Interleukin-33/ST2 axis involvement in atrial remodeling and arrhythmogenesis.

Interleukin (IL)-33, a cytokine involved in immune responses, can activate its receptor, suppression of tumorigenicity 2 (ST2), is elevated during atrial fibrillation (AF). However, the role of IL-33/ST2 signaling in atrial arrhythmia is unclear. This study explored the pathological effects of the IL-33/ST2 axis on atrial remodeling and arrhythmogenesis. Patch clamping, confocal microscopy, and Western blotting were used to analyze the electrical characteristics of and protein activity in atrial myocytes (HL-1) treated with recombinant IL-33 protein and/or ST2-neutralizing antibodies for 48 hrs. Telemetric electrocardiographic recordings, Masson's trichrome staining, and immunohistochemistry staining of the atrium were performed in mice receiving tail vein injections with nonspecific immunoglobulin (control), IL-33, and IL-33 combined with anti-ST2 antibody for 2 weeks. IL-33-treated HL-1 cells had a reduced action potential duration, lower L-type Ca2+ current, greater sarcoplasmic reticulum (SR) Ca2+ content, increased Na+/Ca2+ exchanger (NCX) current, elevation of K+ currents, and increased intracellular calcium transient. IL-33-treated HL-1 myocytes had greater activation of the calcium-calmodulin-dependent protein kinase II (CaMKII)/ryanodine receptor 2 (RyR2) axis and nuclear factor kappa B (NF-κB) / NLR family pyrin domain containing 3 (NLRP3) signaling than did control cells. IL-33 treated cells also had greater expression of Nav1.5, Kv1.5, NCX, and NLRP3 than did control cells. Pretreatment with neutralizing anti-ST2 antibody attenuated IL-33-mediated activation of CaMKII/RyR2 and NF-κB/NLRP3 signaling. IL-33-injected mice had more atrial ectopic beats and increased AF episodes, greater atrial fibrosis, and elevation of NF-κB/NLRP3 signaling than did controls or mice treated with IL-33 combined with anti-ST2 antibody. Thus, IL-33 recombinant protein treatment promotes atrial remodeling through ST2 signaling. Blocking the IL-33/ST2 axis might be an innovative therapeutic approach for patients with atrial arrhythmia and elevated serum IL-33.

Ketogenic Diet Regulates Cardiac Remodeling and Calcium Homeostasis in Diabetic Rat Cardiomyopathy.

A ketogenic diet (KD) might alleviate patients with diabetic cardiomyopathy. However, the underlying mechanism remains unclear. Myocardial function and arrhythmogenesis are closely linked to calcium (Ca2+) homeostasis. We investigated the effects of a KD on Ca2+ homeostasis and electrophysiology in diabetic cardiomyopathy. Male Wistar rats were created to have diabetes mellitus (DM) using streptozotocin (65 mg/kg, intraperitoneally), and subsequently treated for 6 weeks with either a normal diet (ND) or a KD. Our electrophysiological and Western blot analyses assessed myocardial Ca2+ homeostasis in ventricular preparations in vivo. Unlike those on the KD, DM rats treated with an ND exhibited a prolonged QTc interval and action potential duration. Compared to the control and DM rats on the KD, DM rats treated with an ND also showed lower intracellular Ca2+ transients, sarcoplasmic reticular Ca2+ content, sodium (Na+)-Ca2+ exchanger currents (reverse mode), L-type Ca2+ contents, sarcoplasmic reticulum ATPase contents, Cav1.2 contents. Furthermore, these rats exhibited elevated ratios of phosphorylated to total proteins across multiple Ca2+ handling proteins, including ryanodine receptor 2 (RyR2) at serine 2808, phospholamban (PLB)-Ser16, and calmodulin-dependent protein kinase II (CaMKII). Additionally, DM rats treated with an ND demonstrated a higher frequency and incidence of Ca2+ leak, cytosolic reactive oxygen species, Na+/hydrogen-exchanger currents, and late Na+ currents than the control and DM rats on the KD. KD treatment may attenuate the effects of DM-dysregulated Na+ and Ca2+ homeostasis, contributing to its cardioprotection in DM.

Vitamin D level regulates serum lipids discrepantly in adults with and without dyslipidemia.

Vitamin D deficiency is associated with hyperlipidemia, but it remains unclear whether vitamin D supplementation reduces serum lipid levels. The aims of this study were to investigate the associations between increased serum 25-hydroxyvitamin D (25(OH)D) concentrations and lipid levels and identify the characteristics of people with or without lipid reduction associated with increased 25(OH)D levels. The medical records of 118 individuals (53 men; mean age, 54.4 ± 10.6 years) whose serum 25(OH)D levels increased between 2 consecutive measurements were retrospectively reviewed. People with increased 25(OH)D levels (from 22.7 (17.6-29.2) to 32.1 (25.6-36.8) mg/dL; P < 0.01) had a significant reduction in serum levels of triglycerides (TGs) (from 111.0 (80-164) to 104.5 (73-142) mg/dL; P < 0.01) and total cholesterol (TC) (from 187.5 (155-213) to 181.0 (150-210) mg/dL; P < 0.05). The individuals who responded to vitamin D (≥10% reduction in TG or TC levels) exhibited significantly higher baseline TG and TC levels than those who did not. Only patients with hyperlipidemia (not those without hyperlipidemia) at baseline exhibited significantly reduced TG and TC levels at follow-up. However, increasing serum 25(OH)D concentrations were significantly correlated with decreasing lipid levels in individuals with baseline 25(OH)D levels less than 30 ng/mL and in individuals aged 50-65 years (not in patients younger than 50 years or older than 65 years). In conclusion, increasing serum 25(OH)D concentrations may be potentially helpful for the treatment of hyperlipidemia in people with vitamin D deficiency.

PAUSE: principled feature attribution for unsupervised gene expression analysis.

As interest in using unsupervised deep learning models to analyze gene expression data has grown, an increasing number of methods have been developed to make these models more interpretable. These methods can be separated into two groups: post hoc analyses of black box models through feature attribution methods and approaches to build inherently interpretable models through biologically-constrained architectures. We argue that these approaches are not mutually exclusive, but can in fact be usefully combined. We propose PAUSE ( https://github.com/suinleelab/PAUSE ), an unsupervised pathway attribution method that identifies major sources of transcriptomic variation when combined with biologically-constrained neural network models.

Ketogenic diet modulates cardiac metabolic dysregulation in streptozocin-induced diabetic rats.

The ketogenic diet (KD) might improve cardiac function in diabetic cardiomyopathy, but the mechanisms remain unclear. This study investigated the effects of KD on myocardial fatty acid (FA), glucose, and ketone metabolism in diabetic cardiomyopathy. Echocardiograms, biochemistry, and micro-positron emission tomography were performed to evaluate cardiac function and glucose uptake in control rats and streptozotocin-induced diabetes mellitus (DM) rats with normal diet (ND) or KD for 6 weeks. Histopathology, adenosine triphosphate measurement, and Western blot were performed in the ventricular myocytes to analyze fibrosis, FA, ketone body, and glucose utilization. The ND-fed DM rats exhibited impaired left ventricular systolic function and increased chamber dilatation, whereas control and KD-fed DM rats did not. The KD reduced myocardial fibrosis and apoptosis in the DM rats. Myocardial glucose uptake in the micro-positron emission tomography was similar between ND-fed DM rats and KD-fed DM rats and was substantially lower than the control rats. Compared with the control rats,  ND-fed DM rats had increased phosphorylation of acetyl CoA carboxylase and higher expressions of CD-36, carnitine palmitoyltransferase-1ß, tumor necrosis factor-α, interleukin-1ß, interleukin6, PERK, and e-IF2α as well as more myocardial fibrosis and apoptosis (assessed by Bcl-2, BAX, and caspase-3 expression); these increases were attenuated in the KD-fed DM rats. Moreover, ND-fed DM rats had significantly lower myocardial adenosine triphosphate, BHB, and OXCT1 levels than the control and KD-fed DM rats. The KD may improve the condition of diabetic cardiomyopathy by suppressing FA metabolism, increasing ketone utilization, and decreasing endoplasmic reticulum stress and inflammation.

Differential serum interferon-ß levels in autoimmune thyroid diseases.

Introduction: Interferon (IFN)-ß is known as an environmental trigger for the occurrence of autoimmune thyroid disease (AITD). However, the association of another type-1 IFN, IFN-ß, with AITD is unknown. Material and methods: In the study, we explored the association of serum IFN-ß levels with AITD in an ethnic Chinese (i.e., Taiwanese) population. We enrolled 160 patients with Graves' disease (GD), 47 patients with Hashimoto's thyroiditis (HT), and 119 healthy controls. Serum IFN-ß and B-cell activating factor (BAFF) levels were quantified in healthy controls at the baseline and in patients with AITD either prior to receiving medication or while under medication. Thyroid function and thyroid-stimulating hormone receptor antibody (TSHRAb) levels were measured at the time of serum collection. Results: Serum IFN-ß levels were lower in the HT group than in the control group (p = 0.031). A significant inverse correlation was observed between IFN-ß and TSHRAb levels in men with GD (r = -0.433, p = 0.044). Serum IFN-ß levels were also negatively associated with BAFF levels in men with GD, HT, and AITD (r = -0.320, p = 0.032; r = -0.817, p = 0.047; and r = -0.354, p = 0.011, respectively), but not in women with GD, HT, or AITD. Conclusions: Serum IFN-ß levels were lower in HT patients. Correlations of serum IFN-ß with TSHRAb and BAFF levels were found to be gender-specific. Further well-designed studies with larger sample sizes are required to confirm our findings.

Lifestyle factors associated with muscle quality in community-dwelling older people with type 2 diabetes in Japan and Taiwan: a cross-sectional study.

BACKGROUND: Type 2 diabetes mellitus (T2DM), common in older people, is an important reason for muscle loss in Japanese and Taiwanese populations. However, little is known about the association between lifestyle behaviours and muscle quality. We aimed to compare the lifestyle behaviours of Japanese and Taiwanese older adults with T2DM and to the identify lifestyle factors associated with muscle quality. METHODS: This cross-sectional study was conducted among community-dwelling individuals with T2DM aged ≥65 years in Taiwan and Japan. Totally, 114 Japanese and 226 Taiwanese participants were enrolled in the study. Outcomes were measured by blood biochemical examinations, body composition analyses and structured self-reported questionnaires to assess lifestyle behaviours and muscle quality. Linear regression models were used to examine the relationship between lifestyle factors and muscle quality using SPSS version 27.0 with a statistical significance level of P < 0.05. RESULTS: Japanese subjects were more likely to be smokers and alcohol consumers, and they were less likely to have well-balanced diets and engage in more physical activity as compared to Taiwanese subjects. The muscle quality in the Japanese subjects was significantly poorer than that in the Taiwanese subjects. Physical activity, dietary habits and smoking were associated with muscle quality, after adjusting for age, gender and body mass index. CONCLUSIONS: Physical activity of insufficient intensity, unhealthy dietary habits and smoking could be risk factors for poor muscle quality. These findings can contribute to the development of effective strategies to improve muscle quality in community-dwelling older Asian people with T2DM.

Effects of Psychological Capital and Sport Anxiety on Sport Performance in Collegiate Judo Athletes.

Objectives: In this paper, we explore the relationship between the psychological capital, sport anxiety, and sport performance of collegiate judo athletes. Methods: The research object is the collegiate first-division judo athletes in Taiwan. Convenience sampling was used to conduct an online survey. A total of 106 questionnaires were issued, 102 valid questionnaires were returned, and the effective response rate was 96.23%. The data were analyzed by using confirmatory factor analysis (CFA) and structural equation modeling (SEM). Results: The psychological capital of collegiate judo athletes has a significant positive impact on sport performance; moreover, the sport anxiety of collegiate judo athletes has a significant negative impact on psychological capital. Through psychological capital, sport performance can be improved. Therefore, psychological capital has an intermediary effect. Conclusion: This study shows the higher the level of mental capital of collegiate judo athletes, the better the positive impact on sport performance; in addition, the higher the sport anxiety, the lower the psychological capital. However, sport anxiety can improve sport performance through psychological capital; therefore, we recommend that the training plan of collegiate judo athletes focus on strengthening the athletes' mental skills to improve their sport performance.

Social Media-Delivered Patient Education to Enhance Self-management and Attitudes of Patients with Type 2 Diabetes During the COVID-19 Pandemic: Randomized Controlled Trial.

BACKGROUND: The use of mobile health technologies has been necessary to deliver patient education to patients with diabetes during the COVID-19 pandemic. OBJECTIVE: This open-label randomized controlled trial evaluated the effects of a diabetes educational platform-Taipei Medical University-LINE Oriented Video Education-delivered through a social media app. METHODS: Patients with type 2 diabetes were recruited from a clinic through physician referral. The social media-based program included 51 videos: 10 about understanding diabetes, 10 about daily care, 6 about nutrition care, 21 about diabetes drugs, and 4 containing quizzes. The intervention group received two or three videos every week and care messages every 2 weeks through the social media platform for 3 months, in addition to usual care. The control group only received usual care. Outcomes were measured at clinical visits through self-reported face-to-face questionnaires at baseline and at 3 months after the intervention, including the Simplified Diabetes Knowledge Scale (true/false version), the Diabetes Care Profile-Attitudes Toward Diabetes Scales, the Summary of Diabetes Self-Care Activities, and glycated hemoglobin (HbA1c) levels. Health literacy was measured at baseline using the Newest Vital Sign tool. Differences in HbA1c levels and questionnaire scores before and after the intervention were compared between groups. The associations of knowledge, attitudes, and self-care activities with health literacy were assessed. RESULTS: Patients with type 2 diabetes completed the 3-month study, with 91 out of 181 (50.3%) patients in the intervention group and 90 (49.7%) in the control group. The change in HbA1c did not significantly differ between groups (intervention group: mean 6.9%, SD 0.8% to mean 7.0%, SD 0.9%, P=.34; control group: mean 6.7%, SD 0.6% to mean 6.7%, SD 0.7%, P=.91). Both groups showed increased mean knowledge scores at 12 weeks, increasing from 68.3% (SD 16.4%) to 76.7% (SD 11.7%; P<.001) in the intervention group and from 64.8% (SD 18.2%) to 73.2% (SD 12.6%; P<.001) in the control group. Positive improvements in attitudes and self-care activities were only observed in the intervention group (attitudes: mean difference 0.2, SD 0.5, P=.001; self-care activities: mean difference 0.3, SD 1.2, P=.03). A 100% utility rate was achieved for 8 out of 21 (38%) medication-related videos. Low health literacy was a significant risk factor for baseline knowledge scores in the intervention group, with an odds ratio of 2.80 (95% CI 1.28-6.12; P=.01); this became insignificant after 3 months. CONCLUSIONS: The social media-based program was effective at enhancing the knowledge, attitudes, and self-care activities of patients with diabetes. This intervention was also helpful for patients with low health literacy in diabetes knowledge. The program represents a potentially useful tool for delivering diabetes education to patients through social media, especially during the COVID-19 pandemic. TRIAL REGISTRATION: ClinicalTrials.gov NCT04876274; https://clinicaltrials.gov/ct2/show/results/NCT04876274.

Sex and Age Differences Modulate Association of Vitamin D with Serum Triglyceride Levels.

The sex and age differences in the relationship between vitamin D and lipid levels remain unclear. This retrospective study investigated the correlations between serum 25-hydroxyvitamin D levels and various biomarkers, along with the sex and age differences in these associations, among 573 men and 436 women during physical check-ups. The mean age of the study population was 51.4 years, and 66% of people had serum 25(OH)D levels below 30 ng/mL. People aged over 65 years had higher 25(OH)D levels than those younger than 65 years, and women had lower 25(OH)D levels than men. Younger age (odds ratio (OR) per year = 1.044, 95% CI, 1.029−1.059, p < 0.0001), female sex (OR = 1.779, 95% CI, 1.149−2.755, p = 0.0097), and elevated serum triglyceride (TG) levels (OR per 1 mg/dL = 1.005, 95% CI, 1.002−1.007, p = 0.0002) were all independent risk factors for vitamin D deficiency. Serum 25(OH)D levels were inversely associated with TG levels. The positive association between vitamin D deficiency and hypertriglyceridemia was significant in men (not in women) and in those aged between 50 and 65 years. In conclusion, younger individuals, women, and middle-aged men with hypertriglyceridemia are at higher risk of vitamin D deficiency.

Galectin-3 enhances atrial remodelling and arrhythmogenesis through CD98 signalling.

AIM: Galectin-3 (Gal-3) is a biomarker of atrial fibrillation (AF) that mediates atrial inflammation. CD98 is the membrane surface receptor for Gal-3. Nevertheless, the role of the Gal-3/CD98 axis in atrial arrhythmogenesis is unclear. In this study, we investigated the effects of Gal-3/CD98 signalling on atrial pathogenesis. METHODS: Whole cell patch clamp and western blotting were used to analyse calcium/potassium homeostasis and calcium-related signalling in Gal-3-administrated HL-1 atrial cardiomyocytes with/without CD98 neutralized antibodies. Telemetry electrocardiographic recording, Masson's trichrome staining and immunohistochemistry staining of atrium were obtained from mice having received tail-vein injections with Gal-3. RESULTS: Gal-3-treated HL-1 myocytes had a shorter action potential duration, smaller L-type calcium current, increased sarcoplasmic reticulum (SR) calcium content, Na+ /Ca2+ exchanger (NCX) current, transient outward potassium current, and ultrarapid delayed rectifier potassium current than control cells had. Gal-3-treated HL-1 myocytes had greater levels of SR Ca2+ ATPase, NCX, Nav1.5, and NLR family pyrin domain containing 3 (NLRP3) expression and increased calcium/calmodulin-dependent protein kinase II (CaMKII), ryanodine receptor 2 (RyR2), and nuclear factor kappa B (NF-κB) phosphorylation than control cells had. Gal-3-mediated activation of CaMKII/RyR2 pathway was diminished in the cotreatment of anti-CD98 antibodies. Mice that were injected with Gal-3 had more atrial ectopic beats, increased atrial fibrosis, and activated NF-κB/NLRP3 signalling than did control mice (nonspecific immunoglobulin) or mice treated with Gal-3 and anti-CD98 antibodies. CONCLUSION: Gal-3 recombinant protein administration increases atrial fibrosis and arrhythmogenesis through CD98 signalling. Targeting Gal-3/CD98 axis might be a novel therapeutic strategy for patients with AF and high Gal-3 levels.

Histone deacetylase inhibition improves metabolism and mitochondrial dynamics: A potential novel therapeutic strategy for sarcopenia coexisting with diabetes mellitus.

Sarcopenia, the age-associated-fragility with loss of skeletal muscle mass and function, often coexists with type 2 diabetes (T2D) in older individuals. Derangement of muscle metabolism and mitochondrial dynamics is critical, particularly in high-energy-demand organs in patients with metabolic disorder. However, targeted therapies to halt or reverse the pathological progression of sarcopenia coexisting with T2D are unavailable. Studies have identified the pathological roles of class I histone deacetylases (HDACs) in both T2D and sarcopenia. In addition to their proinflammatory properties, HDACs are known to modify muscle metabolism and mitochondrial dynamics in both the development of sarcopenia and pathogenesis of diabetes. Proper quality control of mitochondrial dynamics through protein degradation and the synthesis of new proteins may improve skeletal muscle function in sarcopenia. Class I HDAC inhibitors improve energy metabolism and modulate autophagy-related genes in skeletal muscle. However, class IIa HDAC4 plays a protective role in preserving skeletal muscle structure following long-term denervation, and selective inhibition of class IIa HDAC activity had no impact on oxidative metabolism of muscle mitochondria. These findings suggest the vital role of class I HDAC modulation in bioenergetics and mitochondria quality control, and may lead to a novel therapeutic strategy targeting sarcopenia that coexists with T2D. HDAC inhibitors have been approved for clinical applications, and interventions targeting on HDACs may be promising for the treatment of sarcopenia.

Correlation between short- and mid-term hemoglobin A1c and glycemic control determined by continuous glucose monitoring.

BACKGROUND: Glucose monitoring is vital for glycemic control in patients with diabetes mellitus (DM). Continuous glucose monitoring (CGM) measures whole-day glucose levels. Hemoglobin A1c (HbA1c) is a vital outcome predictor in patients with DM. METHODS: This study investigated the relationship between HbA1c and CGM, which remained unclear hitherto. Data of patients with DM (n = 91) who received CGM and HbA1c testing (1-3 months before and after CGM) were retrospectively analyzed. Diurnal and nocturnal glucose, highest CGM data (10%, 25%, and 50%), mean amplitude of glycemic excursions (MAGE), percent coefficient of variation (%CV), and continuous overlapping net glycemic action were compared with HbA1c values before and after CGM. RESULTS: The CGM results were significantly correlated with HbA1c values measured 1 (r = 0.69) and 2 (r = 0.39) months after CGM and 1 month (r = 0.35) before CGM. However, glucose levels recorded in CGM did not correlate with the HbA1c values 3 months after and 2-3 months before CGM. MAGE and %CV were strongly correlated with HbA1c values 1 and 2 months after CGM, respectively. Diurnal blood glucose levels were significantly correlated with HbA1c values 1-2 months before and 1 month after CGM. The nocturnal blood glucose levels were significantly correlated with HbA1c values 1-3 months before and 1-2 months after CGM. CONCLUSIONS: CGM can predict HbA1c values within 1 month after CGM in patients with DM.

Generation and characterization of a tractable C. elegans model of tauopathy.

Alzheimer's disease(AD) is an age-associated neurodegenerative disease that results in deterioration of memory and cognitive function. As a currently untreatable disorder, AD has emerged as one of the defining biomedical challenges of our time. Thus, new approaches that can examine the cellular and molecular mechanisms underlying age-related AD pathology are sorely needed. One of the hallmarks of Alzheimer's disease is the hyperphosphorylation of the tau protein. Caenorhabditis elegans have been previously used to study the genetic pathways impacted by tau proteotoxic stress; however, currently, available C. elegans tau models express the human protein solely in neurons, which are unresponsive to global RNA interference (RNAi). This limits powerful RNAi screening methods from being utilized effectively in these disease models. Our goal was to develop a C. elegans tau model that has pronounced tau-induced disease phenotypes in cells that can be modified by feeding RNAi methods. Towards this end, we generated a novel C. elegans transgenic line with codon-optimized human 0N4R V337M tau expressed in the body wall muscle under the myo-3 promoter. Immunoblotting experiments revealed that the expressed tau is phosphorylated on epitopes canonically associated with human AD pathology. The tau line has significantly reduced health metrics, including egg laying, growth rate, paralysis, thrashing frequency, crawling speed, and lifespan. These defects are suppressed by RNAi directed against the tau mRNA. Taken together, our results suggest that this alternative tau genetic model could be a useful tool for uncovering the mechanisms that influence the hyperphosphorylation and toxicity of human tau via RNAi screening and other approaches.

Sugar Fructose Triggers Gut Dysbiosis and Metabolic Inflammation with Cardiac Arrhythmogenesis.

Fructose is a main dietary sugar involved in the excess sugar intake-mediated progression of cardiovascular diseases and cardiac arrhythmias. Chronic intake of fructose has been the focus on the possible contributor to the metabolic diseases and cardiac inflammation. Recently, the small intestine was identified to be a major organ in fructose metabolism. The overconsumption of fructose induces dysbiosis of the gut microbiota, which, in turn, increases intestinal permeability and activates host inflammation. Endotoxins and metabolites of the gut microbiota, such as lipopolysaccharide, trimethylamine N-oxide, and short-chain fatty acids, also influence the host inflammation and cardiac biofunctions. Thus, high-fructose diets cause heart-gut axis disorders that promote cardiac arrhythmia. Understanding how gut microbiota dysbiosis-mediated inflammation influences the pathogenesis of cardiac arrhythmia may provide mechanisms for cardiac arrhythmogenesis. This narrative review updates our current understanding of the roles of excessive intake of fructose on the heart-gut axis and proposes potential strategies for inflammation-associated cardiac vascular diseases.

Learning from the past: Taiwan's responses to COVID-19 versus SARS.

OBJECTIVES: To evaluate the prevalence of infection prevention behaviors in Taiwan-wearing facemasks and alcohol-based hand hygiene (AHH)-and compare their practice rates during SARS and COVID-19. METHODS: We surveyed 2328 Taiwanese from July 29 to August 6, 2020, assessing demographics, information sources, and preventive behaviors during the 2003 SARS outbreaks, 2009 pandemic influenza H1N1, COVID-19, and with post-survey intentions. Characteristics associated with the practice of preventive behaviors in 2020 were identified through logistic regression. RESULTS: Preventive behaviors were conscientiously practiced by 70.2% of participants. Compared with 2003 SARS/2009 H1N1, the percentages of facemask use (66.6% vs 99.2% [indoors], P < 0.001) and on-person AHH (44.2% vs 65.4% [hand sanitizers], P < 0.001) significantly increasedduring 2020 COVID-19. Highest adherence to preventive behaviors in 2020 was among females (adjusted odds ratio [aOR], 1.72), those receiving government COVID-19 information (aOR, 1.52), participants recruited from primary-care clinics (aOR, 1.43), and those who practiced AHH during 2003 SARS/2009 H1N1 (aOR, 1.37). CONCLUSIONS: Government leadership, healthcare providers risk communication, and public cooperation rapidly mitigated the spread of COVID-19 in Taiwan even before vaccination. Future global efforts must implement such population-based preventive behaviors at a level above the viral-transmission-threshold, particularly in areas with fast-spreading SARS-CoV-2 variants.

Empagliflozin and Liraglutide Differentially Modulate Cardiac Metabolism in Diabetic Cardiomyopathy in Rats.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are antihyperglycemic agents with cardioprotective properties against diabetic cardiomyopathy (DCM). However, the distinctive mechanisms underlying GLP-1RAs and SGLT2is in DCM are not fully elucidated. The purpose of this study was to investigate the impacts of GLP1RAs and/or SGLT2is on myocardial energy metabolism, cardiac function, and apoptosis signaling in DCM. Biochemistry and echocardiograms were studied before and after treatment with empagliflozin (10 mg/kg/day, oral gavage), and/or liraglutide (200 µg/kg every 12 h, subcutaneously) for 4 weeks in male Wistar rats with streptozotocin (65 mg/kg intraperitoneally)-induced diabetes. Cardiac fibrosis, apoptosis, and protein expression of metabolic and inflammatory signaling molecules were evaluated by histopathology and Western blotting in ventricular cardiomyocytes of different groups. Empagliflozin and liraglutide normalized myocardial dysfunction in diabetic rats. Upregulation of phosphorylated-acetyl coenzyme A carboxylase, carnitine palmitoyltransferase 1ß, cluster of differentiation 36, and peroxisome proliferator-activated receptor-gamma coactivator, and downregulation of glucose transporter 4, the ratio of phosphorylated adenosine monophosphate-activated protein kinase α2 to adenosine monophosphate-activated protein kinase α2, and the ratio of phosphorylated protein kinase B to protein kinase B in diabetic cardiomyocytes were restored by treatment with empagliflozin or liraglutide. Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3, interleukin-1ß, tumor necrosis factor-α, and cleaved caspase-1 were significantly downregulated in empagliflozin-treated and liraglutide-treated diabetic rats. Both empagliflozin-treated and liraglutide-treated diabetic rats exhibited attenuated myocardial fibrosis and apoptosis. Empagliflozin modulated fatty acid and glucose metabolism, while liraglutide regulated inflammation and apoptosis in DCM. The better effects of combined treatment with GLP-1RAs and SGLT2is may lead to a potential strategy targeting DCM.

Fibroblast Growth Factor 23 Stimulates Cardiac Fibroblast Activity through Phospholipase C-Mediated Calcium Signaling.

Fibroblast growth factor (FGF)-23 induces hypertrophy and calcium (Ca2+) dysregulation in cardiomyocytes, leading to cardiac arrhythmia and heart failure. However, knowledge regarding the effects of FGF-23 on cardiac fibrogenesis remains limited. This study investigated whether FGF-23 modulates cardiac fibroblast activity and explored its underlying mechanisms. We performed MTS analysis, 5-ethynyl-2'-deoxyuridine assay, and wound-healing assay in cultured human atrial fibroblasts without and with FGF-23 (1, 5 and 25 ng/mL for 48 h) to analyze cell proliferation and migration. We found that FGF-23 (25 ng/mL, but not 1 or 5 ng/mL) increased proliferative and migratory abilities of human atrial fibroblasts. Compared to control cells, FGF-23 (25 ng/mL)-treated fibroblasts had a significantly higher Ca2+ entry and intracellular inositol 1,4,5-trisphosphate (IP3) level (assessed by fura-2 ratiometric Ca2+ imaging and enzyme-linked immunosorbent assay). Western blot analysis showed that FGF-23 (25 ng/mL)-treated cardiac fibroblasts had higher expression levels of calcium release-activated calcium channel protein 1 (Orai1) and transient receptor potential canonical (TRPC) 1 channel, but similar expression levels of α-smooth muscle actin, collagen type IA1, collagen type Ⅲ, stromal interaction molecule 1, TRPC 3, TRPC6 and phosphorylated-calcium/calmodulin-dependent protein kinase II when compared with control fibroblasts. In the presence of ethylene glycol tetra-acetic acid (a free Ca2+ chelator, 1 mM) or U73122 (an inhibitor of phospholipase C, 1 µM), control and FGF-23-treated fibroblasts exhibited similar proliferative and migratory abilities. Moreover, polymerase chain reaction analysis revealed that atrial fibroblasts abundantly expressed FGF receptor 1 but lacked expressions of FGF receptors 2-4. FGF-23 significantly increased the phosphorylation of FGF receptor 1. Treatment with PD166866 (an antagonist of FGF receptor 1, 1 µM) attenuated the effects of FGF-23 on cardiac fibroblast activity. In conclusion, FGF-23 may activate FGF receptor 1 and subsequently phospholipase C/IP3 signaling pathway, leading to an upregulation of Orai1 and/or TRPC1-mediated Ca2+ entry and thus enhancing human atrial fibroblast activity.

Effect of antidiabetic drugs on the risk of atrial fibrillation: mechanistic insights from clinical evidence and translational studies.

Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF), which is the most common sustained arrhythmia and is associated with substantial morbidity and mortality. Advanced glycation end product and its receptor activation, cardiac energy dysmetabolism, structural and electrical remodeling, and autonomic dysfunction are implicated in AF pathophysiology in diabetic hearts. Antidiabetic drugs have been demonstrated to possess therapeutic potential for AF. However, clinical investigations of AF in patients with DM have been scant and inconclusive. This article provides a comprehensive review of research findings on the association between DM and AF and critically analyzes the effect of different pharmacological classes of antidiabetic drugs on AF.

Use and effectiveness of dapagliflozin in patients with type 2 diabetes mellitus: a multicenter retrospective study in Taiwan.

AIMS/INTRODUCTION: To investigate the clinical outcomes of patients with type 2 diabetes mellitus (T2DM) who initiated dapagliflozin in real-world practice in Taiwan. MATERIALS AND METHODS: In this multicenter retrospective study, adult patients with T2DM who initiated dapagliflozin after May 1st 2016 either as add-on or switch therapy were included. Changes in clinical and laboratory parameters were evaluated at 3 and 6 months. Baseline factors associated with dapagliflozin response in glycated hemoglobin (HbA1c) were analyzed by univariate and multivariate logistic regression. RESULTS: A total of 1,960 patients were eligible. At 6 months, significant changes were observed: HbA1c by -0.73% (95% confidence interval [CI] -0.80, -0.67), body weight was -1.61 kg (95% CI -1.79, -1.42), and systolic/diastolic blood pressure by -3.6/-1.4 mmHg. Add-on dapagliflozin showed significantly greater HbA1c reduction (-0.82%) than switched therapy (-0.66%) (p = 0.002). The proportion of patients achieving HbA1c <7% target increased from 6% at baseline to 19% at Month 6. Almost 80% of patients experienced at least 1% reduction in HbA1c, and 65% of patients showed both weight loss and reduction in HbA1c. Around 37% of patients had at least 3% weight loss. Multivariate logistic regression analysis indicated patients with higher baseline HbA1c and those who initiated dapagliflozin as add-on therapy were associated with a greater reduction in HbA1c. CONCLUSIONS: In this real-world study with the highest patient number of Chinese population to date, the use of dapagliflozin was associated with significant improvement in glycemic control, body weight, and blood pressure in patients with T2DM. Initiating dapagliflozin as add-on therapy showed better glycemic control than as switch therapy.