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Background: This study aimed to evaluate the performance of a modified U.S. (MUS) model for risk prediction of cardiovascular (CV) events in Asian patients and compare it to European and Japanese models., Methods: The MUS model, based on the US ACC/AHA 2018 lipid treatment guideline, was employed to stratify patients under primary or secondary prevention. Two multi-center prospective observational registry cohorts, T-SPARCLE and T-PPARCLE, were used to validate the scoring system, and the primary outcome was the time to first occurrence/recurrence of major adverse cardiac events (MACEs). The MUS model's performance was compared to other models from Europe and Japan., Results: A total of 10,733 patients with the mean age of 64.2 (SD: 11.9) and 36.5% female were followed up for a median of 5.4 years. The MUS model was validated, with an AUC score of 0.73 (95% CI 0.68-0.78). The European and Japanese models had AUC scores ranging from 0.6 to 0.7. The MUS model categorized patients into four distinct CV risk groups, with hazard ratios (HRs) as follows: very high- vs. high-risk group (HR = 1.91, 95% CI 1.53-2.39), high- vs. moderate-risk group (HR = 2.08, 95% CI 1.60-2.69), and moderate- vs. low-risk group (HR = 3.14, 95% CI 1.63-6.03). After adjusting for the MUS model, a history of atherosclerotic vascular disease (ASCVD) was not a significant predictor of adverse cardiovascular outcomes within each risk group., Conclusion: The MUS model is an effective tool for risk stratification in Asian patients with and without ASCVD, accurately predicting MACEs and performing comparably or better than other established risk models. Our findings suggest that patient management should focus on background risk factors instead of solely on primary or secondary prevention., Competing Interests: Conflicts of interest The authors declared no conflicts of interest., (© 2023 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Retinopathy is a well-known ocular complication that occurs in patients with type 2 diabetes (T2D). Recent evidence also indicates that diabetic patients have an increased prevalence of dry eye syndrome. However, the etiologies of both diabetic retinopathy (DR) and dry eye disease are complex, and their associations with T2D remains to be fully understood. Patient-derived human induced pluripotent stem cells (hiPSCs) enable the generation of disease-specific retinal tissues such as retinal pigment epithelium and lacrimal gland to model disease pathogenesis. Here, we describe the establishment of three hiPSC lines from T2D patients with PDR or dry eye disease., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: We aimed to examine the association of serum high mobility group box 1 (HMGB1) level with cardiovascular risk in patients undergoing coronary angiography with no history of diabetes., Methods: We enrolled patients with no history of diabetes who had been admitted for coronary angiography due to suspected or known coronary artery disease. Two to four weeks after the patients were discharged from the hospital, an oral glucose tolerance test (OGTT) was conducted and serum HMGB1 level was measured. Patients' 10-year coronary heart disease (CHD) risk was assessed using the Framingham Risk Scoring., Results: A total of 476 patients were enrolled. Overall, mean serum HMGB1 level was 6.1 ± 1.3 pg/ml. Using linear regression analysis, high-density lipoprotein cholesterol was negatively associated with serum HMGB1 (β coefficient - 0.033, 95% CI -0.063 to -0.003, p = 0.033) after adjustment for several confounders. With regard to cardiovascular risk, levels of serum HMGB1 were positively associated with 10-year CHD risk (β coefficient 0.506, 95% CI 0.030 to 0.983, p = .037), independent of patients' undiagnosed abnormal glucose regulation., Conclusions: In patients undergoing coronary angiography with no history of diabetes, levels of serum HMGB1 were positively associated with 10-year CHD risk, independent of patients' undiagnosed abnormal glucose regulation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Arterial stiffening blunts postprandial vasodilatation. We hypothesized that brain-derived neurotrophic factor (BDNF) may modulate postprandial central pulse pressure, a surrogate marker for arterial stiffening., Methods: A total of 82 non-diabetic subjects received a 75-g oral glucose tolerance test (OGTT) after overnight fasting. Serum BDNF concentrations were determined at 0, 30, and 120min to calculate the area under the curve (AUC). Brachial and central blood pressures were measured using a noninvasive central blood pressure monitor before blood withdrawals at 0 and 120min., Results: With the median AUC of BDNF of 45(ng/ml)∗h as the cutoff value, the central pulse pressure after glucose intake was significantly higher in the subjects with a low BDNF than in those with a high BDNF (63±16 vs. 53±11mmHg, P=0.003), while the brachial pulse pressure was not significantly different between the 2 groups (P=0.099). In a multivariate linear regression model, a lower AUC of BDNF was an independent predictor of a higher central pulse pressure after oral glucose intake (linear regression coefficient-0.202, 95% confidence interval-0.340 to -0.065, P=0.004)., Conclusion: After oral glucose challenge, a lower serum BDNF response is significantly associated with a higher central pulse pressure., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: We investigated the associations of fibroblast growth factor 21 (FGF-21) with cardiovascular risk and β-cell function in patients who had no history of diabetes., Methods: We enrolled 269 outpatients who had been referred for an oral glucose tolerance test (OGTT). Plasma glucose, insulin, and FGF-21 were measured before and at 2h after the OGTT. β-cell function was assessed using the insulinogenic index, corrected for insulin resistance. Patients' 10-year coronary heart disease (CHD) risk was assessed using the Chinese Multi-provincial Cohort Study functions., Results: Overall, there was a 10% decrease in FGF-21 after OGTT (p<0.001). The decrease of FGF-21 after OGTT in patients with normal glucose tolerance, prediabetes, and diabetes was 8%, 10%, and 21%, respectively (all p<0.05). Patients with a history of admission for coronary angiography had a higher 10-year CHD risk and fasting FGF-21 (both p<0.001). In multivariate regression analysis, fasting FGF-21 was positively associated with 10-year CHD risk, while FGF-21 relative change 2h after OGTT was positively associated with β-cell function., Conclusions: In patients who had no history of diabetes, fasting FGF-21 was positively associated with 10-year CHD risk, while FGF-21 relative change 2h after OGTT was positively associated with β-cell function., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Brain-derived neurotrophic factor (BDNF) is important for neural protection and energy homeostasis. In this study, we examined the effects of vascular cell adhesion molecule-1 (VCAM-1) and coronary artery disease (CAD) on BDNF., Methods: Subjects who had undergone diagnostic angiography for angina were recruited, and a total of 240 subjects (144 with CAD and 96 without CAD) were enrolled. Serum BDNF was determined at 0, 30, and 120min during an oral glucose tolerance test (OGTT) to calculate the area under the curve (AUC) for BDNF. Serum VCAM-1 was determined at fasting., Results: Significantly lower AUC of BDNF (42.8±10.7 vs. 47.4±11.7ng-h/ml, P=0.002) and higher serum VCAM-1 (583±383 vs. 482±171ng/ml, P=0.017) were noted in subjects with CAD compared to those without CAD. High VCAM-1 level was an independent predictor of low AUC of BDNF in subjects with and without CAD (95%CI between -0.011 and -0.002, P=0.008; -0.033 and -0.002, P=0.029, respectively). Serum BDNF was lowest in the CAD subjects with high VCAM-1 levels at all time points during OGTT., Conclusion: Our results showed that CAD was associated with low serum BDNF in response to OGTT, and VCAM-1 had a synergistic effect with CAD on the BDNF., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: We investigated the effect of statin treatment on the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and insulin resistance in patients without history of heart failure., Methods: Patients without history of heart failure and diabetes were recruited to undergo an oral glucose tolerance test. Blood samples were collected for measurements of NT-proBNP, glucose, and insulin. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Linear mixed model analysis was used to examine the correlation between NT-proBNP and HOMA-IR., Results: A total of 219 patients (mean age 61.1±11.8y, median NT-proBNP 64.3 [32.1-154.5] pg/ml) were analyzed. Overall, NT-proBNP was negatively correlated with HOMA-IR after an adjustment for confounders (β coefficient -0.335, 95% CI [-0.516, -0.153], p=0.001). This correlation was significant in patients on statin treatment (n=91, β coefficient -0.558, 95% CI [-0.802, -0.312], p<0.001), but was insignificant in patients not on statin treatment (n=128, β coefficient -0.147, 95% CI [-0.412, 0.118], p=0.274, p for interaction=0.040)., Conclusions: Statin treatment is associated with a negative correlation between NT-proBNP and insulin resistance in patients without history of heart failure. Our findings suggest that NT-proBNP may be related to insulin resistance associated with statin treatment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: We investigated factors associated with fibroblast growth factor 19 (FGF-19) increment after oral glucose loading (OGL) in human subjects., Methods: A total of 240 outpatients without known diabetes who were previously admitted for coronary angiography underwent an oral glucose tolerance test. FGF-19 increment (pg/ml) was calculated as FGF-19 2h after OGL minus fasting FGF-19., Results: Overall, FGF-19 significantly increased after OGL (from 123 [78-201] to 141 [80-237], p=0.001). By age tertiles (≦ 54, 55-64, ≧ 65), FGF-19 significantly increased only in patients aged ≧ 65 (from 143 [98-209] to 189 [124-332], p<0.001). By glucose regulation status, FGF-19 significantly increased in patients with normal glucose tolerance (from 117 [78-211] to 153 [106-325], p=0.014) and in patients with prediabetes (from 117 [73-179] to 123 [70-204], p=0.043), but not in patients with diabetes (from 181 [102-243] to 178 [111-275], p=0.139). FGF-19 significantly increased in patients on statin treatment (from 120 [78-207] to 145 [86-264], p<0.001), but not in patients not on statin therapy (from 125 [86-196] to 128 [68-230] pg/ml, p=0.676). These findings remained significant after adjustment for confounders., Conclusions: FGF-19 increment after OGL was positively associated with age, and negatively associated with abnormal glucose regulation and statin treatment., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Angiogenesis is critical in the development of cancer, which involves several angiogenic factors in its peritoneal dissemination. The role of protein tumor progression locus 2 (Tpl2) in angiogenic factor-related endothelial cell angiogenesis is still unclear. To understand the precise mechanism(s) of Tpl2 inhibition in endothelial cells, this study investigated the role of Tpl2 in mediating angiogenic signals using in vitro, in vivo, and ex vivo models. Results showed that inhibition of Tpl2 inhibitor significantly reduced peritoneal dissemination in a mouse model by positron emission tomography/computed tomography imaging. Simultaneously, inhibiting Tpl2 blocked angiogenesis in tumor nodules and prevented angiogenic factor-induced proliferating cell nuclear antigen (PCNA) in endothelial cells. Vascular endothelial growth factor (VEGF) or chemokine (C-X-C motif) ligand 1 (CXCL1) increased Tpl2 kinase activity and phosphorylation in a dose- and time-dependent manner. Furthermore, Tpl2 inhibition or ablation by siRNA prevented the angiogenic signal-induced tube formation in Matrigel plug assay or aortic ring assay. Inhibiting Tpl2 also prevented the angiogenic factor-induced chemotactic motility and migration of endothelial cells. Tpl2 inhibition by CXCL1 or epidermal growth factor in endothelial cells was associated with inactivation of CCAAT/enhancer binding protein β, nuclear factor κ light-chain enhancer of activated B cells, and activating protein 1 and suppression of VEGF expression. Thus, Tpl2 inhibitors thwart Tpl2-regulated VEGF by inactivating transcription factors involved in angiogenic factor-triggered endothelial cell angiogenesis. These results suggest that the therapeutic inhibition of Tpl2 may extend beyond cancer and include the treatment of other diseases involving pathologic angiogenesis.

Background: Excessive visceral fat with unbalanced adipokines is a critical pathogenic factor of metabolic syndrome (MetS), which is associated with disorders of the central nervous system and cardiovascular disease. Because brain-derived neurotrophic factor (BDNF) plays an important role in neurons, we examined the relationship of BDNF to MetS, adipose tissue and biomarkers in men., Methods: Thirty-four non-diabetic men with MetS and another 24 age-matched men without MetS were enrolled. In addition to fasting blood samples, the area of adipose tissue at the waist was assessed by magnetic resonance imaging (MRI)., Results: There was no significant difference in serum BDNF concentrations between men with or without MetS (40.9±8.0 vs. 43.2±6.1 ng/ml, P=0.235). However, the serum concentration of soluble vascular cell adhesion molecule-1 (VCAM-1) was higher in the subjects with a lower BDNF level (737±230 vs. 628±115 ng/ml, P=0.025). An inverse correlation between VCAM-1 and BDNF was observed (r=-0.391, P=0.002). After adjusting for visceral adipose tissue, VCAM-1 was found to be independently associated with BDNF [95% confidence interval (-0.025, -0.005), P=0.004]., Conclusion: These data show no difference in serum BDNF levels between the men with MetS and controls. However, serum BDNF was inversely correlated with serum VCAM-1 in men without diabetes., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Resistin, an adipocytokine, plays a potential role in cardiovascular disease and may contribute to increased atherosclerotic risk by modulating the activity of endothelial cells. A growing body of evidence suggests that aspirin is a potent antioxidant. We investigated whether aspirin mitigates resistin-induced endothelial dysfunction via modulation of reactive oxygen species (ROS) generation and explored the role that AMP-activated protein kinase (AMPK), a negative regulator of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, plays in the suppressive effects of aspirin on resistin-induced endothelial dysfunction., Methods: Human umbilical vein endothelial cells (HUVECs) were pretreated with various doses of aspirin (10-500 μg/mL) for 2 hours and then incubated with resistin (100 ng/mL) for an additional 48 hours. Fluorescence produced by the oxidation of dihydroethidium (DHE) was used to quantify the production of superoxide in situ; superoxide dismutase (SOD) and catalase activities were determined by an enzymatic assay; and protein levels of AMPK-mediated downstream signaling were investigated by Western blot., Results: Treatment of HUVECs with resistin for 48 hours resulted in a 2.9-fold increase in superoxide production; however, pretreatment with aspirin resulted in a dose-dependent decrease in production of superoxide (10-500 μg/mL; n = 3 experiments; all P < .05). Resistin also suppressed the activity of superoxide dismutase and catalase by nearly 50%; that result, however, was not observed in HUVECs that had been pretreated with aspirin at a concentration of 500 μg/mL. The membrane translocation assay showed that the levels of NADPH oxidase subunits p47(phox)and Rac-1 in membrane fractions of HUVECs were threefold to fourfold higher in cells that had been treated with resistin for 1 hour than in untreated cells; however, pretreatment with aspirin markedly inhibited resistin-induced membrane assembly of NADPH oxidase via modulating AMPK-suppressed PKC-α activation. Application of AMPKα1-specific siRNA resulted in increased activation of PKC-α and p47(phox). In addition, resistin significantly decreased AMPK-mediated downstream Akt/endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling and induced the phosphorylation of p38 mitogen-activated protein kinases, which in turn activated NF-κB-mediated inflammatory responses such as the release of interleukin (IL)-6 and IL-8, the overexpression of adhesion molecules, and stimulation of monocytic THP-1 cell attachment to HUVECs (2.5-fold vs control; n = 3 experiments). Furthermore, resistin downregulated eNOS and upregulated inducible NO synthase (iNOS) expression, thereby augmenting the formation of NO and protein nitrosylation. Pretreatment with aspirin, however, exerted significant cytoprotective effects in a dose-dependent manner (P < .05)., Conclusions: Our findings suggest a direct connection between adipocytokines and endothelial dysfunction and provide further insight into the protective effects of aspirin in obese individuals with endothelial dysfunction., (Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Background: LOX-1, a lectin-like receptor on endothelial cells, facilitates the uptake of oxidized low-density lipoprotein (oxLDL). Expression of LOX-1 is involved in the pathobiological effects of oxLDL in endothelial cells, including reactive oxygen species (ROS) generation, suppression of endothelial nitric oxide synthase (eNOS) activity, and leukocytic adhesion. Moderate consumption of phenolic-enriched food may have a protective effect against the development of atherosclerosis via the antioxidant capacity of phenolic compounds at the endothelial level. In this study, we determined whether ellagic acid, a polyphenolic compound widely distributed in fruits and nuts, protects against oxLDL-induced endothelial dysfunction by modulating the LOX-1-mediated signaling pathway., Methods: Human umbilical vein endothelial cells (HUVECs) were pretreated with ellagic acid at doses of 5, 10, 15, and 20 μM for 2 hours and then incubated with oxLDL (150 μg/mL) for an additional 24 hours., Results: LOX-1 protein expression was markedly lower after exposure to oxLDL in HUVECs pretreated with ellagic acid or diphenyleneiodonium, a well-known inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, than in HUVECs exposed to oxLDL alone, suggesting that ellagic acid deactivates NADPH oxidase. We also found that oxLDL activated the membrane assembly of p47phox, Rac1, gp91 and p22phox, and the subsequent induction of ROS generation; however, ROS generation was markedly suppressed in cells pretreated with ellagic acid or anti-LOX-1 monoclonal antibody. In addition, oxLDL down-regulated eNOS and up-regulated inducible NO synthase (iNOS), thereby augmenting the formation of NO and protein nitrosylation. Furthermore, oxLDL induced the phosphorylation of p38 mitogen-activated protein kinase, activated the NF-κB-mediated inflammatory signaling molecules interleukin-(IL) 6 and IL-8 and the adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin, and stimulated the adherence of THP-1 (a human acute monocytic leukemia cell line) to HUVECs. Pretreatment with ellagic acid, however, exerted significant cytoprotective effects in all events., Conclusion: Findings from this study may provide insight into a possible molecular mechanism by which ellagic acid inhibits LOX-1-induced endothelial dysfunction. Our data indicate that ellagic acid exerts its protective effects by inhibiting NADPH oxidase-induced overproduction of superoxide, suppressing the release of NO by down-regulating iNOS, enhancing cellular antioxidant defenses, and attenuating oxLDL-induced LOX-1 up-regulation and eNOS down-regulation., (Copyright © 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Adipocyte cytokines regulate glucose metabolism and insulin resistance and adiponectin is thought to have a protective effect against atherosclerosis. Studies have shown that adiponectin expression is decreased in obese subjects and those with metabolic syndrome or diabetes mellitus. The purpose of this study was to investigate the relationship between circulating adipocyte cytokine concentrations and angiographic coronary artery disease (CAD) progression in patients with chest pain. Patients with stable angina pectoris who underwent repeat coronary angiograms and had serum samples at the time of first catheterization between March 1999 and January 2004 were enrolled. A modified Gensini scoring system was used to define angiographic coronary artery progression between the index and follow-up angiograms. Those who had significant angiographic progression of coronary lesions were classified into the progression group (N=55). Those who did not have CAD progression were classified into the non-progression group (N=102). Univariate analysis showed that CAD progression was associated with male gender (93% vs. 78%, p=0.038), higher baseline total cholesterol (187+/-43 vs. 173+/-39 mg/dl, p=0.037) and higher baseline fasting blood glucose (128+/-57 vs. 110+/-40 mg/dl, p=0.037). Patients in the progression group had a significantly lower serum adiponectin level (14.3+/-7.9 vs. 18.9+/-13.2 mug/ml, p=0.007) than, but resistin (28.9+/-13.4 vs. 34.4+/-26.0 ng/ml, p=0.142) and leptin (7.4+/-4.6 vs. 7.7+/-6.5 ng/ml, p=0.675) levels similar to, those in the non-progression group. In a multivariate binary logistic regression model, male gender (odds ratio 4.283, p=0.015), higher serum cholesterol (odds ratio 1.010, p=0.032) and lower serum adiponectin (odds ratio 0.959, p=0.030) were all significant independent predictors of CAD progression. In conclusion, we found that a decreased circulating level of adiponectin is associated with angiographic CAD progression in patients with angina pectoris.

Background: Statins may improve lipid profiles and inflammation-associated biomarkers, but the effect on insulin sensitivity is controversial. We investigated the effects of 2 doses of pravastatin (40 and 10 mg/day) on insulin sensitivity and serum inflammatory markers in nondiabetic hypercholesterolemic patients., Methods: This was a randomized, parallel, comparative design study. A total of 40 nondiabetic subjects with elevated low-density lipoprotein (LDL) cholesterol were randomized to either the 40 mg pravastatin/day group (n=21) or the 10 mg pravastatin/day group (n=19) for 8 weeks. The fasting serum lipid profile, homeostasis model assessment (HOMA), glucose and insulin response of the two-hour glucose tolerance test (2 h-OGTT), and several inflammatory markers were determined., Results: Eight weeks of pravastatin treatment in both dose groups led to a significant reduction in serum LDL cholesterol, total cholesterol, triglycerides, and total cholesterol/ high-density lipoprotein (HDL) cholesterol ratios (all p< 0.01 in 40 mg group and all p<0.05 in 10 mg group), though the 40 mg group had greater effects. Although the fasting HOMA insulin resistance did not change significantly in either group, glucose and insulin areas under the curve of 2 h-OGTT were significantly decreased, suggesting improvement in insulin sensitivity post glucose challenge. Serum CD-40 ligand concentration was significantly reduced in the 40 mg pravastatin/day group and soluble P-selectin significantly reduced in both groups., Conclusions: Pravastatin treatment, at 10 mg or 40 mg daily for 8 weeks, reduced serum lipids and some inflammatory markers in nondiabetic hypercholesterolemic subjects. Furthermore, insulin resistance was improved even in short-term treatment by pravastatin.

Background: Metabolic syndrome is gaining more attention as a special cluster of cardiovascular risks. However, its role, with or without diabetes, in predicting atherosclerosis progression, remains largely undetermined. We investigated the predictors for angiographic coronary atherosclerosis progression in patients with metabolic syndrome and angina pectoris., Methods: Patients with metabolic syndrome and angina pectoris who underwent repeat coronary angiograms and had serum samples at the time of first catheterization were enrolled for analysis (N=113). A modified Gensini scoring system was used to define CAD progression between the index and follow-up angiograms. Those who had significant angiographic progression of coronary disease were classified as the progression group (N=42) and those who did not as the non-progression group (N=71)., Results: There were more cases of diabetes mellitus (52% vs. 31%, p=0.040) in the CAD progression group. The progression group also had higher baseline fasting blood glucose (150+/-73 vs. 117+/-46 mg/dl, p=0.010) but similar LDL cholesterol (114+/-38 vs. 109+/-33 mg/dl, p=0.421) than the non-progression group. In terms of inflammatory markers, there was no difference in hs-CRP (p=0.208), MCP-1 (p=0.514), or sCD40L (p=0.549) between the groups. In binary logistic regression, diabetes mellitus remained a significant predictor of CAD progression (OR 2.43, p=0.030) for patients with metabolic syndrome and angina pectoris, but hs-CRP and LDL-C were not., Conclusion: Diabetes mellitus, but not inflammatory marker hs-CRP or LDL-C, is a significant predictor of angiographic CAD progression in patients with metabolic syndrome and angina pectoris.

Background: Coronary artery disease (CAD) is a major cause of death worldwide. Epidemiological studies have documented conventional risk factors; however, no studies to date have addressed the roles of soluble CD40 ligand (sCD40L) and monocyte chemoattractant protein-1 (MCP-1), and there have been few reports on other novel risk factors in CAD progression. The aim of the present study was to explore the roles of novel and conventional risk factors in CAD progression., Methods: Patients with stable angina pectoris who underwent repeat coronary angiograms and had serum samples at the time of their first catheterization between March 1999 and January 2004 were enrolled. Those who had progression of coronary atherosclerosis were classified into the progression group (n = 66). Those who did not have CAD progression were classified into the nonprogression group (n = 124)., Results: There were more cases of diabetes mellitus (36% versus 20%; P = 0.024) and more men (92% versus 81%; P = 0.040) in the CAD progression group than in the nonprogression group, respectively. The progression group also had poorer lipid profiles than the nonprogression group, including higher total cholesterol (188+/-42 mg/dL versus 173+/-39 mg/dL, respectively; P = 0.014) and low density lipoprotein cholesterol (122+/-38 mg/dL versus 112+/-36 mg/dL, respectively; P = 0.025). In terms of inflammatory markers, progression patients had higher baseline high-sensitivity C-reactive protein (hs-CRP) concentrations (P = 0.018), which was also related to the subsequent angiographic severity score changes; however, sCD40L (6182+/-4352 pg/mL versus 6244+/-4602 pg/mL; P = 0.961), MCP-1 (427+/-540 pg/mL versus 341+/-128 pg/mL; P = 0.580) and adhesion molecules concentrations were indifferent between the progression group and the nonprogression group, respectively. Using a multivariate logistical regression model, the ORs for predicting progression were 2.19 for diabetes mellitus, 2.04 for hypercholesterolemia and 1.52 for hs-CRP (P < 0.05)., Conclusion: In the present study, only conventional risk factors, and particularly hs-CRP, were markers for predicting CAD progression. Novel risk factors, such as concentrations of sCD40L, MCP-1 and adhesion molecules, did not play significant roles.

Honokiol, a compound extracted from Chinese medicinal herb Magnolia officinalis, has several biological effects. However, its protective effects against endothelial injury remain unclarified. In this study, we examined whether honokiol prevented oxidized low-density lipoprotein (oxLDL)-induced vascular endothelial dysfunction. Incubation of oxLDL with honokiol (2.5-20 microM) inhibited copper-induced oxidative modification as demonstrated by diene formation, thiobarbituric acid reactive substances (TBARS) assay and electrophoretic mobility assay. Expression of adhesion molecules (ICAM, VCAM and E-selectin) and endothelial NO synthase (eNOS) affected by oxLDL was investigated by flow cytometry and Western blot. We also measured the production of reactive oxygen species (ROS) using the fluorescent probe 2',7'-dichlorofluorescein acetoxymethyl ester (DCF-AM). Furthermore, several apoptotic phenomena including increased cytosolic calcium, alteration of mitochondrial membrane potential, cytochrome c release and activation of caspase-3 were also investigated. Apoptotic cell death was characterized by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) stain. The results showed that honokiol prevented the copper-induced oxidative modification of LDL. Honokiol also ameliorated the oxLDL-diminished eNOS protein expression and reduced the oxLDL-induced adhesion molecules and the adherence of THP-1 cells to HUVECs. Furthermore, honokiol attenuated the oxLDL-induced cytotoxicity, apoptotic features, ROS generation, intracellular calcium accumulation and the subsequent mitochondrial membrane potential collapse, cytochrome c release and activation of caspase-3. Our results suggest that honokiol may have clinical implications in the prevention of atherosclerotic vascular disease.

Rosiglitazone, an insulin sensitizer, is known to offer beneficial effects in retarding atherosclerotic vascular diseases. Since proliferation and angiogenesis are involved in initiation and plaque instability, two critical steps in the cardiovascular events, this study was designed to evaluate the mechanisms of rosiglitazone on endothelial proliferation and angiogenesis. Rosiglitazone-treated human umbilical vein endothelial cells were analyzed for growth rate by use of cell number counting, 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay as well as 3H-thymidine incorporation. Cell cycle analysis was detected by flow cytometry and cell cycle-related proteins were measured by Western blot. Effects of rosiglitazone on angiogenesis were assessed by vascular endothelial growth factor (VEGF)-induced tube formation and wound-healing migration. Furthermore, effects of rosiglitazone on actin stress fiber were observed under confocal microscopy. Our data showed that rosiglitazone inhibits endothelial proliferation in a dose-dependent manner. Rosiglitazone caused endothelial arrest at G1 phase via affecting several cell cycle-related proteins that led to attenuate phosphorylation of retinoblastoma protein. Rosiglitazone markedly decreased VEGF-induced tube formation and endothelial cell migration, which might be explained by a disorganization of the actin cytoskeleton. Our data suggest that both anti-proliferative and anti-angiogenic activities in endothelial cells might account for the greater than expected beneficial effects of rosiglitazone for the treatment and prevention of atherosclerosis.

Elevated total homocysteine concentrations and obesity are both associated with an increased risk of cardiovascular disease. However, previous studies of weight reduction on serum homocysteine concentrations have obtained inconsistent reports. We investigated the effect of folic acid supplementation on serum homocysteine concentrations via a randomized, double-blinded, placebo-controlled study. Seventy-four obese women [age (mean +/- SEM) 41 +/- 1 years; body mass index, 29.6 +/- 0.5 kgs/m2] completed a 12 weeks weight reduction program with dietary advice and light exercise. They were also randomized to take either folic acid supplementation (5 mg daily, n = 36) or placebo (n = 38) groups. This program led to a weight reduction of 7.7% and 8.9% of initial weight for folic acid supplementation and placebo groups, respectively. Serum folate concentrations increased for 3 folds (p < 0.001) in the folic acid group. In the folic acid group, there was a trend of lower fasting serum homocysteine concentrations (7.6 +/- 0.2 vs. 7.3 +/- 0.3 micromol/L), but it did not reach statistical significance (p = 0.170). However, we found that serum homocysteine concentrations decreased significantly in those with higher baseline homocysteine concentrations (8.7 +/- 1.3 vs. 7.8 +/- 1.5 micromol/L, p = 0.004), while it did not change in those with lower baseline homocysteine concentrations (6.6 +/- 0.6 vs. 6.8 +/- 1.2 micromol/L, p = 0.334). Reduction of serum homocysteine concentrations did not correlate with elevation of serum folate concentrations (p = 0.646) in obese women with higher baseline homocysteine concentrations. In conclusion, serum homocysteine concentrations can be maintained in obese women during mild to moderate weight loss. Folic acid supplementation decreased serum homocysteine concentrations in those women who had higher serum homocysteine concentrations before participating in the weight reduction program.

Studies on cell adhesion molecules and high-sensitivity C-reactive protein (hs-CRP) in systemic arterial diseases are limited in numbers and some results not consistent. It also remains undefined whether, for how long and to what extent these markers are perturbed after angioplasty. Patients with systemic arterial diseases admitted for percutaneous transluminal angioplasty (PTA) by standard procedures and techniques were prospectively studied. Fasting morning blood samples were collected to determine general biochemistry and relevant molecules by commercially available methods at baseline, 2 weeks and 3 months post-PTA/stenting. A group of equally numbered sex- and age-matched asymptomatic subjects without illness were selected as control. A total of 33 patients (28 M/5 F, aged 72 +/- 2 years) were recruited. Patients with systemic arterial disease had significantly higher baseline serum creatinine, circulating VCAM-1, ICAM-1, and hs-CRP, but lower p-selectin and HDL-C than control subjects. Except ICAM-1, cell adhesion molecules and hs-CRP levels were aroused significantly for at least 2 weeks after PTA/stenting, returned to baseline by 3 months, but p-selectin remained elevated beyond 3 months. ICAM-1 only showed a modest rise after PTA but the overall change was insignificant. In conclusion, cell adhesion molecules and hs-CRP did play a significant role in patients with advanced systemic arterial diseases who underwent PTA/stenting.