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author:("Huang, Po-sun")
1.  Pulmonary Arterial Thrombosis in a Patient With an Atrial Septal Defect and Eisenmenger Syndrome 
Korean Circulation Journal  2012;42(11):772-775.
Pulmonary hypertension is characterized by elevated pulmonary arterial pressure and secondary right ventricular failure. A thromboembolic occlusion of the proximal or distal pulmonary vasculature results in chronic thromboembolic pulmonary hypertension. We report an uncommon case that presented to our hospital with symptoms of dyspnea on exertion over 2 years. The patient had been treated for profound pulmonary thrombosis and right ventricular failure with adequate anticoagulation and sildenafil. Our echocardiography disclosed a large atrial septal defect with severe pulmonary hypertension and right ventricular failure. A diagnosis of Eisenmenger syndrome with pulmonary artery thrombosis was made. Although Eisenmenger syndrome with pulmonary thrombosis is well described in western societies, a huge pulmonary thrombosis is seldom reported in eastern countries. Profound pulmonary thrombosis may obfuscate the actual diagnosis of pulmonary artery hypertension with underlying congenital heart disease. A physical examination and echocardiography are essential in patients with pulmonary hypertension.
PMCID: PMC3518712  PMID: 23236330
Pulmonary embolism; Eisenmenger syndrome
2.  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
3.  Rare cell isolation and analysis in microfluidics 
Lab on a chip  2014;14(4):626-645.
Rare cells are low-abundance cells in a much larger population of background cells. Conventional benchtop techniques have limited capabilities to isolate and analyze rare cells because of their generally low selectivity and significant sample loss. Recent rapid advances in microfluidics have been providing robust solutions to the challenges in the isolation and analysis of rare cells. In addition to the apparent performance enhancements resulting in higher efficiencies and sensitivity levels, microfluidics provides other advanced features such as simpler handling of small sample volumes and multiplexing capabilities for high-throughput processing. All of these advantages make microfluidics an excellent platform to deal with the transport, isolation, and analysis of rare cells. Various cellular biomarkers, including physical properties, dielectric properties, as well as immunoaffinities, have been explored for isolating rare cells. In this Focus article, we discuss the design considerations of representative microfluidic devices for rare cell isolation and analysis. Examples from recently published works are discussed to highlight the advantages and limitations of the different techniques. Various applications of these techniques are then introduced. Finally, a perspective on the development trends and promising research directions in this field are proposed.
PMCID: PMC3991782  PMID: 24406985
4.  Superhydrophobic Surface Enhanced Raman Scattering Sensing using Janus Particle Arrays Realized by Site-Specific Electrochemical Growth 
Site-specific electrochemical deposition is used to prepare polystyrene (PS)-Ag Janus particle arrays with superhydrophobic properties. The analyte molecules can be significantly enriched using the superhydrophobic property of the PS-Ag Janus particle array before SERS detections, enabling an extremely sensitive detection of molecules in a highly diluted solution (e.g., femtomolar level). This superhydrophobic surface enhanced Raman scattering sensing concept described here is of critical significance in biosensing and bioanalysis. Most importantly, the site-specific electrochemical growth method we developed here is a versatile approach that can be used to prepare Janus particle arrays with different properties for various applications.
PMCID: PMC3989947  PMID: 24748991
5.  Accelerating drug discovery via organs-on-chips 
Lab on a chip  2013;13(24):4697-4710.
Considerable advances have been made in the development of micro-physiological systems that seek to faithfully replicate the complexity and functionality of animal and human physiology in research laboratories. Sometimes referred to as “organs-on-chips”, these systems provide key insights into physiological or pathological processes associated with health maintenance and disease control, and serve as powerful platforms for new drug development and toxicity screening. In this Focus article, we review the state-of-the-art designs and examples for developing multiple “organs-on-chips”, and discuss the potential of this emerging technology to enhance our understanding of human physiology, and to transform and accelerate the drug discovery and pre-clinical testing process. This Focus article highlights some of the recent technological advances in this field, along with the challenges that must be addressed for these technologies to fully realize their potential.
PMCID: PMC3998760  PMID: 24193241
6.  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
7.  An acoustofluidic micromixer based on oscillating sidewall sharp-edges† 
Lab on a chip  2013;13(19):3847-3852.
Rapid and homogeneous mixing inside a microfluidic channel is demonstrated via the acoustic streaming phenomenon induced by the oscillation of sidewall sharp-edges. By optimizing the design of the sharp-edges, excellent mixing performance and fast mixing speed can be achieved in a simple device, making our sharp-edge-based acoustic micromixer a promising candidate for a wide variety of applications.
PMCID: PMC3988907  PMID: 23896797
8.  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
9.  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
10.  Dysregulated miR-361-5p/VEGF Axis in the Plasma and Endothelial Progenitor Cells of Patients with Coronary Artery Disease 
PLoS ONE  2014;9(5):e98070.
Dysfunction and reduction of circulating endothelial progenitor cell (EPC) is correlated with the onset of cardiovascular disorders including coronary artery disease (CAD). VEGF is a known mitogen for EPC to migrate out of bone marrow to possess angiogenic activities, and the plasma levels of VEGF are inversely correlated to the progression of CAD. Circulating microRNAs (miRNAs) in patient body fluids have recently been considered to hold the potential of being novel disease biomarkers and drug targets. However, how miRNAs and VEGF cooperate to regulate CAD progression is still unclear. Through the small RNA sequencing (smRNA-seq), we deciphered the miRNome patterns of EPCs with different angiogenic activities, hypothesizing that miRNAs targeting VEGF must be more abundant in EPCs with lower angiogenic activities. Candidates of anti-VEGF miRNAs, including miR-361-5p and miR-484, were enriched in not only diseased EPCs but also the plasma of CAD patients. However, we found out only miR-361-5p, but not miR-484, was able to suppress VEGF expression and EPC activities. Reporter assays confirmed the direct binding and repression of miR-361-5p to the 3′-UTR of VEGF mRNA. Knock down of miR-361-5p not only restored VEGF levels and angiogenic activities of diseased EPCs in vitro, but further promoted blood flow recovery in ischemic limbs of mice. Collectively, we discovered a miR-361-5p/VEGF-dependent regulation that could help to develop new therapeutic modalities not only for ischemia-related diseases but also for tumor angiogenesis.
PMCID: PMC4035317  PMID: 24865854
11.  Tunable Nanowire Patterning Using Standing Surface Acoustic Waves 
ACS nano  2013;7(4):3306-3314.
Patterning of nanowires in a controllable, tunable manner is important for the fabrication of functional nanodevices. Here we present a simple approach for tunable nanowire patterning using standing surface acoustic waves (SSAW). This technique allows for the construction of large-scale nanowire arrays with well-controlled patterning geometry and spacing within 5 seconds. In this approach, SSAWs were generated by interdigital transducers (IDTs), which induced a periodic alternating current (AC) electric field on the piezoelectric substrate and consequently patterned metallic nanowires in suspension. The patterns could be deposited onto the substrate after the liquid evaporated. By controlling the distribution of the SSAW field, metallic nanowires were assembled into different patterns including parallel and perpendicular arrays. The spacing of the nanowire arrays could be tuned by controlling the frequency of the surface acoustic waves. Additionally, we observed 3D spark-shape nanowire patterns in the SSAW field. The SSAW-based nanowire-patterning technique presented here possesses several advantages over alternative patterning approaches, including high versatility, tunability, and efficiency, making it promising for device applications.
PMCID: PMC3989880  PMID: 23540330
Surface Patterning; Nanowire; Standing Surface Acoustic Waves (SSAW); Virtual Electrodes
12.  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
13.  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
14.  Reduced circulating endothelial progenitor cells in reversible cerebral vasoconstriction syndrome 
The pathophysiology of reversible cerebral vasoconstriction syndrome (RCVS) remains elusive. Endothelial dysfunction might play a role, but direct evidence is lacking. This study aimed to explore whether patients with RCVS have a reduced level of circulating circulating endothelial progenitor cells (EPCs) to repair the dysfunctional endothelial vasomotor control.
We prospectively recruited 24 patients with RCVS within one month of disease onset and 24 healthy age- and sex-matched controls. Flow cytometry was used to quantify the numbers of circulating EPCs, defined as KDR+CD133+, CD34+CD133+, and CD34+KDR+ double-positive mononuclear cells. The Lindegaard index, an index of vasoconstriction, was calculated by measuring the mean flow velocity of middle cerebral arteries and distal extracranial internal carotid arteries via color-coded sonography on the same day as blood drawing. A Lindegaard index of 2 was chosen as the cutoff value for significant vasoconstriction of middle cerebral arteries based on our previous study.
Patients with RCVS had a reduced number of CD34+KDR+ cells (0.009 ± 0.006% vs. 0.014 ± 0.010%, p = 0.031) but not KDR+CD133+ cells or CD34+CD133+ EPCs, in comparison with controls. The number of CD34+KDR+ cells was inversely correlated with the Lindegaard index (rs = -0.418, p = 0.047). Of note, compared to controls, patients with a Lindegaard index > 2 (n = 13) had a reduced number of CD34+KDR+ cells (0.007 ± 0.005% vs. 0.014 ± 0.010%, p = 0.010), but those with a Lindegaard index ≤ 2 did not.
Patients with RCVS had reduced circulating CD34+KDR+ EPCs, which were correlated with the severity of vasoconstriction. Endothelial dysfunction might contribute to the pathogenesis of RCVS.
PMCID: PMC4266547  PMID: 25466718
Reversible cerebral vasoconstriction syndrome; Thunderclap headaches; Endothelial progenitor cells; Endothelial dysfunction; Cerebral arteries
15.  GroEL1, a Heat Shock protein 60 of Chlamydia pneumoniae, Impairs Neovascularization by Decreasing Endothelial Progenitor Cell Function 
PLoS ONE  2013;8(12):e84731.
The number and function of endothelial progenitor cells (EPCs) are sensitive to hyperglycemia, hypertension, and smoking in humans, which are also associated with the development of atherosclerosis. GroEL1 from Chlamydia pneumoniae has been found in atherosclerotic lesions and is related to atherosclerotic pathogenesis. However, the actual effects of GroEL1 on EPC function are unclear. In this study, we investigate the EPC function in GroEL1-administered hind limb-ischemic C57BL/B6 and C57BL/10ScNJ (a toll-like receptor 4 (TLR4) mutation) mice and human EPCs. In mice, laser Doppler imaging, flow cytometry, and immunohistochemistry were used to evaluate the degree of neo-vasculogenesis, circulating level of EPCs, and expression of CD34, vWF, and endothelial nitric oxide synthase (eNOS) in vessels. Blood flow in the ischemic limb was significantly impaired in C57BL/B6 but not C57BL/10ScNJ mice treated with GroEL1. Circulating EPCs were also decreased after GroEL1 administration in C57BL/B6 mice. Additionally, GroEL1 inhibited the expression of CD34 and eNOS in C57BL/B6 ischemic muscle. In vitro, GroEL1 impaired the capacity of differentiation, mobilization, tube formation, and migration of EPCs. GroEL1 increased senescence, which was mediated by caspases, p38 MAPK, and ERK1/2 signaling in EPCs. Furthermore, GroEL1 decreased integrin and E-selectin expression and induced inflammatory responses in EPCs. In conclusion, these findings suggest that TLR4 and impaired NO-related mechanisms could contribute to the reduced number and functional activity of EPCs in the presence of GroEL1 from C. pneumoniae.
PMCID: PMC3871664  PMID: 24376840
16.  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
17.  Progression of Kidney Disease in Non-Diabetic Patients with Coronary Artery Disease: Predictive Role of Circulating Matrix Metalloproteinase-2, -3, and -9 
PLoS ONE  2013;8(7):e70132.
Circulating matrix metalloproteinase (MMP)-2, -3 and -9 are well recognized in predicting cardiovascular outcome in coronary artery disease (CAD), but their risks for chronic kidney disease (CKD) are lacking. Therefore, the present study aimed to investigate whether circulating MMP levels could independently predict future kidney disease progression in non-diabetic CAD patients.
The prospective study enrolled 251 non-diabetic subjects referred for coronary angiography, containing normal coronary artery (n = 30) and CAD with insignificant (n = 95) and significant (n = 126) stenosis. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula. eGFR decline rate was calculated and the primary endpoint was a decline in eGFR over 25% from baseline.
The eGFR decline rate (ml/min/1.73 m2 per year) in patients with CAD (1.22 [−1.27, 1.05]) was greater than that in those with normal coronary artery (0.21 [−2.63, 0.47], P<0.01). The circulating MMP-2, -3 and -9 were independently associated with faster eGFR decline among CAD patients. The mean follow-up period was 8.5±2.4 years, and 39 patients reached the primary endpoint. In multivariate Cox regression model, the adjusted hazard ratios of MMP-2 ≥861 ng/mL, MMP-3 ≥227 ng/mL and MMP-9 ≥49 ng/mL for predicting CKD progression were 2.47 (95% CI, 1.21 to 5.07), 2.15 (1.12 to 4.18), and 4.71 (2.14 to 10.4), respectively. While added to a model of conventional risk factors and baseline eGFR, MMP-2, -3 and -9 further significantly improved the model predictability for CKD progression (c statistic, 0.817). In the sensitivity analyses, the results were similar no matter if we changed the endpoints of a decline of >20% in eGFR from baseline or final eGFR < 60 mL/min/1.73 m2.
Circulating MMP-2, -3 and -9 are independently associated with kidney disease progression in non-diabetic CAD patients and add incremental predictive power to conventional risk factors.
PMCID: PMC3724836  PMID: 23922934
18.  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
19.  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
20.  Distinct angiogenesis roles and surface markers of early and late endothelial progenitor cells revealed by functional group analyses 
BMC Genomics  2013;14:182.
Endothelial progenitor cells (EPCs) play a fundamental role in post-natal vascular repair. Currently EPCs are defined as either early and late EPCs based on their biological properties and their time of appearance during in vitro culture. EPCs are rare and therefore optimizing isolation and culture is required before they can be applied as part of clinical therapies.
We compared the gene profiles of early/late EPCs to their ancestors CD133+ or CD34+ stem cells and to matured endothelial cells pinpointing novel biomarkers and stemness genes. Late EPCs were enriched with proliferation and angiogenesis genes, participating in endothelial tubulogenesis and hence neovascularization. Early EPCs expressed abundant inflammatory cytokines and paracrine angiogenic factors, thereby promoting angiogenesis in a paracrine manner. Transcription factors involved in EPC stemness were pinpointed in early EPCs (MAF/MAFB) and in late EPCs (GATA6/IRF6).
The detailed mRNA expression profiles and functional module analysis for different EPCs will help the development of novel therapeutic modalities targeting cardiovascular disease, tumor angiogenesis and various ischemia-related diseases.
PMCID: PMC3652793  PMID: 23496821
21.  Endothelial Progenitor Cell Dysfunction in Cardiovascular Diseases: Role of Reactive Oxygen Species and Inflammation 
BioMed Research International  2012;2013:845037.
Endothelial progenitor cells (EPCs) move towards injured endothelium or inflamed tissues and incorporate into foci of neovascularisation, thereby improving blood flow and tissue repair. Patients with cardiovascular diseases have been shown to exhibit reduced EPC number and function. It has become increasingly apparent that these changes may be effected in response to enhanced oxidative stress, possibly as a result of systemic and localised inflammatory responses. The interplay between inflammation and oxidative stress affects the initiation, progression, and complications of cardiovascular diseases. Recent studies suggest that inflammation and oxidative stress modulate EPC bioactivity. Clinical medications with anti-inflammatory and antioxidant properties, such as statins, thiazolidinediones, angiotensin II receptor 1 blockers, and angiotensin-converting enzyme inhibitors, are currently administered to patients with cardiovascular diseases. These medications appear to exert beneficial effects on EPC biology. This review focuses on EPC biology and explores the links between oxidative stress, inflammation, and development of cardiovascular diseases.
PMCID: PMC3591199  PMID: 23484163
22.  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
23.  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
24.  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
25.  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

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