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1.  Vascular endothelial function and circulating endothelial progenitor cells in patients with cardiac syndrome X 
Heart  2007;93(9):1064-1070.
Endothelial dysfunction and microvascular abnormalities have been reported in patients with cardiac syndrome X (CSX), but the underlying mechanisms are unclear. Recent insights suggest that the injured endothelial monolayer is regenerated by circulating bone marrow‐derived endothelial progenitor cells (EPCs).
To test the hypothesis that the biology of altered EPCs might contribute to the pathophysiology of CSX.
34 subjects (mean (SD) age: 62 (7) years) were enrolled in the study, including 12 patients with CSX, 12 stable subjects with coronary artery disease (CAD) and 10 healthy controls. The number and adhesive function of EPCs were measured in peripheral‐blood samples from these study participants.
The baseline characteristics in patients with CSX and CAD were enhanced Framingham risk scores, more hypertension and lower high‐density lipoproteins than the controls. Patients with CSX and CAD had significantly decreased endothelium‐dependent flow‐mediated vasodilation (FMD) compared with normal controls (normal controls vs CSX vs CAD: 10.6% (3.5%) vs 6.1% (1.8%) vs 4.1% (1.9%), p<0.001), but the difference was not found in endothelium‐independent nitroglycerine‐mediated vasodilation (p = 0.159). Reduced numbers of colony‐forming units (CFU) of EPCs were noted in patients with CSX and CAD (normal vs CSX vs CAD: 41 (9) vs 30 (7) vs 14 (7) CFU/well, p<0.001). Levels of EPCs were shown to be associated with FMD (r = 0.557, p = 0.001) and high‐density lipoprotein (r = 0.339, p = 0.049). Also, attenuated fibronectin adhesion function of EPCs was found in patients with CSX and CAD compared with normal subjects (104 (12) vs 80 (20) vs 65 (13)/well, p<0.001).
This study clearly showed for the first time that compared with normal subjects, patients with CSX have decreased levels and adhesive function of circulating EPCs. These findings may explain the underlying mechanisms which contribute to the endothelial dysfunction and microvascular abnormalities observed in patients with CSX.
PMCID: PMC1954999  PMID: 17488770
2.  Serum Bilirubin and Ferritin Levels Link Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic Patients  
Diabetes Care  2008;31(8):1615-1620.
OBJECTIVE—Heme oxygenase (HO) leads to the generation of free iron, carbon monoxide, and bilirubin. A length polymorphism of GT repeats in the promoter of human HO-1 gene has been shown to modulate gene transcription. The aim of this study was to assess the association of the length of (GT)n repeats in the HO-1 gene promoter with serum bilirubin, markers of iron status, and the development of coronary artery disease (CAD).
RESEARCH DESIGN AND METHODS—We screened the allelic frequencies of (GT)n repeats in the HO-1 gene promoter in 986 unrelated individuals who underwent coronary angiography. Serum bilirubin and markers of iron status were evaluated.
RESULTS—The distribution of numbers of (GT)n repeats was divided into two subclasses: class S included shorter (<27) repeats, and class L included longer (≥27) repeats. Among those with diabetes, subjects with the L/L genotype had significantly lower bilirubin levels than those with S/S and S/L genotypes (0.70 ± 0.22 vs. 0.81 ± 0.24 mg/dl, P = 0.001) and higher serum ferritin values (4.76 ± 0.72 vs. 4.28 ± 1.05 μg/l for log ferritin, P = 0.001). Compared with those carrying the S allele, diabetic subjects with the L/L genotype had an almost threefold increase in CAD risk after controlling for conventional risk factors (odds ratio 2.81, [95% CI 1.22–6.47], P = 0.015). With adjustment for both serum bilirubin and ferritin, the effect of HO-1 promoter polymorphism on susceptibility to CAD disappeared.
CONCLUSIONS—Length polymorphism in the HO-1 gene promoter is correlated with susceptibility to CAD in diabetic patients, and this effect might be conveyed through its influence on serum bilirubin and ferritin.
PMCID: PMC2494663  PMID: 18443197
3.  Prognostic value of hyponatremia in heart failure patients: an analysis of the Clinical Characteristics and Outcomes in the Relation with Serum Sodium Level in Asian Patients Hospitalized for Heart Failure (COAST) study 
Hyponatremia is a well-known risk factor for poor outcomes in Western studies of heart failure (HF) patients. We evaluated the predictive value of hyponatremia in hospitalized Asian HF patients.
The Clinical Characteristics and Outcomes in the Relation with Serum Sodium Level in Asian Patients Hospitalized for Heart Failure (the COAST) study enrolled hospitalized patients with systolic HF (ejection fraction < 45%) at eight centers in South Korea, Taiwan, and China. The relationship between admission sodium level and clinical outcomes was analyzed in 1,470 patients.
The mean admission sodium level was 138 ± 4.7 mmol/L, and 247 patients (16.8%) had hyponatremia defined as Na+ < 135 mmol/L. The 12-month mortality was higher in hyponatremic patients (27.9% vs. 14.6%, p < 0.001), and hyponatremia was an independent predictor of 12-month mortality (hazard ratio, 1.72; 95% confidence interval, 1.12 to 2.65). During hospital admission, 57% of hyponatremic patients showed improvement without improvement in their clinical outcomes (p = 0.620). The proportion of patients with optimal medical treatment was only 26.5% and 44.2% at admission and discharge, respectively, defined as the combined use of angiotensin-converting-enzyme inhibitor/angiotensin receptor blocker and β-blocker. Underuse of optimal medical treatment was more pronounced in hyponatremic patients.
In hospitalized Asian HF patients, hyponatremia at admission is common and is an independent predictor of poor clinical outcome. Furthermore, hyponatremic patients receive less optimal medical treatment than their counterparts.
PMCID: PMC4497333  PMID: 26161012
Hyponatremia; Predictor of clinical outcomes; Hospitalized heart failure; East Asians
4.  Rivaroxaban, a factor Xa inhibitor, improves neovascularization in the ischemic hindlimb of streptozotocin-induced diabetic mice 
Factor Xa inhibitor is used for preventing venous thromboembolism (VTE) in adult patients receiving orthopedic operation. However, the role of factor Xa inhibitor, rivaroxaban, in angiogenesis is still unknown.
Methods and results
Streptozotocin (STZ)–induced diabetic mice with model of hind-limb ischemia, were divided into non-diabetic control, diabetic control, and low- and high-dose rivaroxaban treatment groups, in order to evaluate the effect of rivaroxaban in angiogenesis. Doppler perfusion imaging showed that blood flow recovery was significantly increased, and more capillary density occurred in the rivaroxaban treatment group. In vitro studies, human endothelial progenitor cells (EPCs) treated with rivaroxaban had significant functional improvement in migration and senescence under hyperglycemic conditions. Rivaroxaban also increased endothelial nitric oxide synthase (eNOS) as well as vascular endothelial growth factor (VEGF) expressions in hyperglycemia-stimulated EPCs.
Rivaroxaban promoted vessel formation in diabetic mice and improved endothelial progenitor cell function under hyperglycemic conditions. These effects may be associated with enhancement of expression of eNOS and VEGF.
PMCID: PMC4473833  PMID: 26077117
Factor Xa inhibitor; Diabetes; Angiogenesis; Endothelial progenitor cells
5.  Metformin use in patients with type 2 diabetes mellitus is associated with reduced risk of deep vein thrombosis: a non-randomized, pair-matched cohort study 
Metformin, an insulin-sensitizer, may correct several physiologic abnormalities owing to insulin resistance in patients with type 2 diabetes mellitus (DM). The effects of metformin on venous thrombosis in patient with type 2 DM have not been reported. Our study strived to explore the relationship of metformin therapy and the subsequent development of deep vein thrombosis (DVT) using a nationwide, population-based database.
From 1997 to 2003, we identified a study cohort consisting of patients with type 2 DM using metformin 7154 cases in the National Health Insurance Research Database. A control cohort without metformin, matched for age, sex, comorbidities, and medications was selected for comparison.
Of the 14945 patients (7167 patients with metformin vs. 7778 control), 60 (0.40%) patients developed DVT during a mean follow-up period of 3.74 years, including 16 (0.21%) from the cohort with metformin and 44 (0.56%) from the control group. Subjects with metformin experienced a 0.427 fold (95% confidence interval 0.240-0.758; P = 0.004) changes of risk reduction in development of DVT, which was independent of age, sex and co-morbidities. Kaplan-Meier analysis also revealed metformin therapy is associated with lower occurrence of DVT (log-rank test, P = 0.001).
Metformin may have protective effect in patients with type 2 DM for DVT.
PMCID: PMC4274716  PMID: 25510597
Deep vein thrombosis; Metformin; Type 2 diabetes mellitus
6.  Asymmetric dimethylarginine and long-term adverse cardiovascular events in patients with type 2 diabetes: relation with the glycemic control 
Background and aims
Elevated plasma asymmetric dimethylarginine (ADMA) levels have been observed in patients with insulin resistance and diabetes, and have been reported to predict adverse cardiovascular events in type 2 diabetic patients. However, the relationship between ADMA and glycemic control in patients with type 2 diabetes remained controversial.
Methods and results
We evaluated 270 patients with type 2 diabetes and measured their plasma ADMA and hemoglobin A1c (HbA1c) levels by high performance liquid chromatography. The mean age was 67 ± 12 years. The mean plasma ADMA and HbA1c level were 0.46 ± 0.09 μmol/l and 7.8 ± 1.6%, respectively. There was no significant correlation between plasma ADMA level and HbA1c level (r = −0.09, p = 0.13). During the median follow-up period of 5.7 years (inter-quartile range: 5.0 − 7.3 years), major adverse cardiovascular event (MACE, including cardiovascular death, myocardial infarction and stroke) was observed in 55 patients (20.4%). Multivariate Cox regression analysis revealed that the ADMA tertile was an independent risk factor for MACE (ADMA tertile III versus ADMA tertile I: p = 0.026, HR: 2.31, 95% CI: 1.10 − 4.81). The prognosis predictive power of ADMA disappeared in patients with well glycemic control (HbA1c ≤6.5%), and the ADMA-HbA1c interaction p value was 0.01.
In patients with type 2 diabetes, ADMA might be an independent risk factor for long-term adverse cardiovascular events. However, ADMA was not correlated with serum HbA1c level, and in diabetic patients with HbA1c ≤6.5%, elevated ADMA level was no longer associated with increased risk of long-term prognosis. Our findings suggested that the prognosis predictive value of ADMA in type 2 diabetes might be modified by the glycemic control.
PMCID: PMC4262144  PMID: 25467091
Asymmetric dimethylarginine; Diabetes; Hemoglobin A1c; Nitric oxide
7.  Effects of pitavastatin versus atorvastatin on the peripheral endothelial progenitor cells and vascular endothelial growth factor in high-risk patients: a pilot prospective, double-blind, randomized study 
Circulating endothelial progenitor cells (EPCs) reflect endothelial repair capacity and may be a significant marker for the clinical outcomes of cardiovascular disease. While some high-dose statin treatments may improve endothelial function, it is not known whether different statins may have similar effects on EPCs.This study aimed to investigate the potential class effects of different statin treatment including pitavastatin and atorvastatin on circulating EPCs in clinical setting.
A pilot prospective, double-blind, randomized study was conducted to evaluate the ordinary dose of pitavastatin (2 mg daily) or atorvastatin (10 mg daily) treatment for 12 weeks on circulating EPCs in patients with cardiovascular risk such as hypercholesterolemia and type 2 diabetes mellitus (T2DM). Additional in vitro study was conducted to clarify the direct effects of both statins on EPCs from the patients.
A total of 26 patients (19 with T2DM) completed the study. While the lipid-lowering effects were similar in both treatments, the counts of circulating CD34+KDR+EPCs were significantly increased (from 0.021 ± 0.015 to 0.054 ± 0.044% of gated mononuclear cells, P < 0.05) only by pitavastatin treatment. Besides, plasma asymmetric dimethylarginine level was reduced (from 0.68 ± 0.10 to 0.53 ± 0.12 μmol/L, P < 0.05) by atorvastatin, and plasma vascular endothelial growth factor (VEGF) level was increased (from 74.33 ± 32.26 to 98.65 ± 46.64 pg/mL, P < 0.05) by pitavastatin. In the in vitro study, while both statins increased endothelial nitric oxide synthase (eNOS) expression, only pitavastatin increased the phosphorylation of eNOS in EPCs. Pitavastatin but not atorvastatin ameliorated the adhesion ability of early EPCs and the migration and tube formation capacities of late EPCs.
While both statins similarly reduced plasma lipids, only pitavastatin increased plasma VEGF level and circulating EPCs in high-risk patients, which is probably related to the differential pleiotropic effects of different statins.
Trial registration
This trial is registered at, NCT01386853.
PMCID: PMC4223413  PMID: 25027585
Pitavastatin; Atorvastatin; Hypercholesterolemia; Endothelial progenitor cell; Endothelial nitric oxide synthase; Vascular endothelial growth factor
8.  The Impact of Endothelial Progenitor Cells on Restenosis after Percutaneous Angioplasty of Hemodialysis Vascular Access 
PLoS ONE  2014;9(6):e101058.
We prospectively investigate the relation between baseline circulating endothelial progenitor cells and the subsequent development of restenosis after angioplasty of hemodialysis vascular access.
Effect of angioplasty for hemodialysis vascular access is greatly attenuated by early and frequent restenosis. Circulating endothelial progenitor cells (EPCs) play a key role in vascular repair but are deficient in hemodialysis patients.
After excluding 14 patients due to arterial stenosis, central vein stenosis, and failed angioplasty, 130 patients undergoing angioplasty for dysfunctional vascular access were prospectively enrolled. Flow cytometry with quantification of EPC markers (defined as CD34+, CD34+KDR+, CD34+KDR+CD133+) in peripheral blood immediately before angioplasty procedures was used to assess circulating EPC numbers. Patients were followed clinically for up to one year after angioplasty.
During the one-year follow-up, 95 patients (73%) received interventions for recurrent access dysfunction. Patients in the lower tertile of CD34+KDR+ cell count had the highest restenosis rates (46%) at three month (early restenosis), compared with patients in the medium and upper tertiles of CD34+KDR+ cell count (27% and 12% respectively, p = 0.002). Patients in the lower tertile of CD34+KDR+ cell count received more re-interventions during one year. Patients with early restenosis had impaired EPC adhesive function and increased senescence and apoptosis. In multivariate analysis, the CD34+KDR+ and CD34+KDR+CD133+ cell counts were independent predictors of target-lesion early restenosis.
Our results suggest that the deficiency of circulating EPCs is associated with early and frequent restenosis after angioplasty of hemodialysis vascular access.
PMCID: PMC4071067  PMID: 24964143
9.  A Novel SNP Associated with Nighttime Pulse Pressure in Young-Onset Hypertension Patients Could Be a Genetic Prognostic Factor for Cardiovascular Events in a General Cohort in Taiwan 
PLoS ONE  2014;9(6):e97919.
Pulse pressure (PP) is a risk factor for cardiovascular disease. It has been reported that ambulatory blood pressure (BP) and nighttime BP parameters are heritable traits. However, the genetic association of pulse pressure and its clinical impact remain undetermined.
Method and Results
We conducted a genome-wide association study of PP using ambulatory BP monitoring in young-onset hypertensive patients and found a significant association between nighttime PP and SNP rs897876 (p = 0.009) at chromosome 2p14, which contains the predicted gene FLJ16124. Young-onset hypertension patients carrying TT genotypes at rs897876 had higher nighttime PP than those with CT and CC genotypes (TT, 41.6±7.3 mm Hg; CT, 39.1±6.0 mm Hg; CC, 38.9±6.3 mm Hg; p<0.05,). The T risk allele resulted in a cumulative increase in nighttime PP (β = 1.036 mm Hg, se. = 0.298, p<0.001 per T allele). An independent community-based cohort containing 3325 Taiwanese individuals (mean age, 50.2 years) was studied to investigate the genetic impact of rs897876 polymorphisms in determining future cardiovascular events. After an average 7.79±0.28 years of follow-up, the TT genotype of rs897876 was independently associated with an increased risk (in a recessive model) of coronary artery disease (HR, 2.20; 95% CI, 1.20–4.03; p = 0.01) and total cardiovascular events (HR, 1.99; 95% CI, 1.29–3.06; p = 0.002), suggesting that the TT genotype of rs897876C, which is associated with nighttime pulse pressure in young-onset hypertension patients, could be a genetic prognostic factor of cardiovascular events in the general cohort.
The TT genotype of rs897876C at 2p14 identified in young-onset hypertensive had higher nighttime PP and could be a genetic prognostic factor of cardiovascular events in the general cohort in Taiwan.
PMCID: PMC4043733  PMID: 24892410
10.  Reduction of Circulating Endothelial Progenitor Cell Level Is Associated with Contrast-Induced Nephropathy in Patients Undergoing Percutaneous Coronary and Peripheral Interventions 
PLoS ONE  2014;9(3):e89942.
Reduced number and impaired function of circulating endothelial progenitor cells (EPCs) in patients with chronic kidney disease have been reported. However, there is little data about the association between circulating EPC levels and risk of contrast-induced nephropathy (CIN). The aim of this study was to investigate the relationship between circulating EPCs and CIN in patients after angiography.
Methods and Results
A total of 77 consecutive patients undergoing elective percutaneous coronary intervention (PCI) and percutaneous transluminal angioplasty (PTA) were enrolled. Flow cytometry with quantification of EPC markers (defined as CD34+, CD34+KDR+, and CD34+KDR+CD133+) in peripheral blood samples was used to assess EPC number before the procedure. CIN was defined as an absolute increase ≧0.5 mg/dl or a relative increase ≧25% in the serum creatinine level at 48 hours after the procedure. Eighteen (24%) of the study subjects developed CIN. Circulating EPC levels were significantly lower in patients who developed CIN than in those without CIN (CD34+KDR+, 4.11±2.59 vs. 9.25±6.30 cells/105 events, P<0.001). The incidence of CIN was significantly greater in patients in the lowest EPC tertile (CD34+KDR+; from lowest to highest, 52%, 15%, and 4%, P<0.001). Using univariate logistic regression, circulating EPC number (CD34+KDR+) was a significant negative predictor for development of CIN (odds ratio 0.69, 95% CI 0.54–0.87, P = 0.002). Over a two-year follow-up, patients with CIN had a higher incidence of major adverse cardiovascular events including myocardial infarction, stroke, revascularization of treated vessels, and death (66.7% vs. 25.4%, P = 0.004) than did patients without CIN.
Decreased EPC level is associated with a greater risk of CIN, which may explain part of the pathophysiology of CIN and the poor prognosis in CIN patients.
PMCID: PMC3960102  PMID: 24646509
11.  Diabetes Mellitus and the Risk of Alzheimer’s Disease: A Nationwide Population-Based Study 
PLoS ONE  2014;9(1):e87095.
Possible association between diabetes mellitus (DM) and Alzheimer’s disease (AD) has been controversial. This study used a nationwide population-based dataset to investigate the relationship between DM and subsequent AD incidence.
Data were collected from Taiwan’s National Health Insurance Research Database, which released a cohort dataset of 1,000,000 randomly sampled people and confirmed it to be representative of the Taiwanese population. We identified 71,433 patients newly diagnosed with diabetes (age 58.74±14.02 years) since January 1997. Using propensity score, we matched them with 71,311 non-diabetic subjects by time of enrollment, age, gender, hypertension, hyperlipidemia, and previous stroke history. All the patients were followed up to December 31, 2007. The endpoint of the study was occurrence of AD.
Over a maximum 11 years of follow-up, diabetic patients experienced a higher incidence of AD than non-diabetic subjects (0.48% vs. 0.37%, p<0.001). After Cox proportional hazard regression model analysis, DM (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.50–2.07, p<0.001), age (HR, 1.11; 95% CI, 1.10–1.12, p<0.001), female gender (HR, 1.24; 95% CI, 1.06–1.46, p = 0.008), hypertension (HR, 1.30; 95% CI, 1.07–1.59, p = 0.01), previous stroke history (HR, 1.79; 95% CI, 1.28–2.50, p<0.001), and urbanization status (metropolis, HR, 1.32; 95% CI, 1.07–1.63, p = 0.009) were independently associated with the increased risk of AD. Neither monotherapy nor combination therapy with oral antidiabetic medications were associated with the risk of AD after adjusting for underlying risk factors and the duration of DM since diagnosis. However, combination therapy with insulin was found to be associated with greater risk of AD (HR, 2.17; 95% CI, 1.04–4.52, p = 0.039).
Newly diagnosed DM was associated with increased risk of AD. Use of hypoglycemic agents did not ameliorate the risk.
PMCID: PMC3906115  PMID: 24489845
12.  Increased Risk of Ischemic Stroke in Patients with Benign Paroxysmal Positional Vertigo: A 9-Year Follow-Up Nationwide Population Study in Taiwan 
Benign paroxysmal positional vertigo (BPPV) is a common form of vertigo and is characterized by episodic dizziness related to changes in head position relative to gravity. BPPV symptoms can be similar to those of central nervous system vascular diseases. The association between BPPV and ischemic stroke has not yet been investigated. The study cohort consisted of patients who were diagnosed with BPPV at least twice in the previous year as an outpatient or for whom BPPV was the primary diagnosis as an inpatient (n = 4104). An age- and gender-matched sample that excluded patients with a diagnosis of any form of vertigo was selected as the comparison cohort (n = 8397). All cases were followed up from January 1, 2000, to December 31, 2008. The demographic characteristics, medical comorbidities, and use of medications in both groups were investigated using chi-square tests. A stratified analysis of stroke risk factors was performed to determine the hazard ratios of BPPV. During the 9-year follow-up period, 185 of the 4104 (4.5%) subjects with BPPV and 240 of the 8379 (2.9%) subjects without BPPV developed ischemic strokes. The crude hazard ratio of BPPV for developing ischemic strokes was 1.708. After adjusting for stroke risk factors, the risk of developing ischemic strokes in BPPV subjects was 1.415-fold higher than the risk among those without BPPV (confidence interval: 1.162–1.732, p = 0.001). After a subgroup analysis stratified according to stroke risk factors, BPPV remained independently associated with a higher risk of developing future ischemic stroke. We conclude that BPPV is independently associated with a risk of subsequent ischemic stroke. More aggressive control of modifiable risk factors for ischemic strokes should be conducted in patients with BPPV.
PMCID: PMC4040439  PMID: 24917815
stroke; benign paroxysmal positional vertigo; dizziness; vertigo; risk factors
13.  Association between CHADS2 Score and the Preventive Effect of Statin Therapy on New-Onset Atrial Fibrillation in Patients with Acute Myocardial Infarction 
PLoS ONE  2013;8(8):e74709.
New-onset atrial fibrillation (AF) commonly occurs in patients with acute myocardial infarction (AMI). Data regarding the value of the CHADS2 score in patients hospitalized for AMI is limited. This study aimed to determine whether the CHADS2 score is associated with new-onset AF and if it can help identify the patients who will benefit most from statin use for the prevention of arrhythmia after AMI.
A total of 724 consecutive AMI patients were enrolled in this study. The patients were divided into 3 groups according to their CHADS2 scores: group 1, score 0; group 2, score 1–2; and group 3, score 3–6. The study endpoint was an episode of new-onset AF that lasted more than 30 seconds during hospitalization at the coronary care unit.
Seventy-eight (10.8%) patients developed new-onset AF, and 273 (37.7%) were on a statin upon admission. The incidence of new-onset AF increased significantly from 5.8% in group 1 to 11.3% in group 2 and 14.3% in group 3 (χ2 for linear trend, P = 0.017). Statin use (odds ratio [OR], 0.22; 95% CI, 0.06–0.85) and CHADS2 score (OR, 1.53; 95% CI, 1.02–2.28) were independent predictors of new-onset AF in AMI patients. Patients with CHADS2 score ≤2 had significantly reduced C-reactive protein level and lower risk of developing new-onset AF if they were taking statins (P < 0.05). Multivariate logistic regression analysis demonstrated the benefit of statin use for preventing new-onset AF in patients with CHADS2 scores ≤2 (OR, 0.34; 95% CI, 0.14–0.81).
The CHADS2 score is a convenient scoring system for predicting the incidence of new-onset AF and may help in identifying the patients who will benefit most from statin use for the prevention of arrhythmia after AMI.
PMCID: PMC3753238  PMID: 23991226
14.  Increased Circulating Endothelial Apoptotic Microparticle to Endothelial Progenitor Cell Ratio Is Associated with Subsequent Decline in Glomerular Filtration Rate in Hypertensive Patients 
PLoS ONE  2013;8(7):e68644.
Recent research indicates hypertensive patients with microalbuminuria have decreased endothelial progenitor cells (EPCs) and increased levels of endothelial apoptotic microparticles (EMP). However, whether these changes are related to a subsequent decline in glomerular filtration rate (GFR) remains unclear.
Methods and Results
We enrolled totally 100 hypertensive out-patients with eGFR ≥30 mL/min/1.73 m2. The mean annual rate of GFR decline (△GFR/y) was −1.49±3.26 mL/min/1.73 m2 per year during the follow-up period (34±6 months). Flow cytometry was used to assess circulating EPC (CD34+/KDR+) and EMP levels (CD31+/annexin V+) in peripheral blood. The △GFR/y was correlated with the EMP to EPC ratio (r = −0.465, p<0.001), microalbuminuria (r = −0.329, p = 0.001), and the Framingham risk score (r = −0.245, p = 0.013). When we divided the patients into 4 groups according to the EMP to EPC ratio, there was an association between the EMP to EPC ratio and the ΔGFR/y (mean ΔGFR/y: 0.08±3.04 vs. −0.50±2.84 vs. −1.25±2.49 vs. −4.42±2.82, p<0.001). Multivariate analysis indicated that increased EMP to EPC ratio is an independent predictor of ΔeGFR/y.
An increased circulating EMP to EPC ratio is associated with subsequent decline in GFR in hypertensive patients, which suggests endothelial damage with reduced vascular repair capacity may contribute to further deterioration of renal function in patients with hypertension.
PMCID: PMC3709900  PMID: 23874701
15.  Activation of TRPV1 Prevents OxLDL-Induced Lipid Accumulation and TNF-α-Induced Inflammation in Macrophages: Role of Liver X Receptor α 
Mediators of Inflammation  2013;2013:925171.
The transient receptor potential vanilloid type 1 (TRPV1) is crucial in the pathogenesis of atherosclerosis; yet its role and underlying mechanism in the formation of macrophage foam cells remain unclear. Here, we show increased TRPV1 expression in the area of foamy macrophages in atherosclerotic aortas of apolipoprotein E-deficient mice. Exposure of mouse bone-marrow-derived macrophages to oxidized low-density lipoprotein (oxLDL) upregulated the expression of TRPV1. In addition, oxLDL activated TRPV1 and elicited calcium (Ca2+) influx, which were abrogated by the pharmacological TRPV1 antagonist capsazepine. Furthermore, oxLDL-induced lipid accumulation in macrophages was ameliorated by TRPV1 agonists but exacerbated by TRPV1 antagonist. Treatment with TRPV1 agonists did not affect the internalization of oxLDL but promoted cholesterol efflux by upregulating the efflux ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Moreover, the upregulation of ABC transporters was mainly through liver X receptor α- (LXRα-) dependent regulation of transcription. Moreover, the TNF-α-induced inflammatory response was alleviated by TRPV1 agonists but aggravated by the TRPV1 antagonist and LXRα siRNA in macrophages. Our data suggest that LXRα plays a pivotal role in TRPV1-activation-conferred protection against oxLDL-induced lipid accumulation and TNF-α-induced inflammation in macrophages.
PMCID: PMC3710635  PMID: 23878415
16.  Epidemiology of Idiopathic Central Serous Chorioretinopathy in Taiwan, 2001–2006: A Population-based Study 
PLoS ONE  2013;8(6):e66858.
The epidemiology of idiopathic central serous chorioretinopathy (CSCR) is not well understood in an Asian population. The present study aimed to investigate the incidence and risk factors for corticosteroid-unrelated CSCR using Taiwan’s National Health Insurance Research Database.
Methods and Results
From 2001 to 2006, a total of 786 patients (500 [63.6%] males) who were newly diagnosed with CSCR, aged from 20 to 64 years and had no history of corticosteroid prescription were identified as incident cases of idiopathic CSCR. 3606 age-, gender-, and enrollment time-matched subjects were randomly selected as the control group. The mean annual incidence was 0.21‰ (0.27‰ for males, and 0.15‰ for females; P<0.001), with a male/female ratio of 1.74. The peak incidence was in the 35- to 39-year-old age group (0.30‰), followed by the 40- to 44-year-old age group (0.26‰). Males had a significantly higher mean annual incidence than female only in the middle age groups. Conditional logistic regression was used to estimate the odds ratios (ORs) for potential risk factors of idiopathic CSCR. Only exposure to anti-anxiety drugs (OR, 1.63; 95% confidence interval, 1.09–2.44) was found to be independently associated with idiopathic CSCR among males. No risk factors of idiopathic CSCR were found for females.
This study provides the nationwide, population-based data on the incidence of idiopathic CSCR in adult Asians, and suggests that exposure to anti-anxiety drugs is an independent risk factor for idiopathic CSCR among males.
PMCID: PMC3691239  PMID: 23826160
17.  Atomic Layer Deposition of Titania on Cellulose Acetate for Enhanced Hemostasis 
Biotechnology journal  2011;6(2):213-223.
TiO2 films may be used to alter the wettability and hemocompatibility of cellulose materials. In this study, pure and stoichiometric TiO2 films were grown using atomic layer deposition on both silicon and cellulose substrates. The films were grown with uniform thicknesses and with a growth rate in agreement with literature results. The TiO2 films were shown to profoundly alter the water contact angle values of cellulose depending upon processing characteristics. Higher rates of protein adsorption were noted on TiO2-coated cellulose acetate than on uncoated cellulose acetate. These results suggest that atomic layer deposition is an appropriate method for improving the biological properties of hemostatic agents and other blood-contacting biomaterials.
PMCID: PMC3517083  PMID: 21298806
atomic layer deposition; cellulose; titanium oxide; hemostatic agent; hemocompatibility
18.  Gastroesophageal Reflux Disease and Atrial Fibrillation: A Nationwide Population-Based Study 
PLoS ONE  2012;7(10):e47575.
Precise mechanisms of atrial fibrillation (AF) are uncertain, but their association with esophageal disorders has been recently proposed. The association between gastroesophageal reflux disease (GERD), the most common gastroesophageal disorder, and AF remains undetermined. We therefore aimed to investigate the association between GERD and later development of AF.
Methods and Results
Patients with GERD were identified from the 1,000,000-person cohort dataset sampled from the Taiwan National Health Insurance database. The study cohort comprised 29,688 newly diagnosed adult GERD patients; 29,597 randomly selected age-, gender-, comobidity-matched subjects comprised the comparison cohort. Cox proportional hazard regressions were performed as a means of comparing the AF-free survival rate for the two cohorts. During a maximum three years of follow-up, a total of 351 patients experienced AF, including 184 (0.62%) patients in the GERD cohort and 167 (0.56%) in the control group. The log-rank test showed that patients with GERD had significantly higher incidence of AF than those without GERD (p = 0.024). After Cox proportional hazard regression model analysis, GERD was independently associated with the increased risk of AF (hazard ratio, 1.31; 95% confidence interval, 1.06–1.61, p = 0.013).
GERD was independently associated with an increased risk of future AF in a nationwide population-based cohort.
PMCID: PMC3471851  PMID: 23077642
19.  Low-Dose Dextromethorphan, a NADPH Oxidase Inhibitor, Reduces Blood Pressure and Enhances Vascular Protection in Experimental Hypertension 
PLoS ONE  2012;7(9):e46067.
Vascular oxidative stress may be increased with age and aggravate endothelial dysfunction and vascular injury in hypertension. This study aimed to investigate the effects of dextromethorphan (DM), a NADPH oxidase inhibitor, either alone or in combination treatment, on blood pressure (BP) and vascular protection in aged spontaneous hypertensive rats (SHRs).
Methodology/Principal Findings
Eighteen-week-old WKY rats and SHRs were housed for 2 weeks. SHRs were randomly assigned to one of the 12 groups: untreated; DM monotherapy with 1, 5 or 25 mg/kg/day; amlodipine (AM, a calcium channel blocker) monotherapy with 1 or 5 mg/kg/day; and combination therapy of DM 1, 5 or 25 mg/kg/day with AM 1 or 5 mg/kg/day individually for 4 weeks. The in vitro effects of DM were also examined. In SHRs, AM monotherapy dose-dependently reduced arterial systolic BP. DM in various doses significantly and similarly reduced arterial systolic BP. Combination of DM with AM gave additive effects on BP reduction. DM, either alone or in combination with AM, improved aortic endothelial function indicated by ex vivo acetylcholine-induced relaxation. The combination of low-dose DM with AM gave most significant inhibition on aortic wall thickness in SHRs. Plasma total antioxidant status was significantly increased by all the therapies except for the combination of high-dose DM with high-dose AM. Serum nitrite and nitrate level was significantly reduced by AM but not by DM or the combination of DM with AM. Furthermore, in vitro treatment with DM reduced angiotensin II-induced reactive oxygen species and NADPH oxidase activation in human aortic endothelial cells.
Treatment of DM reduced BP and enhanced vascular protection probably by inhibiting vascular NADPH oxidase in aged hypertensive animals with or without AM treatment. It provides the potential rationale to a novel combination treatment with low-dose DM and AM in clinical hypertension.
PMCID: PMC3457948  PMID: 23049937
20.  A Genome-Wide Association Study Reveals a Quantitative Trait Locus of Adiponectin on CDH13 That Predicts Cardiometabolic Outcomes 
Diabetes  2011;60(9):2417-2423.
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.
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).
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.
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.
PMCID: PMC3161336  PMID: 21771975
21.  Far infra-red therapy promotes ischemia-induced angiogenesis in diabetic mice and restores high glucose-suppressed endothelial progenitor cell functions 
Far infra-red (IFR) therapy was shown to exert beneficial effects in cardiovascular system, but effects of IFR on endothelial progenitor cell (EPC) and EPC-related vasculogenesis remain unclear. We hypothesized that IFR radiation can restore blood flow recovery in ischemic hindlimb in diabetic mice by enhancement of EPCs functions and homing process.
Materials and methods
Starting at 4 weeks after the onset of diabetes, unilateral hindlimb ischemia was induced in streptozotocine (STZ)-induced diabetic mice, which were divided into control and IFR therapy groups (n = 6 per group). The latter mice were placed in an IFR dry sauna at 34°C for 30 min once per day for 5 weeks.
Doppler perfusion imaging demonstrated that the ischemic limb/normal side blood perfusion ratio in the thermal therapy group was significantly increased beyond that in controls, and significantly greater capillary density was seen in the IFR therapy group. Flow cytometry analysis showed impaired EPCs (Sca-1+/Flk-1+) mobilization after ischemia surgery in diabetic mice with or without IFR therapy (n = 6 per group). However, as compared to those in the control group, bone marrow-derived EPCs differentiated into endothelial cells defined as GFP+/CD31+ double-positive cells were significantly increased in ischemic tissue around the vessels in diabetic mice that received IFR radiation. In in-vitro studies, cultured EPCs treated with IFR radiation markedly augmented high glucose-impaired EPC functions, inhibited high glucose-induced EPC senescence and reduced H2O2 production. Nude mice received human EPCs treated with IFR in high glucose medium showed a significant improvement in blood flow recovery in ischemic limb compared to those without IFR therapy. IFR therapy promoted blood flow recovery and new vessel formation in STZ-induced diabetic mice.
Administration of IFR therapy promoted collateral flow recovery and new vessel formation in STZ-induced diabetic mice, and these beneficial effects may derive from enhancement of EPC functions and homing process.
PMCID: PMC3472269  PMID: 22894755
Far infra-red therapy; Endothelial progenitor cell; Diabetes; Ischemia
22.  Association of Serum Bilirubin with Contrast-Induced Nephropathy and Future Cardiovascular Events in Patients Undergoing Coronary Intervention 
PLoS ONE  2012;7(8):e42594.
Enhanced reactive oxygen species formation within the kidney following the administration of contrast media may play a key role in the development of contrast-induced nephropathy (CIN). Bilirubin has emerged as an important endogenous antioxidant molecule. This study was undertaken to determine whether bilirubin is associated with CIN and future cardiovascular events in patients undergoing coronary intervention.
Totally, 544 consecutive patients received coronary intervention were enrolled. All patients were followed up for at least 3 years or until the occurrence of a major event. The primary endpoint was CIN, defined as a rise in serum creatinine (SCr) of 0.5 mg/dl or a 25% increase from the baseline value within 48 hours after the procedure. The secondary endpoint was the combined occurrence of major adverse cardiovascular events (MACE), including death, nonfatal myocardial infarction, and ischemic stroke.
Overall, CIN occurred in 85 (15.6%) patients. All patients were stratified into 3 groups (low/normal/high) according to the serum bilirubin levels. In a multivariate logistic analysis, the odds ratio for CIN with low-bilirubin levels relative to high-bilirubin levels was 11.82 (95% CI, 3.25–43.03). By Cox regression analysis, serum bilirubin levels was an independent predictor of MACE in patients undergoing coronary intervention (low vs. high hazard ratio 2.26; 95% CI, 1.05–4.90).
CIN is a serious complication of coronary intervention. Higher serum bilirubin concentrations were associated with lower risk of CIN and fewer cardiovascular events. The development of interventions that promote bilirubin levels may be a potential target to reduce CIN and future MACE in patients undergoing coronary intervention.
PMCID: PMC3412818  PMID: 22880046
23.  Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells 
PLoS ONE  2012;7(7):e41065.
Bisphosphonates are a class of pharmacologic compounds that are commonly used to treat postmenopausal osteoporosis and malignant osteolytic processes. Studies have shown that bone marrow-derived endothelial progenitor cells (EPCs) play a significant role in postnatal neovascularization. Whether the nitrogen-containing bisphosphonate zoledronate inhibits ischemia-induced neovascularization by modulating EPC functions remains unclear.
Methodology/Principal Findings
Unilateral hindlimb ischemia was surgically induced in wild-type mice after 2 weeks of treatment with vehicle or zoledronate (low-dose: 30 μg/kg; high-dose: 100 μg/kg). Doppler perfusion imaging demonstrated that the ischemic limb/normal side blood perfusion ratio was significantly lower in wild-type mice treated with low-dose zoledronate and in mice treated with high-dose zoledronate than in controls 4 weeks after ischemic surgery (control vs. low-dose vs. high-dose: 87±7% vs. *61±18% vs. **49±17%, *p<0.01, **p<0.005 compared to control). Capillary densities were also significantly lower in mice treated with low-dose zoledronate and in mice treated with high-dose zoledronate than in control mice. Flow cytometry analysis showed impaired mobilization of EPC-like cells (Sca-1+/Flk-1+) after surgical induction of ischemia in mice treated with zoledronate but normal levels of mobilization in mice treated with vehicle. In addition, ischemic tissue from mice that received zoledronate treatment exhibited significantly lower levels of the active form of MMP-9, lower levels of VEGF, and lower levels of phosphorylated eNOS and phosphorylated Akt than ischemic tissue from mice that received vehicle. Results of the in vitro studies showed that incubation with zoledronate inhibited the viability, migration, and tube-forming capacities of EPC.
Zoledronate inhibited ischemia-induced neovascularization by impairing EPC mobilization and angiogenic functions. These findings suggest that administration of zoledronate should be withheld in patients with ischemic events such as acute limb ischemia.
PMCID: PMC3405104  PMID: 22848429
24.  Ginkgo biloba extract reduces high-glucose-induced endothelial adhesion by inhibiting the redox-dependent interleukin-6 pathways 
Chronic elevation of glucose level activates vascular inflammation and increases endothelial adhesiveness to monocytes, an early sign of atherogenesis. This study aimed to elucidate the detailed mechanisms of high-glucose-induced endothelial inflammation, and to investigate the potential effects of Ginkgo biloba extract (GBE), an antioxidant herbal medicine, on such inflammation.
Materials and methods
Human aortic endothelial cells were cultured in high glucose or mannitol as osmotic control for 4 days. The expression of cytokines and adhesion molecules and the adhesiveness of endothelial cells to monocytes were examined. The effects of pretreatment of GBE or N-acetylcysteine, an antioxidant, were also investigated.
Either high glucose or mannitol significantly increased reactive oxygen species (ROS) production, interleukin-6 secretion, intercellular adhesion molecule-1 (ICAM-1) expression, as well as endothelial adhesiveness to monocytes. The high-glucose-induced endothelial adhesiveness was significantly reduced either by an anti-ICAM-1 antibody or by an interleukin-6 neutralizing antibody. Interleukin-6 (5 ng/ml) significantly increased endothelial ICAM-1 expression. Piceatannol, a signal transducer and activator of transcription (STAT) 1/3 inhibitor, but not fludarabine, a STAT1 inhibitor, suppressed high-glucose-induced ICAM-1 expression. Pretreatment with GBE or N-acetylcysteine inhibited high-glucose-induced ROS, interleukin-6 production, STAT1/3 activation, ICAM-1 expression, and endothelial adhesiveness to monocytes.
Long-term presence of high glucose induced STAT3 mediated ICAM-1 dependent endothelial adhesiveness to monocytes via the osmotic-related redox-dependent interleukin-6 pathways. GBE reduced high-glucose-induced endothelial inflammation mainly by inhibiting interleukin-6 activation. Future study is indicated to validate the antioxidant/anti-inflammatory strategy targeting on interleukin-6 for endothelial protection in in vivo and clinical hyperglycemia.
PMCID: PMC3434011  PMID: 22553973
Antioxidant, Endothelial cells; Ginkgo biloba extract; Glucose; Intercellular adhesion molecule −1; Interleukin −6
25.  Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as Hypertension Susceptibility Genes in Han Chinese with a Genome-Wide Gene-Based Association Study 
PLoS ONE  2012;7(3):e32907.
Hypertension is a complex disorder with high prevalence rates all over the world. We conducted the first genome-wide gene-based association scan for hypertension in a Han Chinese population. By analyzing genome-wide single-nucleotide-polymorphism data of 400 matched pairs of young-onset hypertensive patients and normotensive controls genotyped with the Illumina HumanHap550-Duo BeadChip, 100 susceptibility genes for hypertension were identified and also validated with permutation tests. Seventeen of the 100 genes exhibited differential allelic and expression distributions between patient and control groups. These genes provided a good molecular signature for classifying hypertensive patients and normotensive controls. Among the 17 genes, IGF1, SLC4A4, WWOX, and SFMBT1 were not only identified by our gene-based association scan and gene expression analysis but were also replicated by a gene-based association analysis of the Hong Kong Hypertension Study. Moreover, cis-acting expression quantitative trait loci associated with the differentially expressed genes were found and linked to hypertension. IGF1, which encodes insulin-like growth factor 1, is associated with cardiovascular disorders, metabolic syndrome, decreased body weight/size, and changes of insulin levels in mice. SLC4A4, which encodes the electrogenic sodium bicarbonate cotransporter 1, is associated with decreased body weight/size and abnormal ion homeostasis in mice. WWOX, which encodes the WW domain-containing protein, is related to hypoglycemia and hyperphosphatemia. SFMBT1, which encodes the scm-like with four MBT domains protein 1, is a novel hypertension gene. GRB14, TMEM56 and KIAA1797 exhibited highly significant differential allelic and expressed distributions between hypertensive patients and normotensive controls. GRB14 was also found relevant to blood pressure in a previous genetic association study in East Asian populations. TMEM56 and KIAA1797 may be specific to Taiwanese populations, because they were not validated by the two replication studies. Identification of these genes enriches the collection of hypertension susceptibility genes, thereby shedding light on the etiology of hypertension in Han Chinese populations.
PMCID: PMC3315540  PMID: 22479346

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