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Osteopontin (OPN) is a noncollagenous matricellular protein which is mainly present in bone matrix. A high OPN level has been associated with heart failure and acute coronary syndrome, however data on patients with chronic coronary syndrome (CCS) are lacking. The present study aimed to evaluate the association between OPN and the prognosis of Taiwanese patients with CCS.We enrolled participants from the Biosignature Registry, a nationwide prospective cohort study conducted at nine different medical centers throughout Taiwan. The inclusion criteria were participants who had received successful percutaneous coronary intervention at least once previously, and stable under medical therapy for at least 1 month before enrollment. They were followed for at least 72 months. Logistic regression and Cox proportional hazard model were used to investigate the association between OPN and clinical outcomes. The outcomes of this study were the first occurrence of hard cardiovascular events and composite cardiovascular outcomes including cardiovascular mortality, revascularization, hospitalization for acute myocardial infarction (AMI) or heart failure.A total of 666 patients with both hs-CRP and osteopontin measurements were enrolled and followed for 72 months. OPN was correlated positively with AMI-related hospitalization, where the highest tertile (Tertile 3) of baseline OPN had the highest risk of AMI-related hospitalization, which remained significant after multivariate adjustments (HR 3.20, p = 0.017). In contrast, combining OPN and hs-CRP did not improve the prediction of CV outcomes.OPN may be a potentially valuable biomarker in predicting CV outcomes. During 6 years of follow-up period, an OPN level4810 pg/ml was associated with a significantly higher incidence of AMI-related hospitalization in CCS patients who received successful PCI before the enrollment.

Background and aims Hyperuricemia is independently associated with cardiovascular disease (CVD) and is considered to be one of the major risk factors for CVD. However, the impact of inter-visit uric acid (UA) variability on cardiovascular risk remains undetermined. Methods We enrolled 3202 patients with coronary artery disease (CAD), who received successful coronary intervention, in a cohort from Taipei Veterans General Hospital from 2006 to 2015. All post-baseline visits UA measurements using standard deviation (SD) were analyzed to correlate with long-term outcome. The primary outcome was the composite of cardiac death, nonfatal MI, nonfatal stroke (MACE). The secondary event was MACE and hospitalization for heart failure. Results During an average 65.06 ± 32.1-month follow-up, there were 66 cardiovascular deaths, 175 nonfatal myocardial infarctions, 64 nonfatal strokes, 287 hospitalizations for heart failure, and 683 revascularization procedures. There was a linear association between high UA SD and future adverse events. Compared to the lowest quartile SD, subjects in the highest quartile SD had a higher risk of MACE (HR: 2.53, 95% CI: 1.78–3.59), myocardial infarction (HR: 2.43, 95% CI: 1.53–3.86), cardiovascular death (HR: 6.45, 95% CI: 2.52–16.55), heart failure-related hospitalization (HR: 3.43, 95% CI: 2.32–5.05), and total major CV events (HR: 2.72, 95% CI: 2.09–3.56). Furthermore, compared to the average achieved on-treatment UA value, increasing UA SD had a stronger association of higher risk of developing MACE (HR: 1.51, 95% CI: 1.36–1.68), myocardial infarction (HR: 1.37, 95% CI: 1.38–1.68), ischemic stroke (HR: 1.43, 95% CI: 1.13–1.82), CV death (HR: 1.77, 95% CI: 1.50–2.11), HF (HR: 1.43, 95% CI: 1.29–1.58), and total major CV events (HR: 1.46, 95% CI: 1.34–1.58). Conclusions High UA variability is associated with a higher risk of developing future cardiovascular events, suggesting the importance of maintaining stable serum UA levels and avoiding large fluctuations in CAD patients after percutaneous coronary intervention (PCI).

Background: Some personality types are associated with cardiovascular (CV) diseases and may be related to clinical outcomes in coronary artery disease (CAD). This study investigates the association between type D personality and clinical outcomes in stable CAD patients in an Asian cohort. Methods: Stable CAD patients were enrolled and prospectively followed up for at least 1 year in Taiwan. The inclusion criteria were at least one successful percutaneous coronary intervention (PCI) and stable medical treatment for at least 1 month before enrollment. Vulnerability to psychological distress was measured by the Type D Personality Scale (DS14) after enrollment. The end point was the occurrence of total CV events. Cox regression models of CV events were used to investigate the role of type D personality in clinical outcomes. Results: The study included 777 patients, among which 122 (15.77%) had type D personality. Forty-two CV events were identified: 3 cardiac deaths, 5 nonfatal myocardial infarctions, 1 stroke, 4 congestive heart failures (CHF), 6 peripheral arterial occlusive disorder cases, and 23 readmissions for angina/revascularization treatment. Patients with type D personality had significantly higher incidence of future CV events (9.84% vs. 4.58%, p = 0.018%) and admission for angina/revascularization (5.74% vs. 2.44%, p = 0.049). Patients with subsequent CV events were more likely to have type D personality (28.57% vs. 14.97%, p=0.018). After proportional Cox regression analysis, type D personality remained an independent predictor of future CV events (HR: 3.21, 95% CI: 1.06–9.69). In subgroup analyses, type D personality was especially associated with higher risk of total CV events among females, the elderly, hypertension patients, diabetes patients, and non-smokers. Conclusion: Type D personality was an independent predictor of CV outcomes in an Asian cohort of stable CAD patients. This personality type may be identified in risk stratification for secondary prevention after PCI. Keywords: Type D personality, Coronary artery disease

Bilirubin is a potential endogenous inhibitor of atherosclerosis. We investigated the association of bilirubin and cardiovascular (CV) and all-cause mortality including potential improvements in bilirubin risk reclassification in asymptomatic diabetic patients.We enrolled 2936 asymptomatic diabetic subjects. The serum bilirubin was measured, and future CV and all-cause death were the primary endpoints.The follow-up period was 5.4 ± 3.0 y. There were 218 deaths including 95 cardiovascular deaths. The occurrence of CV death and all-cause death were negatively correlated with increasing serum bilirubin quintiles and actual bilirubin values. Serum bilirubin was negatively associated with incident cardiovascular death (hazard ratio: 0.26, 95% CI, 0.11-0.61, p = .01) and all-cause death (hazard ratio: 0.30, 95% CI, 0.17-0.51, p ≤.001). The addition of bilirubin for cardiovascular death increased the C-statistic from 0.713 (95% CI, 0.664-0.762) to 0.729 (95% CI, 0.681-0.776) (P = .008) and showed an integrated discrimination improvement (IDI) of 0.012 (P .0171) with 8.57% improvement in net reclassification analysis (P = .0224). These results suggest additional predictive value is possible via total bilirubin levels for future CV deaths in diabetic patients. In terms of all-death, the addition of bilirubin significantly increased the C-statistic (from 0.769 to 0.78, P = .0064)-a 3.52% net reclassification improvement (P = .0307). It did not improve the IDI (p = .1505).Higher serum concentrations of bilirubin are associated with a decreased risk of developing CV and all-cause death in diabetic patients. Bilirubin improved the risk prediction of cardiovascular death but provided only a slightly better prediction of all-cause death than conventional risk factors.

Current risk model for long-term survival prediction in isolated coronary artery bypass graft surgery is complicated, whereas a simple useful model is still lacking. We aim to investigate if CHADS2 score could predict long-term outcome for patients after coronary artery bypass graft surgery. From 2000 to 2007, we identified a study cohort consisting of patients who underwent coronary bypass surgery in the Taiwan National Health Insurance Research Database. After operation, all cases were followed to track the incidence of major adverse cardiovascular events and overall mortality. During a mean 5.1-year follow-up, 638 patients experienced major cardiovascular events. Six hundred twenty-five patients passed away at the end of follow-up, whereas 204 died of cardiovascular cause. Subjects with higher CHADS2 scores had significantly higher 10-year overall mortality and cardiovascular death, as well as the incidence of major adverse cardiovascular events. After adjustment with co-morbid condition and prescribed medications, CHADS2 was independently associated with increased risks of all-cause mortality (hazard ratio 1.36, 95% CI 1.29 to 1.44) and cardiovascular mortality (hazard ratio 1.37, 95% CI 1.24 to 1.52). In conclusion, CHADS2 score provides a quick and useful tool in predicting long-term outcome for patients after coronary artery bypass surgery.

Background: Atrial fibrillation (AF) is associated with an increased risk of dementia. However, limited data are available on the predictors of dementia in patients with AF. This study aimed to evaluate whether the CHADS2 score could be a useful tool for risk stratification with regard to dementia occurrence among patients with AF. Methods: AF patients were identified from the National Health Insurance sampling database, which has accumulated a total of 1,000,000 participants since 2000. After excluding patients diagnosed with dementia prior to the index day of enrollment, CHADS2 score was measured to investigate its association with the occurrence of dementia, including vascular dementia and Alzheimer's disease. Results: During the mean follow-up period of 3.71 ± 2.78 years, 1135 dementia cases (7.36%) were identified, including 241 cases of vascular dementia and 894 cases of Alzheimer's disease. In multivariate analysis, an increase of 1 point in the CHADS2 score was independently associated with a 54% increase in the risk of vascular dementia (hazard ratio = 1.54; 95% confidence interval, 1.41–1.69; p

Background: Sleep apnea (SA) was associated with increased prevalence of aortic dissection (AD) in studies that were criticized for either their small sample size or lack of prospective observation. Using a considerably larger nationwide, population-based database and a long-term prospective cohort design, our study strived to explore the relationship between SA and the subsequent development of AD. Methods: From 2000 to 2007, we gathered a study cohort consisting of 15,848 newly diagnosed cases of SA from Taiwan’s National Health Insurance Research Database. For the control group, another 39,826 individuals without SA were matched for age, sex, and comorbidity. The two cohorts were followed-up to observe the occurrence of AD. Results: During an average 3.59 ± 2.41 years of follow-up, we observed 33 cases of new AD occurrence [non-SA (22, 0.1%) vs. SA (11, 0.1%), p=0.669], and the incidence of AD was similar for both groups. After adjusting for age, sex, and comorbidity, only age [hazard ratio (HR) 1.03; 95% confidence interval (CI), 1.01–1.06; p=0.006], male gender (HR 2.49; 95% CI, 1.07–5.79; p=0.034), and hypertension (HR 6.28; 95% CI, 2.36–16.67; p

Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor superfamily, is an antiapoptotic soluble receptor considered to play an important role in immune modulation and has pro-inflammatory functions. This study was designed to test whether circulating DcR3 levels are associated with coronary artery disease (CAD) severity and predict future major adverse cardiovascular events (MACEs) in patients with CAD. Circulating DcR3 levels and the Syntax score (SXscore) were determined in patients with multivessel CAD. The primary end point was the MACE within 12 months. In total, 152 consecutive patients with angiographically confirmed multivessel CAD who had received percutaneous coronary intervention were enrolled and were divided into 3 groups according to CAD lesion severity. Group 1 was defined as low SXscore (≤13), group 2 as intermediate SXscore (>13 and ≤22), and group 3 as high SXscore (>22). DcR3 levels were significantly higher in the high SXscore group than the other 2 groups (13,602 ± 7,256 vs 8,025 ± 7,789 vs 4,637 ± 4,403 pg/ml, p

Benign paroxysmal positional vertigo (BPPV) is one of the most frequently encountered primary complaints in dizziness clinics. The incidence of BPPV has been proven to increase with age. The relationship between BPPV and another neurodegenerative disease, Parkinson's disease (PD), has not been previously discussed. This study aimed to investigate the relationship of BPPV and PD with oxidative stress. A total of 30,811 subjects participated in our cohort study. The study cohort comprised 5057 BPPV patients and a comparison cohort of 25,754 nonBPPV patients. SIRT1 axis gene expression was investigated in BPPV patient blood samples and a PD cell model of 6-hydroxydopamine (6-OHDA)-treated PC-12 cells to elucidate the potential in vitro and in vivo mechanisms of degeneration in PD and BPPV. Our data suggest that BPPV patients with histories of head injuries show a significantly higher hazard to develop subsequent PD (hazard ratio, 3.942; confidence interval, 1.523-10.205, p = 0.005). We also observed that oxidative status is increased in blood samples from patients with BPPV. Our in vitro study suggests that SIRT1 function is inhibited by oxidative stress, which thereby promotes 6-hydroxydopamine-induced cell death. We conclude that BPPV is independently associated with an increased risk of PD. This finding may be attributed to oxidative stress-mediated inhibition of SIRT1 expression levels.

The hypothesis that treatment with phytosterols in patients with nonalcoholic fatty liver disease (NAFLD) may increase circulating endothelial progenitor cells (EPCs) levels was tested in the study. Forty patients with an abdominal ultrasonographic diagnosis of NAFLD were randomly assigned to phytosterols powder treatment at 1.8 g/day for 4 weeks (n = 20) or a control group, with crossover to the alternate therapy for another 4 weeks after a 2-week wash-out period. Flow cytometry with quantification of EPC markers in peripheral blood samples was used to assess circulating EPC levels. Phytosterols treatment significantly decreased levels of low-density lipoproteins, fasting glucose, and hemoglobin-A1C. Treatment with phytosterols in patients with NAFLD markedly suppressed high sensitivity C-reactive protein concentrations, and enhanced superoxide dismutase, as compared to baseline. We also showed that administration of phytosterols significantly increased the insulin-like growth factor-1 concentrations (change from baseline of 22.47%, P

Asthma and atrial fibrillation (AF) have been reported to be related to an increased risk of cardiovascular events. However, the relationship between asthma and AF has not been fully elucidated. The purpose of this study was to examine the association between asthma and AF risk.We conducted a population-based nested case-control study including a total of 7439 newly-diagnosed adult patients with AF and 10,075 age-, gender-, comorbidity-, and cohort entry date-matched subjects without AF from the Taiwan National Health Insurance database. Exposure to asthma as well as medications including bronchodilators and corticosteroid before the index date was evaluated to investigate the association between AF and asthma as well as concurrent medications.AF patients were 1.2 times (adjusted OR 1.2, 95% CI 1.109-1.298) more likely to be associated with a future occurrence of asthma independent of comorbidities and treatment with corticosteroids and bronchodilator. In addition, the risks of new-onset AF were significantly higher among current users of inhaled corticosteroid, oral corticosteroids, and bronchodilators. Newly users (within 6 months) have the highest risk (inhaled corticosteroid: OR, 2.13; 95% CI, 1.226-3.701, P=0.007; oral corticosteroid: OR, 1.932; 95% CI, 1.66-2.25, P0.001; non-steroid bronchodilator: OR, 2.849; 95% CI, 2.48-3.273, P0.001). A graded association with AF risk was also observed among subjects treated with corticosteroid (inhaled and systemic administration) and bronchodilators. New users (within 6 months) of these medications had the highest risk of AF (ICS: OR, 2.13; 95% CI, 1.226-3.701, P=0.007; oral corticosteroid: OR, 1.932; 95% CI, 1.66-2.25, P0.001; non-steroid bronchodilator: OR, 2.849; 95% CI, 2.48-3.273, P0.001). A graded association with AF risk was also observed among subjects treated with ICS or bronchodilator.Asthma was associated with an increased risk of developing future AF.

Vinorelbine (VNR), a semisynthetic vinca alkaloid acquired from vinblastine, is frequently used as the candidate for intervention of solid tumors. Nevertheless, VNR-caused endothelial injuries may lead a mitigative effect of clinical treatment efficiency. A growing body of evidence reveals that aspirin is a potent antioxidant and anti-inflammation drug. We investigated whether aspirin attenuate VNR-induced endothelial dysfunction. Human endothelial cells (EA.hy 926) were treated with VNR to cause endothelial inflammation. Western blotting, ROS assay, ELISA were used to confirm the anti-inflammatory effect of aspirin. We confirmed that VNR supresses SIRT1 expression, reduced LKB1 and AMPK phosphorylation as well as enriched PKC activation in treated endothelial cells. Furthermore, the membrane translocation assay displayed that the levels of NADPH oxidase subunits p47phox and Rac-1 in membrane fractions of endothelial cells were higher in cells that had been treated with VNR for than in untreated cells. We corroborated that treatment of Aspirin significantly diminishes VNR-repressed SIRT1, LKB1 and AMPK phosphorylation and VNR-promoted NADPH oxidase activation, however, those findings were vanished by SIRT1 and AMPK siRNAs. Our data also shown that Aspirin represses VNR-activated TGF-beta-activated kinase-1 (TAK1) activation, inhibited the interaction of TAK1/TAK-binding protein1 (TAB1), suppressed NF-kappa B activation and pro-inflammatory cytokine secretion. We demonstrated a novel connection between VNR-caused oxidative damages and endothelial dysfunction, and provide further insight into the protective effects of aspirin in VNR-caused endothelial dysfunction.

Metformin is a kind of oral hypoglycemic agents commonly prescribed to patients with diabetes mellitus. Although past studies had proven its protective effect on cardiovascular risk and related mortality, the evidence of metformin on stroke prevention was still insufficient and conflicting. Our study randomly selected 14,856 patients with diabetes from the database provided by the Taiwan National Health Research Institute, and 2 cohorts were formulated according to whether metformin was in the prescription record. All cases were followed up for 4 years to track their stroke incidence. As a result, 701 (17.5%) of 3999 diabetic patients had stroke without metformin use, whereas 994 (9.2%) of 10,857 patients had stroke with metformin use. Cox proportional hazard regressions showed that the stroke hazard ratio (HR) of metformin was .383. After adjustment for the patients' age, gender, hypertension, atrial fibrillation, hyperlipidemia, coronary artery disease, and medications including antiplatelets, coumadin, statin, and estrogen use, the HR was still .468. Further stratified analysis revealed that metformin had more protective effect in the patients with higher risk of stroke. Therefore, metformin should be placed in priority when prescribing oral hypoglycemic agents for diabetic patients when considering stroke prevention according to our study.

Background Accumulative evidence suggested that oxidative stress and inflammation were involved in the pathogenesis of atrial fibrillation (AF). Thiazolidinediones (TZDs), agonists of peroxisome proliferator-activated receptor gamma (PPAR-γ), have been proven to have anti-inflammatory and anti-oxidant effects in addition to their anti-diabetic activity. The goal of this nationwide, population based cohort study was to evaluate whether the use of TZDs will protect diabetic patients from AF. Methods The study population was comprised of 12,065 non-insulin dependent diabetic patients identified from the "National Health Insurance Research Database" released by the Taiwan National Health Research Institutes. Among the study patients, a total of 4137 patients with TZD use were recognized as the study cohort and 7928 patients without TZD use were included as the comparison cohort. The study endpoint was defined as AF occurrence during the follow up period. Results During the follow up of 63±25months, 194 patients (1.6% of the study population) developed AF: 49 from the study cohort (1.2% of the TZD group) and 145 from the comparison cohort (1.8% of the non-TZD group). After an adjustment for the baseline characteristics and medications, the TZDs independently protected diabetic patients from new-onset AF with a hazard ratio of 0.69 (95% confidence interval=0.49–0.91, p value=0.028). Conclusion In this cohort study, we demonstrated that TZDs had obvious protective effects on the development of AF in diabetic patients. Drugs acting as ligands to the PPAR-γ may be potential up-stream therapies for AF prevention.

Purpose Measurements of coronary artery calcium (CAC) and of high sensitivity C -reactive protein (hsCRP) are used to predict the risk of cardiovascular events in patients with coronary artery disease (CAD). The aim of our study was to investigate the hypothesis that combining the hsCRP level and CAC score can increase the predictive value of these parameters for future cardiovascular events in male patients with suspected CAD. Methods We included 90 male patients with stable angina. We measured their serum hsCRP and CAC scores by using electron-beam computerized tomography. These baseline parameters were correlated to the clinical cardiovascular events within the follow-up period. Results During the follow-up period of up to 50 months (median 27 months), 13 major cardiovascular events were recorded. In multivariate regression analysis, after being adjusted for conventional risk factors, hsCRP and CAC score, hsCRP level was the only independent predictor of cardiovascular events. Further analysis was performed among the four groups classified by CAC score (CAC score ≥100 or p = 0.018) for the cardiovascular events. Conclusion We concluded that risk stratification on the basis of both hsCRP level and CAC score might be of benefit to male patients with suspected CAD, as the combined use of these two markers allowed significantly more accurate prediction of cardiovascular events.

Recently, concerns have been raised that angiotensin II receptor blockers (ARBs) may be associated with an increased risk for cancer development. However, the relation between ARBs and cancer is still unclear. Therefore, a nationwide population-based study was conducted to investigate the possible influence of ARBs on the occurrence of new cancers in patients with hypertension by using the Taiwan National Health Insurance database. A total of 109,002 patients with newly diagnosed hypertension were identified from a cohort database of 1 million individuals from January 1, 1998, to December 31, 2006. Among them, 40,124 (36.8%) had received ARBs for hypertension. The end point was the development of any type of cancer before the end of 2007. During an average of 5.7 ± 2.6 years of follow-up, a total of 9,067 cases of new cancer occurrence were observed. The log-rank test showed that the occurrence rate of newly diagnosed cancers in the subjects receiving ARBs was significantly lower than those receiving treatment without ARBs (ARBs vs controls 3,082 vs 5,985, p

We aimed to investigate the correlation between non-alcoholic fatty liver disease (NAFLD) and risk of cardiovascular disease (CVD).We analyzed 724 subjects without CVD according to presence or absence of NAFLD. Logistic regression model was used to determine if NAFLD was an independent risk factor of CVD.Subjects with NAFLD had increased percentage of 10-year cardiovascular risk ≧10% compared to those without NAFLD (p0.001). The severity of NAFLD significantly correlated with increasing Framingham risk score and C-relative protein (CRP) value. After adjusting for conventional CVD risk factors, the presence of NAFLD was an independent predictor for future CVD risk ≧10% [odds ratio: 1.89, p=0.004]. Subgroup analysis showed the predictive value of NAFLD was significant among aged subjects and those with increased baseline hsCRP level.NAFLD is independently associated with increased CVD risk, especially among elderly subjects and those with increased CRP level.

Basic research indicates that tumor necrosis factor superfamily 14 (TNFSF14) may be involved in the pathogenesis of atherosclerosis. Given the requirements of new biomarkers for risk classification in coronary artery disease (CAD), we conducted a longitudinal analysis to investigate if circulating

Recent studies have suggested that proton pump inhibitors (PPIs) might reduce the inhibitory effect of clopidogrel on platelet aggregation, possibly through inhibition of the hepatic cytochrome P450 2C19 (CYP2C19) isoenzyme. The prevalence of CYP2C19 loss-of-function alleles is much greater among East Asians than among other populations. Thus, potential drug interactions might be more apparent. Therefore, we conducted a nationwide, population-based study using the Taiwan National Health Insurance database. We identified 3,278 patients (mean age 65.9 +/- 11.9 years, 71.9% men) with coronary artery disease who had taken clopidogrel after percutaneous coronary intervention from the 1 million sampling cohort data set since January 1, 2002. Of the 3,278 patients, 572 had received concomitant PPIs for underlying gastrointestinal disease and 2,706 had not used PPIs. To the end of 2007, 1,410 patients had been rehospitalized, 970 patients had undergone revascularization, and 499 patients had died. According to the Kaplan-Meier analysis, the incidence of rehospitalization (p = 0.001) and mortality (p0.001) was significantly greater for the patients with concomitant PPI use than for those without concomitant PPI use. However, the incidence of revascularization was similar in the 2 groups. Multivariate analyses showed that concomitant PPI use was associated with an increased risk of rehospitalization (hazard ratio 1.23, 95% confidence interval 1.07 to 1.41, p = 0.003) and mortality (hazard ratio 1.65, 95% confidence interval 1.35 to 2.01, p0.001). In conclusion, the concomitant use of clopidogrel and PPIs should be done with care to avoid adverse outcome in East Asians patients who have undergone percutaneous coronary intervention.

This study aimed to investigate whether baseline serum levels of matrix metalloproteinases (MMPs) could predict long-term prognosis of coronary revascularizations.Ninety-one consecutive patients receiving coronary revascularizations (58 percutaneous coronary interventions and 33 coronary artery bypass graft surgeries) for stable coronary artery disease (CAD) were studied. Baseline serum levels of high-sensitive C-reactive protein (hsCRP), MMP-2, -3 and -9 drawn before revascularization were correlated to the clinical adverse events within12 months after revascularizations.Baseline characteristics were similar between the two groups. There were total 22 major adverse cardiovascular events during a mean period of 27 months. Only baseline serum MMP-9 level independently predicted future cardiovascular events after coronary revascularization either by multivariate analysis (relative risk 3.18, p=0.028) or by Kaplan-Meier analysis (p=0.021).Baseline serum MMP-9 level predicted the prognosis after coronary revascularizations, suggesting its potential role in risk stratification before revascularization strategies for stable CAD.

Matrix metalloproteinase (MMP) is critical to the progression of atherosclerosis and neointima hyperplasia after vascular injury. We investigated the effects of carvedilol, a pharmacological antioxidant with alpha- and beta-adrenergic blocking activity, on MMP-2 and MMP-9 expression. Vascular injury was induced with the balloon catheters on abdominal aortas of high-cholesterol-fed rabbits. On Day 21, there was significant aortic neointima formation with increased oxidative DNA damage by immunostaining with 8-hydroxy-2'-deoxyguanosine and enhanced MMP-2 and MMP-9 expressions by Western blotting, which were significantly reduced by oral administration of carvedilol (20 mg/kg/day) or probucol (100 mg/kg/day). Vascular expression (by Western blot), activity (by gelatin zymography), and mRNA levels of MMP-2 and MMP-9 were also reduced by carvedilol or probucol. Besides, pretreatment with carvedilol or probucol but not propranolol, a beta-blocker, or prazocin, an alpha-blocker, inhibited tumor necrosis factor-alpha-stimulated expressions and activities of MMP-2 and MMP-9 in human aortic smooth muscle cells. On electrophoretic mobility-shift assay, carvedilol inhibited the binding activities of activator protein-1 and specific protein-1, two major transcription factors for MMP promoter regions. Accordingly, carvedilol, a pharmacological antioxidant, inhibited in vivo and in vitro expression of MMP-2 and MMP-9 properly by modulating the redox-related pathways, suggesting its potential clinical implications.

Background Heparin cofactor II (HCII) could inactivate thrombin after binding to dermatan sulfate at injured arterial walls, and has been shown to be a novel and independent antiatherosclerotic factor. However, the relation between plasma HCII activity and peripheral vascular endothelial function remains unclear. Methods A total of 199 patients (mean age, 63±14 years) were enrolled and followed up for a median period of 24 months. Endothelial function was assessed using brachial ultrasonography to determine endothelium dependent flow-mediated vasodilation (FMD). Cox regression analyses were conducted for the 199 subjects, with cardiovascular events being defined as myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), ischemic stroke, and peripheral artery revascularization. Results A total of 31 patients (16%) had cardiovascular events. Patients with cardiovascular events had significantly lower HCII activity (112±34 versus 127±34%, p =0.027) and lower antithrombin III (ATIII) activity (82±12 versus 88±13%, p =0.014) than those without events. By multivariate analysis, age ( p =0.012), hsCRP ( p =0.020) and HCII activity ( p =0.035) were correlated with FMD. Kaplan-Meier analysis was performed and showed plasma HCII ( p =0.036) and ATIII activities ( p =0.005) were predictors of cardiovascular events. By Cox regression analysis, plasma HCII activity ( p =0.026) could be an independent predictor of future cardiovascular events, but not ATIII. Conclusions The present study demonstrates that plasma HCII activity is positively correlated with endothelial vasodilator function. Furthermore, plasma HCII activity could be a predictor of future cardiovascular events in patients with suspected coronary artery disease, suggesting its role in atherosclerosis.

Increased oxidative stress and vascular inflammation have been shown in patients with cardiac syndrome X (CSX; angina, exercise-induced ischemia, and normal coronary angiogram). This study was conducted to assess the impact of basal superoxide generation by circulating mononuclear cells (MNCs), a contributor to intravascular oxidative stress, and serum inflammatory biomarkers, including high-sensitivity C-reactive protein, homocysteine, soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and von Willebrand factor, on the long-term prognosis of CSX. During a mean follow-up of 31.5 ± 14.2 months (maximum 5 years), a total of 12 events were recorded in 92 consecutive CSX patients. There were no deaths or myocardial infarctions, but 8 hospitalizations for acute coronary syndrome, 3 for stroke, and 1 for congestive heart failure due to left ventricular systolic dysfunction. Under univariate analysis, only basal superoxide generation by MNCs was associated with the risk for cardiovascular event. Based on multivariate analysis, basal superoxide generation by MNCs could still independently predict future events (relative risk for the highest compared to the lowest tertile, 3.87; 95% confidence interval, 1.42–10.54, p = 0.008). These findings demonstrate that long-term prognosis is fair in patients with CSX. Basal superoxide production of MNCs independently predicts future cardiovascular events, suggesting its potential role in measuring disease progression and risk stratification in these patients.

Study objectives: To evaluate the implication of plasma biomarkers to future cardiovascular events in nondiabetic patients with stable coronary artery disease (CAD). Designs and settings: Prospective, follow-up study at a tertiary referral center. Patients and measurement: Serial plasma biomarkers including high-sensitivity C-reactive protein (hsCRP), homocysteine, soluble adhesion molecules, von Willebrand factor, and lipid profiles were determined before coronary angiograms in a series of nondiabetic CAD patients with stable angina. Among them, 75 consecutive patients who received coronary revascularization (48 coronary interventions and 27 coronary bypass surgeries) later and another 75 age- and gender-matched patients who preferred medical treatment were both enrolled. In patients of each group, major cardiovascular events including cardiac death, nonfatal myocardial infarction, new or repeated coronary revascularization, and hospitalization for unstable angina, stroke, or peripheral artery disease were prospectively followed up for at least 6 months. Results: Patients were followed up to 40 months (median, 18 months). The incidences of major cardiovascular events were similar between the two groups. For patients with medical treatment, plasma levels of hsCRP, homocysteine, low-density lipoprotein, and the ratio of total cholesterol (TC) to high-density lipoprotein cholesterol (HDL-C) were significantly higher in those with cardiovascular events than those without. However, only hsCRP > 0.1 mg/dL (relative risk [RR], 2.78; 95% confidence interval [CI], 1.21 to 6.41; p = 0.016) and TC/HDL-C ratio > 4.8 (RR, 2.42; 95% CI, 1.04 to 5.65; p = 0.041) were independent predictors by multivariable analysis. For patients with revascularization, basal plasma hsCRP levels were higher in those with cardiovascular events than those without (p = 0.04). However, no biochemical markers could predict future major cardiovascular events in these patients. Conclusions: In nondiabetic patients with CAD, basal plasma hsCRP levels were increased with future cardiovascular events regardless of different treatment strategies. Both plasma hsCRP level and TC/HDL-C ratio independently predict future cardiovascular events, confirming the role of plasma biomarkers in clinical risk stratification especially in patients with medical treatment.

Attenuated heart rate recovery after graded exercise, which is associated with decreased vagal activity, is a powerful predictor of overall mortality. Endothelial function plays a key role in determining the clinical manifestations of established atherosclerotic lesions and has shown to be suppressed by increased sympathetic tone. We designed this study to determine whether patients with an attenuated heart rate recovery after exercise could predict endothelium dysfunction. Sixty-six patients with suspected coronary artery disease were enrolled, and a noninvasive method of brachial ultrasound was used to measure endothelium-dependent flow-mediated vasodilation and endothelium-independent nitroglycerin-mediated vasodilation. The patients were divided equally into 3 groups according to heart rate recovery in 1 minute after peak exercise (n = 22 in each group): group 1 had heart rate recovery of/=19 beats in the first minute; group 2, 20 to 28 beats; and group 3 had/=29 beats. The endothelium-dependent flow-mediated vasodilation responses were significantly decreased in group 1 compared with groups 2 and 3 (2.5 +/- 3.0 vs 5.0 +/- 3.4 vs 5.4 +/- 2.7%, p = 0.006), but responses to sublingual nitroglycerin showed no difference among the 3 groups (p = 0.332). According to multivariate analysis, heart rate recovery after exercise was an independent predictor of endothelial function.

Objective The effects of influenza vaccination on ischemic heart disease (IHD) patients remain controversial. The purpose of this study was to evaluate the effects of influenza vaccination on all-cause mortality and hospitalization for cardiovascular disease in elderly IHD patients. Methods Elderly patients (> 65 years old) with IHD, including ischemic heart failure and coronary artery disease between January 1997 and September 2002 were identified by using the Taiwan National Health Insurance Research Database. The association between influenza vaccination and all-cause mortality and hospitalization due to cardiovascular disease was analyzed. Results We included 5048 patients. During the influenza season, influenza vaccination was associated with a reduced risk of all-cause mortality [hazard ratio (HR), 0.42; 95% confidence interval (CI) 0.35–0.49] and hospitalization for cardiovascular disease (HR, 0.84; 95% CI, 0.76–0.93). During the non-influenza season, vaccination was associated with a reduced risk of mortality (HR, 0.78; 95% CI, 0.68–0.90) in elderly IHD patients. Conclusion Influenza vaccination was associated with a reduced risk of all-cause mortality in elderly IHD patients throughout the whole year, as well as a reduced risk of hospitalization during the influenza season.

Immune thrombocytopenic purpura (ITP) is a bleeding disorder characterized by premature platelet destruction mediated by autoantibodies. We report a 71-year-old ITP patient with concomitant acute coronary syndrome. Cardiac catheterization was performed through the right radial artery and premedicated with immunoglobulin. Left anterior descending artery was stented, followed by clopidogrel treatment for 7 weeks without major bleeding complication. The patient has been observed for 2 years without clinical restenosis. We suggest that stent implantation is a safe treatment in this special condition. Treatment should be individualized, but it is still a challenge to balance bleeding and thrombosis complication.

Purpose To investigate the relationship between age-related macular degeneration (AMD) and future development of Alzheimer's disease (AD) or senile dementia. Design A longitudinal case-control study using the Taiwan National Health Insurance Research Database. Participants From 2001 to 2009, the newly diagnosed AMD cases aged ≥65 years in the database were recruited as the AMD cohort (n = 4993). Of those, there were 540 with and 4453 without exudative AMD diagnoses. Subjects without any AMD, matched for age, gender, and time of enrollment, were randomly sampled as the control cohort (n = 24 965) for comparison. Methods Alzheimer's disease/senile dementia-free survival analysis was assessed using a Kaplan–Meier method. Cox proportional hazard regressions were performed to calculate the hazard ratios (HR) of AD or senile dementia for the 2 cohorts after adjusting for preexisting comorbidities and number of clinical visits. Main Outcome Measures The first-ever diagnosis of AD or senile dementia during the observation period. Results Of the 29 958 sampled subjects, 1589 (5.3%) were diagnosed with AD or senile dementia during a mean follow-up period of 4.4 years, including 294 (5.9%) from the AMD cohort and 1295 (5.2%) from the control cohort. The incidence of AD or senile dementia was higher in patients with AMD than in the controls ( P = 0.044), with an HR of 1.44 (95% confidence interval [CI], 1.26–1.64) after adjusting for covariates. The stratified analysis showed that the adjusted HR for AD or senile dementia was 1.35 (95% CI, 0.89–2.06) for exudative AMD versus the controls and 1.44 (95% CI, 1.26–1.65) for nonexudative AMD versus the controls. Conclusions This study provides large-scale, population-based evidence that AMD, especially nonexudative AMD, is independently associated with an increased risk of subsequent AD or senile dementia development.

Metformin, an insulin-sensitizer, may improve several physiologic abnormalities owing to insulin resistance and vascular function in patients with type 2 diabetes mellitus (DM). The effects of metformin on venous thrombosis in DM patients have not been previously reported. Our study strived to

Purpose To explore the relationship of sleep apnea and the subsequent development of retinal vein occlusion (RVO). Design A retrospective nonrandomized, matched-control cohort study using the Taiwan National Health Insurance Research Database. Methods From 1997 through 2007, we identified newly diagnosed sleep apnea cases in the database. A control group without sleep apnea, matched for age, gender, and comorbidities, was selected for comparison. The 2 cohorts were followed up, and the occurrence of RVO was observed. Results Of the 35 634 sampled patients (5965 sleep apnea patients vs 29 669 controls), 52 (0.15%) experienced RVO during a mean follow-up period of 3.72 years, including 13 (0.22%, all branch RVO) from the sleep apnea cohort and 39 (0.13%, 39 branch RVO and 10 central RVO) from the control group. Kaplan-Meier analysis revealed the tendency of sleep apnea patients toward RVO development ( P = .048, log-rank test). Patients with sleep apnea experienced a 1.94-fold increase (95% confidence interval, 1.03 to 3.65; P = .041) in incident RVO, which was independent of age, gender, and comorbidities. Conclusions Sleep apnea may be an independent risk factor for RVO.