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Naoyuki Akashi,1 Tomio Umemoto,1 Hodaka Yamada,2 Takayuki Fujiwara,3 Kei Yamamoto,1 Yousuke Taniguchi,1 Kenichi Sakakura,1 Hiroshi Wada,1 Shin-ichi Momomura,1 Hideo Fujita1 1Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan; 2Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, Saitama, Japan; 3Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, JapanCorrespondence: Tomio Umemoto, Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan, Tel +81-48-647-2111, Fax +81-48-648-5188, Email to-ume@omiya.jichi.ac.jpPurpose: Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endothelial progenitor cells (EPCs) in peripheral blood circulation. However, the underlying mechanisms and effects on vascular endothelial function remain unclear. We evaluated whether the DPP-4 inhibitor teneligliptin increases circulating EPCs by inhibiting stromal-derived factor-1α (SDF-1α) and improves flow-mediated vascular dilatation (FMD) in type 2 diabetes mellitus patients with acute coronary syndrome (ACS) or its risk factors.Patients and Methods: This single-center, open-label, prospective, randomized controlled trial evaluated 17 patients (hemoglobin A1c ≤ 7.5% and peak creatinine phosphokinase < 2000 IU/mL) with ACS or a history of ACS or multiple cardiovascular risk factors. Metabolic variables of glucose and lipids, circulating EPCs, plasma DPP-4 activity, and SDF-1α levels, and FMD were evaluated at baseline and 28 ± 4 weeks after enrollment. Patients were randomly assigned to either the teneligliptin (n = 8) or control (n = 9) groups.Results: The DPP-4 activity (∆− 509.5 ± 105.7 vs ∆32.8 ± 53.4 μU/mL) and SDF-1α levels (∆− 695.6 ± 443.2 vs ∆11.1 ± 193.7 pg/mL) were significantly decreased after 28 weeks in the teneligliptin group than those in the control group. The number of EPCs showed an increasing trend in the teneligliptin treated group; albeit this did not reach statistical significance. Glucose and lipid levels were not significantly different between the groups before and after 28 weeks. However, FMD was significantly improved in the teneligliptin group when compared to the control group (∆3.8% ± 2.1% vs ∆− 0.3% ± 2.9%, P=0.006).Conclusion: Teneligliptin improved FMD through a mechanism other than increasing the number of circulating EPCs.Keywords: endothelial progenitor cell, teneligliptin, DPP-4 inhibitor, flow-mediated dilation, type 2 diabetes mellitus

Periaortitis is one of the less common manifestations of the aorta pathology. Periaortitis mostly arises from the outer layers of the abdominal aorta and iliac arteries. However, other large arteries may also be involved, but rarely the thoracic aorta. Here we present a successful conservative treatment using prednisolone therapy for periaortitis of the aortic arch which shows various clinical symptoms.

Background: DPP-4 inhibitors have been reported to have beneficial effects on endothelial function as sitagliptin increases circulating endothelial progenitor cells (EPCs) via inhibition of plasma stromal derived factor-1 alpha (SDF-1α). However, its mechanisms are unclear. We evaluated whether DPP-4 inhibitor teneligliptin increases the number of circulating EPCs through inhibition of SDF-1α metabolism and improves flow mediated vascular dilatation (FMD) in type 2 diabetes mellitus (T2DM) patients with acute coronary syndrome (ACS) or its risk factors. Methods: This study was a prospective, single-center, open-label, randomized controlled trial. A total of 16 patients with present or past history of ACS or multiple cardiovascular risk factors were enrolled, and who take any medicine for diabetes, whose HbA1c > 7.5% and/or peak CPK > 2000 IU/ml, were excluded. Variable of glucose and lipids, the number of EPCs, activity levels of DPP-4 and SDF-1α and FMD were evaluated at baseline and at 28±4 weeks after enrollment in all patients. They were randomly assigned into 2 groups either 20mg per day teneligliptin or control. Finally, 8 patients were included in teneligliptin group and 8 in control. All data were analyzed by paired t-test, and p < 0.05 was considered statistically significant. Results: DPP-4 activity (∆-509.5±105.7 vs. ∆32.8±53.4 μU/ml) and SDF-1α levels (∆-695.6±443.2 vs. ∆11.1±193.7 pg/ml) were significantly decreased after 28 weeks in teneligliptin group compared to control, respectively. Number of EPCs, and variables of glucose and lipids were not significantly different between two groups before and after 28 weeks. However, FMD was significantly improved in the teneligliptin group compared to control (∆3.8±2.1 vs. ∆-0.3±2.9%, p = 0.006) after 28 weeks treatment. Conclusion: These results indicate that teneligliptin improves FMD by different mechanisms from the increase of blood EPC number via SDF-1α. Disclosure N. Akashi: None. T. Umemoto: None. Y. Hodaka: None. T. Fujiwara: None. K. Yamamoto: None. Y. Taniguchi: None. K. Sakakura: None. H. Wada: None. S. Momomura: None. H. Fujita: None.

Hypereosinophilic syndrome (HES) is characterized by multi-organ damage that is associated with tissue hypereosinophilia. A persistently elevated eosinophilic count is also required for the diagnosis of HES. Although HES affects various organs, damage to pulmonary artery is rarely reported. We present a case of a 39-year-old man who was diagnosed with pulmonary hypertension (PH) associated with idiopathic HES. Although the pulmonary arterial hypertension specific drugs including intravenous epoprostenol could not control his PH, corticosteroid was effective for both hypereosinophilia and PH. Our case suggests the importance of steroid therapy as well as specific drugs for pulmonary arterial hypertension in the treatment of PH associated with HES.

Previous studies suggested that right ventricular pacing was associated with pacing-induced cardiac dysfunction (PICD). The purpose of this study was to investigate the clinical characteristics including the incidence of undiagnosed cardiac sarcoidosis (CS) in patients with atrioventricular block (AVB) who manifest PICD. We retrospectively investigated consecutive patients with permanent pacemaker (PPM) undergoing a first-generator replacement surgery with a new PPM or an upgrade procedure to a cardiac resynchronization therapy (CRT) device between December 1, 2011 and June 30, 2017. Patients with AVB showing normal echocardiographic findings before PPM implantation were included and divided into 2 groups: patients with post-PPM left ventricular ejection fraction (LVEF)

Diabetes mellitus and impaired glucose tolerance are well-known risk factors for coronary artery disease (CAD) and adverse clinical events after percutaneous coronary intervention (PCI). Postprandial hyperglycemia is an important risk factor for CAD and serum 1,5-anhydroglucitol (1,5-AG) reflects postprandial hyperglycemia more robustly than hemoglobin (Hb)A1c. We aimed to clarify the relationship between serum 1,5-AG level and adverse clinical events after PCI. We enrolled 141 patients after PCI with follow-up coronary angiography. We evaluated associations between glycemic biomarkers including HbA1c and 1,5-AG and cardiovascular events during follow-up. Median serum 1,5-AG level was significantly lower in patients with any coronary revascularization and target lesion revascularization (TLR) [13.4 µg/ml (first quartile, third quartile 9.80, 18.3) vs. 18.7 (12.8, 24.2), p = 0.005; 13.4 µg/ml (10.2, 16.4) vs. 18.7 (12.9, 24.2), p = 0.001, respectively]. Multivariate logistic analysis showed lower 1,5-AG was independently associated with any coronary revascularization and TLR (odds ratio 0.93, 95 % confidence interval 0.86-0.99, p = 0.04; 0.90, 0.81-0.99, p = 0.044, respectively), whereas higher HbA1c was not. Postprandial hyperglycemia and lower 1,5-AG are important risk factors for adverse clinical events after PCI.

Background Saturated fatty acids have been shown to cause insulin resistance and low-grade chronic inflammation, whereas unsaturated fatty acids suppress inflammation via G-protein coupled receptor 120 (GPR120) in macrophages. However, the anti-inflammatory effects of unsaturated fatty acids in adipocytes have yet to be elucidated. Hence, the aims of the present study were to evaluate the anti-inflammatory effects of eicosapentaenoic acid (EPA) via GPR120 in adipocytes. Methods We used 250 μM palmitate as a representative saturated fatty acid. 3T3-L1 adipocytes were used for in vitro studies. We further evaluated the effect of EPA supplementation in a high-fat/high-sucrose (HFHS) diet-induced adipose tissue inflammatory mouse model. Results EPA attenuated palmitate-induced increases in inflammatory gene expression and NF-κB phosphorylation in 3T3-L1 adipocytes. Silencing of GPR120 abolished the anti-inflammatory effects of EPA. In GPR120 downstream signal analysis, EPA was found to decrease palmitate-induced increases in TAK1/TAB1 complex expression. EPA supplementation suppressed HFHS-induced crown-like structure formation in epididymal adipose tissue and altered macrophage phenotypes from M1 to M2 in the stromal vascular fraction. Moreover, the EPA-containing diet attenuated increases in adipose p-JNK and phospho-p65 NF-κB levels. Conclusions In conclusion, the findings of the present study demonstrate that EPA suppresses palmitate-induced inflammation via GPR120 by inhibiting the TAK1/TAB1 interaction in adipocytes. EPA supplementation reduced HFHS diet-induced inflammatory changes in mouse adipose tissues. These results demonstrate adipose GPR120 as a potential therapeutic target for decreasing inflammation. Electronic supplementary material The online version of this article (doi:10.1186/s12986-017-0188-0) contains supplementary material, which is available to authorized users.

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias, and carries an increased risk of cardiogenic embolism. Oral anticoagulants (OACs) including warfarin and/or non-vitamin K antagonists can prevent the majority of these events. The Saitama AF Registry was a community-based survey of patients with AF in Saitama City, which represents an urban community in Japan. A total of 75 institutions participated in the registry and attempted to enroll consecutive patients with AF from September 2014 to August 2015. The aim of the present study was to examine the clinical characteristics of patients with AF using data of the Saitama AF Registry. In addition, we investigated the difference in clinical characteristics of the patients between small-sized hospitals and large-sized hospitals. A total of 3591 patients were enrolled; 57.7% of all patients were enrolled from small-sized hospitals, whereas 42.3% were from large-sized hospitals. The patients from small-sized hospitals had higher CHADS2 score than those from large-sized hospitals. Approximately, 80% of all patients were treated with OACs, and the prescription rate was higher in patients with CHADS2 score ≥ 2 from both small-sized hospitals and large-sized hospitals. In conclusion, the present study demonstrated an appropriate use of OACs for high-risk patients with CHADS2 score ≥2 in Saitama City regardless of hospital size.

Rationale: Macrophage accumulation in adipose tissue associates with insulin resistance and increased cardiovascular disease risk. We previously have shown that generation of reactive oxygen species and monocyte chemotactic factors after exposure of adipocytes to saturated fatty acids, such as palmitate, occurs via translocation of NADPH oxidase 4 into lipid rafts (LRs). The anti-inflammatory effects of apolipoprotein AI (apoAI) and high-density lipoprotein (HDL) on macrophages and endothelial cells seem to occur via cholesterol depletion of LRs. However, little is known concerning anti-inflammatory effects of HDL and apoAI on adipocytes. Objective: To determine whether apoAI and HDL inhibit inflammation in adipocytes and adipose tissue, and whether this is dependent on LRs. Methods and Results: In 3T3L-1 adipocytes, apoAI, HDL, and methyl-β-cyclodextrin inhibited chemotactic factor expression. ApoAI and HDL also disrupted LRs, reduced plasma membrane cholesterol content, inhibited NADPH oxidase 4 translocation into LRs, and reduced palmitate-induced reactive oxygen species generation and monocyte chemotactic factor expression. Silencing ATP-binding cassette A-1 abrogated the effect of apoAI, but not HDL, whereas silencing ATP-binding cassette G-1 or scavenger receptor B-1 abrogated the effect of HDL but not apoAI. In vivo, apoAI transgenic mice fed a high-fat, high-sucrose, cholesterol-containing diet showed reduced chemotactic factor and proinflammatory cytokine expression and reduced macrophage accumulation in adipose tissue. Conclusions: ApoAI and HDL have anti-inflammatory effects in adipocytes and adipose tissue similar to their effects in other cell types. These effects are consistent with disruption and removal of cholesterol from LRs, which are regulated by cholesterol transporters, such as ATP-binding cassette A-1, ATP-binding cassette G-1, and scavenger receptor B-1.

Revascularization therapy such as percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) should be considered for heart failure with reduced ejection fraction (HFrEF). However, revascularization therapy does not always improve left ventricular ejection fraction (LVEF). The purpose of this study was to investigate the determinants of LVEF improvement following revascularization in HFrEF patients. From 2,229 consecutive decompensated heart failure patients, a total of 47 HFrEF patients who underwent revascularization were included in the analysis. Improvement of LVEF was defined as [(LVEF during chronic phase) - (LVEF during acute phase)] ≥ 10%. Univariate and multivariate logistic regression analyses were applied to investigate the determinants of LVEF improvement. The prevalence of revascularization by PCIs including chronic total occlusion (CTO) was significantly greater in the improved EF group (45.0%) as compared to the non-improved EF group (11.1%) (P = 0.02). Multivariate logistic regression analysis revealed that revascularization by PCIs including CTO was the significant determinant of the LVEF improvement after adjusting for confounding factors (OR 5.43, 95% CI 1.06-27.74, P = 0.04). Optimal medical therapy (angiotensin-converting enzyme (ACE) inhibitor and/or angiotensin II receptor blocker (ARB) and beta-blockers) was less frequently prescribed in patients with CABG (50.0% for ACE inhibitor and/or ARB and 41.7% for beta-blocker) than in patients without CABG (94.3% for both) (P < 0.01 and P < 0.001, respectively). In conclusion, revascularization by PCIs including CTO was the significant determinant of LVEF improvement in HFrEF patients. Our results underscore the importance of optimal medical therapy even if patients receive complete revascularization such as CABG.

Adipose tissue inflammation is associated with insulin resistance and increased cardiovascular disease risk in obesity. We previously showed that addition of cholesterol to a diet rich in saturated fat and refined carbohydrate significantly worsens dyslipidemia, insulin resistance, adipose tissue macrophage accumulation, systemic inflammation, and atherosclerosis in LDL receptor-deficient (Ldlr(-/-)) mice. To test whether inhibition of intestinal cholesterol absorption would improve metabolic abnormalities and adipose tissue inflammation in obesity, we administered ezetimibe, a dietary and endogenous cholesterol absorption inhibitor, to Ldlr(-/-) mice fed chow or high-fat, high-sucrose (HFHS) diets without or with 0.15% cholesterol (HFHS+C). Ezetimibe blunted weight gain and markedly reduced plasma lipids in the HFHS+C group. Ezetimibe had no effect on glucose homeostasis or visceral adipose tissue macrophage gene expression in the HFHS+C fed mice, although circulating inflammatory markers serum amyloid A (SSA) and serum amyloid P (SSP) levels decreased. Nevertheless, ezetimibe treatment led to a striking (85%) reduction in atherosclerotic lesion area with reduced lesion lipid and macrophage content in the HFHS+C group. Thus, in the presence of dietary cholesterol, ezetimibe did not improve adipose tissue inflammation in obese Ldlr(-/-) mice, but it led to a major reduction in atherosclerotic lesions associated with improved plasma lipids and lipoproteins.

Excess glucose and free fatty acids delivered to adipose tissue causes local inflammation, which contributes to insulin resistance. Glucose and palmitate generate reactive oxygen species (ROS) in adipocytes, leading to monocyte chemotactic factor gene expression. Docosahexaenoate (DHA) has the opposite effect. In this study, we evaluated the potential sources of ROS in the presence of excess nutrients. Differentiated 3T3-L1 adipocytes were exposed to palmitate and DHA (250 μM) in either 5 or 25 mM glucose to evaluate the relative roles of mitochondrial electron transport and NADPH oxidases (NOX) as sources of ROS. Excess glucose and palmitate did not increase mitochondrial oxidative phosphorylation. However, glucose exposure increased glycolysis. Of the NOX family members, only NOX4 was expressed in adipocytes. Moreover, its activity was increased by excess glucose and palmitate and decreased by DHA. Silencing NOX4 inhibited palmitate- and glucose-stimulated ROS generation and monocyte chemotactic factor gene expression. NADPH, a substrate for NOX, and pentose phosphate pathway activity increased with glucose but not palmitate and decreased with DHA exposure. Inhibition of the pentose phosphate pathway by glucose-6-phosphate dehydrogenase inhibitors and siRNA suppressed ROS generation and monocyte chemotactic factor gene expression induced by both glucose and palmitate. Finally, both high glucose and palmitate induced NOX4 translocation into lipid rafts, effects that were blocked by DHA. Excess glucose and palmitate generate ROS via NOX4 rather than by mitochondrial oxidation in cultured adipocytes. NOX4 is regulated by both NADPH generated in the PPP and translocation of NOX4 into lipid rafts, leading to expression of monocyte chemotactic factors.

Background: To explore the acute effects of submaximal exercise on blood rheology and sympathetic nerve activity. Methods and Results: The effects of exercise (20 or 80 Watts (W)) on blood rheology and sympathetic nerve activity were assessed in 10 healthy Japanese men. Blood sampling and heart rate variability (HRV) recording were performed during 20-min supine rest and standing ergometric exercise (20 W for 10 min, 80 W for 10 min) and recovery. Blood passage time across the microchannels (diameter, 7 μm) as a parameter of blood rheology, and the number of adhesive leukocytes on microchannel terraces as a parameter of leukocyte activation were measured. Sympathetic nerve activity was evaluated by plasma noradrenalin levels and the ratio of low-frequency (LF)/high-frequency (HF) by spectral analysis of HRV. Compared with values while supine at rest, significant increases in hematocrit, leukocyte count, noradrenalin level and blood passage time were seen after strenuous ergometer exercise at 80 W (P

Endothelial dysfunction leading to cardiovascular disease risk involves a decrease in nitric oxide (NO) production. In physiological conditions shear stress is a potent stimulation of endothelium-derived NO production and flow mediated NO production is regulated by the activation of endothelial NO synthase (eNOS). In endothelial cells, eNOS, aldose reductase (AR), a rate limiting enzyme of polyol pathway, and glutathione reductase (GR) share a NADPH as an obligate cofactor. In diabetec condition intracellular polyol pathway is activated and this may decrease shear stress-induced endothelial NO production and increase intracellular oxidative stress via inhibition of eNOS and GR by NADPH consumption. Therefore we investigated whethter AR inhibitor epalrestat improved endothelial NO production under high glucose condition to elucidate the mechanism of endothelial dysfunction in diabetes. We incubated human umbilical vein endothelial cells (HUVECs) in normal (5mM) and high (30mM) glucose condition for 72 hours, with or without epralrestat, or 100U/ml superoxide dismutase (SOD), respectively. After exchange of medium for Krebs’ buffer, HUVECs were exposed to 12dyne/cm2 steady laminar fluid shear stress for 5 minutes. NO release from HUVECs was measured as NO2 using a NOx analyzing HPLC system by Griess reaction. Next we harvested the cells in lysis buffer and analyzed phosphorylation of Akt (shear induced intracellular signal transduction) and eNOS by western blotting, and measured intracellular 8-OHdG and ratio of NADPH/NADP. In high glucose condition NO2 was decreased and 8-OHdG increased compared to low glucose. NO2 was restored and 8-OHdG was reduced by epalrestat significantly (p These results showed that polyol pathway activation plays a key role in endothelial NO production under high glucose condition via a cofactor NADPH.

Background: Adipose tissue inflammation induces inflammatory molecules production leading to insulin resistance and increased cardiovascular disease risk. Recently it has become apparent that innate immune system is activated by saturated fatty acids (SFAs) by a process involved in TLR4 signaling. HDL and apoA-I has anti-inflammatory effects, however the mechanisms are not well understood in adipocytes. Aims: We examined to elucidate the effect of HDL and/or ApoA-I mediated cholesterol efflux on induction of inflammatory gene expression by palmitate in adipocytes via TLR4 dependent immune system. Methods: 3T3-L1 adipocytes are exposure to 250uM palmitate for periods of up to 24 hours with or without HDL or Apo A-I. Antisense directed to ABCG-1 or ABCA-1 is added 24 hours prior to each reagent challenge. Cells were harvested and estimated for expression of Saa 3 gene using real-time PCR or detection of TLR4 in raft or non raft by western blotting. Lipid rafts were purified by ultracentrifugation on discontinuous sucrose gradient, and identified by the presence of caveolin-1. Results: TLR4 was translocated into lipid raft from non raft within 15 minutes and dislocated by 60 minutes after palmitate exposure. Saa 3 gene expression was significantly up-regulated by 24 hours palmitate exposure in adipocytes. TLR4 translocation to raft and Saa 3 gene up- regulation induced by palmitate was significantly inhibited by pretreatment of HDL or Apo A-I for 6 hours. Antisense directed to ABCG-1 or SRB1 abrogated these inhibitory effects by HDL, but not ApoA-I whereas antisense to ABCA-1 did by Apo A-I but not HDL. Conclusions: These findings suggest that TLR4 mediates palmitate-induced Saa 3 gene expression in adipocytes. A reduction in membrane cholesterol mediated by ABCG-1, SRB1 or ABCA-1 can account for the ability of HDL or ApoA-I to disrupt stimulation of inflammatory cytokines by palmitate

A 54-year-old woman came to our office because of pretibial edema. She had no gastrointestinal symptoms. Laboratory tests revealed severe hypoproteinemia. Upper gastrointestinal endoscopy demonstrated enlarged gastric folds and multiple aphthoid nodules on the body and the fornix of the stomach. The biopsy specimen revealed a large number of CD8 positive intraepithelial T-lymphocytes infiltrating the gastric mucosa. Both serum total protein and the gastric lesions improved eight months after her first visit without any therapy for peptic ulcer or eradication of Helicobacter pylori. The data suggest that spontaneous remission may occur in lymphocytic gastritis without any gastrointestinal symptoms.

We thank Abdelwahid and Smith (1) for their interest and comments concerning our studies of the cardioprotective effects of a peptide designed to mimic the 3D surface structure of a portion of helix B [helix B-surface peptide (HBSP)] of erythropoietin (EPO) (2). This peptide has been shown to have similar tissue protective and regenerative activities as EPO, but lacks hematopoietic effects (3). On the basis of a variety of evidence (4), we believe different EPO receptor isoforms are responsible for these differences. In the study (2), a combination of in vivo and in vitro experiments were performed that confirmed antiapoptotic activity of HBSP in the …

Coronary spastic angina (CSA) may become refractory when pa-tients discontinue medication, resume smoking, are overworked, areunder mental stress, or are hyperventilation [1]. Calcium channelblockers (CCBs) are effective standard therapeutic agents for CSA. Insomecases,however,acombinationofmedicationssuchasCCBs,nitro-gen, and nicorandil fails to relieve CSA. We report a case of refractoryCSA,whichwaseventuallyrelievedbysuper-selectiveintracoronaryin-jection of a Rho-kinase inhibitor, fasudil.An84-year-oldmancomplainedofchestpainatrest,andwastrans-ferred to our hospital. He was diagnosed with CSA in 2008, and hadreceived treatment with two CCBs (diltiazem and nifedipine) andnicorandil. However, he discontinued these medications 2 days priorto the onset of his chest pain. An electrocardiogram (ECG) showed ST–T elevations in leads V3–V6 (Fig. 1A). Laboratory data showed a whiteblood cell count of 9250/mm

Erythropoietin (EPO), originally identified for its critical hormonal role in regulating production and survival of erythrocytes, is a member of the type 1 cytokine superfamily. Recent studies have shown that EPO has cytoprotective effects in a wide variety of tissues, including the heart, by preventing apoptosis. However, EPO also has undesirable effects, such as thrombogenesis. In the present study, we investigated whether a helix B-surface peptide (HBSP), a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin, protects cardiomyocytes from apoptosis in vitro and in vivo. In cultured neonatal rat cardiomyocytes, HBSP clearly inhibited apoptosis (approximately 80%) induced by TNF-alpha, which was comparable with the effect of EPO, and activated critical signaling pathways of cell survival, including Akt, ERK1/2, and STAT3. Among these pathways, Akt was shown to play an essential role in HBSP-induced prevention of apoptosis, as assessed by using a small interfering RNA approach. In the dilated cardiomyopathic hamster (J2N-k), whose cardiac tissues diffusely expressed TNF-alpha, HBSP also inhibited apoptosis (approximately 70%) and activated Akt in cardiomyocytes. Furthermore, the levels of serum creatine kinase activity and of cardiac expression of atrial natriuretic peptide, a marker of chronic heart failure, were down-regulated in animals treated with HBSP. These data demonstrate that HBSP protects cardiomyocytes from apoptosis and leads to a favorable outcome in failing hearts through an Akt-dependent pathway. Because HBSP does not have the undesirable effects of EPO, it could be a promising alternative for EPO to treat cardiovascular diseases, such as myocardial infarction and heart failure.

Background: This study explored the clinical significance of CD34+/133+ circulating progenitor cell (CPC) counts in patients with stable angina pectoris (AP) who underwent percutaneous coronary intervention (PCI). Methods and Results: Subjects comprised 52 patients with stable AP requiring PCI and 50 control patients without AP. In the AP group, blood samples were taken before and 20 min and 24 h after PCI to measure CPC counts by fluorescence-activated cell sorter analysis. The baseline number of CPCs was smaller in the AP group than in controls. In the AP group, body mass index (BMI) correlated positively with the baseline number of CPCs and was an independent predictor of CPC count in multivariate regression analysis. Other conventional risk factors, daily exercise activity and statin administration showed no association with CPC count. CPC counts remained unchanged within 24 h after PCI. Conclusions: CPC counts in patients with AP are influenced by BMI, but not by other coronary risk factors. CPC counts remain unchanged within 24 h after PCI. (Circ J 2010; 74: 1929 - 1935)

Background: Because postprandial hypertriglyceridemia and hyperglycemia may promote atherosclerosis, the present study investigated the effects of a clinical dose of pitavastatin on endothelial function and blood rheology in patients with coronary artery disease (CAD) before and after eating a test meal. Methods and Results: The 16 patients with stable CAD and mild dyslipidemia and 6 age-matched healthy men as controls were recruited. In each group, forearm blood flow (FBF) was measured during postischemic reactive hyperemia and blood samples were taken before and 2 h after the test meal. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also measured. The patients were started on pitavastatin 2 mg/day. The tests were repeated after 6 months. Maximum FBF during hyperemia in the baseline fasting phase was significantly lower in CAD patients than in control subjects (P=0.040). Fasting and postprandial FBF during reactive hyperemia significantly improved after pitavastatin treatment (P

C-reactive protein (CRP) has been suggested to directly induce the inflammatory response leading to the progression of atherosclerosis. However, recent in vitro studies raised the possibility that the effects of CRP are caused by biologically active contaminants such as sodium azide and endotoxin. In this study, we tested whether azide- and endotoxin-free CRP induces endothelial cell apoptosis and production of proinflammatory mediators. In human endothelial cells, CRP significantly inhibited cell proliferation and increased endothelial cell apoptosis evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and caspase-3 activity assay, which is reversed by a function-blocking antibody to Fc gamma RIIIB by 78%. Western blot analysis showed that CRP significantly attenuated flow-mediated activation of Akt, a key molecule for endothelial cell survival pathways. In human mononuclear cells, CRP-induced production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and matrix metalloproteinase-9 (MMP-9) in a concentration-dependent manner. This CRP-induced MMP-9 production was significantly inhibited by function-blocking antibodies to TNF-alpha, IL-1 beta, and Fc gamma RIIA. These findings suggest that CRP itself induces endothelial cell apoptosis and production of proinflammatory mediators. Because endothelial cell apoptosis and MMP-9 production are critical for the destabilization of atherosclerotic plaque, this study may provide insight into a role of CRP in the development of plaque rupture.

A 45-year-old woman presented with triple valve infective endocarditis and ventricular septal defect. There were vegetations on the tricuspid valve, pulmonary valve, and aortic valve. She had multiple complications such as nephrotic syndrome, severe anemia, congestive heart failure, and convulsion. Her general condition was extremely poor. Intensive medical therapy, such as blood transfusion, mechanical ventilation, and continuous venovenous hemofiltration, allowed her to tolerate surgery. Triple valve replacement and ventricular septal defect closure was successfully performed without major complication. She was ambulatory at the time of discharge.

Diabetes mellitus is one of the major risk factors for coronary artery disease (CAD). A recent study reported that glimepiride, a new third-generation sulfonylurea, inhibited the formation of atheromatous plaques in high-cholesterol fed rabbits. However, the mechanism by which glimepiride induces atheroprotection remains unknown. In the present study, we tested the hypothesis that glimepiride may stimulate NO production in vascular endothelial cells. Human coronary artery endothelial cells (HCAECs) were treated with glimepiride, glibenclamide or vehicle, and NO release was measured. Akt phosphorylation was evaluated by Western blot. The effects of LY294002, a specific PI3-kinase inhibitor, and antisense oligonucleotides directed to Akt, on glimepiride-induced NO production were examined. Glimepiride (0.1-10 microM), but not glibenclamide, induced NO production, significantly increasing it by 1.8-fold (n=6, p0.05). LY294002 inhibited glimepiride-induced NO production by 68%. Akt was rapidly phosphorylated by glimepiride and antisense oligonucleotides directed to Akt completely inhibited glimepiride-induced NO production. These data demonstrate that glimepiride induces NO production in HCAECs by activating PI3-kinase and Akt, and also suggest that use of glimepiride in type 2 diabetes may show promise for preventing CAD in addition to lowering glucose levels.