Wei-Shiang Lin

Mesenchymal Stem Cells from Human Umbilical Cord Express Preferentially Secreted Factors Related to Neuroprotection, Neurogenesis, and Angiogenesis

Mesenchymal stem cells (MSCs) are promising tools for the treatment of diseases such as infarcted myocardia and strokes because of their ability to promote endogenous angiogenesis and neurogenesis via a variety of secreted factors. MSCs found in the Wharton’s jelly of the human umbilical cord are easily obtained and are capable of transplantation without rejection. We isolated MSCs from Wharton’s jelly and bone marrow (WJ-MSCs and BM-MSCs, respectively) and compared their secretomes. It was found that WJ-MSCs expressed more genes, especially secreted factors, involved in angiogenesis and neurogenesis. Functional validation showed that WJ-MSCs induced better neural differentiation and neural cell migration via a paracrine mechanism. Moreover, WJ-MSCs afforded better neuroprotection efficacy because they preferentially enhanced neuronal growth and reduced cell apoptotic death of primary cortical cells in an oxygen-glucose deprivation (OGD) culture model that mimics the acute ischemic stroke situation in humans. In terms of angiogenesis, WJ-MSCs induced better microvasculature formation and cell migration on co-cultured endothelial cells. Our results suggest that WJ-MSC, because of a unique secretome, is a better MSC source to promote in vivo neurorestoration and endothelium repair. This study provides a basis for the development of cell-based therapy and carrying out of follow-up mechanistic studies related to MSC biology.

Clinical outcome of catheter ablation in patients with nonparoxysmal atrial fibrillation: results of 3-year follow-up.

Background—Catheter ablation of atrial fibrillation (AF) became an effective therapy for patients with drug-refractory AF, and the indications have broadened to include nonparoxysmal AF patients. However, data about the long-term effectiveness of ablation in patients with nonparoxysmal AF are lacking. The aim of the present study was to investigate the long-term outcomes of catheter ablation in patients with nonparoxysmal AF. Methods and Results—A total of 88 nonparoxysmal AF patients who received a stepwise catheter ablation (isolation of the pulmonary veins plus substrate modification) from 2006 to 2008 were enrolled. Freedom of recurrence was defined as the absence of atrial arrhythmias without using any antiarrhythmic agents after the catheter ablation. There were 63 patients (71.6%) with recurrences (47 patients with AF and 16 patients with atrial flutter/atrial tachycardia) after the initial procedure during a median follow-up period of 36.8 months. A CHADS2 score of ≥3 and the left atrial (LA) diameter were significant predictors of recurrences in the multivariable analysis. Of the patients with CHADS2 scores of ≥3 and an LA dimension ≥44 mm, all had recurrences within 1 year after the initial procedure. The overall recurrence-free rate could increase to 47.7% after the second procedure and 51.1% after the third procedure. Conclusions—The long-term recurrence-free rate of ablation in nonparoxysmal AF was only 28.4% after a single procedure, and multiple procedures were necessary to raise the recurrence-free rate. The CHADS2 score and LA dimension may help us to identify patients who will have recurrences after catheter ablations of nonparoxysmal AF.

miR-146a-5p circuitry uncouples cell proliferation and migration, but not differentiation, in human mesenchymal stem cells

Administration of mesenchymal stem cells (MSCs) has the potential to ameliorate degenerative disorders and to repair damaged tissues. The homing of transplanted MSCs to injured sites is a critical property of engraftment. Our aim was to identify microRNAs involved in controlling MSC proliferation and migration. MSCs can be isolated from bone marrow and umbilical cord Wharton’s jelly (BM-MSCs and WJ-MSCs, respectively), and WJ-MSCs show poorer motility yet have a better amplification rate compared with BM-MSCs. Small RNA sequencing revealed that miR-146a-5p is significantly overexpressed and has high abundance in WJ-MSCs. Knockdown of miR-146a-5p in WJ-MSCs inhibited their proliferation yet enhanced their migration, whereas overexpression of miR-146a-5p in BM-MSCs did not influence their osteogenic and adipogenic potentials. Chemokine (C-X-C motif) ligand 12 (CXCL12), together with SIKE1, which is an I-kappa-B kinase epsilon (IKKε) suppressor, is a direct target of miR-146a-5p in MSCs. Knockdown of miR-146a-5p resulted in the down-regulation of nuclear factor kappa-B (NF-κB) activity, which is highly activated in WJ-MSCs and is known to activate miR-146a-5p promoter. miR-146a-5p is also downstream of CXCL12, and a negative feedback loop is therefore formed in MSCs. These findings suggest that miR-146a-5p is critical to the uncoupling of motility and proliferation of MSCs. Our miRNome data also provide a roadmap for further understanding MSC biology.

Is an Oral Anticoagulant Necessary for Young Atrial Fibrillation Patients With a CHA2DS2‐VASc Score of 1 (Men) or 2 (Women)?

Background Recent studies demonstrated that oral anticoagulants (OACs) should be considered for patients with atrial fibrillation and 1 risk factor in addition to sex. Because age is an important determinant of ischemic stroke, the strategy for stroke prevention may be different for these patients in different age strata. The aim of this study was to investigate whether OACs should be considered for patients aged 20 to 49 years with atrial fibrillation and a CHA2DS2‐VASc score of 1 (men) or 2 (women). Methods and Results Using the Taiwan National Health Insurance Research Database, 7374 male patients with atrial fibrillation and a CHA2DS2‐VASc score of 1 and 4461 female patients with atrial fibrillation and a CHA2DS2‐VASc score of 2 and all without antithrombotic therapies were identified and stratified into 3 groups by age. The threshold for the initiation of OACs for stroke prevention was set at a stroke rate of 1.7% per year for warfarin and 0.9% per year for non–vitamin K antagonist OACs. Among male patients aged 20 to 49 years with a CHA2DS2‐VASc score of 1, the risk of ischemic stroke was 1.30% per year and ranged from 0.94% per year for those with hypertension to 1.71% for those with congestive heart failure. Among female patients aged 20 to 49 years with a CHA2DS2‐VASc score of 2, the risk of ischemic stroke was 1.40% per year and ranged from 1.11% per year for those with hypertension to 1.67% for those with congestive heart failure. Conclusions For atrial fibrillation patients aged 20 to 49 years with 1 risk factor in addition to sex, non–vitamin K antagonist OACs should be considered for stroke prevention to minimize the risk of a potentially fatal or disabling event.

Carvedilol use is associated with reduced cancer risk: A nationwide population-based cohort study

BACKGROUND To investigate the effect of carvedilol on the incidence of cancer in a large population-based cohort study. METHODS Data were obtained from the Taiwan National Health Insurance Research Database. The cohort study included 6771 patients who received long-term carvedilol treatment between 2000 and 2010 (carvedilol cohort) and 6771 matched controls (noncarvedilol cohort). A Cox proportional hazards model was used to evaluate the risk of cancer in the patients treated with carvedilol. RESULTS With the mean follow-up period of 5.17 years and 4.93 years in the carvedilol and noncarvedilol cohorts, respectively, the patients in the carvedilol cohort had a 26% reduction of cancer risk compared with those in the noncarvedilol cohort (hazard ratio [HR]=0.74; 95% confidence interval [CI]=0.63-0.87; p<.001). The sex-specific carvedilol to noncarvedilol relative risk was lower for both women (HR=0.73; 95% CI=0.56-0.94) and men (HR=0.75; 95% CI=0.61-0.92). Moreover, stratified by cancer site, treatment with carvedilol in the carvedilol cohort resulted in significantly lower incidence of stomach and lung cancers than in the noncarvedilol cohort. CONCLUSION This nationwide population-based cohort study demonstrated that long-term treatment with carvedilol is associated with reduced upper gastrointestinal tract and lung cancer risk, indicating that carvedilol could be a potential agent in these cancers prevention.

Magnesium lithospermate B mediates anti-inflammation targeting activator protein-1 and nuclear factor-kappa B signaling pathways in human peripheral T lymphocytes

The activation of T lymphocytes contributes to the inflammatory processes of atherosclerotic diseases. Danshen is a traditional Chinese medicine and has shown therapeutic effects in patients with cardiovascular and cerebrovascular diseases. We investigated the effects of aqueous extract of Danshen (magnesium lithospermate B (MLB)) on phorbol 12-myristate acetate+ionomycin and anti-CD3+anti-CD28 monoclonal antibody-activated T cells. We showed that MLB inhibited interleukin (IL)-2, IL-4, tumor necrosis factor-alpha and interferon-gamma production from activated T cells. The expressions of T cell activation markers CD 25 and CD 69 were effectively reduced. EMSA analysis indicated that MLB down-regulated activator protein-1 (AP-1), nuclear factor kappa B (NF-κB) and octamer binding transcription factor (Oct-1) DNA-binding activity. In addition, MLB inhibited c-jun N-terminal kinase (JNK) but not extracellular signal regulated protein kinase activity. MLB also inhibited IκBα degradation, nuclear translocation of p65 and p50 as well as decreased IκBα kinase (IKK) activity. Through suppressing JNK-AP-1, IKK-IκBα-NF-κB and Oct-1 signaling pathways by MLB in activated T cells, our results provide support for efficacy of MLB in inflammatory diseases and raise its therapeutic potential in activated T cell-mediated pathologies.

Atrial fibrillation is associated with increased risk of erectile dysfunction: A nationwide population-based cohort study

BACKGROUND Our study aimed to investigate the association between atrial fibrillation (AF) and erectile dysfunction (ED). METHODS A total of 3853 male patients with AF were identified as the AF cohort, and 15,405 male patients without AF were selected randomly as the control group and matched by age and index years of AF diagnosis. The endpoint of interest in this study was the occurrence of ED. Individuals with prior history of ED, female patients, those with missing information, and those aged 20 years and younger were excluded. RESULTS The mean follow-up duration was 4.67 ± 3.20 years for the AF patients and 5.04 ± 3.30 years for the non-AF patients. During the follow-up period, the incidence of ED in the AF cohort was 1.65-fold higher than the non-AF cohort (20.6 vs 12.5 per 10,000 person-years, P < .001). Stratified by age, the incidence of ED was consistently higher in the AF cohort. After adjustment for patient characteristics, multivariate Cox regression analysis demonstrated that AF and hyperlipidemia remained independent risk factors for ED (hazard ratio [HR] = 1.53, 95% confidence interval [CI] = 1.05-2.24 and HR = 1.96, 95% CI = 1.36-2.81, respectively). Relative to the non-AF cohort without hyperlipidemia, the AF patients with hyperlipidemia were at a higher risk of ED (HR=2.76, 95% CI = 1.52-5.00). CONCLUSION In a large-scale cohort, the incidence of ED was significantly higher in male patients with AF than those without AF.

Novel assessment of temporal variation in fractionated electrograms using histogram analysis of local fractionation interval in patients with persistent atrial fibrillation.

Background—The characteristics of atrial electrograms associated with atrial fibrillation (AF) termination are controversial. We investigated the electrogram characteristics that indicate procedural AF termination during continuous complex fractionated electrogram ablation. Methods and Results—Fifty-two consecutive patients with persistent AF (47 men; aged 54±9 years), who underwent electrogram-based catheter ablation in the left atrium and coronary sinus after pulmonary vein isolation, were enrolled. The intracardiac bipolar atrial electrogram recordings were characterized by (1) fractionation interval (FI) analysis (>6 seconds), (2) kurtosis (shape of the FI histogram), and (3) skewness (asymmetry of the FI histogram). Sites showing complex, fractionated electrograms (mean FI ⩽60 ms) were targeted, and AF was terminated in 20 patients (38%) after the pulmonary vein isolation. The conventional complex fractionated electrogram sites (mean ⩽120 ms) in patients with AF termination exhibited higher median kurtosis (2.69 [interquartile range, 2.03–3.46] versus 2.35 [interquartile range, 1.79–2.48]; P=0.024) and higher complex fractionated electrogram-mean interval (102.7±19.8 versus 87.7±15.0; P=0.008) than patients without AF termination. Furthermore, AF termination sites had higher median kurtosis than targeted sites without AF termination (5.13 [interquartile range, 3.51–6.47] versus 4.18 [interquartile range, 2.91–5.34]; P<0.01) in patients with procedural termination. In addition, patients with AF termination had a higher sinus rhythm maintenance rate after a single procedure than patients without AF termination (log-rank test, P=0.007). Conclusions—A kurtosis analysis using the FI histogram may be a useful tool in identifying the critical substrate for persistent AF and potential responders to catheter ablation.

Traumatic intracranial haemorrhage is in association with an increased risk of subsequent atrial fibrillation

Objective Traumatic intracranial haemorrhage (ICH) leads to systemic inflammatory response and arrhythmia. Atrial fibrillation (AF), the most common arrhythmia, is associated with systemic inflammation. However, limited evidence is available regarding the association between traumatic ICH and AF. Methods This study used the National Health Insurance Research Database, a nationwide population-based cohort, in Taiwan and total 130 171 individuals with traumatic ICH from 2000 to 2011 were identified. Furthermore, individuals without traumatic ICH were selected as a comparison cohort by the propensity score method. Individuals with prior history of AF were excluded from this study. The endpoint of interest was the occurrence of AF and the follow-up was terminated by the occurrence of AF, loss of follow-up or the passing of 31 December 2011. Results During the follow-up period, the incidence of AF was higher in patients with traumatic ICH than in those without traumatic ICH (4.24 vs 4.12 per 1000 person-years). After adjustment for age, sex and all AF-associated comorbidities, the individuals with traumatic ICH had a 1.25-fold increased risk of AF (HR=1.25, 95% CI=1.18 to 1.32; p<0.001). Stratified by sex and age, the incidence of AF was consistently higher in the traumatic ICH group. Relative to the individuals without traumatic ICH and without comorbidities, the risk of AF was the highest in the individuals with both traumatic ICH and comorbidities; this risk was higher than that of the individuals with only traumatic ICH; it was also higher than the risk for those only with comorbidities. Conclusion In this large-scale cohort study, the future risks of AF are higher in patients with traumatic ICH compared with the comparison cohort. Carefully monitoring the occurrence of AF and proper anticoagulation therapy might be important in patients with traumatic ICH.

Stimulatory Influences of Far Infrared Therapy on the Transcriptome and Genetic Networks of Endothelial Progenitor Cells Receiving High Glucose Treatment.

BACKGROUND Endothelial progenitor cells (EPCs) play a fundamental role in vascular repair and angiogenesis- related diseases. It is well-known that the process of angiogenesis is faulty in patients with diabetes. Long-term exposure of peripheral blood EPCs to high glucose (HG-EPCs) has been shown to impair cell proliferation and other functional competencies. Far infrared (FIR) therapy can promote ischemia-induced angiogenesis in diabetic mice and restore high glucose-suppressed endothelial progenitor cell functions both in vitro and in vivo. However, the detail mechanisms and global transcriptome alternations are still unclear. METHODS In this study, we investigated the influences of FIR upon HG-EPC gene expressions. EPCs were obtained from the peripheral blood and treated with high glucose. These cells were then subjected to FIR irradiation and functional assays. RESULTS Those genes responsible for fibroblast growth factors, Mitogen-activated protein kinases (MAPK), Janus kinase/signal transducer and activator of transcription and prostaglandin signaling pathways were significantly induced in HG-EPCs after FIR treatment. On the other hand, mouse double minute 2 homolog, genes involved in glycogen metabolic process, and genes involved in cardiac fibrosis were down-regulated. We also observed complex genetic networks functioning in FIR-treated HG-EPCs, in which several genes, such as GATA binding protein 3, hairy and enhancer of split-1, Sprouty Homolog 2, MAPK and Sirtuin 1, acted as hubs to maintain the stability and connectivity of the whole genetic network. CONCLUSIONS Deciphering FIR-affected genes will not only provide us with new knowledge regarding angiogenesis, but also help to develop new biomarkers for evaluating the effects of FIR therapy. Our findings may also be adapted to develop new methods to increase EPC activities for treating diabetes-related ischemia and metabolic syndrome-associated cardiovascular disorders. KEY WORDS Endothelial progenitor cell; Far infrared; Microarray; Systems biology.