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Abstract Background Lifestyle modification is an essential component of prevention and management of hypertension. Existing instruments in Taiwan focus on assessing lifestyle modifications by evaluating medication adherence or confidence in controlling blood pressure. However, other self-care activities, such as diet, physical activity, weight management, smoking, and alcohol consumption are also important. The Hypertension Self-Care Activity Level Effects (H-SCALE) is one such instrument, but there are no similar tools available in Taiwan. Aim This study aimed to translate the H-SCALE into Chinese and test its validity, and reliability in a sample of adults with hypertension. Methods The English version of the 31-item H-SCALE was translated into Chinese using the forward-backward method. The content validity index (CVI) of the translated scale was determined by five experts in hypertension. Item analysis was conducted with a pilot sample of 20 patients with hypertension. Cronbach’s α was used to establish the internal consistency reliability for the Chinese version of the H-SCALE (H-SCALE-C). Exploratory factor analysis (EFA) explored the structure of the H-SCALE-C. Additionally, construct validity was examined with confirmatory factor analysis (CFA). Patients with hypertension were recruited by convenience sampling from a cardiovascular outpatient clinic of a medical center in northern Taiwan. A total of 318 patients met the inclusion criteria and participated in factor analysis in the study. Results Pilot testing of the scale items indicated most patients could not accurately estimate the number of days of alcohol consumption for the previous week. Therefore, three alcohol-related items were removed. The adaptation resulted in a 28-item H-SCALE-C. EFA revealed a 4-factor solution with 13 items that explained 63.93% of the total variance. CFA indicated a good fit for a 4-factor model and construct validity was acceptable. Internal consistency reliability was acceptable (Cronbach’s alpha for the four subscales ranged from 0.65 to 0.94). Convergent validity was acceptable, and discriminant validity was significant. Conclusions The H-SCALE-C is a valid, reliable tool for promptly assessing life-style activities for patients with hypertension in Taiwan. The instrument is suitable for assisting healthcare providers in evaluating self-care activities, which could be used to facilitate lifestyle modifications for patients with hypertension.

Abstract Objectives The choice of optimal antithrombotic therapy in atrial fibrillation (AF) patients with acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) remains controversial. The aim of this longitudinal cohort study is to investigate the prescribing pattern of antithrombotic regimen in different cohorts and its subsequent impact. Setting and design Longitudinal data from the Tri-Service General Hospital-Coronary Heart Disease (TSGH-CHD) registry, between January 2016 and August 2018 was screened. Participants and method Patients with prior history of nonvalvular AF, who had ACS presentation or underwent PCI were selected, and these patients were divided into cohort 1 and cohort 2, according to the index date of antithrombotic prescription before and after the PIONEER AF-PCI study. Primary and secondary outcomes The primary safety endpoints were composites of major bleeding and/or clinically relevant non-major bleeding. The secondary efficacy endpoints included the occurrence of all-cause mortality, stroke/systemic embolization, nonfatal myocardial infarction (MI), and >30-days coronary revascularization. Results A total of 121 patients were included into analysis (cohort 1=35; cohort 2=86). Comparing with cohort 1, the prescription rate of triple antithrombotic therapy (TAT) increased from 17.1 to 38.4%, especially the regimen with dual antiplatelet therapy (DAPT) plus low-dose non-vitamin-K dependent oral anticoagulation (NOAC). However, the prescription rate of dual antithrombotic therapy (DAT) decreased (14.3–10.5%), as well as the prescription rate of DAPT (68.6–51.2%). These changes of antithrombotic prescription across different cohorts were not associated with risk of adverse safety (HR= 0.87; 95% CI, 0.42-1.80, p=0.710) and efficacy outcomes (HR=0.96; 95% CI, 0.40-2.32, p=0.930). Conclusions Entering the NOAC era, the prescription of TAT increased alongside the decrease in DAT. As the prescription rate of DAPT without anticoagulation remained high, future efforts are mandatory to improve the implementation of guidelines and clinical practice.

Type 2 diabetes is a major threat to human health in the 21st century. More than half a billion people may suffer from this pandemic disease in 2030, leading to a huge burden of cardiovascular complications. Recently, 2 novel antidiabetic agents, glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, reduced cardiovascular complications in a number of randomized control trials. To integrate new information and to achieve a streamlined process for better patient care, a working group was appointed by the Taiwan Society of Cardiology to formulate a stepwise consensus pathway for these therapies to reduce cardiovascular events in patients with type 2 diabetes. This consensus pathway is complementary to clinical guidelines, acting as a reference to improve patient care.

The intracellular sensor NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome controls caspase-1 activity and the maturation and release of the cytokines interleukin (IL)−1β and IL−18. The NLRP3 inflammasome has attracted the attention of the pharmaceutical industry because it promotes the pathogenesis of many diseases, making it a promising target for drug development. Litsea cubeba (Lour.) is a plant traditionally used as a seasoning in Taiwan and in other Asian countries. In this study, we investigated the inhibitory activity of the leaves of L. cubeba against the NLRP3 inflammasome. We found that the ethanol extract of L. cubeba leaves (MLE) inhibited the NLRP3 inflammasome in macrophages by reducing caspase−1 activation and IL−1β secretion. MLE reduced pyroptosis in macrophages and inhibited the release of NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC). In a mechanistic study, MLE reduced mitochondrial reactive oxygen species (ROS) production and preserved mitochondrial integrity, which led to reduced mitochondrial DNA release into the cytosol. MLE did not reduce the expression levels of NLRP3, IL−1β precursor or TNF-α in lipopolysaccharide (LPS)-activated macrophages. These results indicated that MLE inhibited the NLRP3 inflammasome by suppressing the activation signals of the NLRP3 inflammasome but not by reducing the priming signal induced by LPS. In addition, oral administration of MLE (20−80 mg/kg) ameliorated dextran sulfate sodium (DSS)−induced colitis in a mouse model. Notably, mice that received MLE (1 and 2 g/kg) daily for 7 days did not exhibit visible side effects. Gas chromatography-mass spectrometry (GC-MS) analysis found that α-Terpinyl acetate (27.2%) and 1,8−Cineole (17.7%) were the major compounds in MLE. These results indicated that L. cubeba leaves have the potential to be a nutraceutical for preventing and improving NLRP3 inflammasome-related diseases.

Aberrant activation of the NLRP3 inflammasome promotes the pathogenesis of many inflammatory diseases. The development of the NLRP3 inflammasome inhibitors from existing drugs for new therapeutic purposes is becoming more important. Candesartan is an angiotensin II receptor antagonist widely used as a blood pressure-lowering drug; however, the inhibitory potential of candesartan on the NLRP3 inflammasome has not yet been investigated. We demonstrated that candesartan significantly inhibited the NLRP3 inflammasome and pyroptosis in macrophages. Mechanistic analysis revealed that candesartan inhibited the expression of NLRP3 and proIL-1β by suppressing NF-κB activation and reducing the phosphorylation of ERK1/2 and JNK1/2. Candesartan reduced mitochondrial damage and inhibited the NLRP3 inflammasome assembly by suppressing NLRP3 binding to PKR, NEK7 and ASC. In addition, candesartan inhibited IL-1β secretion partially through autophagy induction. Furthermore, oral administration of candesartan reduced peritoneal neutrophil influx, NLRP3 and ASC expression in peritoneal cells, and lavage fluid concentrations of active caspase-1, IL-1β, IL-6 and MCP-1 in uric acid crystal-injected mice. These results indicated that candesartan has board anti-inflammatory effects and has the potential to be repositioned to ameliorate inflammatory diseases or NLRP3-associated complications.

Cardiovascular events such as myocarditis following mRNA COVID-19 vaccination are increasing. We present a 67-year-old postmenopausal woman with Takotsubo Syndrome and Graves’ disease after mRNA COVID-19 vaccination. She developed chest pain and shortness of breath one week after vaccination. An electrocardiogram revealed ST elevation in the precordial leads. Coronary angiography revealed the absence of obstructive coronary artery disease, and the left ventriculography showed a typical feature with apical ballooning. Laboratory workup showed the elevation of free T4 and thyrotropin receptor antibodies. It was presumed that Takotsubo Syndrome and Graves’ disease were probably related to the COVID-19 mRNA vaccination. The patient was treated with low-dose bisoprolol, diuretics, carbimazole, and steroid and discharged uneventfully. The mRNA COVID-19 vaccination is still safe and effective to defend against COVID-19 pandemic. However, clinicians should be aware of the possible cardiovascular adverse events other than myocarditis following vaccination.

BackgroundAtrial fibrillation (AF) is related to a variety of chronic diseases and life-threatening complications. It is estimated that by 2050, there will be 72 million patients with AF in Asia, of which 2.9 million will have AF-associated stroke. AF has become a major issue for health care systems. ObjectiveWe aimed to evaluate the effects of a web-based integrated management program on improving coping strategies, medication adherence, and health-related quality of life (HRQoL) in patients with AF, and to detect the effect on decreasing readmission events. MethodsThe parallel-group, single-blind, prospective randomized controlled trial recruited patients with AF from a medical center in northern Taiwan and divided them randomly into intervention and control groups. Patients in the intervention group received the web-based integrated management program, whereas those in the control group received usual care. The measurement tools included the Brief Coping Orientation to Problems Experienced (COPE) scale, Medication Adherence Rating Scale (MARS), the three-level version of the EuroQoL five-dimension self-report questionnaire (EQ-5D-3L), and readmission events 2 years after initiating the intervention. Data were collected at 4 instances (baseline, 1 month, 3 months, and 6 months after initiating the intervention), and analyzed with generalized estimating equations (GEEs). ResultsA total of 231 patients were recruited and allocated into an intervention (n=115) or control (n=116) group. The mean age of participants was 73.08 (SD 11.71) years. Most participants were diagnosed with paroxysmal AF (171/231, 74%), and the most frequent comorbidity was hypertension (162/231, 70.1%). Compared with the control group, the intervention group showed significantly greater improvement in approach coping strategies, medication adherence, and HRQoL at 1, 3, and 6 months (all P

Pulmonary arterial hypertension (PAH) is characterized as a progressive and sustained increase in pulmonary vascular resistance, which may induce right ventricular failure. In 2014, the Working Group on Pulmonary Hypertension of the Taiwan Society of Cardiology (TSOC) conducted a review of data and developed a guideline for the management of PAH.4 In recent years, several advancements in diagnosis and treatment of PAH has occurred. Therefore, the Working Group on Pulmonary Hypertension of TSOC decided to come up with a focused update that addresses clinically important advances in PAH diagnosis and treatment. This 2018 focused update deals with: (1) the role of echocardiography in PAH; (2) new diagnostic algorithm for the evaluation of PAH; (3) comprehensive prognostic evaluation and risk assessment; (4) treatment goals and follow-up strategy; (5) updated PAH targeted therapy; (6) combination therapy and goal-orientated therapy; (7) updated treatment for PAH associated with congenital heart disease; (8) updated treatment for PAH associated with connective tissue disease; and (9) updated treatment for chronic thromboembolic pulmonary hypertension. Keywords: Guideline, Pulmonary arterial hypertension, Pulmonary hypertension

Conjugated polyenes are a class of widely occurring natural products with various biological functions. We previously identified 4-hydroxy auxarconjugatin B (4-HAB) as anti‐inflammatory agent with an IC50 of ~20 µM. In this study, we synthesized a new anti‐inflammatory 4-HAB analogue, F240B, which has an IC50 of less than 1 µM. F240B dose-dependently induced autophagy by increasing autophagic flux, LC3 speck formation and acidic vesicular organelle formation. F240B inhibited NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome activation through autophagy induction. In a mechanistic study, F240B inhibited interleukin (IL)-1β (IL-1β) precursor expression, promoted degradation of NLRP3 and IL-1β, and reduced mitochondrial membrane integrity loss in an autophagy-dependent manner. Additionally, F240B inhibited apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and speck formation without affecting the interaction between NLRP3 and ASC or NIMA-related kinase 7 (NEK7) and double-stranded RNA-dependent kinase (PKR). Furthermore, F240B exerted in vivo anti-inflammatory activity by reducing the intraperitoneal influx of neutrophils and the levels of IL-1β, active caspase-1, IL-6 and monocyte chemoattractant protein-1 (MCP-1) in lavage fluids in a mouse model of uric acid crystal-induced peritonitis. In conclusion, F240B attenuated the NLRP3 inflammasome through autophagy induction and can be developed as an anti-inflammatory agent in the future.

Background: In the era of drug-eluting stents, although bare-metal stent (BMS) remains an option for percutaneous coronary intervention (PCI), restenosis remains the Achilles' heel of BMS implantation. A recent study demonstrated several pleiotropic anti-inflammatory effects of dextromethorphan (DXM). This study aims to evaluate the effects of DXM on the outcome of PCI with BMS implantation.Methods: In this prospective, double-blind, randomized trial, we enrolled 55 patients who underwent PCI with BMS implantation from May 2006 to February 2009. The patients were divided into DXM (60 mg once daily) and placebo groups. We compared mortality rates, myocardial infarction (MI), target lesion revascularization (TLR), restenosis, stent thrombosis, and plasma levels of high-sensitivity C-reactive protein (hs-CRP) with repeated coronary angiography 6 months after the initial procedure.Results: During the 6-month follow-up period, no events of death, MI and stent thrombosis were reported in both groups. The TLR rate was 16.7% in patients receiving DXM compared to 24% receiving a placebo (P = 0.521). The restenosis rate was 30% in patients receiving DXM as compared to 40% receiving the placebo (P = 0.571). Although nonsignificant, the percentage of hs-CRP elevation was lower in the DXM group (20%) compared to the placebo group 32%; P = 0.363).Conclusions: DXM is safe to use in patients who underwent PCI. Although DXM therapy following BMS implantation did not significantly reduce the TLR and restenosis rates, it implied a trend toward a lower TLR and restenosis and reduced inflammation in the DXM group compared to the placebo group. Nonetheless, further extensive studies are warranted to elucidate the anti-restenosis effects of DXM.

[This corrects the article DOI: 10.1371/journal.pone.0205953.].

Statins constitute the mainstay treatment for atherosclerotic cardiovascular disease, which is associated with the risk of new-onset diabetes mellitus (NODM). However, the effects of individual statins on the risk of NODM remain unclear. We recruited 48,941 patients taking one of the three interested statins in a tertiary hospital between 2006 and 2018. Among them, 8337 non-diabetic patients taking moderate-intensity statins (2 mg/day pitavastatin, 10 mg/day atorvastatin, and 10 mg/day rosuvastatin) were included. The pitavastatin group had a higher probability of being NODM-free than the atorvastatin and rosuvastatin groups during the 4-year follow-up (log-rank test: p = 0.038). A subgroup analysis revealed that rosuvastatin had a significantly higher risk of NODM than pitavastatin among patients with coronary artery disease (CAD) (adjusted HR [aHR], 1.47, 95% confidence interval [CI], 1.05–2.05, p = 0.025), hypertension (aHR, 1.26, 95% CI, 1.00–1.59, p = 0.047), or chronic obstructive pulmonary disease (COPD) (aHR, 1.74, 95% CI, 1.02–2.94, p = 0.04). We concluded that compared with rosuvastatin, reduced diabetogenic effects of pitavastatin were observed among patients treated with moderate-intensity statin who had hypertension, COPD, or CAD. Additional studies are required to prove the effects of different statins on the risk of NODM.

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.

Uncertainty in illness is regarded as a source of stress in many chronic diseases and is negatively related to health-related quality of life (HRQoL). However, studies on the relationship between uncertainty and HRQoL in patients with heart failure are limited. This study used Mishel's theory of uncertainty in illness to investigate the mediating role of uncertainty in illness and depressive symptoms between symptom distress and HRQoL in patients with heart failure. This study used a cross-sectional correlation design. Participants were recruited by convenience sampling from outpatient services and medical wards of cardiology departments of a medical center in northern Taiwan. Data were collected for uncertainty, depressive symptoms, symptoms distress of heart failure, and HRQoL using self-report questionnaires. Demographics and clinical characteristics were analyzed with descriptive statistics. The mutual effects of disease characteristics, symptom distress, uncertainty in illness, depressive symptoms and HRQoL, as well as the overall model fitness, were analyzed by with structural equation modeling. We collected 147 qualified questionnaires. The mean score for the Mishel Uncertainty in Illness Scale for patients with heart failure was 73.5 (SD = 18.55); 65.3% of participants had a score of ≧13 on the Beck Depressive Inventory-II, indicating mild depression. Uncertainty, depressive symptoms, and HRQoL were directly related to symptom distress. Symptom distress and depressive symptoms were both mediators between uncertainty and depressive symptoms. Depressive symptoms also mediated emotional support and HRQoL. Uncertainty and depressive symptoms were important factors in the pathway between symptom distress and HRQoL for heart failure patients. We suggest providing heart failure patients with tailored interventions for effective self-management of symptoms based on Mishel's theory of uncertainty in illness, which could help control disease symptoms, alleviate uncertainty and depression as well as improve HRQoL.

Background: Ventilator-associated pneumonia (VAP) occurs in patients requiring mechanical ventilators for more than 48 h. VAP is the most common nosocomial infection and the leading cause of complications and death in intensive care units (ICUs). Materials and Methods: Two historical comparison groups of 375 patients who used mechanical ventilators for more than 48 h in the medical ICU (MICU) from December 1, 2011 to May 31, 2012 and December 1, 2013 to May 31, 2014 were enrolled in this study. There were 194 adult patients in the control group that received traditional care, and there were 181 patients in the experimental VAP care bundle group. Our VAP care bundle entailed several preventive strategies including daily assessments of sedation, daily consideration of weaning and extubation by the doctors and respiratory therapists charged with the care of the patients, maintenance of the intra-cuff pressure values at approximately 20-30 cm H 2 O, hand hygiene, daily oral hygiene, personal protective equipment for suctioning, the placement of patients in semi-recumbent positions with the head of the bed elevated to at least 30°, aspiration of an endotracheal tube and oral cavity prior to position changes, daily cleaning of the ventilator and suction bottle with sterile distilled water, weekly replacement of the ventilator circuit and heater, sterilization of the circuit by pasteurization, and the use of an independent care room. The data were collected by reviewing the patients′ medical records and by retrieving information from the Nosocomial Infection Control Unit of one medical center in Northern Taiwan. Results: The incidence of VAP in the VAP care bundle group (0.281 cases per 1000 ventilator days) was significantly lower than that in the control group (0.495 cases per 1000 ventilator days). We estimated that the occurrence of VAP in the MICU increased the medical costs by an average of NT $68317 per patient. Conclusions: VAP care bundle is an effective strategy to reduce the incidence of VAP in the MICU and to reduce healthcare costs.

Background: Revascularization within a 90-min door-to-balloon time is a strict policy enacted in Taiwan. Prompt diagnosis is critical to avoid an unnecessary procedure and catheterization laboratory activation. This study was aimed to investigate the clinical and prognostic characteristics of the patients with ST-elevation myocardial infarction (STEMI) referred for primary percutaneous coronary intervention (PCI) and normal coronary arteries found following coronary angiography (CAG). Materials and Methods: From October 2009 to December 2012, 216 consecutive patients with STEMI referred for primary PCI were enrolled. The data of clinical history, physical examination, laboratory results, electrocardiography, echocardiography, CAG findings, diagnosis, and outcomes were collected and analyzed. Results: A total of 17 patients were proved normal coronaries angiographically. The incidence of the conditions mimicking as STEMI is 7.9%. Alternative diagnosis was coronary spasm (n = 7), peri-myocarditis (n = 6), apical ballooning syndrome (n = 3), anaphylactic shock (n = 1). Compared with STEMI group, patients in normal coronaries group were younger, with a less premature family history of coronary artery disease (CAD), and reported angina. The 30-day mortality rate in the normal coronaries group was 5.9%. Conclusions: Cautiously evaluating CAD risk factors and symptoms of angina and awareness of alternative diagnosis are important to make a prompt diagnosis without compromising accuracy in the patients presenting as suspected STEMI.

Functional impairment of endothelial colony-forming cells (ECFCs), a specific cell lineage of endothelial progenitor cells (EPCs) is highly associated with the severity of coronary artery disease (CAD), the most common type of cardiovascular disease (CVD). Emerging evidence show that circulating microRNAs (miRNAs) in CAD patients' body fluid hold a great potential as biomarkers. However, our knowledge of the role of circulating miRNA in regulating the function of ECFCs and the progression of CAD is still in its infancy. We showed that when ECFCs from healthy volunteers were incubated with conditioned medium or purified exosomes of cultured CAD ECFCs, the secretory factors from CAD ECFCs dysregulated migration and tube formation ability of healthy ECFCs. It is known that exosomes influence the physiology of recipient cells by introducing RNAs including miRNAs. By using small RNA sequencing (smRNA-seq), we deciphered the circulating miRNome in the plasma of healthy individual and CAD patients, and found that the plasma miRNA spectrum from CAD patients was significantly different from that of healthy control. Interestingly, smRNA-seq of both healthy and CAD ECFCs showed that twelve miRNAs that had a higher expression in the plasma of CAD patients also showed higher expression in CAD ECFCs when compared with healthy control. This result suggests that these miRNAs may be involved in the regulation of ECFC functions. For identification of potential mRNA targets of the differentially expressed miRNA in CAD patients, cDNA microarray analysis was performed to identify the angiogenesis-related genes that were down-regulated in CAD ECFCs and Pearson's correlation were used to identify miRNAs that were negatively correlated with the identified angiogenesis-related genes. RT-qPCR analysis of the five miRNAs that negatively correlated with the down-regulated angiogenesis-related genes in plasma and ECFC of CAD patients showed miR-146a-5p and miR-146b-5p up-regulation compared to healthy control. Knockdown of miR-146a-5p or miR-146b-5p in CAD ECFCs enhanced migration and tube formation activity in diseased ECFCs. Contrarily, overexpression of miR-146a-5p or miR-146b-5p in healthy ECFC repressed migration and tube formation in ECFCs. TargetScan analysis showed that miR-146a-5p and miR-146b-5p target many of the angiogenesis-related genes that were down-regulated in CAD ECFCs. Knockdown of miR-146a-5p or miR-146b-5p restores CAV1 and RHOJ levels in CAD ECFCs. Reporter assays confirmed the direct binding and repression of miR-146a-5p and miR-146b-5p to the 3'-UTR of mRNA of RHOJ, a positive regulator of angiogenic potential in endothelial cells. Consistently, RHOJ knockdown inhibited the migration and tube formation ability in ECFCs. Collectively, we discovered the dysregulation of miR-146a-5p/RHOJ and miR-146b-5p/RHOJ axis in the plasma and ECFCs of CAD patients that could be used as biomarkers or therapeutic targets for CAD and other angiogenesis-related diseases.

BackgroundRecent 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 ResultsUsing 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. ConclusionsFor 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.

Diabetes mellitus (DM) is a metabolic disease that is increasing worldwide. Furthermore, it is associated with the deregulation of vascular-related functions, which can develop into major complications among DM patients. Endothelial colony forming cells (ECFCs) have the potential to bring about medical repairs because of their post-natal angiogenic activities; however, such activities are impaired by high glucose- (HG) and the DM-associated conditions. Far-infrared radiation (FIR) transfers energy as heat that is perceived by the thermoreceptors in human skin. Several studies have revealed that FIR improves vascular endothelial functioning and boost angiogenesis. FIR has been used as anti-inflammatory therapy and as a clinical treatment for peripheral circulation improvement. In addition to vascular repair, there is increasing evidence to show that FIR can be applied to a variety of diseases, including cardiovascular disorders, hypertension and arthritis. Yet mechanism of action of FIR and the biomarkers that indicate FIR effects remain unclear. MicroRNA-134 (miR-134-5p) was identified by small RNA sequencing as being increased in high glucose (HG) treated dfECFCs (HG-dfECFCs). Highly expressed miR-134 was also validated in dmECFCs by RT-qPCR and it is associated with impaired angiogenic activities of ECFCs. The functioning of ECFCs is improved by FIR treatment and this occurs via a reduction in the level of miR-134 and an increase in the NRIP1 transcript, a direct target of miR-134. Using a mouse ischemic hindlimb model, the recovery of impaired blood flow in the presence of HG-dfECFCs was improved by FIR pretreatment and this enhanced functionality was decreased when there was miR-134 overexpression in the FIR pretreated HG-dfECFCs. In conclusion, our results reveal that the deregulation of miR-134 is involved in angiogenic defects found in DM patients. FIR treatment improves the angiogenic activity of HG-dfECFCs and dmECFCs and FIR has potential as a treatment for DM. Detection of miR-134 expression in FIR-treated ECFCs should help us to explore further the effectiveness of FIR therapy.

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.

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.

The global incidence and prevalence of type 2 diabetes have been escalating in recent decades. The total diabetic population is expected to increase from 415 million in 2015 to 642 million by 2040. Patients with type 2 diabetes have an increased risk of atherosclerotic cardiovascular disease (ASCVD). About two-thirds of patients with type 2 diabetes died of ASCVD. The association between hyperglycemia and elevated cardiovascular (CV) risk has been demonstrated in multiple cohort studies. However, clinical trials of intensive glucose reduction by conventional antidiabetic agents did not significantly reduce macrovascular outcomes. In December 2008, U.S. Food and Drug Administration issued a mandate that every new antidiabetic agent requires rigorous assessments of its CV safety. Thereafter, more than 200,000 patients have been enrolled in a number of randomized controlled trials (RCTs). These trials were initially designed to prove noninferiority. It turned out that some of these trials demonstrated superiority of some new antidiabetic agents versus placebo in reducing CV endpoints, including macrovascular events, renal events, and heart failure. These results are important in clinical practice and also provide an opportunity for academic society to formulate treatment guidelines or consensus to provide specific recommendations for glucose control in various CV diseases. In 2018, the Taiwan Society of Cardiology (TSOC) and the Diabetes Association of Republic of China (DAROC) published the first joint consensus on the “Pharmacological Management of Patients with Type 2 Diabetes and Cardiovascular Diseases.” In 2020, TSOC appointed a new consensus group to revise the previous version. The updated 2020 consensus was comprised of 5 major parts: (1) treatment of diabetes in patients with multiple risk factors, (2) treatment of diabetes in patients with coronary heart disease, (3) treatment of diabetes in patients with stage 3 chronic kidney disease, (4) treatment of diabetes in patients with a history of stroke, and (5) treatment of diabetes in patients with heart failure. The members of the consensus group thoroughly reviewed all the evidence, mainly RCTs, and also included meta-analyses and real-world evidence. The treatment targets of HbA1c were finalized. The antidiabetic agents were ranked according to their clinical evidence. The consensus is not mandatory. The final decision may need to be individualized and based on clinicians’ discretion. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the association between ischaemic stroke (IS) and heart failure (HF) in the absence of atrial fibrillation (AF) or atrial flutter (AFL) using a population-based nation-wide cohort database.Method: Newly diagnosed patients with HF without previous stroke and acute myocardial infarction (AMI) were enrolled. Based on the propensity scores matching age, sex and all comorbidities, our studies comprised 12 179 patients with HF and 12 179 patients without HF. Cox proportion hazard regression models and competing-risk regression models were used to evaluate the risk of IS among patients with HF without AF or AFL.Results: In the multivariable analysis, older age (adjusted HR (95% CI)=1.05 (1.04 to 1.05)), male sex (adjusted HR (95% CI)=1.36 (1.24 to 1.50)), diabetes (adjusted HR (95% CI)=2.22 (1.97 to 2.49)) and hypertension (adjusted HR (95% CI)=1.60 (1.41 to 1.82)) were markedly associated with IS in patients with HF. The HF group had a markedly higher risk of IS than did the non-HF group (subdistribution HR (SHR)=1.51, 95% CI: 1.37 to 1.66) and AMI (SHR=3.40, 95% CI: 2.71 to 4.28). Additionally, according to the Kaplan-Meier analysis, patients with HF were at a significantly higher risk of cumulative incidence of IS and AMI than did patients with non-HF (p value of log-rank test <0.001).Conclusion: This study indicated that HF is a strong independent risk factor for IS, even in the absence of AF or AFL. Clinical physicians should investigate IS through routine screening and careful monitoring of patients with HF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Endothelial progenitor cells (EPCs) play a fundamental role in not only blood vessel development but also post-natal vascular repair. Currently EPCs are defined as early and late EPCs based on their biological properties and their time of appearance during in vitro culture. Both EPC types assist angiogenesis and have been linked to ischemia-related disorders, including coronary artery disease (CAD). Results: We found late EPCs are more mobile than early EPCs and matured endothelial cells (ECs). To pinpoint the mechanism, microRNA profiles of early EPCs late EPCs, and ECs were deciphered by small RNA sequencing. Obtained signatures made up of both novel and known microRNAs, in which anti-angiogenic microRNAs such as miR-221 and miR-222 are more abundant in matured ECs than in late EPCs. Overexpression of miR-221 and miR-222 resulted in the reduction of genes involved in hypoxia response, metabolism, TGF-beta signalling, and cell motion. Not only hamper late EPC activities in vitro, both microRNAs (especially miR-222) also hindered in vivo vasculogenesis in a zebrafish model. Reporter assays showed that miR-222, but not miR-221, targets the angiogenic factor ETS1. In contrast, PIK3R1 is the target of miR-221, but not miR-222 in late EPCs. Clinically, both miR-221-PIK3R1 and miR-222-ETS1 pairs are deregulated in late EPCs of CAD patients. Conclusions: Our results illustrate EPCs and ECs exploit unique miRNA modalities to regulate angiogenic features, and explain why late EPC levels and activities are reduced in CAD patients. These data will further help to develop new plasma biomarkers and therapeutic approaches for ischemia-related diseases or tumor angiogenesis. [ABSTRACT FROM AUTHOR]

Background: 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. Results: 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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

Natriuretic peptides (NPs) have been found to be useful markers in differentiating acute dyspneic patients presenting to the emergency department (ED) and emerged as potent prognostic markers for patients with congestive heart failure (CHF). The best-established and widely used clinical application of BNP and NT-proBNP testing is for the emergent diagnosis of CHF in patients presenting with acute dyspnea. Nevertheless, elevated NPs levels can be found in many circumstances involving left ventricular (LV) dysfunction or hypertrophy; right ventricular (RV) dysfunction secondary to pulmonary diseases; cardiac inflammatory or infectious diseases; endocrinology diseases and high output status without decreased LV ejection fraction. Even in the absence of significant clinical evidence of volume overload or LV dysfunction, markedly elevated NP levels can be found in patients with multiple comorbidities with a certain degree of prognostic value. Potential clinical applications of NPs are expanded accompanied by emerging reports regarding screening the presence of secondary cardiac dysfunction; monitoring the therapeutic responses, risk stratifications and providing prognostic values in many settings. Clinicians need to have expanded knowledge regarding the interpretation of elevated NPs levels and potential clinical applications of NPs. Clinicians should recognize that currently the only reasonable application for routine practice is limited to differentiation of acute dyspnea, rule-out-diagnostic-tests, monitoring of therapeutic responses and prognosis of acute or decompensated CHF. The rationales as well the potential applications of NPs in these settings are discussed in this review article. [ABSTRACT FROM AUTHOR]

1. Irbesartan is a promising antihypertensive drug with beneficial effects on atherosclerotic processes. In the progression of atherosclerosis, human T-lymphocytes play an important role, but it is not yet known how irbesartan modulates human T-lymphocytes activation. To gain insight into the mechanisms by which irbesartan acts, we investigated its effects on human T-lymphocytes. 2. Primary human T-lymphocytes were isolated from whole blood. Cytokines were determined by ELISA. Activator protein-1 (AP-1) and related protein activities were determined by electrophoretic mobility shift assays, kinase assays. Western blotting and transfection assays. 3. Irbesartan inhibited the production of both tumor necrosis factor-alpha and interferon-gamma by activated T-cells, especially at therapeutic concentrations. Further investigation at the molecular level indicated that the inhibition of activated human T-lymphocytes specifically correlated with the downregulation of AP-1 DNA-binding activity. In the Jurkat T-cell line, irbesartan also inhibited AP-1 transcriptional activity. Finally, we revealed that irbesartan is unique in its ability to inhibit the activation of both c-Jun NH2-terminal protein kinase and p38 MAPK. 4. Our studies show that irbesartan may modulate inflammation-based atherosclerotic diseases through a cell-mediated mechanism involving suppression of human T-lymphocytes activation via downregulation of AP-1 activity. [ABSTRACT FROM AUTHOR]

Chronic inflammation is one of the important mechanisms involved in atherosclerosis formation. The activated monocytes and their secreted cytokines contribute significantly to this inflammatory process. Here we examined the effects of carvedilol, a recently introduced cardio-protective alpha-1- and beta-receptor blocker, on cytokine production from various stimuli-activated human immune effector cells. By ELISA analysis, we showed that carvedilol inhibited interferon-gamma (IFN-γ), but enhanced interleukin (IL)-12 production in phytohemagglutinin (PHA)- and concanavalin A (ConA)-stimulated human peripheral blood mononuclear cells (PBMCs). The production of tumor necrosis factor-alpha (TNF-α) was marginally affected. When purified monocytes were examined, we observed the consistent up-regulation of IL-12 production while both IL-10 and TNF-α were unaffected or marginally down-regulated, respectively, by carvedilol. In agreement with the observation in monocytes, the production of IL-12 from activated macrophages was also up-regulated by carvedilol. We concluded that carvedilol might mediate its therapeutic effects through differentially regulating cytokine production from activated mononuclear cells, including at least monocytes and macrophages. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]