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Arterial stiffness contributes to the development of cardiovascular disease (CVD). However, the relationship between the arterial stiffness and exercise tolerance in CVD patients with preserved ejection fraction (pEF) and those with reduced EF (rEF) is unclear. We enrolled 358 patients who participated in cardiac rehabilitation and underwent cardiopulmonary exercise testing at Juntendo University Hospital. After excluding 195 patients who had undergone open heart surgery and 20 patients with mid-range EF, the patients were divided into pEF (n = 99) and rEF (n = 44) groups. Arterial stiffness was assessed using arterial velocity pulse index (AVI) and arterial pressure volume index (API) at rest. The patients in the pEF group were significantly older and had a higher prevalence of coronary artery disease than the rEF group. The pEF group had significantly lower AVI levels and higher API levels than the rEF group. In the pEF group, the peak oxygen uptake (peak VO2) and the anaerobic threshold was significantly higher than those in the rEF group. The peak VO2 was significantly and negatively correlated with AVI and API in the pEF group (All, P < 0.05), but not in the rEF group. Multivariate linear regression analyses demonstrated that AVI was independently associated with peak VO2 (β = -0.34, P < 0.05) in the pEF group. In conclusion, AVI may be a useful factor for assessing exercise tolerance, particularly in CVD patients with pEF.

Background: The frailty state consists of not only physical but also psycho-emotional problems, such as cognitive dysfunction and depression as well as social problems. However, few reports have examined the relationship between frailty and anxiety levels in elderly patients undergoing cardiac rehabilitation (CR). Methods: We analyzed 255 patients (mean age: 74.9 ± 5.8 years, 67% male) who participated in early phase II CR at Juntendo University Hospital. At the beginning of CR, patients carried out self-assessments based on the Kihon Checklist (KCL) and the State Trait Anxiety Inventory Form (STAI). Patients were divided into three groups: frailty group (n = 99, 39%), pre-frailty group (n = 81, 32%), and non-frailty group (n = 75, 29%) according to the KCL. We assessed results from the KCL scores and its relationship with anxiety levels. Results: Among the three groups, there were no significant differences in age, underlying illnesses, or the prevalence of coronary risk factors. Depressive mood domains of the KCL were significantly higher in the frailty and pre-frailty groups than in the non-frailty groups (3.0 ± 1.5 vs. 1.4 ± 1.2 vs. 0.4 ± 0.6; P < 0.01). The state anxiety level was significantly higher in the frailty group than in the non-frailty group (41.6 ± 0.9 vs. 34.9 ± 1.0; P < 0.01). The trait anxiety levels were significantly higher in the frailty group and pre-frailty group than in the non-frailty group (45.5 ± 0.9 vs. 39.2 ± 1.0 vs. 35.1 ± 1.1; P < 0.01). State anxiety and trait anxiety also showed a significantly positive correlations with the KCL scores (r = 0.32 vs. 0.41, P < 0.01). Conclusions: Frailty scores were positively correlated not only with physical function but also with depression mood and anxiety levels in elderly patients undergoing early phase II CR. These results suggest that assessment of depressive mood and anxiety is also important in elderly patients undergoing early phase II CR. Cardiol Res. 2020;11(6):405-411 doi: https://doi.org/10.14740/cr1165

Background: The Japanese Ministry of Health, Labour and Welfare reported that the overall constipation complaint rates among men and women are 2.5% and 4.6%, respectively. To evaluate the impact of constipation on patients with cardiovascular diseases, we investigated the association between constipation and frailty components in patients undergoing cardiac rehabilitation (CR). Methods: We enrolled 102 consecutive patients undergoing late phase II CR (mean age: 62.7 ± 13.4 years; 68 (67%) were men). We investigated clinical characteristics, observed defecation status and evaluated frailty components assessed by the Kihon checklist. According to the Clinical Guidelines for Chronic Constipation, the subjects were divided into constipation and non-constipation groups. Results: Constipation was noted in 33 patients (32%). Interestingly, the constipation complaint rate was only 15%. Age was significantly higher in the constipation group than in the non-constipation group; however, no differences in sex, underlying diseases and prevalence rates of coronary risk factors were observed between the two groups. Body mass index, hemoglobin level, albumin level and estimated glomerular filtration rate were significantly lower in the constipation group than in the non-constipation group. The prevalence of frailty was significantly higher in the constipation group than in the non-constipation group. Physical ability, seclusion and depression scores were significantly higher in the constipation group than the non-constipation group. Conclusions: Constipation was associated with physical function and depression score as components of frailty in patients undergoing CR. Cardiol Res. 2021;12(3):169-176 doi: https://doi.org/10.14740/cr1246

Arterial stiffness contributes to the development of cardiovascular disease (CVD). However, the relationship between the arterial stiffness and exercise tolerance in CVD patients with preserved ejection fraction (pEF) and those with reduced EF (rEF) is unclear. We enrolled 358 patients who participated in cardiac rehabilitation and underwent cardiopulmonary exercise testing at Juntendo University Hospital. After excluding 195 patients who had undergone open heart surgery and 20 patients with mid-range EF, the patients were divided into pEF (n = 99) and rEF (n = 44) groups. Arterial stiffness was assessed using arterial velocity pulse index (AVI) and arterial pressure volume index (API) at rest. The patients in the pEF group were significantly older and had a higher prevalence of coronary artery disease than the rEF group. The pEF group had significantly lower AVI levels and higher API levels than the rEF group. In the pEF group, the peak oxygen uptake (peak VO

OBJECTIVE: Results of the use of the transluminal attenuation gradient (TAG) at coronary CT angiography (CCTA) to predict hemodynamically significant disease vary widely. This study tested whether diagnostic performance of TAG to predict fractional flow reserve (FFR) ≤ 0.8 is improved when applied separately to subsets of coronary arteries that carry similar physiological flow. METHODS: 28 patients with 64 × 0.5 mm CCTA and invasive FFR in ≥1 major coronary artery were retrospectively evaluated. Two readers assessed TAG in each artery. The receiver operating characteristic (ROC) area under the curve (AUC) was used to assess the diagnostic performance of TAG to detect hemodynamically significant disease following a clinical use rule [negative: FFR > 0.8 or ≤ 25% diameter stenosis (DS) at invasive catheter angiography; positive: FFR ≤ 0.8 or ≥ 90% DS at invasive catheter angiography]. ROC AUC was compared for all arteries pooled together, vs separately for arteries carrying similar physiological flow (Group 1: all left anterior descending plus right-dominant left circumflex; Group 2: right-dominant RCA plus left/co-dominant left circumflex). RESULTS: Of the 84 arteries, 30 had FFR measurements, 30 had ≤25% DS and 13 had ≥90% DS. 11 arteries with 26–89% DS and no FFR measurement were excluded. TAG interobserver reproducibility was excellent (Pearson r = 0.954, Bland–Altman bias: 0.224 Hounsfield unit cm(–1)). ROC AUC to detect hemodynamically significant disease was higher when considering arteries separately (Group 1 AUC = 0.841, p = 0.039; Group 2 AUC = 0.840, p = 0.188), than when pooling all arteries together (AUC = 0.661). CONCLUSION: Incorporating information on the physiology of coronary flow via the particular vessel interrogated and coronary dominance may improve the accuracy of TAG, a simple measurement that can be quickly performed at the time of CCTA interpretation to detect hemodynamically significant stenosis in individual coronary arteries. ADVANCES IN KNOWLEDGE: The interpretation of TAG may benefit by incorporating information regarding which coronary artery is being interrogated.

Aims Recent study suggests that algorithms such as the Duke Clinical score (DCS) may overestimate the pretest probability. The Agatston score representing the grade of coronary artery calcification can be simply calculated from low-radiation exposure ECG-gated plain CT. In this study, we investigated whether or not more superior diagnostic performance for obstructive coronary artery disease (CAD) can be obtained by combining DCS with the Agatston score. Methods and results Of 3939 consecutive patients suspected of having stable angina without known CAD who underwent Coronary Computed Tomography Angiography (CCTA) as well as calculation of the DCS and Agatston score at our hospital, 3688 patients were selected as subjects. Obstructive CAD was defined as >50% diameter stenosis on CCTA; we investigated the diagnostic performance based on the area under the curve (AUC) of a receiver operating characteristic (ROC) curve, Net Reclassification Improvement (NRI), and Integrated Discrimination Improvement (IDI). The AUCs of ROCs prepared using the DCS alone and combination of the DCS and Agatston score were 0.7137 and 0.8057, respectively, showing that the diagnostic performance of the combination was significantly superior to DCS alone ( P < 0.001). NRI was 0.8132 and IDI was 0.1374, showing that the diagnostic performance was improved by the combination of the DCS and Agatston score compared with DCS alone ( P < 0.001). NRI (0.3522) and IDI (0.0287) were improved compared with those of the Agatston score alone ( P < 0.001). Conclusion The combination of the DCS and Agatston score improved the diagnostic performance for obstructive CAD compared with DCS alone and Agatston score.

Radiation exposure remains a concern in the use of coronary CT angiography (CCTA). Full reconstruction (Full) and reconstruction using advanced patient motion correction (APMC) could obtain a lower radiation dose using low tube current scanning in a 320-row Area Detector CT (320-ADCT). The radiation dose for an imaging protocol using Full and APMC in daily practice was estimated. A total of 209 patients who underwent CCTA in 1 rotation scanning with 100 kv and adaptive iterative dose reduction 3D in 320-ADCT were enrolled. Imaging protocols were classified into 3 groups based on estimated slow filling time: (1) slow filling time ≥ 275 msec, Full with 30% of usual tube current (N = 43)(Full30%mA) (2) 206.3 msec ≤ slow filling time

Aim Very long chain saturated fatty acid (VLCFA) levels in erythrocytes are associated with metabolic syndrome (MS). However, the relationship between levels of the VLCFA ligonoceric acid (C24:0) in erythrocytes and the atherogenic lipoprotein profiles and inflammatory state in MS remain unclear. Methods Based on the International Diabetes Federation (IDF) definition of MS, 195 apparently healthy males were assigned to either an MS group (n = 38) or a non-MS group (n = 157). Fatty acid composition of erythrocytes was determined by gas liquid chromatography. Results Erythrocytes from the MS group had a significantly higher level of C24:0 than cells from the non-MS group (4.06 ± 0.48% versus 3.88 ± 0.34%; p = 0.03). C24:0 levels were significantly correlated with several components of MS. The C24:0 levels showed a significant negative correlation with LDL and HDL particle size. Multivariate linear regression analysis showed that C24:0 levels were independently correlated with LDL particle size after adjusting for age and each MS criterion. C24:0 levels were also positively correlated with log-transformed high-sensitivity CRP levels (p = 0.04). Conclusion C24:0 levels in erythrocytes are associated with specific atherogenic lipoprotein profiles and inflammation status in subjects with MS.

Nonalcoholic steatohepatitis (NASH) is associated with obesity and type 2 diabetes, and an increased risk for liver cirrhosis and cancer. ELOVL family member 6, elongation of very long chain fatty acids (Elovl6), is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids (FAs). We have shown previously that Elovl6 is a major target for sterol regulatory element binding proteins in the liver and that it plays a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further investigate the role of Elovl6 in the development of NASH and its underlying mechanism, we used three independent mouse models with loss or gain of function of Elovl6, and human liver samples isolated from patients with NASH. Our results demonstrate that (1) Elovl6 is a critical modulator for atherogenic high-fat diet-induced inflammation, oxidative stress, and fibrosis in the liver; (2) Elovl6 expression is positively correlated with severity of hepatosteatosis and liver injury in NASH patients; and (3) deletion of Elovl6 reduces palmitate-induced activation of the NLR family pyrin domain-containing 3 inflammasome; this could be at least one of the underlying mechanisms by which Elovl6 modulates the progress of NASH. Conclusion Hepatic long-chain fatty acid composition is a novel determinant in NASH development, and Elovl6 could be a potential therapeutic target for the prevention and treatment of NASH.

Background: Acute coronary syndrome (ACS) is an amplified state of inflammation and immune reaction. Dendritic cells (DCs) expressing various Toll-like receptors (TLRs) have been observed in atherosclerotic lesions, however, the clinical significance of DCs in pathogenesis of ACS has not been completely investigated. Methods: Ten patients with ACS and 10 patients with stable angina pectoris (SAP) were enrolled in this study. Monocyte-derived DCs were generated from CD14+ cells by culturing with granulocyte macrophage colony-stimulating factor and interleukin (IL)-4 for 6 days. Expression of cell surface CD86 and CD83 were measured by flowcytometry. Expression of genes, including CD86, CD83, CCL19, CCR7, TLR2, TLR4, TLR5, TLR8, and TLR9, were measured by real-time PCR. Plasma IL-6 and tumor necrosis factor (TNF)-α levels were also measured. Results: The number of CD86+CD83+DCs in the ACS group was significantly higher than that in the SAP group (P P P +CD83+ cells and plasma levels of IL-6 (P = 0.88, P +CD83+ cells TNF-α levels (r = 0.78, P < 0.0001). Conclusions: These results demonstrated that mono-cyte-derived DCs are activated in patients with ACS, suggesting that activated DCs may play an important role in the pathogenesis of ACS.

Background: Patients with arteriosclerosis obliterans (ASO) often have co-existing atherosclerotic diseases. The purpose of this study was to examine the clinical features of patients with ASO, including the overlap of atherosclerotic risk factors, characteristics of car-diovascular events, and clinical prognosis. Method: We enrolled 205 consecutive patients who had ankle brachial index (ABI) of ?0.9 between January 2008 and December 2009. Fontaine (F) classification and clinical background were evaluated and clinical events including mortality and major adverse cardiocerebro-vascular events (MACCEs) were determined. Results: There was a high prevalence of each risk factor. Sixty- five percent of subjects had three or more of the four overlapping risk factors, including hypertension, dia- betes, dyslipidemia, and smoking. After a maximum follow-up of 800 days, the incidence of MACCEs and mortality was 46% and 10%, respectively. We divided the patients into two groups according to the presence of ASO symptoms (F1 and F2-4) and compared the incidence of events. The incidence of MACCEs and mortality in the F2-4 group was significantly higher than that in the F1 group (P = 0.048, P = 0.044, respectively). After excluding lower extremity revascularization, coronary artery disease was a common cause of MACCEs, and the mortality rates after MACCEs increased in a stepwise manner according to F classification severity (P = 0.028). Conclusion: Patients with ASO had overlapping coronary risk factors and a high incidence rate of cardiovascular events. The incidence of coronary events was common, especially in symptomatic patients, and the mortality rates after MACCEs were high in accordance with F classification severity.

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can develop into liver cirrhosis and cancer. Elongation of very long chain fatty acids (ELOVL) family member 6 (Elovl6) is a microsomal enzyme that regulates the elongation of C12–16 saturated and monounsaturated fatty acids (FAs). We have previously shown that Elovl6 plays an important role in the development of hepatic insulin resistance and NASH by modifying FA composition. Recent studies have linked altered hepatic cholesterol homeostasis and cholesterol accumulation to the pathogenesis of NASH. In the present study, we further investigated the role of Elovl6 in the progression of lithogenic diet (LD)-induced steatohepatitis. We showed that the absence of Elovl6 suppresses hepatic lipid accumulation, plasma total cholesterol and total bile acid (BA) levels in LDL receptor-deficient (Ldlr−/−) mice challenged with a LD. The absence of Elovl6 also decreases hepatic inflammation, oxidative stress and liver injury, but increases the formation of cholesterol crystals in the less dilated gallbladder. These findings suggest that Elovl6-mediated changes in hepatic FA composition, especially oleic acid (C18:1n-9), control handling of hepatic cholesterol and BA, which protects against hepatotoxicity and steatohepatitis, but promotes gallstone formation in LD-fed Ldlr−/− mice.

Aim: We assessed levels of polyunsaturated fatty acid (PUFA) in serum and red blood cells (RBCs) among groups stratified by generation and its clinical significance in Japanese subjects living in an urban area.Methods: We enrolled 200 apparently healthy Japanese (126 males, mean age: 50.3±9.2 years) living in an urban area. Levels of PUFA, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-gamma-linolenic acid (DGLA) in serum and RBCs were measured for each generation (G1

Background: Post-prandial hyperglycemia, hyperlipidemia, and endothelial dysfunction play an important role in the pathogenesis of atherosclerosis. Improvement in post-prandial hyperglycemia on α-glucosidase inhibitors (α-GIs) is associated with a risk reduction of cardiovascular diseases, but the post-prandial effects of α-GIs on endothelial function and incretin secretion in type 2 diabetic patients with coronary artery disease (CAD) remain unclear. Methods and Results: The post-prandial effects of a single administration of miglitol and voglibose on endothelial function and changing levels of glucose, insulin, lipids, glucagon-like peptide (GLP)-1, and gastric inhibitory polypeptide (GIP) were compared after a standard meal loading in 11 diabetic patients with CAD, using a placebo-controlled cross-over design. The changing levels of glucose, insulin and triglycerides at 60 min were significantly lower in the miglitol group than in the voglibose and placebo groups (all P

Aim: A sedentary lifestyle with insufficient exercise is associated with cardiovascular disease. Previous studies have demonstrated that endurance exercise benefits atherosclerosis and cardiovascular disorders; however, the mechanisms by which physical activity, such as voluntary exercise (Ex), produces these effects are not fully understood.Methods and Results: Eight-week-old male apolipoprotein (ApoE)-deficient mice were fed a standard diet (STD) or high fat diet (HFD) for 10 weeks. The HFD+Ex group mice performed Ex on a running wheel for 10 weeks. No significant differences in lipid profiles were observed between the HFD and HFD+Ex groups. Although changes in body and brown adipose tissue weights were comparable between the HFD and HFD+Ex groups, white adipose tissue weight was significantly lower in the HFD+Ex group than in the HFD group. The areas of atherosclerotic lesions in the aortic sinus and thoracoabdominal aorta were significantly reduced in the HFD+Ex group than in the HFD group (p

Background Cardiac events after revascularization are equally attributable to recurrence at site of culprit lesions and development of nonculprit lesions. We evaluated the hypothesis that coronary computed tomography ( CT ) angiography and coronary artery calcium score ( CACS ) performed before revascularization predicts cardiac events after treatment. Methods and Results Among 2238 consecutive patients without known coronary artery disease who underwent coronary CT angiography and CACS , 359 patients underwent revascularization within 30 days after CT ; in 337 of 359 (93.9%) follow‐up clinical information was available. In addition to known cardiac risk factors, CT findings were evaluated as predictors of cardiac events after revascularization: CACS and the presence of CT ‐verified high‐risk plaque ( CT ‐ HRP ). Improvement of predictive accuracy by including CT findings was evaluated from a discrimination (Harrell's C‐statistics) standpoint. During the follow‐up period (median: 673, interquartile range: 47 to 1529 days), a total of 98 cardiac events occurred. Cox proportional hazard model revealed that age, diabetes, triglyceride, CACS , and nonculprit CT ‐ HRP were significant predictors of overall cardiac events. Although not statistically significant, discriminatory power was greater for the model with CACS (C‐stat: 63.2%) and the model with both CACS and CT ‐ HRP (65.8%) compared to the model including neither CACS nor CT ‐ HRP (60.7%). Conclusions High CACS and the presence of nonculprit CT ‐ HRP performed before revascularization are significant predictors of cardiac events after revascularization.

A 54-year-old woman was referred to our hospital for symptomatic sinus bradyarrhythmia with a sinus pause of 8 seconds. She was diagnosed with dextrocardia during childhood and discovered to have heterotaxy syndrome when she had an appendectomy during her teenager years. Chest and abdominal examinations by computed tomography showed multiple spleens located on the right side and abnormal drainages of the superior and inferior vena cava. Left isomerism was diagnosed by bilaterally bilobed lungs. Because of a patent bilateral superior vena cava, pacemaker leads were implanted using the right cephalic vein approach. Her fainting symptoms disappeared after pacemaker implantation.

Background Dietary intake of ω3 polyunsaturated fatty acids (ω3-PUFAs) reduces progression of atherosclerosis and prevents future cardiovascular events. Macrophages are key players in the pathogenesis of aortic aneurysm. The effects of ω3-PUFAs on abdominal aortic aneurysm (AAA) formation and macrophage-mediated inflammation remain unclear. METHODS AND RESULTS: The AAA model was developed by angiotensin II infusion in apolipoprotein E-deficient mice. Mice were supplemented with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). The development of AAA lesions and macrophage infiltration in the aorta were analyzed. Gene expression of inflammatory markers in aortic tissues and peritoneal macrophages were measured by using quantitative polymerase chain reaction. AAA formation and macrophage infiltration were significantly suppressed after EPA and DHA administration. EPA administration and DHA administration significantly decreased the expression of tumor necrosis factor-α, monocyte chemoattractant protein-1, transforming growth factor-β, matrix metalloproteinases (MMP)-2, MMP-9, and vascular cell adhesion molecule-1 in the aortas. The expression of arginase 2, which is a marker of pro-inflammatory macrophages, was significantly lower and that of Ym1, which is a marker of anti-inflammatory macrophages, and was significantly higher after EPA and DHA administration. The same trends were observed in peritoneal macrophages after EPA and DHA administration. Conclusions Dietary intake of EPA and DHA prevented AAA development through the inhibition of aortic and macrophage-mediated inflammation.

Background The incremental prognostic value of the plaque features in coronary computed tomographic angiography (CTA) has not been well assessed. This study was designed to determine whether CTA high-risk plaques have prognostic value incremental to the Framingham risk score (FRS) and the severity of luminal obstruction. Methods A total of 628 newly symptomatic patients without known coronary artery disease underwent CTA. They were followed for a median of 677 days during which there were 26 cardiac events, including cardiac death, acute myocardial infarction, and hospitalization for unstable angina. Incremental prognostic value of adding plaque characteristics to the number of diseased vessels and the FRS was evaluated using 3 Cox models and net reclassification indexes. Results The discrimination index was significantly increased by adding the number of diseased vessels to the FRS (change in c-statistic from 65.8% to 78.6%, p = 0.028) but not significantly by further adding plaque characteristics (change in c-statistic from 78.6% to 80.0%, p = 0.812). However, improved model-fitting by adding plaque characteristics into the linear combination with risk score and the number of diseased vessels (p = 0.007 from likelihood ratio test) and the lowest value of Akaike's information criteria of that model indicated that plaque characteristics improved both predictive accuracy and discrimination perspective. More subjects reclassified by plaque characteristics were moved to directions consistent with their subsequent cardiac event status than in an inconsistent direction. Conclusions Evaluation of CTA plaque characteristics may provide incremental prognostic value to the number of diseased vessels and the FRS.

Aims Levels of saturated very long chain fatty acids (VLCFAs) are associated with coronary risk factors, including metabolic syndrome (MS), atherogenic lipoproteins, and systemic inflammation. However, the relationship between circulating levels of saturated VLCFA and coronary artery disease (CAD) remains unclear. Method We enrolled 100 consecutive CAD patients and 40 age-, gender-, and body mass index (BMI)-matched healthy control subjects. The levels of hexacosanoic acid (C26:0), a VLCFA, in whole blood were measured by gas–liquid chromatography mass spectrometry. Results C26:0 levels were significantly higher in the CAD group than in the control group (2.42 ± 0.32 vs. 2.27 ± 0.24 μg/ml, P = 0.01) and positively correlated with BMI ( r = 0.23, P = 0.008), triglyceride levels ( r = 0.22, P = 0.01), and hypertension ( P = 0.01). CAD patients with MS showed the highest C26:0 levels adjusted by hematocrit. Furthermore, adjusted C26:0 levels in CAD patients without MS were higher than those in controls ( P = 0.02), suggesting that C26:0 levels increased with the presence of CAD independent of MS. Our multivariate analysis revealed that high C26:0 levels in whole blood is an independent marker for CAD even after adjustment for age, gender, BMI, lipid profiles, fasting plasma glucose, and blood pressure. Conclusion High C26:0 levels in whole blood may be an independent marker for identifying the risks of CAD.

Nonalcoholic steatohepatitis (NASH) is associated with obesity and type 2 diabetes, and an increased risk for liver cirrhosis and cancer. ELOVL family member 6, elongation of very long chain fatty acids (Elovl6), is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids (FAs). We have shown previously that Elovl6 is a major target for sterol regulatory element binding proteins in the liver and that it plays a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further investigate the role of Elovl6 in the development of NASH and its underlying mechanism, we used three independent mouse models with loss or gain of function of Elovl6, and human liver samples isolated from patients with NASH. Our results demonstrate that (1) Elovl6 is a critical modulator for atherogenic high-fat diet-induced inflammation, oxidative stress, and fibrosis in the liver; (2) Elovl6 expression is positively correlated with severity of hepatosteatosis and liver injury in NASH patients; and (3) deletion of Elovl6 reduces palmitate-induced activation of the NLR family pyrin domain-containing 3 inflammasome; this could be at least one of the underlying mechanisms by which Elovl6 modulates the progress of NASH.Hepatic long-chain fatty acid composition is a novel determinant in NASH development, and Elovl6 could be a potential therapeutic target for the prevention and treatment of NASH.

BackgroundRecently, much attention has been focused on cardio-renal interaction. Urinary liver-type fatty acid binding protein (U-L-FABP), which is produced in the proximal tubule by renal hypoxia and oxidative stress, has been identified as a useful marker for diagnosis of acute kidney disease and a predictor of future events in chronic kidney disease. However, the clinical significance of U-L-FABP measurements in patients with acute coronary syndrome (ACS) has not been completely evaluated.Methods and resultsThis study included 50 consecutive patients with ACS [37 with acute myocardial infarction (AMI) and 13 with unstable angina pectoris (UAP)] and 47 subjects without coronary artery disease (control group). U-L-FABP levels, urinary albumin (U-Alb), and other serum parameters were measured at admission and at 24h after percutaneous coronary intervention.ResultsU-L-FABP levels in patients with AMI were significantly higher (p=0.0019), than in control subjects, while patients with UAP did not exhibit such an increase. U-L-FABP levels at admission were positively correlated with brain natriuretic protein levels (p=0.001) and duration of hospitalization (p=0.025). At follow-up angiography, patients with restenosis had significantly higher U-L-FABP (p=0.047) and U-Alb levels (p

Background Hypertension is associated with impaired glucose tolerance and insulin resistance. Medical treatment that interferes with various steps in the renin-angiotensin system improves glucose tolerance and insulin resistance. However, it remains unclear if long-acting calcium channel blockers (CCBs) such as azelnidipine and amlodipine affect glucose tolerance and insulin resistance in clinical practice. Methods Seventeen non-diabetic patients with essential hypertension who had controlled blood pressure levels using amlodipine (5 mg/day) were enrolled in this study. After randomization, either azelnidipine (16 mg/day) or amlodipine (5 mg/day) was administered in a crossover design for 12-weeks. At baseline and the end of each CCB therapy, samples of blood and urine were collected and 75 g oral glucose tolerance test (OGTT) was performed. In addition, hematopoietic progenitor cells (HPCs) were measured at each point by flow cytometry and endothelial functions were measured by fingertip pulse amplitude tonometry using EndoPAT. Results Although blood pressure levels were identical after each CCB treatment, the heart rate significantly decreased after azelnidipine administration than that after amlodipine administration (P < 0.005). Compared with amlodipine administration, azelnidipine significantly decreased levels of glucose and insulin 120 min after the 75 g OGTT (both P < 0.05). Serum levels of high-sensitivity C-reactive protein (P = 0.067) and interleukin-6 (P = 0.035) were decreased. Although endothelial functions were not different between the two medication groups, the number of circulating HPCs was significantly increased after azelnidipine administration (P = 0.016). Conclusions These results suggest that azelnidipine treatment may have beneficial effects on glucose tolerance, insulin sensitivity, the inflammatory state, and number of circulating progenitor cells in non-diabetic patients with essential hypertension.

Objective— Elovl6, a long-chain fatty acid elongase, is a rate-limiting enzyme that elongates saturated and monounsaturated fatty acids and has been shown to be related to obesity-induced insulin resistance via modification of fatty acid composition. In this study, we investigated the roles of Elovl6 in foam cell formation in macrophages and atherosclerosis in mice. Methods and Results— To investigate the roles of Elovl6 in macrophages in the progression of atherosclerosis, we transplanted bone marrow cells of wild-type or Elovl6 −/− mice into irradiated LDL-R −/− mice that were fed a western diet. Aortic atherosclerotic lesion areas and infiltration of macrophages were significantly smaller in Elovl6 −/− bone marrow cells-transplanted LDL-R −/− mice than in wild-type. Accumulation of esterified cholesterol on exposure to acetylated-LDL was less severe in peritoneal macrophages from Elovl6 −/− mice than those from wild-type. Cholesterol efflux and expression of cholesterol efflux transporters were increased in Elovl6 −/− macrophages, although no difference in uptake of acetylated-LDL was found between the two groups. On analysis of fatty acid composition of the esterified cholesterol fraction in macrophages, n-6 polyunsaturated fatty acids were decreased by absence of Elovl6. Conclusion— These findings suggest that Elovl6 in macrophages may contribute to foam cell formation and progression of atherosclerosis.

Post-prandial hyperglycemia, hyperlipidemia, and endothelial dysfunction play an important role in the pathogenesis of atherosclerosis. Improvement in post-prandial hyperglycemia on alpha-glucosidase inhibitors (alpha-GIs) is associated with a risk reduction of cardiovascular diseases, but the post-prandial effects of alpha-GIs on endothelial function and incretin secretion in type 2 diabetic patients with coronary artery disease (CAD) remain unclear.The post-prandial effects of a single administration of miglitol and voglibose on endothelial function and changing levels of glucose, insulin, lipids, glucagon-like peptide (GLP)-1, and gastric inhibitory polypeptide (GIP) were compared after a standard meal loading in 11 diabetic patients with CAD, using a placebo-controlled cross-over design. The changing levels of glucose, insulin and triglycerides at 60 min were significantly lower in the miglitol group than in the voglibose and placebo groups (all P0.01). GLP-1 levels were significantly higher at 120 min (P0.05) and GIP levels were significantly lower at 30 min and 60 min (P0.05) in the miglitol group compared to other treatments. The reactive hyperemia duration at 120 min was significantly maintained in the miglitol group compared to the other groups.A single administration of miglitol significantly improved post-prandial glucose/lipid metabolism, incretin secretion, and endothelial dysfunction in diabetic patients with CAD, suggesting that miglitol may be a useful anti-atherogenic agent (UMIN000002264).

Background : Vascular endothelial dysfunction through the production of reactive oxygen species (ROS) plays an important role in the initiation and progression of atherosclerosis. Immunoglobulin Fc receptor (FcR) involves the activation of immune and inflammatory reaction, however, the role of FcR in endothelial function, ROS production, and atherogenesis, has not clearly elucidated. To examine the hypothesis that FcR deletion blunts the progression of atherosclerotic lesions via improvements of superoxide production and endothelial dysfunction, we generated FcR/LDL receptor double-knockout (DKO) mice. Methods : Mice (8 weeks) with LDL receptor knockout (LDLR-KO) and DKO were fed a high cholesterol diet for 10 weeks. We examined the endothelium-dependent relaxation of isolated thoracic aorta, superoxide production by dihydroethidium-derived fluorescence (DHE) staining before and after high cholesterol feeding. We also assessed atherosclerotic lesions by Oil Red O-staining, macrophage infiltration, and p22phox expression by immnohistochemical analysis. Results : Vascular endothelial-dependent relaxation induced by high cholesterol diet was significantly higher in DKO mice than in LDLR-KO mice (−53 ± 7% vs −22 ± 9, p < 0.05). Superoxide production was significantly lower in DKO mice than in LDLR-KO mice (13.6 ± 10 vs 38.8 ± 20 ×10 3 μ m 2 p < 0.05). The expression of p22phox in DKO mice was significantly lower than in LDLR-KO mice (90 ± 19 vs 141 ± 42 × 10 3 μm 2 p < 0.05). The area of macrophage infiltration of the vascular wall was significantly lower in DKO mice than LDLR-KO mice (34 ± 5 vs 59 ± 17 × 10 3 μ m 2 p < 0.05). The Oil -Red O staining showed the significant reduction of atherosclerotic lesions in DKO mice than in LDLR-KO mice (73 ± 24 vs 133 ± 31 × 10 4 μ m 2 p < 0.005). Conclusion : Deletion of FcR attenuated the production of ROS, vascular inflammation, and endothelial dysfunction, resulting in prevention of atherosclerotic formation in LDLR-KO mice. These data suggested that FcR might be involved in atherosclerotic process through not only vascular inflammation, but also oxidative stress in vasculature.

Velocity (baPWV) and conventional coronary risk factors. The relationship between this new parameter and coronary artery sclerosis was evaluated in comparison with other indexes. Results: CAD patients were characteristic of more hypertensive and diabetic with higher CAVI and baPWV than nonCAD subjects. Multivariate logistic analysis after adjustment for hypertension, diabetes mellitus, Dyslipidemia, current smoke, sex and age, still verified that CAD risk was significantly related to CAVI (OR; 3.60, for the difference between the first and the fourth quartile [95% Confidence Interval; 1.60 8.10, p = 0.002]), whereas the same relationship with baPWV statistically diminished (OR; 1.99, 95% Confidence Interval; 0.88 4.49, p = 0.097). CAVI also showed a more remarkable ability to predict CAD than baPWV and age among patients without hypertension and diabetes mellitus under age of 70 (CAVI; OR = 3.98, p = 0.020, baPWV; OR = 0.90, p = 0.631, age; OR = 1.15, p = 0.043). Conclusions: CAVI is more useful in predicting coronary artery stenosis than baPWV in all CAD-suspected subjects and even in their relative low-risk groups, which may lead to a possibility of CAVI for helping detecting CAD among those who are not easily screened out by coronary risk factors and baPWV.