Wen-Yu 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.

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.

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

BACKGROUNDnOur study aimed to investigate the association between atrial fibrillation (AF) and erectile dysfunction (ED).nnnMETHODSnA 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.nnnRESULTSnThe 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).nnnCONCLUSIONnIn a large-scale cohort, the incidence of ED was significantly higher in male patients with AF than those without AF.

Differential Expression of Distinct Surface Markers in Early Endothelial Progenitor Cells and Monocyte-Derived Macrophages

Bone marrow-derived endothelial progenitor cells (EPCs) play a fundamental role in postnatal angiogenesis. Currently, EPCs are defined as early and late EPCs based on their biological properties and their time of appearance during in vitro culture. Reports have shown that early EPCs share common properties and surface markers with adherent blood cells, especially CD14+ monocytes. Distinguishing early EPCs from circulating monocytes or monocyte-derived macrophages (MDMs) is therefore crucial to obtaining pure endothelial populations before they can be applied as part of clinical therapies. We compared the gene expression profiles of early EPCs, blood cells (including peripheral blood mononuclear cells, monocytes, and MDMs), and various endothelial lineage cells (including mature endothelial cells, late EPCs, and CD133+ stem cells). We found that early EPCs expressed an mRNA profile that showed the greatest similarity to MDMs than any other cell type tested. The functional significance of this molecular profiling data was explored by Gene Ontology database search. Novel plasma membrane genes that might potentially be novel isolation biomarkers were also pinpointed. Specifically, expression of CLEC5A was high in MDMs, whereas early EPCs expressed abundant SIGLEC8 and KCNE1. These detailed mRNA expression profiles and the identified functional modules will help to develop novel cell isolation approaches that will allow EPCs to be purified; these can then be used to target cardiovascular disease, tumor angiogenesis, and various ischemia-related diseases.

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.

The Prognostic Role of QTc Interval in Acute Myocarditis.

BACKGROUNDnAcute myocarditis is an inflammatory disease of the myocardium. Although a fulminant course of the disease is difficult to predict, it may lead to acute heart failure and death. Previous studies have demonstrated that reduced left ventricular systolic function and prolonged QRS duration can predict the fulminant course of acute myocarditis. This study aimed to identify whether prolonged QTc interval could also be predictive of fulminant disease in this population.nnnMETHODSnWe retrospectively included 40 patients diagnosed with acute myocarditis who were admitted to our hospital between 2002 and 2013. They were divided into the fulminant group (n = 9) and the non-fulminant group (n = 31). Clinical symptoms, laboratory findings, electrocardiographic, and echocardiographic parameters were analyzed. Multivariate logistic regression analysis was used to identify the independent factors predictive of fulminant disease.nnnRESULTSnPatients with fulminant myocarditis had a higher mortality rate than those with non-fulminant disease (55.6% vs. 0%, p < 0.001). Multivariate analysis revealed that wider QRS durations (133.22 ± 45.85 ms vs. 92.81 ± 15.56 ms, p = 0.030) and longer QTc intervals (482.78 ± 69.76 ms vs. 412.00 ± 33.31 ms, p = 0.016) were significant predictors associated with a fulminant course of myocarditis.nnnCONCLUSIONSnProlonged QRS duration and QTc interval, upon patient admission, may be associated with an increased risk of fulminant disease and increased in-hospital mortality. Therefore, early recognition of fulminant myocarditis and early mechanical support could provide improved patient outcomes.nnnKEY WORDSnFulminant myocarditis • Predictors • QRS complex • QTc interval.

Association of atrial fibrillation and erectile dysfunction: Reply

We thank Dr Aksu et al. for their interests regarding our report of the association between atrialfibrillation (AF) and erectile dysfunction (ED) [1]. Dr Aksu and his colleague raised two concerns regarding the risk of ED in patients with AF [2]. First, they questioned if the increased ED risk in patients with AF is confounded by the underlying comorbidities, such as coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), diabetes mellitus, and previous stroke. Indeed, similar to our findings, patients with AF are associated with more comorbidities than those without AF [3–5]. In the present study, we did our best to minimize the bias with taking these comorbidities into cox regression analysismodel [1]. Thepresence of AF, diabetes mellitus, and hyperlipidemia did predict the risk of ED, however, others comorbidities, such CAD, COPD, CKD, hypertension, and previous stroke could not reach the statistic significances. After adjusting for the covariates of AF, diabetesmellitus and hyperlipidemia, both of AF and hyperlipidemia associated with the increased risk of ED independently [1]. These results clearly pointed out the association between AF and ED is not simply due to the underlying comorbidities of AF. Second, they questioned the insufficient drugs information in our study population, which might be another confounder in evaluation the risk of ED [6,7]. It is difficult to obtain the information of all potential drugs from the National Health Insurance Research Database and we acknowledge this in our study limitation. However, the information regarding the use of beta-blockers and spironolactone, two common drugs used in the study population, has been provided. Their effects on ED risk have been evaluated and fully addressed in the present article. In summary,we admit that the evidence derived froma retrospective cohort study is generally lower methodological quality than that from the prospectively randomized trial because a retrospective cohort study is subject to have many biases due to lack of the necessary adjustments or possibly unmeasured or unknown confounding factors. However, based on the previous basic data indicating the shared pathophysiology linking AF and ED, such as systemic inflammation, oxidative stress and endothelial dysfunction [8,9], our study provides the first clinical evidence suggesting the association between AF and ED. Future prospective randomized studies are necessary to clarify the effects of AF on ED.

Torsade de pointes indicates early neurologic damage in acute ischemic stroke.

Torsade de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia that is related to QT prolongation. Although QT prolongation is commonly seen in acute stroke, TdP is rare. We report the case of a 78-year-old woman with ischemic stroke who presented with TdP as the initial manifestation of early neurologic deterioration. We hypothesized that an increase in intracranial pressure may result in neurohormonal activation, QT prolongation, and then myocardial damage, leading to TdP. We highlight that new onset of TdP in a patient with stroke may reflect neurologic deterioration, requiring further evaluation and specific intervention.

Repositioning of the β-Blocker Carvedilol as a Novel Autophagy Inducer That Inhibits the NLRP3 Inflammasome

The NLRP3 inflammasome is a multiprotein complex that plays a key role in the innate immune system, and aberrant activation of this complex is involved in the pathogenesis of inflammatory diseases. Carvedilol (CVL) is an α-, β-blocker used to treat high blood pressure and congestive heart failure; however, some benefits beyond decreased blood pressure were observed clinically, suggesting the potential anti-inflammatory activity of CVL. In this report, the inhibitory potential of CVL toward the NLRP3 inflammasome and the possible underlying molecular mechanisms were studied. Our results showed that CVL attenuated NLRP3 inflammasome activation and pyroptosis in mouse macrophages, without affecting activation of the AIM2, NLRC4 and non-canonical inflammasomes. Mechanistic analysis revealed that CVL prevented lysosomal and mitochondrial damage and reduced ASC oligomerization. Additionally, CVL caused autophagic induction through a Sirt1-dependent pathway, which inhibited the NLRP3 inflammasome. In the in vivo mouse model of NLRP3-associated peritonitis, oral administration of CVL reduced (1) peritoneal recruitment of neutrophils; (2) the levels of IL-1β, IL-18, active caspase-1, ASC, IL-6, TNF-α, MCP-1, and CXCL1 in the lavage fluids; and (3) the levels of NLRP3 and HO-1 in the peritoneal cells. Our results indicated that CVL is a novel autophagy inducer that inhibits the NLRP3 inflammasome and can be repositioned for ameliorating NLRP3-associated complications.