Enhancement of bicycle exercise capacity in patients with chronotropic incompetence through closed-loop stimulation: a randomized crossover trial.

AIMS: This study aimed to investigate the effectiveness of closed-loop stimulation (CLS) pacing compared with the traditional DDD mode in patients with chronotropic incompetence (CI) using bicycle-based cardiopulmonary exercise testing (CPET). METHODS AND RESULTS: This single-centre, randomized crossover trial involved 40 patients with CI. Patients were randomized to receive either DDD-CLS or DDD mode pacing for 2 months, followed by a crossover to the alternative mode for an additional 2 months. Bicycling-based CPET was conducted at the 3- and 5-month follow-up visits to assess exercise capacity. Other cardiopulmonary exercise outcome measures and health-related quality of life (QoL) were also assessed. DDD-CLS mode pacing significantly improved exercise capacity, resulting in a peak oxygen uptake (14.8 ± 4.0 vs. 12.0 ± 3.6 mL/kg/min, P < 0.001) and oxygen uptake at the ventilatory threshold (10.0 ± 2.2 vs. 8.7 ± 1.8 mL/kg/min, P < 0.001) higher than those of the DDD mode. However, there were no significant differences in other cardiopulmonary exercise outcome measures such as ventilatory efficiency of carbon dioxide production slope, oxygen uptake efficiency slope, and end-tidal carbon dioxide between the two modes. Patients in the DDD-CLS group reported a better QoL, and 97.5% expressed a preference for the DDD-CLS mode. CONCLUSION: DDD-CLS mode pacing demonstrated improved exercise capacity and QoL in patients with CI, highlighting its potential as an effective pacing strategy for this patient population.

Rationale and Study Design of the TSOC-Fully Organized Registry for the Management of Symptomatic ACS Study (T-FORMOSA Study).

Background: Successful implementation of practice guidelines has been challenging in the treatment of acute coronary syndrome (ACS), leaving room for improvement. A nationwide registry can provide more information than that recorded in the National Health Insurance Research Database (NHIRD). Methods: We conducted a prospective, nationwide, multi-center ACS full spectrum registry involving 3600 patients admitted to hospitals within 24 hours of the onset of myocardial infarction with ST-segment elevation or ACS without ST-segment elevation. In total, 41 sites including medical centers and regional hospitals were selected across Taiwan. The data for each patient are collected at 3 time points for the main study: during hospitalization, 6 months, and 12 months after the discharge. The milestone for first patient in was reached on January 7, 2022, and complete enrollment is expected before October 2023. The primary aims of the main study are to determine the degree of guideline-directed medical therapies and to identify prognostic predictors associated with 1-year composite outcomes, including death, myocardial infarction, stroke, and unplanned coronary revascularization in ACS patients. Thereafter, the patient data will be analyzed every 3 to 5 years for up to 20 years after discharge using the NHIRD in the extended study. Conclusions: We hypothesized that a greater increase in the implementation of guideline-directed medical therapies can be observed. The results of the current study will add new and important information regarding a broad spectrum of ACS to drive further investigations.

The Efficacy and Safety of Short-Term Tolvaptan Usage in Patients with Acute Decompensated Heart Failure.

Background: Patients admitted with acute decompensated heart failure (ADHF) have a poor prognosis and poor quality of life due to dyspnea and edema. Tolvaptan, a vasopressin V2 receptor antagonist, is an effective water diuretic. This study aimed to evaluate the efficacy and safety of a short course of tolvaptan to treat volume overload in patients with ADHF. Methods: We conducted a phase III, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a short course of tolvaptan (15 mg/day for 4 days) in hospitalized ADHF patients with volume overload despite the use of conventional diuretics. The primary end-point was the change in body weight after 4 days of treatment. The secondary end-points were the change in intake/output balance, change in serum sodium/potassium concentrations, physician/patient assessed signs and symptoms of heart failure after 4 days of treatment, and all-cause mortality in 1 month. Results: A total of 110 patients were screened, and 91 were randomized to receive 15 mg/day of tolvaptan for 4 days (n = 46) or matching placebo (n = 45). Compared to the placebo-treated patients, tolvaptan significantly reduced body weight (-1.36 ± 2.13 kg in the tolvaptan group vs. -0.59 ± 1.27 kg in the placebo group, p = 0.0394). The tolvaptan group also had a negative intake/urine volume balance compared to the placebo group (-509.3 ± 2788.2 ml vs. 975.5 ± 1903.1 ml, p = 0.0059). The safety profile of tolvaptan was acceptable. Conclusions: Tolvaptan significantly reduced volume overload in hospitalized ADHF patients with volume overload despite the use of conventional diuretics.

Exosomal MALAT1 Derived from High Glucose-Treated Macrophages Up-Regulates Resistin Expression via miR-150-5p Downregulation.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a crucial role in the pathophysiological process associated with diabetes-related complications. The effect of high glucose levels on macrophage-derived exosomal MALAT1 is unknown. Therefore, we investigated the molecular regulatory mechanisms controlling exosomal MALAT1 in macrophages under high glucose treatment and the therapeutic target of macrophage-derived exosomal MALAT1 using a balloon injury model of vascular disease in diabetic rats. High glucose (25 mM) significantly increased MALAT1 expression in macrophage-derived exosomes. MALAT1 suppressed miR-150-5p expression in macrophage-derived exosomes under high-glucose conditions. Silencing MALAT1 using MALAT1 siRNA significantly reversed miR-150-5p expression induced by macrophage-derived exosomes. Macrophage-derived exosomes under high-glucose treatment significantly increased resistin expression in macrophages. Silencing MALAT1 and overexpression of miR-150-5p significantly decreased resistin expression induced by macrophage-derived exosomes. Overexpression of miR-150-5p significantly decreased resistin luciferase activity induced by macrophage-derived exosomes. Macrophage-derived exosome significantly decreased glucose uptake in macrophages and silencing MALAT1, resistin or overexpression of miR-150-5p significantly reversed glucose uptake. Balloon injury to the carotid artery significantly increased MALAT1 and resistin expression and significantly decreased miR-150-5p expression in arterial tissue. Silencing MALAT1 significantly reversed miR-150-5p expression in arterial tissue after balloon injury. Silencing MALAT1 or overexpression of miR-150-5p significantly reduced resistin expression after balloon injury. In conclusion, high glucose up-regulates MALAT1 to suppress miR-150-5p expression and counteracts the inhibitory effect of miR-150-5p on resistin expression in macrophages to promote vascular disease. Macrophage-derived exosomes containing MALAT1 may serve as a novel cell-free approach for the treatment of vascular disease in diabetes mellitus.

Chrysin boosts KLF2 expression through suppression of endothelial cell-derived exosomal microRNA-92a in the model of atheroprotection.

PURPOSE: Atherosclerosis and its related clinical complications are the leading cause of death. MicroRNA (miR)-92a in the inflammatory endothelial dysfunction leads to atherosclerosis. Krüppel-like factor 2 (KLF2) is required for vascular integrity and endothelial function maintenance. Flavonoids possess many biological properties. This study investigated the vascular protective effects of chrysin in balloon-injured carotid arteries. MATERIALS AND METHODS: Exosomes were extracted from human coronary artery endothelial cell (HCAEC) culture media. Herb flavonoids and chrysin were the treatments in these atheroprotective models. Western blotting and real-time PCRs were performed. In situ hybridization, immunohistochemistry, and immunofluorescence analyses were employed. RESULTS: MiR-92a increased after balloon injury and was present in HCAEC culture media. Chrysin was treated, and significantly attenuated the miR-92a levels after balloon injury, and similar results were obtained in HCAEC cultures in vitro. Balloon injury-induced miR-92a expression, and attenuated KLF2 expression. Chrysin increased the KLF2 but reduced exosomal miR-92a secretion. The addition of chrysin and antagomir-92a, neointimal formation was reduced by 44.8 and 49.0% compared with balloon injury after 14 days, respectively. CONCLUSION: Chrysin upregulated KLF2 expression in atheroprotection and attenuated endothelial cell-derived miR-92a-containing exosomes. The suppressive effect of miR-92a suggests that chrysin plays an atheroprotective role. Proposed pathway for human coronary artery endothelial cell (HCAEC)-derived exosomes induced by chrysin to suppress microRNA (miR)-92a expression and counteract the inhibitory effect of miR-92a on KLF2 expression in HCAECs. This provides an outline of the critical role of the herbal flavonoid chrysin, which may serve as a valuable therapeutic supplement for atheroprotection.

Extended-Release Carvedilol in the Treatment of Hypertension: A Double-Blind, Randomized, Placebo-Controlled Trial.

BACKGROUND: Immediate-release carvedilol requires twice-daily dosing and may have low treatment compliance. We assessed the efficacy of a new formulation of once-daily extended-release carvedilol (carvedilol ER) on systolic blood pressure (SBP) and diastolic blood pressure (DBP) among patients with hypertension in this double-blind, randomized, placebo-controlled trial. METHODS: A total of 134 patients with untreated or uncontrolled hypertension were randomly assigned in a 1:1:1 ratio to receive placebo, low-dose carvedilol ER, or high-dose carvedilol ER for 8 weeks. The primary endpoint was the reduction in office SBP at 8 weeks. Secondary endpoints included the reduction in office DBP and the proportion of patients with blood pressure (BP) < 140/90 mm Hg. RESULTS: In the intention-to-treat population, placebo-adjusted changes in SBP/DBP were -2.9 mm Hg [95% confidence interval (CI), -9.6 to 3.7]/-1.7 mm Hg (95% CI, -5.6 to 2.3) and -4.9 mm Hg (95% CI, -11.5 to 1.7)/-3.4 mm Hg (95% CI, -7.3 to 0.5) for low-dose carvedilol ER and high-dose carvedilol ER, respectively. In the per-protocol population, high-dose carvedilol ER was associated with a significant DBP reduction [placebo-adjusted difference, -4.7 mm Hg (95% CI, -8.8 to -0.5); adjusted p = 0.026]. There was a gradational improvement in BP control with carvedilol ER (25%, 37%, and 48% for placebo, low-dose carvedilol ER, and high-dose carvedilol ER, respectively; linear-by-linear association p = 0.028). There were no differences in safety among the three groups. CONCLUSIONS: Carvedilol ER, though well tolerated, did not result in a greater reduction in either SBP or DBP compared with placebo.

Familial Hypercholesterolemia in Asia Pacific: A Review of Epidemiology, Diagnosis, and Management in the Region.

Familial hypercholesterolemia (FH) is a common genetic disease that is estimated to affect at least 15 million people in the Asia Pacific region. Affected individuals are at significantly increased risk of premature atherosclerotic cardiovascular disease. A literature review was undertaken to provide an overview of the epidemiology, diagnosis, and management of FH across the region.Currently, epidemiological data relating to FH are lacking across the Asia Pacific. Of the 15 countries and regions considered, locally conducted studies to determine FH prevalence were only identified for Australia, China, India, and Japan. Although practically all national clinical guidelines for dyslipidemia include some commentary on FH, specific guidelines on the management of FH are available for only one third of the countries and regions evaluated. Estimates of current FH diagnosis rates suggest that most affected individuals remain undiagnosed and untreated. Although innovative medications such as proprotein convertase subtilisin/kexin type 9 inhibitors have been approved and are available in most countries and regions considered, they are currently reimbursed in only one quarter.Despite these shortcomings, there is cause for optimism. Early experience with cascade screening in Hong Kong, India, and Vietnam has proven an effective means of identifying family members of probands, as has a reverse screening of family members of children with FH in China. FH registries are gaining momentum across the region, with registries now established in almost half of the countries and regions evaluated. This review concludes with a Call to Action on FH for Asia Pacific to engage healthcare professionals, improve public awareness, and form national FH alliances, comprising all relevant healthcare professional organizations, as a platform to expedite national quality improvement programs in the management of FH.

Cyclic stretching boosts microRNA-499 to regulate Bcl-2 via microRNA-208a in atrial fibroblasts.

MicroRNAs that modulate transcription can regulate other microRNAs and are also up-regulated under pathological stress. MicroRNA-499 (miR-499), microRNA-208a (miR-208a) and B-cell lymphoma 2 (Bcl-2) play roles in cardiovascular diseases, such as direct reprogramming of cardiac fibroblast into cardiomyocyte and cardiomyocyte apoptosis. Whether miR208a, miR499 and Bcl-2 were critical regulators in cardiac fibroblast apoptosis under mechanical stretching conditions in human cardiac fibroblasts-adult atrial (HCF-aa) was investigated. Using negative pressure, HCF-aa grown on a flexible membrane base were cyclically stretched to 20% of their maximum elongation. In adult rats, an aortocaval shunt was used to create an in vivo model of volume overload. MiR208a was up-regulated early by stretching and returned to normal levels with longer stretching cycles, whereas the expression of miR499 and Bcl-2 was up-regulated by longer stretching times. Pre-treatment with antagomir-499 reversed the miR-208a down-regulation, whereas Bcl-2 expression could be suppressed by miR-208a overexpression. In the HCF-aa under stretching for 1 h, miR-499 overexpression decreased pri-miR-208a luciferase activity; this inhibition of pri-miR-208a luciferase activity with stretching was reversed when the miR-499-5p binding site in pri-miR-208a was mutated. The addition of antagomir-208a reversed the Bcl-2-3'UTR suppression from stretching for 1 h. Flow cytometric analysis revealed that pre-treatment with miR-499 or antagomir-208a inhibited cellular apoptosis in stretched HCF-aa. In hearts with volume overload, miR-499 overexpression inhibited myocardial miR-208a expression, whereas Bcl-2 expression could be suppressed by the addition of miR-208a. In conclusion, miR-208a mediated the regulation of miR-499 on Bcl-2 expression in stretched HCF-aa and hearts with volume overload.

2021 Consensus Pathway of the Taiwan Society of Cardiology on Novel Therapy for Type 2 Diabetes.

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.

Association of Heart Rate Trajectory Patterns with the Risk of Adverse Outcomes for Acute Heart Failure in a Heart Failure Cohort in Taiwan.

BACKGROUND: Heart rate trajectory with multiple heart rate measurements is considered to be a more sensitive predictor of outcomes than single heart rate measurements. The association of heart rate trajectory patterns with acute heart failure outcomes has not been well studied. We examined the association of heart rate trajectory patterns with post-discharge outcomes. METHODS: This prospective cohort study was based on an acute heart failure registry in Taiwan. A total of 1509 patients were enrolled in the Taiwan Society of Cardiology - Heart Failure with Reduced Ejection Fraction Registry from May 2013 to October 2015. The outcomes were post-discharge all-cause mortality and heart failure re-admission. RESULTS: Two heart trajectory patterns were identified in group-based trajectory analysis. One started with a higher heart rate and had an increasing trend over 6 months then a subsequent decline (high-increasing-decreasing group; n = 352; 23.9%). The other started with a lower heart rate and had a relatively stable pattern (low-stable group; n = 1121; 76.1%). Compared with those in the low-stable group, patients in the high-increasing-decreasing group had a higher risk of events (all-cause mortality: hazard ratio 3.10 and 95% confidence interval 1.24-7.77; heart failure re-admission: hazard ratio 1.13 and 95% confidence interval 0.55-2.32). CONCLUSIONS: Patients with a high-increasing-decreasing heart rate trajectory pattern had a higher risk of all-cause mortality than those with a low-stable pattern.

Hyperbaric oxygen-induced long non-coding RNA MALAT1 exosomes suppress MicroRNA-92a expression in a rat model of acute myocardial infarction.

Hyperbaric oxygen (HBO) improves angiogenesis. The effect of HBO on metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a pro-angiogenic long non-coding RNA, in cardiac myocyte-derived exosomes and acute myocardial infarction (AMI) is unknown. We aimed to investigate whether MALAT1 is altered in cardiac myocyte-derived exosomes in response to HBO as well as the molecular regulatory mechanisms of MALAT1 in cardiac myocytes treated with HBO. Cardiac myocytes were cultured, and HBO was applied at 2.5 atmosphere absolute in a hyperbaric chamber. Exosomes were extracted from the culture media. A rat model of AMI generated by the ligation of the left anterior descending artery was used. HBO significantly increased MALAT1 expression in cardiac myocytes and HBO-induced MALAT1 and exosomes attenuated miR-92a expression after myocardial infarction. Expression of krüppel-like factor 2 (KLF2) and CD31 was significantly decreased after infarction and HBO-induced exosomes significantly reversed the expression. Silencing of MALAT1 using MALAT1-locked nucleic acid GapmeR significantly attenuated KLF2 and CD31 protein expression after infarction induced by HBO-induced exosomes. HBO-induced exosomes also decreased infarct size significantly. HBO-induced exosomes from cardiac myocytes up-regulate MALAT1 to suppress miR-92a expression and counteract the inhibitory effect of miR-92a on KLF2 and CD31 expression in left ventricular myocardium after myocardial infarction to enhance neovascularization.

2020 Consensus of Taiwan Society of Cardiology on the pharmacological management of patients with type 2 diabetes and cardiovascular diseases.

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.

Antithrombotic Strategies in Patients with Atrial Fibrillation Following Percutaneous Coronary Intervention: A Systemic Review and Network Meta-Analysis of Randomized Controlled Trials.

Up to 10% of patients with atrial fibrillation (AF) undergo percutaneous coronary intervention (PCI). A systematic review and network meta-analysis were conducted by searching PubMed, Embase, and the Cochrane database of systematic reviews for randomized control trials that studied the safety and efficacy of different antithrombotic strategies in these patients. Six studies, including 12,158 patients were included. Compared to that in the triple antithrombotic therapy group (vitamin K antagonist (VKA) plus P2Y12 inhibitor and aspirin), thrombolysis in myocardial infarction (TIMI) major bleeding was significantly reduced in the dual antithrombotic therapy (non-vitamin K oral anticoagulants (NOACs) plus P2Y12 inhibitor) group by 47% (Odds ratio (OR), 0.53; 95% credible interval [CrI], 0.35-0.78; I2 = 0%). Besides, NOAC plus a P2Y12 inhibitor was associated with less intracranial hemorrhage compared to VKA plus single antiplatelet therapy (OR: 0.20, 95% CrI: 0.05-0.77). There was no significant difference in the trial-defined major adverse cardiac events or the individual outcomes of all-cause mortality, cardiovascular death, myocardial infarction, stroke or stent thrombosis among all antithrombotic strategies. In conclusion, antithrombotic strategy of NOACs plus P2Y12 inhibitor is safer than, and as effective as, the strategies including aspirin when used in AF patients undergoing PCI.

(-)-Epigallocatechin Gallate Promotes MicroRNA 145 Expression against Myocardial Hypoxic Injury through Dab2/Wnt3a/ß-catenin.

MicroRNA 145 (miR-145) is a critical modulator of cardiovascular diseases. The downregulation of myocardial miR-145 is followed by an increase in disabled-2 (Dab2) expression in cardiomyocytes. (-)-epigallocatechin gallate (EGCG) is a flavonoid that has been evaluated extensively due to its diverse pharmacological properties including anti-inflammatory effects. The aim of this study was to investigate the cardioprotective effects of EGCG under hypoxia-induced stress in vitro and in vivo. The hypoxic insult led to the suppression of miR-145 expression in cultured rat cardiomyocytes in a concentration-dependent manner. Western blotting and real-time PCR were performed. In rat myocardial infarction study, in situ hybridization, and immunofluorescent analyses were adopted. The western blot and real-time PCR data revealed that hypoxic stress with 2.5% O2 suppressed the expression of miR-145 and Wnt3a/ß-catenin in cultured rat cardiomyocytes but augmented Dab2. Treatment with EGCG attenuated Dab2 expression, but increased Wnt3a and ß-catenin in hypoxic cultured cardiomyocytes. Following in vivo myocardial infarction (MI) study, the data revealed the myocardial infarct area reduced by 48.5%, 44.6%, and 48.5% in EGCG (50mg/kg) or miR-145 dominant or Dab2 siRNA groups after myocardial infarction for 28 days, respectively. This study demonstrated that EGCG increased miR-145, Wnt3a, and ß-catenin expression but attenuated Dab2 expression. Moreover, EGCG ameliorated myocardial ischemia in vivo. The novel suppressive effect was mediated through the miR-145 and Dab2/Wnt3a/ß-catenin pathways.

Cost-effectiveness of statin therapy for secondary prevention among patients with coronary artery disease and baseline LDL-C 70-100 mg/dL in Taiwan.

BACKGROUND: The recommended target low-density lipoprotein cholesterol (LDL-C) level for coronary artery disease (CAD) patients has been lowered from 100 to 70 mg/dL in several clinical guidelines for secondary prevention. We aimed to assess whether initiating statin treatment in CAD patients with baseline LDL-C 70-100 mg/dL in Taiwan could be cost-effective. METHODS: A Markov model was developed to simulate a hypothetical cohort of CAD patients with a baseline LDL-C level of 90 mg/dL. The incidence and recurrence of MI and stroke related to specific LDL-C levels as well as the statin effect, mortality rate, and health state utilities were obtained from the literature. The direct medical costs and rate of fatal events were derived from the national claims database. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) was calculated, and sensitivity analyses were performed. RESULTS: Moderate-intensity statin use, a treatment regimen expected to achieve LDL <70 mg/dL in the base case, resulted in a net gain of 562 QALYs but with an additional expenditure of $11.4 million per 10,000 patients over ten years. The ICER was $20,288 per QALY gained. The probabilities of being cost-effective at willingness-to-pay thresholds of one and three gross domestic product per capita ($24,329 in 2017) per QALY were 51.1% and 94.2%, respectively. Annual drug cost was the most influential factor on the ICER. CONCLUSION: Lowering the target LDL-C level from 100 to 70 mg/dL among treatment-naïve CAD patients could be cost-effective given the health benefits of preventing cardiovascular events and deaths.

Hyperbaric oxygen activates visfatin expression and angiogenesis via angiotensin II and JNK pathway in hypoxic human coronary artery endothelial cells.

Visfatin is an adipocytokine with important roles in endothelial angiogenesis. Hyperbaric oxygen (HBO) has been widely used to treat various medical illness with enhanced angiogenesis. The molecular effects of HBO on visfatin under hypoxia are poorly understood. This study aimed to investigate the effect of HBO on visfatin in hypoxic human coronary arterial endothelial cells (HCAECs). HCAECs under chemical hypoxia (antimycin A, 0.01 mmol/L) were exposed to HBO (2.5 atmosphere absolute; ATA) for 2-4 hours. Western blot, real-time polymerase chain reaction, electrophoretic mobility shift assay, luciferase promoter activity, migration and tube formation assay, and in vitro glucose uptake were measured. Visfatin protein expression increased in hypoxic HCAECs with earlier angiotensin II (AngII) secretion and c-Jun N-terminal kinase (JNK) phosphorylation, which could be effectively suppressed by the JNK inhibitor (SP600125), AngII antibody or AngII receptor blocker (losartan). In hypoxic HCAECs, HBO further induced earlier expression of visfatin and AngII. Hypoxia significantly increased DNA-protein binding activity of hypoxia-inducible factor-1α (HIF-1α) and visfatin. Hypoxia, hypoxia with HBO and exogenous addition of AngII also increased promoter transcription to visfatin; SP600125 and losartan blocked this activity. In HCAECs, glucose uptake, migration and tube formation were increased in the presence of hypoxia with HBO, but were inhibited by visfatin small interfering RNA, SP600125 and losartan. In conclusion, HBO activates visfatin expression and angiogenesis in hypoxic HCAECs, an effect mediated by AngII, mainly through the JNK pathway.

Observational study of dronedarone in Taiwanese patients with atrial fibrillation.

BACKGROUND/PURPOSE: Currently, data on the real-world use of dronedarone, an antiarrhythmic drug for atrial fibrillation (AF), are contradictory and often based on patient populations comprised of Caucasians. We prospectively investigated the efficacy and safety of dronedarone and risk factors related to treatment outcomes in a real-world use setting. METHODS: The prospective, observational, single-arm, multi-center study included a total of 824 Taiwanese patients with a diagnosis of paroxysmal or persistent AF and receiving dronedarone treatment. Risk factors analysis, efficacy, and safety of dronedarone were assessed with a follow-up of six months. RESULTS: Of the 824 patients enrolled (mean age, 75.3 ± 7.2 years), 95.2% had at least one cardiovascular risk factor. An increase in the proportion of patients with sinus rhythm following treatment was seen (52.1% at baseline vs. 67.4% at 6 months). A decrease in the mean duration of AF episodes (388.4 min vs. 62.3 min) and an increase in total AFEQT (65.4 ± 16.2 vs. 74.0 ± 11.8) were also observed after 6 months of treatment. Females, those under the age of 75, and those with symptomatic AF had higher odds of treatment success. At 6 months, 10.5% of patients reported treatment-related AEs. However, only 0.2% of the AEs were both severe in nature and causally related to dronedarone. CONCLUSION: This six-month study showed dronedarone to be relatively safe and efficacious and to improve quality-of-life in Taiwanese patients with atrial fibrillation. Odds of treatment success were related to the patient's gender, age, and AF type.

[Corrigendum] Novel iridium (III)­derived organometallic compound for the inhibition of human platelet activation.

After the publication of the above paper, the authors noted that an incomplete version of the address was presented for the second author affiliation; essentially, 'School of Medicine' had been omitted from the address. Therefore, the author and affiliation details for this paper should have been presented as follows: Kou­Gi Shyu1,2, Marappan Velusamy3, Chih­Wei Hsia2, Chih­Hao Yang2, Chih­Hsuan Hsia2, Duen­Suey Chou2, Thanasekaran Jayakumar2, Joen­Rong Sheu2 And Jiun­Yi Li2,4. 1Division of Cardiology, Shin Kong Wu Ho­Su Memorial Hospital, Taipei 111; 2Graduate Institute of Medical Sciences and Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, R.O.C.; 3Department of Chemistry, North Eastern Hill University, Shillong, Meghalaya 793022, India; 4Department of Cardiovascular Surgery, Mackay Memorial Hospital, and Mackay Medical College, Taipei 104, Taiwan, R.O.C. The authors regret that the error with the second author affiliation was not noticed prior to the publication of their paper, and apologize for any inconvenience caused. [the original article was published in International Journal of Molecular Medicine 41: 2589­2600, 2018; DOI: 10.3892/ijmm.2018.3472].

Metformin was associated with lower all-cause mortality in type 2 diabetes with acute coronary syndrome: A Nationwide registry with propensity score-matched analysis.

BACKGROUND: No randomized controlled trials evaluating metformin therapy efficacy in patients with type 2 diabetes mellitus (DM) and acute coronary syndrome (ACS) have been reported. We aimed to examine the mortality benefit of metformin therapy in patients with type 2 DM and ACS, compared with non-metformin anti-diabetes agents users. METHODS: Data were extracted from the prospective nationwide ACS-DM Taiwan Society of Cardiology registry. Propensity score (PS) matching on baseline characteristics and treatment measures was performed for metformin versus non-metformin users. The Cox proportional hazards model was used to compare mortality outcomes among the PS-matched cohort as the primary analysis. The Cox proportional hazards models adjusting for all pre-determined covariates and quintiles of the PS among the overall population were performed as the secondary analyses. RESULTS: Of 1157 patients with type 2 DM and ACS receiving anti-diabetes agents, 78 patients (6.7%) died over the 2-year follow-up period. After PS matching, 318 metformin users were matched with 318 non-metformin users. Metformin users had a lower all-cause mortality rate (adjusted hazard ratio [aHR] 0.50, 95% confidence interval [CI] 0.26-0.95) in the primary analysis. The survival benefit of metformin therapy was consistent in the secondary analyses (aHR 0.30, 95% CI 0.17-0.54 while adjusting for all pre-determined covariates, and aHR 0.34, 95% CI 0.19-0.59 while adjusting for quintiles of the PS). CONCLUSIONS: Among patients with type 2 DM and ACS, metformin was associated with lower all-cause mortality. However, a detrimental effect of any of the comparators could not be excluded.