Jyh-Hong Chen

Effects of oxidative stress on endothelial function after a high-fat meal

Postprandial lipaemia is known to cause endothelial dysfunction, but its underlying mechanism is still under debate. The present study was undertaken to investigate the effects of postprandial lipaemia on endothelial dysfunction and oxidative stress. We measured plasma glutathione peroxidase (GSH-Px), an antioxidant enzyme, and the urinary excretion of 8-epi-prostaglandin F2alpha (8-PGF2alpha), a free radical-catalysed product from the oxidative modification of arachidonic acid, in 16 healthy subjects (mean age, 30 +/- 5 years) without major coronary risk factors. Plasma high-sensitive C-reactive protein, soluble intercellular cell-adhesion molecule-1 and vascular cell-adhesion molecule-1 were also measured. High-resolution ultrasound was used to assess the flow-mediated vasodilatation (FMD) of the brachial artery. Blood and urine samples were collected before and 2, 4 and 6 h after a standard high-fat meal (3677 J, containing 50 g of fat). Serum triacylglycerol (triglyceride) increased and FMD decreased significantly after a high-fat meal. Plasma GSH-Px significantly decreased from 27.2 +/- 12.3 microg/ml to 25.7 +/- 11.8 microg/ml (P=0.022) 2 h after the meal, and urinary excretion of 8-PGF2alpha significantly increased from 1286 +/- 1401 pg/mg of creatinine to 2197 +/- 1343 pg/mg of creatinine (P=0.014) at 4 h after the meal. However, there were no significant changes in the levels of high-sensitive C-reactive protein and adhesion molecules after a high-fat meal. In conclusion, endothelial dysfunction was observed after consuming a high-fat meal and is associated with augmented oxidative stress manifested by the depletion of serum antioxidant enzymes and increased excretion of oxidative modification products.

Evidence for Statin Pleiotropy in Humans: Differential Effects of Statins and Ezetimibe on Rho-Associated Coiled-Coil Containing Protein Kinase Activity, Endothelial Function, and Inflammation

Background— By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins not only reduce cholesterol biosynthesis but also decrease the formation of isoprenoids, which are important for mediating signaling through the Rho-associated coiled-coil containing protein kinase (ROCK) pathway. Increased ROCK activity has been implicated in endothelial dysfunction and vascular inflammation. We hypothesize that ezetimibe, which inhibits intestinal cholesterol absorption, may not exert similar cholesterol-independent or pleiotropic effects of statins and, when used with a lower dose of statin, have less effect on ROCK activity than a higher dose of statin. Methods and Results— In a prospective, randomized, observer-blinded study, we treated 60 dyslipidemic subjects without cardiovascular disease with simvastatin 40 mg/d, simvastatin/ezetimibe 10/10 mg/d, or placebo tablets for 28 days (n=20 in each arm). We evaluated baseline demographics and lipid levels, ROCK activity, C-reactive protein, and flow-mediated dilation before and after treatment. Compared with the placebo group, both treatment regimens decreased low-density lipoprotein cholesterol by 38% and C-reactive protein by 38% to 40% after 28 days (P<0.01 for both compared with placebo). Although the low-density lipoprotein cholesterol and C-reactive protein reductions were comparable with either lipid-lowering regimen, only simvastatin 40 mg reduced ROCK activity and improved flow-mediated dilation (P<0.01 for both compared with baseline). Reduction in ROCK activity with simvastatin 40 mg remained significant even after controlling for changes in low-density lipoprotein cholesterol (P=0.01) and correlated with improvement in flow-mediated dilation (R2=−0.78, P<0.01). No correlation was found between changes in flow-mediated dilation and changes in low-density lipoprotein cholesterol or C-reactive protein. Conclusion— These results indicate that high-dose statin monotherapy exerts greater effects on ROCK activity and endothelial function, but not on C-reactive protein, than low-dose statin plus ezetimibe. These findings provide additional evidence of statin benefits beyond cholesterol lowering.

Dabigatran Versus Warfarin Effects on Ischemic and Hemorrhagic Strokes and Bleeding in Asians and Non-Asians With Atrial Fibrillation

Background and Purpose— Intracranial hemorrhage rates are higher in Asians than non-Asians, especially in patients receiving warfarin. This randomized evaluation of long-term anticoagulation therapy subgroup analysis assessed dabigatran etexilate (DE) and warfarin effects on stroke and bleeding rates in patients from Asian and non-Asian countries. Methods— There were 2782 patients (15%) from 10 Asian countries and 15 331 patients from 34 non-Asian countries. A Cox regression model, with terms for treatment, region, and their interaction was used. Results— Rates of stroke or systemic embolism in Asians were 3.06% per year on warfarin, 2.50% per year on DE 110 mg BID (DE 110), and 1.39% per year on DE 150 mg BID (DE 150); in non-Asians, the rates were 1.48%, 1.37%, and 1.06% per year with no significant treatment-by-region interactions. Hemorrhagic stroke on warfarin occurred more often in Asians than non-Asians (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.3–4.7; P=0.007), with significant reductions for DE compared with warfarin in both Asian (DE 110 versus warfarin HR, 0.15; 95% CI, 0.03–0.66 and DE 150 versus warfarin HR, 0.22; 95% CI, 0.06–0.77) and non-Asian (DE 110 versus warfarin HR, 0.37; 95% CI, 0.19–0.72 and DE 150 versus warfarin HR, 0.28; 95% CI, 0.13–0.58) patients. Major bleeding rates in Asians were significantly lower on DE (both doses) than warfarin (warfarin 3.82% per year, DE 110 2.22% per year, and DE 150 2.17% per year). Conclusions— Hemorrhagic stroke rates were higher on warfarin in Asians versus non-Asians, despite similar blood pressure, younger age, and lower international normalized ratio values. Hemorrhagic strokes were significantly reduced by DE in both Asians and non-Asians. DE benefits were consistent across Asian and non-Asian subgroups. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

Impact of supplement with Lactobacillus- and Bifidobacterium-containing yogurt on triple therapy for Helicobacter pylori eradication

Aim : To test whether supplements of Lactobacillus‐ and Bifidobacterium‐containing yogurt (AB‐Yogurt) affect the success of Helicobacter pylori eradication.

The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study

Background— During follow-up of between 1 and 3 years in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, 2 doses of dabigatran etexilate were shown to be effective and safe for the prevention of stroke or systemic embolism in patients with atrial fibrillation. There is a need for longer-term follow-up of patients on dabigatran and for further data comparing the 2 dabigatran doses. Methods and Results— Patients randomly assigned to dabigatran in RE-LY were eligible for the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial if they had not permanently discontinued study medication at the time of their final RE-LY study visit. Enrolled patients continued to receive the double-blind dabigatran dose received in RE-LY, for up to 28 months of follow up after RE-LY (median follow-up, 2.3 years). There were 5851 patients enrolled, representing 48% of patients originally randomly assigned to receive dabigatran in RE-LY and 86% of RELY-ABLE–eligible patients. Rates of stroke or systemic embolism were 1.46% and 1.60%/y on dabigatran 150 and 110 mg twice daily, respectively (hazard ratio, 0.91; 95% confidence interval, 0.69–1.20). Rates of major hemorrhage were 3.74% and 2.99%/y on dabigatran 150 and 110 mg (hazard ratio, 1.26; 95% confidence interval, 1.04–1.53). Rates of death were 3.02% and 3.10%/y (hazard ratio, 0.97; 95% confidence interval, 0.80–1.19). Rates of hemorrhagic stroke were 0.13% and 0.14%/y. Conclusions— During 2.3 years of continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00808067.

Intramyocardial Peptide Nanofiber Injection Improves Postinfarction Ventricular Remodeling and Efficacy of Bone Marrow Cell Therapy in Pigs

Background— Growing evidence suggests that intramyocardial biomaterial injection improves cardiac functions after myocardial infarction (MI) in rodents. Cell therapy is another promising approach to treat MI, although poor retention of transplanted cells is a major challenge. In this study, we hypothesized that intramyocardial injection of self-assembling peptide nanofibers (NFs) thickens the infarcted myocardium and increases transplanted autologous bone marrow mononuclear cell (MNC) retention to attenuate cardiac remodeling and dysfunction in a pig MI model. Methods and Results— A total of 40 mature minipigs were divided into 5 groups: sham, MI+normal saline, MI+NFs, MI+MNCs, and MI+MNCs/NFs. MI was induced by coronary occlusion followed by intramyocardial injection of 2 mL normal saline or 1% NFs with or without 1×108 isolated autologous MNCs. NF injection significantly improved diastolic function and reduced ventricular remodeling 28 days after treatment. Injection of MNCs alone ameliorated systolic function only, whereas injection of MNCs with NFs significantly improved both systolic and diastolic functions as indicated by +dP/dt and −dP/dt (1214.5±91.9 and −1109.7±91.2 mm Hg/s in MI+NS, 1693.7±84.7 and −1809.6±264.3 mm Hg/s in MI+MNCs/NFs, respectively), increased transplanted cell retention (29.3±4.5 cells/mm2 in MI+MNCs and 229.4±41.4 cells/mm2 in MI+MNCs/NFs) and promoted capillary density in the peri-infarct area. Conclusions— We demonstrated that NF injection alone prevents ventricular remodeling, whereas cell implantation with NFs improves cell retention and cardiac functions after MI in pigs. This unprecedented combined treatment in a large animal model has therapeutic effects, which can be translated to clinical applications in the foreseeable future.

Increased Rho Kinase Activity in a Taiwanese Population With Metabolic Syndrome

OBJECTIVES We sought to determine whether Rho kinase (ROCK) activity is increased in a Taiwanese population with metabolic syndrome (MetS). BACKGROUND Recent studies suggest that ROCK may be involved in the pathogenesis of MetS, but clinical studies linking ROCK with MetS are lacking. METHODS We studied 40 Taiwanese subjects (60% men, mean age 55.5 +/- 5.6 years) who were diagnosed with MetS with National Cholesterol Educational Program Adult Treatment Panel III criteria and 40 age- and gender-matched control subjects. Subject demographics were recorded, and blood samples were obtained. RESULTS Compared with control subjects, ROCK activity, as determined by phosphorylation of myosin binding subunit (MBS) in leukocytes, was greater in MetS subjects (mean phospho-MBS/MBS ratio 0.46 vs. 0.35, p = 0.002). A cutoff value for ROCK activity of 0.39 predicted the presence of MetS with specificity and sensitivity rates of 70%. Plasma high-sensitivity C-reactive protein was greater (5.5 mg/l, 95% confidence interval [CI] 3.1 to 7.2 mg/l vs. 2.8 mg/l, 95% CI 1.1 to 3.9 mg/l, p = 0.01) and adiponectin was lower (4.9 microg/ml, 95% CI 3.2 to 6.1 microg/ml vs. 5.9 microg/ml, 95% CI 4.2 to 7.5 microg/ml, p = 0.01) in MetS subjects compared with control subjects, but plasma levels of interleukin-6 and tumor necrosis factor-alpha were not different (p > 0.05 for both). Body mass index, waist circumference, fasting glucose, high-sensitivity C-reactive protein, and triglyceride levels were associated with increased levels of ROCK activity. The risk of increased ROCK activity increased with the number of MetS components (p for trend <0.001). CONCLUSIONS Rho kinase activity is increased in Taiwanese subjects with MetS and is associated with each component of MetS and markers of inflammation. These findings suggest that ROCK activity may be a novel serological marker of MetS.

A Genome-Wide Association Study Reveals a Quantitative Trait Locus of Adiponectin on CDH13 That Predicts Cardiometabolic Outcomes

OBJECTIVE The plasma adiponectin level, a potential upstream and internal facet of metabolic and cardiovascular diseases, has a reasonably high heritability. Whether other novel genes influence the variation in adiponectin level and the roles of these genetic variants on subsequent clinical outcomes has not been thoroughly investigated. Therefore, we aimed not only to identify genetic variants modulating plasma adiponectin levels but also to investigate whether these variants are associated with adiponectin-related metabolic traits and cardiovascular diseases. RESEARCH DESIGN AND METHODS We conducted a genome-wide association study (GWAS) to identify quantitative trait loci (QTL) associated with high molecular weight forms of adiponectin levels by genotyping 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 SNP chips. The culpable single nucleotide polymorphism (SNP) variants responsible for lowered adiponectin were then confirmed in another 559 YOH subjects, and the association of these SNP variants with the risk of metabolic syndrome (MS), type 2 diabetes mellitus (T2DM), and ischemic stroke was examined in an independent community–based prospective cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS, n = 3,350). RESULTS The SNP (rs4783244) most significantly associated with adiponectin levels was located in intron 1 of the T-cadherin (CDH13) gene in the first stage (P = 7.57 × 10−9). We replicated and confirmed the association between rs4783244 and plasma adiponectin levels in an additional 559 YOH subjects (P = 5.70 × 10−17). This SNP was further associated with the risk of MS (odds ratio [OR] = 1.42, P = 0.027), T2DM in men (OR = 3.25, P = 0.026), and ischemic stroke (OR = 2.13, P = 0.002) in the CVDFACTS. CONCLUSIONS These findings indicated the role of T-cadherin in modulating adiponectin levels and the involvement of CDH13 or adiponectin in the development of cardiometabolic diseases.

Evidence of Left Ventricular Systolic Dysfunction Detected by Automated Function Imaging in Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction

BACKGROUND Left ventricular ejection fraction (LVEF) cannot reflect cardiac contractile function in patients with heart failure and preserved LVEF (HFPEF). LV systolic impairment is actually debated in HFPEF patients. Automated function imaging (AFI) is a novel algorithm of speckle-tracking echocardiography and efficiently to assess global LV peak systolic longitudinal strain (PSLS), an index for systolic function. The purpose of the study is to examine whether contractile function is impaired in HFPEF patients. METHODS AND RESULTS This study included 49 heart failure patients (23 with systolic dysfunction [SHF] and 26 with HFPEF), and 40 patients, matched for age, sex, as well as concomitant disease and without heart failure as controls. All patients underwent transthoracic echocardiography. LVEF was measured by Simpsons method. Two-dimensional speckle tracking imaging with AFI assessment was applied to measure longitudinal strain. LVEF was 66+/-5% in the controls, 63+/-8% in the HFPEF group (P=.14), and 34+/-10% in the SHF group (P < .001). The value of LV global PSLS (controls: -20%, HFPEF: -14%, SHF: -8%, P < .001) was significantly less negative in both heart failure groups. CONCLUSIONS Deteriorated LV systolic function is demonstrated by decreased global PSLS in HFPEF patients. AFI is an effective and facile method for assessing LV systolic abnormalities.

Elevation of Soluble Adhesion Molecules Is Associated With the Severity of Myocardial Damage in Acute Myocardial Infarction

In 20 patients with acute myocardial infarction, blood samples were taken to study the serial changes in the soluble intercellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1) and E-selectin. Results indicated that soluble ICAM-1 increased significantly and persisted throughout the study period; however, soluble E-selectin was significantly elevated only transiently and decreased rapidly thereafter, and the VCAM-1 did not increase during entire study period. There was a significant correlation between the levels of ICAM-1, E-selectin 6 hours after admission, and peak creatine kinase level; the levels of ICAM-1 and E-selectin were also positively correlated with total leukocyte count at admission.