

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). more...

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. more...

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. more...

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 more...

Vacuolar degeneration of cardiomyocytes is a histological finding commonly encountered during routine light microscopic examination of human endomyocardial biopsy specimens. The vacuoles appear as intracellular clear areas lacking myofibers. By itself, this finding has little diagnostic value, but may have important clinical implications when the vacuolar contents are of etiological significance (e.g., accumulation of abnormal metabolites), and the clinical importance is increased when the disease is treatable. Thanks to its great resolving power, electron microscopy can often reveal the contents of the vacuoles and lead to a correct diagnosis. It can be used to differentially diagnose lysosomal storage diseases such as Fabry, Danon, and Pompe disease, doxorubicin cardiomyopathy, mitochondrial cardiomyopathy, autophagic degeneration, and accumulation of subcellular organelles (mitochondria, lipofuscin, glycogen granules, endoplasmic reticulum, etc.) as a nonspecific finding in failing cardiomyocytes. Nonetheless, undiagnosed cases certainly remain. It is strongly recommended that small pieces of tissue samples be fixed for electron microscopy at every endomyocardial biopsy procedure, and electron microscopic examination should be performed when a marked vacuolar degeneration is found. more...

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 more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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 ) more...

Although beneficial effects of granulocyte colony-stimulating factor (G-CSF) have been demonstrated on post-myocardia infarction (MI) process, the mechanisms and feasibility are not fully agreed yet. We investigated effects of a long-term treatment with a low-dose G-CSF started 1 day after the onset of MI, on post-infarction process. One day after being made MI by left coronary ligation, mice were given G-CSF (10 microg/kg/day) for 4 weeks. The G-CSF treatment resulted in a significant mitigation of cardiac remodelling and dysfunction. In the G-CSF-treated hearts, the infarcted scar was smaller with less fibrosis and abundant vessels while in the non-infarcted area, hypertrophic cardiomyocytes with attenuated degenerative changes and reduced fibrosis were apparent. These effects were accompanied by activation of signal transducer and activator of transcription 3 (STAT3) and Akt and also by up-regulation of GATA-4, myosin heavy chain and matrix metalloproteinases-2 and -9. Apoptosis of cardiomyocytes appeared insignificant at any stages. Parthenolide, a STAT3 inhibitor, completely abolished the beneficial effects of G-CSF on cardiac function and remodelling with loss of effect on both anti-cardiomyocyte degeneration and anti-fibrosis. In contrast, wortmannin, an Akt inhibitor, did not affect G-CSF-induced benefits despite cancelling vessel increase. In conclusion, treatment with G-CSF at a small dose but for a long duration beneficially affects the post-infarction process possibly through STAT3-mediated anti-cardiomyocyte degeneration and anti-fibrosis, but not through anti-cardiomyocyte apoptosis or Akt-mediated angio-genesis. The findings may also imply a more feasible way of G-CSF administration in the clinical settings. more...

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 more...

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 more...

Hepatocyte growth factor (HGF) reportedly exerts beneficial effects on the heart following myocardial infarction and during nonischemic cardiomyopathy, but the precise mechanisms underlying the latter have not been well elucidated. We generated nonischemic cardiomyopathy in mice by injecting them with doxorubicin (15 mg/kg ip). Two weeks later, when cardiac dysfunction was apparent, an adenoviral vector encoding human HGF gene (Ad.CAG-HGF, 1×1011 particles/mouse) was injected into the hindlimb muscles; LacZ gene served as the control. Left ventricular dilatation and dysfunction normally seen 4 wk after doxorubicin administration were significantly mitigated in HGF-treated mice, as were the associated cardiomyocyte atrophy/degeneration and myocardial fibrosis. Myocardial expression of GATA-4 and a sarcomeric protein, myosin heavy chain, was downregulated by doxorubicin, but the expression of both was restored by HGF treatment. The protective effect of HGF against doxorubicin-induced cardiomyocyte atrophy was confirmed in an in vitro experiment, which also showed that neither cardiomyocyte apoptosis nor proliferation plays significant roles in the present model. Upregulation of c-Met/HGF receptor was noted in HGF-treated hearts. Among the mediators downstream of c-Met, the activation of extracellular signal-regulated kinase (ERK) was reduced by doxorubicin, but the activity was restored by HGF. Levels of transforming growth factor-β1 and cyclooxygenase-2 did not differ between the groups. Our findings suggest the HGF gene delivery exerts therapeutic antiatrophic/degenerative and antifibrotic effects on myocardium in cases of established cardiac dysfunction caused by doxorubicin. These beneficial effects appear to be related to HGF-induced ERK activation and upregulation of c-Met, GATA-4, and sarcomeric proteins. more...

Candesartan has been reported to produce nitric oxide (NO) and to decrease oxidative stress in animal studies. We investigated candesartan's effect on the production of NO and oxidative stress as well as on carotid intima-media thickness (IMT) in hypertensive patients. One-hundred age-matched hypertensive patients were enrolled into an angiotensin II receptor blocker (ARB) group (n=50) or a non-ARB group (n=50). The ARB group was treated with candesartan 8 mg and, when needed, Ca channel blockers, angiotesin-converting enzyme (ACE) inhibitors, and/or beta-blockers. The non-ARB group was treated with drugs other than ARB. Carotid IMT was assessed by echocardiography before and 12 and 24 months after treatment. The urine levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), an indicator of oxidative stress, and the serum levels of NOx, an indicator of NO, were measured. Blood pressure decreased to below 140/90 mmHg to the same extent in both groups. Carotid IMT decreased significantly in the ARB group, but not in the non-ARB group, at 12 and 24 months after treatment. The urine levels of 8-OHdG decreased significantly at 6 and 12 months after treatment in the ARB group but did not decrease in the non-ARB group. The serum levels of NOx increased significantly at 6 and 12 months after treatment in the ARB group but not in the non-ARB group. In conclusion, candesartan decreases carotid IMT by enhancing NO production and decreasing oxidative stress in patients with hypertension. more...

Gated single-photon emission computed tomography (G-SPECT) was used to evaluate cardiac risk associated with noncardiac surgery and determine the benefits and indications of this technique for this type of surgery.Patients scheduled to undergo noncardiac surgery under the supervision of anesthesiologists and subjected to preoperative cardiac evaluation using G-SPECT during the 26-month period between June 2000 and August 2002 were followed for the presence/absence of cardiac events (i.e., cardiac death, myocardial infarction, unstable angina, congestive heart failure, or fatal arrhythmia) during surgery and the postoperative period until discharged. Relationships between the occurrence of cardiac events and preoperative G-SPECT findings were evaluated.A total of 39 patients underwent G-SPECT; 6 of the 39 exhibited abnormal ejection fraction (left ventricular ejection fraction, LVEFor=50%) and end-systolic volume (ESVor=50 ml). Surgery was suspended for three of these six patients and cardiac events developed in the remaining three patients. Both abnormal perfusion images (PI) and abnormal wall thickening (WT) were observed in all six patients. All six patients exhibited abnormal LVEF and/or ESV. Three patients had either abnormal PI or WT, and a cardiac event occurred in one of them. Of the five patients who experienced cardiac events during or after surgery, two exhibited a short run of ventricular tachycardia requiring a continuous administering of antiarrhythmic drugs, whereas the remaining three patients exhibited cardiac failure requiring inotropic support following surgery.The results of this study indicate that the occurrence of perioperative cardiac events can be predicted by considering the severity of expected surgical stress and preoperative G-SPECT findings for LVEF, PI, and WT. We conclude that G-SPECT is quite useful for cardiac risk assessment in patients undergoing noncardiac surgery. more...

Angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are frequently used for the treatment for glomerulonephritis and diabetic nephropathy because of their albuminuria- or proteinuria-reducing effects. To many patients who are nonresponsive to monotherapy with these agents, combination therapy appears to be a good treatment option. In the present study, we examined the effects of the addition of an ARB (losartan) followed by titration upon addition and at 3 and 6 months (n=14) and the addition of an ACE-I followed by titration upon addition and at 3 and 6 months (n=20) to the drug regimen treatment protocol in type 2 diabetic patients with nephropathy for whom more than 3-month administration of an ACE-I or the combination of an ACE-I plus a conventional antihypertensive was ineffective to achieve a blood pressure (BP) of 130/80 mmHg and to reduce urinary albumin to more...

QT dispersion has been reported to increase in patients with essential hypertension, and abnormal QT dispersion is associated with arrythmias and sudden cardiac death. However, whether change in QT dispersion is related to oxidative stress is unclear. We examined the effect of the angiotensin II receptor blocker valsartan on QT dispersion and the relationship between oxidative stress and QT dispersion in patients with essential hypertension. Hypertensive patients whose systolic blood pressure (SBP) was more than 140 mmHg and/or diastolic blood pressure (DBP) was more than 90 mmHg were treated with valsartan. Blood pressure was measured once a month for 6 months. The difference between the maximal and minimal QT intervals within a 12-lead surface ECG was measured and QT dispersion and QTc dispersion corrected by heart rate were obtained before and 6 months after treatment. Left ventricular mass (LVM) assessed by echocardiography was obtained at baseline and 6 months after treatment. Venous blood samples were obtained at baseline and 6 months after treatment to measure serum levels of lipoperoxidation (LPO) and type I and III procollagen. Treatment with valsartan significantly decreased SBP and DBP. QTc dispersion decreased significantly 6 months after treatment with valsartan as compared to the baseline values. Valsartan treatment did not affect the LVM. Valsartan significantly decreased the abnormally high LPO levels. The changes in QTc dispersion were positively correlated with changes in the serum levels of LPO and with changes in DBP. The correlation between changes in LPO and QTc dispersion was more close than that between changes in DBP and QTc dispersion. In conclusion, antihypertensive therapy with valsartan reduces QTc dispersion and this may be related to the ability of valsartan to reduce oxidative stress in patients with essential hypertension. more...

Hypoalbuminemia is an important predictor of a poor long-term prognosis in acute heart failure (AHF). However, changes in serum albumin levels in AHF have not been described to date. Therefore, we investigated the changes in serum albumin levels in patients hospitalized for AHF. This observational study included 115 consecutive patients admitted with AHF. Serum albumin was measured on days 1, 2, 4, and 7 of their hospitalization, and the changes in its levels were assessed. Cox multivariate analysis was used to compare the long-term mortality and readmission rate between 2 groups defined according to whether their serum albumin changes showed a rising pattern (serum albumin level increased from day 2 to day 7) or not. The mean serum albumin levels were 3.51 mg/dl on day 1, 3.21 mg/dl on day 2, 3.23 mg/dl on day 4, and 3.35 mg/dl on day 7 (p0.001 by multivariate analysis of variance). The rising pattern group including 66 patients (60.6%) was independently associated with a lower mortality and readmission rate (hazard ratios 0.450 and 0.522; p = 0.01 and 0.02, respectively). Furthermore, based on multiple linear regression analysis, the changes in hemoglobin and C-reactive protein levels during days 1 to 7 were independently correlated with the changes in serum albumin levels over the same period. In conclusion, a rising pattern of serum albumin change in a patient with AHF was correlated with a good long-term prognosis. Furthermore, the change in serum albumin levels was also associated with changes in cachectic factors. more...

Background Adjunctive thrombus aspiration ( TA ) during primary percutaneous coronary intervention ( PCI ) was reported to promote better coronary and myocardial reperfusion. However, long‐term mortality benefit of TA remains controversial. The objective of this study is to investigate the clinical impact of TA on long‐term clinical outcomes in patients with ST ‐segment elevation myocardial infarction (STEMI) undergoing primary PCI . Methods and Results The CREDO ‐Kyoto AMI Registry is a large‐scale cohort study of acute myocardial infarction patients undergoing coronary revascularization in 2005–2007 at 26 hospitals in Japan. Among 5429 patients enrolled in the registry, the current study population consisted of 3536 patients who arrived at the hospital within 12 hours after the symptom onset and underwent primary PCI . Clinical outcomes were compared between the 2 patient groups with or without TA . During primary PCI procedures, 2239 out of 3536 (63%) patients underwent TA ( TA group). The cumulative 5‐year incidence of all‐cause death was significantly lower in the TA group than in the non‐ TA group (18.5% versus 23.9%, log‐rank P TA group was not significantly lower than that in the non‐ TA group (hazard ratio: 0.90, 95% CI : 0.76 to 1.06, P =0.21). The adjusted risks for cardiac death, myocardial infarction, stroke, and target‐lesion revascularization were also not significantly different between the 2 groups. Conclusions Adjunctive TA during primary PCI was not associated with better 5‐year mortality in STEMI patients. more...

Objectives The purpose of the present study was to validate the diagnostic accuracy of optical coherence tomography (OCT), integrated backscatter intravascular ultrasound (IB-IVUS), and conventional intravascular ultrasound (C-IVUS) for tissue characterization of coronary plaques and to evaluate the advantages and limitations of each of these modalities. Background The diagnostic accuracy of OCT for characterizing tissue types is well established. However, comparisons among OCT, C-IVUS, and IB-IVUS have not been done. Methods We examined 128 coronary arterial sites (42 coronary arteries) from 17 cadavers; IVUS and OCT images were acquired on the same slice as histology. Ultrasound signals were obtained using an IVUS system with a 40-MHz catheter and digitized at 1 GHz with 8-bit resolution. The IB values of the ultrasound signals were calculated with a fast Fourier transform. Results Using histological images as a gold standard, the sensitivity of OCT for characterizing calcification, fibrosis, and lipid pool was 100%, 98%, and 95%, respectively. The specificity of OCT was 100%, 94%, and 98%, respectively (Cohen’s κ = 0.92). The sensitivity of IB-IVUS was 100%, 94%, and 84%, respectively. The specificity of IB-IVUS was 99%, 84%, and 97%, respectively (Cohen’s κ = 0.80). The sensitivity of C-IVUS was 100%, 93%, and 67%, respectively. The specificity of C-IVUS was 99%, 61%, and 95%, respectively (Cohen’s κ = 0.59). Conclusions Within the penetration depth of OCT, OCT has a best potential for tissue characterization of coronary plaques. Integrated backscatter IVUS has a better potential for characterizing fibrous lesions and lipid pools than C-IVUS. more...

This study aims to define tissue characteristics of vulnerable plaques before acute coronary syndrome (ACS) by use of integrated backscatter intravascular ultrasound (IB-IVUS).Tissue characterization of coronary plaques is possible with the use of IB-IVUS.The subjects were 140 patients with angina pectoris, and we selected 160 coronary lesions without significant stenosis for evaluation. Ultrasound signals were obtained by an IVUS system using a 40-MHz catheter.At the follow-up (30 +/- 7 months), 12 plaques caused ACS after the initial IVUS examination. Ten of the 12 plaques had IVUS parameters recorded at baseline. These 10 plaques were classified as vulnerable plaques (VP), and the other plaques were classified as stable plaques (SP; n = 143). There was no significant difference of vessel area, lumen area, and plaque area between VP and SP. However, plaque burden (60 +/- 9% vs. 52 +/- 9%; p = 0.014), eccentricity (0.70 +/- 0.10 vs. 0.55 +/- 0.17; p = 0.013), remodeling index (1.30 +/- 0.08 vs. 1.16 +/- 0.16; p = 0.006) and percentage lipid area (72 +/- 10% vs. 50 +/- 16%; p0.0001) were greater in VP than in SP. Percentage fibrous area (23 +/- 6% vs. 47 +/- 14%; p0.0001) was smaller in VP than in SP. The sensitivities, specificities, and positive predictive values of percentage fibrous area (90%, 96%, and 69%, respectively) and percentage lipid area (80%, 90%, and 42%, respectively) for classifying VP were evaluated.Tissue characteristics of VP before ACS were different from those of SP. This suggests that VP and SP as classified by IB-IVUS are useful in predicting ACS. more...

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) more...

It has been suggested that apoptosis may be responsible for a significant amount of cardiomyocyte death during acute myocardial infarction as well as for a progressive loss of surviving cells in failing hearts. Typical apoptosis can indeed be induced in cardiomyocytes at the experimental conditions. In actual heart diseases, in contrast, there is very little direct morphological evidence of apoptosis in cardiomyocytes occurring at any stage of myocardial infarction and heart failure, despite the availability of much indirect evidence that includes detection of DNA fragmentation and apoptosis-related factors. For that reason, the potential efficacy of therapeutic intervention to prevent apoptosis remains controversial. This review will survey available data from both animals and humans to critically assess the role of cardiomyocyte apoptosis during myocardial infarction and its relevance to myocardial remodeling and during progression to heart failure. Also considered will be nonmyocyte interstitial cells, which have received less attention than myocytes despite definitive evidence of their apoptosis in the infarcted heart and recent studies suggesting that blockade of apoptosis among these cells mitigates postinfarction cardiac remodeling and heart failure. We conclude from our survey that there are many hurdles to surmount before regulation of apoptosis can be clinically applied in the treatment of myocardial infarction and heart failure. more...

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. more...

A 75-year-old man without overt heart failure showed an abnormally high level of brain natriuretic peptide (BNP) in plasma: 600 pg/ml. The left ventricular endomyocardial biopsy revealed prominent vacuolar degeneration in the myocytes, most of which were positive for PAS stain and BNP immunoreaction. Ultrastructurally, degenerative changes of myocytes were marked, such as deposits of glycogen and lipofuscin granules in the cytoplasm, but the most prominent finding was giant vacuoles containing degraded mitochondria, glycogen granules, myofibrils, and myelin-like structures (autophagosomes). This case may belong to one of the unclassified cardiomyopathies characterized by prominent autophagic vacuoles. more...

SUMMARY: Aims: We investigated the relationship between levels of plasma soluble Fas (sFas) and stages of diabetic nephropathy, with special reference to apoptosis and clinical features of diabetic nephropathy in 168 patients with diabetic nephropathy. Results: There was a positive correlation between plasma sFas and creatinine levels, between sFas levels and urinary protein levels, and between sFas levels and urinary albumin. There was a negative correlation between plasma sFas levels and creatinine clearance. Plasma sFas levels in the early stage (stages 1, 2, 3A) and advanced stage (stages 3B and 4) were 2.6 ± 0.1 and 5.4 ± 0.5 ng/mL, respectively. Plasma sFas level of the advanced stage was significantly higher than that of the early stage. The number of proliferating cell nuclear antigen (PCNA) positive cells was significantly lower in the advanced stage than in the early stage. The number of in situ nick-end labelling (TUNEL) positive cells was also significantly lower in the advanced stage than in the early stage, suggesting the suppression of apoptosis. Conclusion: These data suggest that apoptosis is involved in the advancement of diabetic nephropathy, and that plasma sFas level might be a predicting factor for prognosis. more...

Background Sarpogrelate, a serotonin receptor blocker, increases collaterals via a platelet anti-aggregation effect and/or vasodilatation. However, a recent report showed a preconditioning effect of sarpogrelate that enhances the translocation of PKC-e of cardiomyocytes, followed by opening of the mitochondrial KATP channel via inhibition of serotonin release from platelets during ischemia, protecting against cellular injury in rabbit hearts without collaterals. The present study used a percutaneous coronary intervention (PCI) model to define the protective effect of sarpogrelate against ischemic injury and its mechanism in human coronary artery disease. Methods and results The study enrolled 20 patients with single vessel disease of 75% or 90% stenosis in the proximal left anterior descending (LAD) artery on coronary angiography (CAG). Patients were randomly divided into a control group (n=10) and a sarpogrelate group (n=10). The STmax (maximum ST elevation) and ΣST (sum of ST elevation) on the 12-lead ECG recorded in the late stages (ie, 90 s and 120 s) after inflation were significantly smaller in the sarpogrelate group than in the controls. There was no significant difference in collaterals on the right and left CAG or between the 2 groups. Conclusions Sarpogrelate improves ischemic injury during PCI and may be related to a preconditioning-like mechanism rather than to stimulating collateral development. (Circ J 2004; 68: 68 - 72) more...

Background Until now, large-scale nationwide surveys of acute myocardial infarction (AMI), such as those performed in Europe and America, have not been performed in Japan. Therefore, in 2000 the Japanese Coronary Intervention Study (JCIS) group conducted a nationwide survey on the incidence of AMI in Japan. Methods and Results Questionnaires were collected from 8,268 facilities throughout Japan. The total annual number of patients with AMI was 66,459 (52.4 patients/105 population), and the AMI incidence rate in Japan was approximately 25% of that in the United States. Most facilities with AMI patients treated less than 50 AMI patients annually, and that number was 45.0% of total AMI patients. The incidence of AMI patients was highest in Kochi, Kumamoto, and Wakayama prefectures, and lowest in Yamanashi, Saitama and Shiga prefectures. The ratio of the highest incidence to the lowest incidence was 2.0. A significant correlation was observed between the mean age of the prefectural population, as a coronary risk factor, and the incidence of AMI. Conclusions The incidence of AMI in Japan is approximately 25% that in the United States and it varies considerably among the prefectures, one of the causes being the difference in the mean age. This provides important information for assessing the guidelines for Japanese patients with AMI. (Circ J 2004; 68: 515 - 519) more...

A patient with distal slow-flow after stenting in the old vein graft intervention was reported. This case is a first in whom guidewire-based serial measurement of pressure-derived fractional flow reserve (FFRmyo) and thermodilution-based coronary flow reserve (CFRthermo) clearly demonstrated the serial change of microvascular circulation. During slow-flow, CFRthermo remained in low value despite significant improvement of FFRmyo from 0.61 to 0.90. After thrombus aspiration and nicorandil injection, coronary flow reestablished immediately. CFRthermo improved significantly from 1.3 during slow-flow to 3.6 after restoration of flow. Catheter Cardiovasc Interv 2003;60:392–398. © 2003 Wiley-Liss, Inc. more...

The significance of DNA breaks reported in failing hearts is controversial, although they may suggest myocyte apoptosis and may thus be responsible for the progression of heart failure. This study attempted to check the validity of the in situ markers for DNA breaks for detecting myocyte death and to evaluate separately two factors, failure or hypertrophy, crucial for DNA breaks in pathological human hearts. In the autopsy study, myocytes showed positivity for in situ nick end-labelling (TUNEL) and of Taq and Pfu polymerase-based in situ ligation assays not only in dilated cardiomyopathy (DCM, n = 9) with failure, but also in hypertrophic cardiomyopathy (HCM, n = 8) and hypertensive heart disease (HHD, n = 4) without failure. There was a significant correlation between each in situ marker and heart weight. The incidence of TUNEL-positive myocytes always exceeded that seen in in situ ligation assays. In addition, there were significant correlations between the in situ markers and the expression of the proliferating cell nuclear antigen (PCNA) and of the spliceosome component of 35 kD (SC-35). Similarly, in the left ventricular biopsy study using 23 DCM, 21 HCM, 11 HHD, and 13 non-hypertrophic hearts, the incidence of the in situ markers showed significant correlations with the left ventricular mass index and myocyte size, but not with cardiac function and dilatation. Positivity of myocytes for in situ markers for DNA breaks, such as TUNEL and in situ ligation assays, may be an epiphenomenon accompanying cardiac hypertrophy, but not myocyte death in pathological human hearts. more...

A 65-year-old woman presenting with cardiac sarcoidosis underwent serial measurement of her serum high-sensitivity cardiac troponin I (Hs-cTnI) and N-terminal proB-type natriuretic peptide (NT-proBNP) concentrations. She was treated with 1,000 mg/day methylprednisolone for 2 days, which was subsequently replaced by 30 mg/day prednisolone, and decreased to 20 mg/day at the time of discharge, 2 months later. Her echocardiogram showed improvements in the left ventricular systolic and diastolic function, along with a decrease in the concentration of Hs-cTnI and NT-proBNP. This is the first report suggesting that Hs-cTnI might be a reliable means of assessing the effects of treatment of cardiac sarcoidosis. more...

Background The long-term prognostic significance of in-hospital worsening renal function (WRF) during treatment of acute cardiac decompensation (ACD) remains controversial. Methods We analyzed data from 100 patients (mean age = 75 years; 53% men) presenting with ACD, in whom the serum cystatin C (Cys-C) concentration was measured upon admission to the hospital and 4 days later. We examined the relationship between changes in Cys-C and primary study endpoint of risk of death and re-hospitalization for management of ACD, up to 180 days, searched for predictors by multiple variable analysis and calculated the hazard ratios (HR) and 95% confidence intervals (CI). Results A median (25th to 75th percentile) increase in Cys-C from 1.29 (0.88–1.66) mg/l on day 1 to 1.31 (1.00–1.84) mg/l on day 4, observed in 66% of all patients, was associated with a significant decrease ( p = 0.040) in the 180-day incidence of primary study endpoint. By multiple variable regression analysis, an increase in Cys-C was an independent predictor of death and re-hospitalization for management of ACD (HR 0.415; 95% CI 0.193–0.885; p = 0.023). Conclusions An increase in serum Cys-C concentration after hospitalization for management of ACD was associated with a decreased, long-term incidence of primary study endpoint. more...

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. more...