Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor Ameliorate Metabolic Disorder and Obesity Induced Cardiomyocyte Injury and Mitochondrial Remodeling.

Sodium-glucose transporter 2 inhibitors (SGLT2is) exert significant cardiovascular and heart failure benefits in type 2 diabetes mellitus (DM) patients and can help reduce cardiac arrhythmia incidence in clinical practice. However, its effect on regulating cardiomyocyte mitochondria remain unclear. To evaluate its effect on myocardial mitochondria, C57BL/6J mice were divided into four groups, including: (1) control, (2) high fat diet (HFD)-induced metabolic disorder and obesity (MDO), (3) MDO with empagliflozin (EMPA) treatment, and (4) MDO with glibenclamide (GLI) treatment. All mice were sacrificed after 16 weeks of feeding and the epicardial fat secretome was collected. H9c2 cells were treated with the different secretomes for 18 h. ROS production, Ca2+ distribution, and associated proteins expression in mitochondria were investigated to reveal the underlying mechanisms of SGLT2is on cardiomyocytes. We found that lipotoxicity, mitochondrial ROS production, mitochondrial Ca2+ overload, and the levels of the associated protein, SOD1, were significantly lower in the EMPA group than in the MDO group, accompanied with increased ATP production in the EMPA-treated group. The expression of mfn2, SIRT1, and SERCA were also found to be lower after EMPA-secretome treatment. EMPA-induced epicardial fat secretome in mice preserved a better cardiomyocyte mitochondrial biogenesis function than the MDO group. In addition to reducing ROS production in mitochondria, it also ameliorated mitochondrial Ca2+ overload caused by MDO-secretome. These findings provide evidence and potential mechanisms for the benefit of SGLT2i in heart failure and arrhythmias.

Characteristics of Ventricular Electrophysiological Substrates in Metabolic Mice Treated with Empagliflozin.

Empagliflozin (EMPA) is a sodium-glucose transporter 2 (SGLT2) inhibitor that functions as a new-generation glucose-lowering agent and has been proven to be beneficial for patients with cardiovascular diseases. However, the possible benefits and mechanisms of its antiarrhythmic effects in cardiac tissue have not yet been reported. In this study, we elucidated the possible antiarrhythmic effects and mechanisms of EMPA treatment in cardiac tissues of metabolic syndrome (MS) mice. A total of 20 C57BL/6J mice (age: 8 weeks) were divided into four groups: (1) control group, mice fed a standard chow for 16 weeks; (2) MS group, mice fed a high-fat diet for 16 weeks; (3) EMPA group, mice fed a high-fat diet for 12 weeks and administered EMPA at 10 mg/kg daily for the following 4 weeks; and (4) glibenclamide (GLI) group, mice fed a high-fat diet for 12 weeks and administered GLI at 0.6 mg/kg daily for the following 4 weeks. All mice were sacrificed after 16 weeks of feeding. The parameters of electrocardiography (ECG), echocardiography, and the effective refractory period (ERP) of the left ventricle were recorded. The histological characteristics of cardiac tissue, including connexin (Cx) expression and fibrotic areas, were also evaluated. Compared with the MS group, the ECG QT interval in the EMPA group was significantly shorter (57.06 ± 3.43 ms vs. 50.00 ± 2.62 ms, p = 0.011). The ERP of the left ventricle was also significantly shorter in the EMPA group than that in the GLI group (20.00 ± 10.00 ms vs. 60.00 ± 10.00 ms, p = 0.001). The expression of Cx40 and Cx43 in ventricular tissue was significantly lower in the MS group than in the control group. However, the downregulation of Cx40 and Cx43 was significantly attenuated in the EMPA group compared with the MS and GLI groups. The fibrotic areas of ventricular tissue were also fewer in the EMPA group than that in the MS group. In this study, the ECG QT interval in the EMPA group was shorter than that in the MS group. Compared with the MS group, the EMPA group exhibited significant attenuation of downregulated connexin expression and significantly fewer fibrotic areas in ventricles. These results may provide evidence of possible antiarrhythmic effects of EMPA.

Effects of Secretome from Fat Tissues on Ion Currents of Cardiomyocyte Modulated by Sodium-Glucose Transporter 2 Inhibitor.

Sodium-glucose transporter 2 (SGLT2) inhibitors were shown to decrease mortality from cardiovascular diseases in the EMPA-REG trial. However, the effects of empagliflozin (EMPA) for cardiac arrhythmia are not yet clarified. A total of 20 C57BL/6J mice were divided into four groups: (1) The control group were fed standard chow, (2) the metabolic syndrome (MS) group were fed a high-fat diet, (3) the empagliflozin (EMPA) group were fed a high-fat diet and empagliflozin 10 mg/kg daily, and (4) the glibenclamide (GLI) group were fed a high-fat diet and glibenclamide 0.6 mg/kg daily. All mice were sacrificed after 16 weeks of feeding. H9c2 cells were treated with adipocytokines from the pericardial and peripheral fat from the study groups. The delayed-rectifier potassium current (IK) and L-type calcium channel current (ICa,L) were measured by the whole-cell patch clamp techniques. Adipocytokines from the peripheral and pericardial fat tissues of mice with MS could decrease the IK and increase the ICa,L of cardiomyocytes. After treating adipocytokines from pericardial fat, the IK in the EMPA and GLI groups were significantly higher than that in the MS group. The IK of the EMPA group was also significantly higher than the GLI group. The ICa,L of the EMPA and GLI groups were significantly decreased overload compared with that of the MS group. However, there was no significant difference of IK and ICa,L among study groups after treating adipocytokines from peripheral fat. Adipocytokines from pericardial fat but not peripheral fat tissues after EMPA therapy attenuated the effects of IK decreasing and ICa,L increasing in the MS cardiomyocytes, which may contribute to anti-arrhythmic mechanisms of sodium-glucose transporter 2 (SGLT2) inhibitors.

The Arrhythmogenic Effect of Protein-Bound Uremic Toxin p-Cresylsulfate: An In Vitro Study.

BACKGROUND: p-Cresylsulfate (PCS) is a protein-bound uremic toxin that accumulates in patients with chronic kidney disease. Previous studies have indicated that serum total PCS levels are significantly increased in the presence of abnormal corrected QT (QTc) intervals, and that they are associated with QTc prolongation. However, the QTc prolongation effect of PCS remains unclear. The current study aimed to investigate the arrhythmogenic effect of PCS using in vitro experiments and computer simulation. METHODS: The arrhythmogenic effect of PCS was evaluated by incubating H9c2 rat ventricular cardiomyocytes in vitro with increasing concentrations of PCS. Electrophysiological studies and mathematical computer simulations were performed. RESULTS: in vitro, the delayed rectifier potassium current (IK ) was significantly decreased in a dose-dependent manner after treatment with PCS. The modulation of PCS on IK was through regulation of the phosphorylation of the major potassium ion channel protein Kv2.1. In computer simulations, the decrease in IK induced by PCS prolonged the action potential duration (APD) and sped up the re-entrant wave, which is known to be a trigger mechanism for lethal ventricular arrhythmias. CONCLUSIONS: PCS significantly downregulated the phosphorylation of the IK channel protein Kv2.1 and IK current activity, which increased the cardiomyocyte APD. This was observed both in vitro and in the computer O'Hara-Rudy dynamic human ventricular model. These findings suggest that PCS may play a key role in the development of cardiac arrhythmias.

The association of the amounts of epicardial fat, P wave duration, and PR interval in electrocardiogram.

BACKGROUND: The relationship of epicardial fat and cardiac arrhythmias has been described in many studies. The association of the amounts of epicardial fat and the characteristics of electrocardiogram (ECG) remains unclear. The purpose of this study was to elucidate the association between the amounts of epicardial fat and the characteristics of ECG. METHODS: A total of 100 consecutive patients who received multi-detector computer tomography (MDCT) were enrolled. The amounts of epicardial fat, including total heart, total atria, total ventricles, right atrium (RA), right ventricle (RV), left atrium (LA), and left ventricle (LV) regions, were measured. The PR interval in lead II, the P wave duration in lead I, the characteristics of inter-atrial conduction block manifested in ECG, the corrected QT interval (QTc) and the QT dispersion of a 12­lead ECG were measured manually by a computer caliper. RESULTS: The PR interval was correlated with the amounts of epicardial fat including total heart, total atria, total ventricles, RA, RV, LA, and LV (R = 0.295, p = 0.003; R = 0.379, p < 0.001; R = 0.284, p = 0.003; R = 0.415, p < 0.001; R = 0.287, p < 0.001; R = 0.33, p < 0.001; R = 0.244, p = 0.014). The P wave duration of lead I was also correlated with the amounts of epicardial fat (R = 0.202, p = 0.043; R = 0.283, p = 0.004; R = 0.225, p = 0.024; R = 0.365, p < 0.001; R = 0.256, p = 0.001; R = 0.20, p = 0.046; R = 0.199, p = 0.048) but the QTc interval and the QT dispersion were not. Inter-atrial conduction block was also associated with the amounts of epicardial fat, including total atria, RA and LA in univariate analysis (odds ratio (OR): 1.04, 95% of confidence interval (CI): 1.01-1.06, p = 0.015; OR: 1.08, 95% CI: 1.02-1.15, p = 0.011; OR: 1.05, 95% CI: 1.01-1.10, p = 0.031). In multivariate analysis of linear regression, the amounts of RA epicardial fat was most significantly associated with the PR interval, and the P wave duration (ß value: 1.30, 95% CI: 0.59-2.02, p < 0.001; ß value: 0.81, 95% CI: 0.34-1.28, p = 0.001). In multivariate analysis of logistic regression, inter-atrial conduction block was also significantly associated with the amounts of RA epicardial fat (odds ratio (OR): 1.08, 95% CI: 1.02-1.15, p = 0.011). CONCLUSIONS: The PR interval, P wave duration and inter-atrial conduction block were associated with the amounts of epicardial fat, which might imply an effect for arrhythmogenesis.

2016 Guidelines of the Taiwan Heart Rhythm Society and the Taiwan Society of Cardiology for the management of atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia. Both the incidence and prevalence of AF are increasing, and the burden of AF is becoming huge. Many innovative advances have emerged in the past decade for the diagnosis and management of AF, including a new scoring system for the prediction of stroke and bleeding events, the introduction of non-vitamin K antagonist oral anticoagulants and their special benefits in Asians, new rhythm- and rate-control concepts, optimal endpoints of rate control, upstream therapy, life-style modification to prevent AF recurrence, and new ablation techniques. The Taiwan Heart Rhythm Society and the Taiwan Society of Cardiology aimed to update the information and have appointed a jointed writing committee for new AF guidelines. The writing committee members comprehensively reviewed and summarized the literature, and completed the 2016 Guidelines of the Taiwan Heart Rhythm Society and the Taiwan Society of Cardiology for the Management of Atrial Fibrillation. This guideline presents the details of the updated recommendations, along with their background and rationale, focusing on data unique for Asians. The guidelines are not mandatory, and members of the writing committee fully realize that treatment of AF should be individualized. The physician's decision remains most important in AF management.

Association of Single Nucleotide Polymorphisms with Atrial Fibrillation and the Outcome after Catheter Ablation.

BACKGROUND: The association of gene variants with atrial fibrillation (AF) type and the recurrence of AF after catheter ablation in Taiwan is still unclear. In this study, we aimed to investigate the relationships between gene variants, AF type, and the recurrence of AF. METHODS: In our investigation, we examined 383 consecutive patients with AF (61.9 ± 14.0 years; 63% men); of these 383 patients, 189 underwent catheter ablation for drug-refractory AF. Thereafter, the single nucleotide polymorphisms rs2200733, and rs7193343 were genotyped using real-time polymerase chain reaction. RESULTS: The rs7193343 variant was independently associated with non-paroxysmal AF (non-PAF). In the PAF group, the rs7193343 variant was independently associated with AF recurrence after catheter ablation. However, the rs2200733 variant was not associated with AF recurrence in this group. The combination of the rs7193343 and rs2200733 risk alleles was associated with a better predictive power in the PAF patients. In contrast, in the non-PAF group, the SNPs were not associated with recurrence. The rs7193343 and rs2200733 variants were not associated with different atrial voltage and activation times. CONCLUSIONS: The rs7193343 variants were associated with AF recurrence after catheter ablation in PAF patients but not in non-PAF patients. The rs7193343 CC variant was independently associated with non-PAF.

Lipid paradox in acute myocardial infarction-the association with 30-day in-hospital mortality.

OBJECTIVES: Elevated low-density lipoprotein cholesterol and triglycerides are major risk factors for coronary artery disease. However, fatty acids from triglycerides are a major energy source, low-density lipoprotein cholesterol is critical for cell membrane synthesis, and both are critical for cell survival. This study was designed to clarify the relationship between lipid profile, morbidity as assessed by Killip classification, and 30-day mortality in patients with acute myocardial infarction. DESIGN: A noninterventional observational study. SETTING: Coronary care unit in a university hospital. PATIENTS: Seven hundred twenty-four patients with acute myocardial infarction in the coronary care program of the Bureau of Health Promotion were analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Low-density lipoprotein cholesterol and triglyceride levels were significantly lower in high-Killip (III+IV) patients compared with low-Killip (I+II) patients and in those who died compared with those who survived beyond 30 days (both p<0.001). After adjustment for risk factors, low-density lipoprotein cholesterol less than 62.5 mg/dL and triglycerides less than 110 mg/dL were identified as optimal threshold values for predicting 30-day mortality and were associated with hazard ratios of 1.65 (95% CI, 1.18-2.30) and 5.05 (95% CI, 1.75-14.54), and the actual mortality rates were 23% in low low-density lipoprotein, 6% in high low-density lipoprotein, 14% in low triglycerides, and 3% in high triglycerides groups, respectively. To test the synergistic effect, high-Killip patients with triglycerides less than 62.5 mg/dL and low-density lipoprotein cholesterol less than 110 mg/dL had a 10.9-fold higher adjusted risk of mortality than low-Killip patients with triglycerides greater than or equal to 62.5 mg/dL and low-density lipoprotein cholesterol greater than or equal to 110 mg/dL (p<0.001). The lipid paradox also improved acute myocardial infarction short-term outcomes prediction on original Killip and thrombolytic in myocardial infarction scores. CONCLUSIONS: Low low-density lipoprotein cholesterol, low triglycerides, and high Killip severity were associated with significantly higher 30-day in-hospital mortality in patients presenting with acute myocardial infarction. The initial lipid profile of patients with acute myocardial infarction may therefore hold prognostic value.

Clinical Aspects of Aconitum Preparations.

Aconite species have played an important role in human history. Aconitum species have been used worldwide as poisons as well as remedies. Their potential in targeting several ailments such as pain, rheumatism, and lethargy has been recognized by Western, Chinese, and Indian health care practitioners. Aconite use in herbal preparations has declined, especially in Europe and the United States, in the first half of the twentieth century due to several reported toxicity cases. The situation has changed with the application of new technologies for the accurate analysis of its toxic components and the development of efficient detoxification protocols. Some Asian countries started small clinical trials to evaluate the potency and safety of different marketed aconite preparations. The current review summarizes therapeutic uses of aconite preparations in China, Taiwan, India, and Japan. It also highlights clinical trial results with special emphasis on their limitations. Modern drugs and pharmacopoeial preparations derived from aconite are also discussed.

Diffuse ST-Segment Depression with ST-Segment Elevation in Lead aVR in 12-Lead Electrocardiography May Indicate Ischemic Change of Severe Aortic Stenosis.

UNLABELLED: Diffuse ST-segment depression with ST-segment elevation in the lead augmented vector right (aVR) in 12-lead electrocardiography may indicate the possibility of coronary artery disease involving the left main coronary artery or proximal left anterior descending artery, pulmonary embolism or takotsubo cardiomyopathy. We report a 69-year-old female with severe aortic stenosis, who had similar electrocardiographic findings which indicated ischemic change and led to cardiogenic shock and ventricular tachycardia. Intubation and insertion of an intra- aortic balloon pump (IABP) were performed and the result of coronary angiography showed only less than 40% stenosis. Her blood pressure gradually stabilized, and diffuse ST-segment depression or ST-segment elevation in lead aVR was not noted in the 12-lead electrocardiography. However, we removed the IABP and after 6 hours, sudden profound shock refractory to combined vasopressors occurred. Electrocardiography again showed ST- segment elevation in aVR with and diffuse ST-segment depression. After several episodes of ventricular tachycardia, cardiopulmonary resuscitation was not successful and the patient expired in our hospital. KEY WORDS: Diffuse ST depression; Severe aortic stenosis; ST elevation in aVR.

Differential effects of central and peripheral fat tissues on the delayed rectifier K(+) outward currents in cardiac myocytes.

OBJECTIVES: The amount of fat tissue is associated with an increasing incidence of cardiac arrhythmias. The purpose of this study was to investigate effects of adipocytokines from different body fat on delayed rectifier K(+) outward currents (IK). METHODS: H9c2 cells were treated with adipocytokine-free medium (the Adipo-free group) and with adipocytokines from epicardial (central fat group) and limb (peripheral fat group) rat fat tissues. IK, as well as expressions of Kv2.1 and Kv2.1 mRNA in H9c2 cells, were measured and compared between different groups. RESULTS: IK measured in H9c2 cells immediately after treatment with adipocytokines were not significantly different from those treated with adipocytokine-free medium. After H9c2 cells were treated with adipocytokines for 18 h, IK were significantly decreased in the peripheral and central fat groups in comparison with the Adipo-free group. Compared with the peripheral fat group, IK were more significantly decreased in the central fat group. Expressions of Kv2.1 and Kv2.1 mRNA in H9c2 cells were not significantly different among the three groups. CONCLUSIONS: Adipocytokines significantly decreased IK in H9c2 cells, and IK was more prominently decreased by adipocytokines from epicardial fat than from limb fat tissues. The decrease in IK by adipocytokines may partially contribute to the mechanisms of arrhythmogenesis by fat tissues.

Epidemiology and clinical characteristics of congenital hypothyroidism in an Asian population: a nationwide population-based study.

BACKGROUND: The incidence of congenital hypothyroidism (CH) has been increasing in Western countries, and some populations, including Asians, have a higher incidence. Delayed diagnosis and early treatment influence the outcome of CH. We investigated the incidence and clinical characteristics of CH in Taiwan. METHODS: In this retrospective database study we identified cases of CH diagnosed during 1997-2008 in the Taiwan National Health Insurance Research Database (NHIRD). Patients who had a Serious Accidents and Diseases certificate were included in the incidence calculation. We focused on CH patients who were born during 1997-2003 and determined their age at diagnosis and CH-related clinical features. Mental retardation and physiological delays were evaluated with respect to age at diagnosis. RESULTS: A total of 1482 cases were identified. Incidence during the 12-year period was 5.02 per 10 000 births. Among 1115 patients, the most common clinical features of CH were developmental delay (9.6%), constipation (11.6%), and delayed physiological development (9.1%). Congenital anomalies of the heart (7.7%), epilepsy (2.7%), and infantile cerebral palsy (3.2%) were also noted. Survival analysis showed that the risks of mental retardation (hazard ratio [HR], 3.180) and delayed physiological development (HR, 1.908) were greater when age at diagnosis was greater than 1 year. CONCLUSIONS: CH incidence was higher in Taiwan than in Western countries. Early diagnosis may decrease the risk of mental and physiological delay.

Areca nut chewing and risk of atrial fibrillation in Taiwanese men: a nationwide ecological study.

BACKGROUND: Areca nut chewing is associated with the risk of obesity, metabolic syndrome, hypertension, and cardiovascular mortality. Although a few case reports or case series have suggested the link between areca nut chewing and cardiac arrhythmias, information about the relationship between areca nut chewing and atrial fibrillation (AF) is lacking. Thus, a nationwide ecological study was conducted to investigate this. METHODS: Two national datasets, the nationwide population-based 2005 Taiwan National Health Insurance Research dataset (NHIRD) and the 2005 National Health Interview Survey (NHIS), were used for analyses. The clinical characteristics, inhabited area and medical histories for 375,360 eligible males were retrieved from the 2005 NHIRD. Health related behaviors including areca nut chewing, cigarette smoking, infrequent vegetable eating, and exercise habit were collected from the 2005 NHIS. The prevalence of AF and the areca nut chewing rate were evaluated by multivariate analysis. RESULTS: Of the 375,360 males (mean age, 44 years old), 1,326 (0.35%) were diagnosed with AF. The higher areca nut chewing rate, the higher prevalence rate of AF in Taiwan (Spearman correlation coefficient r=0.558, p=0.007). After adjusting for other covariates, the current areca nut chewing rate was found to be independently associated with the prevalence of AF. The adjusted odd ratio for areca nut chewing was 1.02 (95% CI=1.00-1.04) in risk of AF prevalence. CONCLUSIONS: Areca nut chewing is independently associated with the prevalence of AF in Taiwanese men. However, further exploration of the underlying mechanisms is necessary.

Association of increased arterial stiffness and p wave dispersion with left ventricular diastolic dysfunction.

BACKGROUND: The association between increased arterial stiffness and left ventricular diastolic dysfunction (LVDD) may be influenced by left ventricular performance. P wave dispersion is not only a significant determinant of left ventricular performance, but is also correlated with LVDD. This study is designed to compare left ventricular diastolic function among patients divided by brachial-ankle pulse wave velocity (baPWV) and corrected P wave dispersion (PWDC) and assess whether the combination of baPWV and PWDC can predict LVDD more accurately. METHODS: This cross-sectional study enrolled 270 patients and classified them into four groups according to the median values of baPWV and PWDC. LVDD was defined as impaired relaxation and pseudonormal/restrictive mitral inflow patterns. RESULTS: The ratio of transmitral E wave velocity to early diastolic mitral annulus velocity (E/Ea) was higher in group with higher baPWV and PWDC than in the other groups (all p <0.001). The prevalence of LVDD was higher in group with higher baPWV and PWDC than in the two groups with lower baPWV (p ≤ 0.001). The baPWV and PWDC were correlated with E/Ea and LVDD in multivariate analysis (p ≤ 0.030). The addition of baPWV and PWDC to a clinical mode could significantly improve the R square in prediction of E/Ea and C statistic and integrated discrimination index in prediction of LVDD (p ≤ 0.010). CONCLUSIONS: This study showed increased baPWV and PWDC were correlated with high E/Ea and LVDD. The addition of baPWV and PWDC to a clinical model improved the prediction of high E/Ea and LVDD. Screening patients by means of baPWV and PWDC might help identify the high risk group of elevated left ventricular filling pressure and LVDD.

Postchallenge responses of nitrotyrosine and TNF-alpha during 75-g oral glucose tolerance test are associated with the presence of coronary artery diseases in patients with prediabetes.

BACKGROUND: Meta-analysis has demonstrated an exponential relationship between 2-hr postchallenge hyperglycemia and coronary artery disease (CAD). Pulsatile hyperglycemia can acutely increase proinflammatory cytokines by oxidative stress. We hypothesized that postchallenge proinflammatory and nitrosative responses after 75 g oral glucose tolerance tests (75 g-OGTT) might be associated with CAD in patients without previously recognized type 2 diabetes mellitus (T2DM). METHODS: Serial changes of plasma glucose (PG), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and nitrotyrosine levels were analyzed during 75 g-OGTT in 120 patients (81 male; age 62 ± 11 years) before coronary angiography. Patients were classified as normal (NGT; 42%), impaired (IGT; 34%) and diabetic (T2DM; 24%) glucose tolerance by 75 g-OGTT. RESULTS: Postchallenge hyperglycemia elicited TNF-α, IL-6 and nitrotyrosine levels time-dependently, and 2-hr median levels of TNF-α (7.1 versus 6.4 pg/ml; P < 0.05) and nitrotyrosine (1.01 versus 0.83 µmol/l; P < 0.05), but not IL-6 or PG, were significantly higher in patients with CAD in either IGT or T2DM groups. After adjusting risk factors and glucose tolerance status, 2-hr nitrotyrosine in highest quartiles (OR: 3.1, P < 0.05) remained an independent predictor of CAD by logistic regression analysis. CONCLUSIONS: These results highlight postchallenge proinflammatory and nitrosative responses by 75 g-OGTT, rather than hyperglycemia per se, are associated with CAD in patients without previous recognized diabetes.

Characteristics of atrial substrates for atrial tachyarrhythmias induced in aged and hypercholesterolemic rabbits.

BACKGROUND: Old age and dyslipidemia increase the occurrence of atrial tachyarrhythmias (ATR). This study investigated the effect of age and hypercholesterolemia on the atrial substrates for ATR. METHODS: Five 3-year-old rabbits fed standard chow were categorized into an old-age group, five 3-month-old rabbits fed high cholesterol chow were used as a hypercholesterolemia group, and five 3-month-old rabbits fed standard chow were controls. Effective refractory period, atrial vulnerability to ATR, expressions of connexin40 (Cx40) and connexin43 (Cx43), phosphorylated c-Jun N-terminal Kinase (P-JNK), and degree of fibrosis in the right (RA) and left (LA) atria were compared. RESULTS: Old-age and hypercholesterolemia rabbits were more vulnerable to ATR than the controls (18,628 ± 13,981 ms and 30,157 ± 39,548 ms vs 639 ± 325 ms, P < 0.05). Old-age rabbits had significantly decreased Cx40 expression in both atria (3.9-fold decrease in RA, P < 0.01 and 4.8-fold in LA, P < 0.01) and significantly decreased Cx43 in RA (14-fold, P < 0.01). Hypercholesterolemia rabbits had significantly decreased Cx40 expression in both atrial (18-fold decrease in RA, P < 0.01 and 17-fold in LA, P < 0.01) and significantly increased Cx43 expression in LA (five-fold increase, P < 0.01). Hypercholesterolemia, but not old-age rabbits, had greater expression of P-JNK in both atria (1.8-fold in RA and 2.3-fold in LA, P < 0.01). There were no significant group differences in ERP or degree of atrial fibrosis in both atria. CONCLUSIONS: ATR is more easily induced in the atria of old-age and hypercholesterolemia rabbits than younger rabbits with normal cholesterol levels. The age and hypercholesterolemia induced changes in gap junctions expression may have partially contributed to the higher atrial vulnerability to ATR.

Effectiveness and safety of antiplatelet therapy in stroke recurrence prevention in patients with liver cirrhosis: a 2-year follow-up study.

BACKGROUND: Data are limited on antiplatelet therapy for ischemic stroke prevention in liver cirrhosis patients. METHODS: This retrospective study identified cases of liver cirrhosis from the National Health Insurance Research Database. Antiplatelet therapy was administered for 2 years to patients who had experienced a first ischemic stroke between 1997 and 2006. Primary outcomes, including death and readmission to hospital for stroke, and secondary outcomes, including death, stroke, or gastrointestinal bleeding, were examined. RESULTS: One thousand one hundred eighty patients experienced a first stroke. According to time-dependent analysis, the hazard ratio for primary outcomes in patients treated with aspirin was 0.915 (95%CI: 0.872-0.960). In secondary outcomes, hazard ratio for readmission for stroke was 0.904 (95%CI: 0.836-0.978) and that for gastrointestinal bleeding was 0.998 (95%CI: 0.946-1.052) in patients treated with aspirin. Subgroup analysis showed that aspirin was more effective in patients with non-alcoholic cirrhosis than in those with other types of liver cirrhosis. Moreover, hyperlipidemia and statins may have decreased the efficacy of antiplatelet therapy in cirrhosis patients. CONCLUSIONS: This study includes the largest sample for evaluating outcomes of antiplatelet therapy in liver cirrhosis patients for preventing recurrent stroke. The study results show that antiplatelet therapy still offers safe and effective treatment for ischemic stroke prevention in patients with cirrhosis.

Chewing areca nut increases the risk of coronary artery disease in Taiwanese men: a case-control study.

BACKGROUND: Areca nut chewing has been reported to be associated with obesity, metabolic syndrome, hypertension, and cardiovascular mortality in previous studies. The aim of this study was to examine whether chewing areca nut increases the risk of coronary artery disease (CAD) in Taiwanese men. METHODS: This study is a hospital-based case-control study. The case patients were male patients diagnosed in Taiwan between 1996 and 2009 as having a positive Treadmill exercise test or a positive finding on the Thallium-201 single-photon emission computed tomography myocardial perfusion imaging. The case patients were further evaluated by coronary angiography to confirm their CAD. Obstructive CAD was defined as a ≥ 50% decrease in the luminal diameter of one major coronary artery. The patients who did not fulfill the above criteria of obstructive CAD were excluded.The potential controls were males who visited the same hospital for health check-ups and had a normal electrocardiogram but no history of ischemic heart disease or CAD during the time period that the case patients were diagnosed. The eligible controls were randomly selected and frequency-matched with the case patients based on age. Multiple logistic regression analyses were used to estimate the odds ratio of areca nut chewing and the risk of obstructive CAD. RESULTS: A total of 293 obstructive CAD patients and 720 healthy controls, all men, were analyzed. Subjects who chewed areca nut had a 3.5-fold increased risk (95% CI = 2.0-6.2) of having obstructive CAD than those without, after adjusting for other significant covariates. The dose-response relationship of chewing areca nut and the risk of obstructive CAD was also noted. After adjusting for other covariates, the 2-way additive interactions for obstructive CAD risk were also significant between areca nut use and cigarette smoking, hypertension and dyslipidemia. CONCLUSIONS: Long-term areca nut chewing was an independent risk factor of obstructive CAD in Taiwanese men. Interactive effects between chewing areca nut and cigarette smoking, hypertension, and dyslipidemia were also observed for CAD risk. Further exploration of their underlying mechanisms is necessary.

The Impact of Urate-Lowering Therapy in Post-Myocardial Infarction Patients: Insights From a Population-Based, Propensity Score-Matched Analysis.

The role of urate-lowering therapy (ULT) for the primary prevention of cardiovascular (CV) events has been widely discussed, but its evidence for the secondary prevention of myocardial infarction (MI) is limited. Therefore, we conduct a population-based, propensity score-matched cohort study to investigate the CV outcomes among patients with post-MI with and without ULT. A total of 19,042 newly diagnosed in-hospital patients with MI were selected using the Taiwan National Health Insurance Database between January 1, 2005, and December 31, 2016. After 1:1 propensity score matching with covariates, patients with MI with (n = 963) and without (n = 963) ULT were selected for further analysis. The primary outcome was the all-cause mortality and the secondary outcomes were composite CV outcomes, including hospitalization for recurrent MI, stroke, heart failure, and cardiac arrhythmias. ULT users were associated with lower all-cause mortality (adjusted hazard ratio (adjHR), 0.67; 95% confidence interval (CI), 0.51-0.87) compared to the ULT nonusers. In addition, ULT users had a significantly lower risk of recurrent MI, which needed revascularization by percutaneous coronary intervention or coronary artery bypass grafting (adjHR, 0.67; 95% CI, 0.53-0.86) than the ULT nonusers. The primary and secondary outcomes were not different between patients with post-MI who received uricosuric agents and xanthine oxidase inhibitors. The anti-inflammatory effect of ULT plays an essential role in MI management. From a real-world setting, this study shows that ULT is associated with the lower risk of all-cause mortality in patients with post-MI. In addition, the result shows the possible lower incidence of repeat revascularization procedures in the ULT users.

Zebrafish Model-Based Assessment of Indoxyl Sulfate-Induced Oxidative Stress and Its Impact on Renal and Cardiac Development.

Kidney disease patients may have concurrent chronic kidney disease-associated mineral bone disorder and hypertension. Cardiovascular disease (CVD) and neuropathy occur due to kidney failure-induced accumulation of uremic toxins in the body. Indoxyl sulfate (IS), a product of indole metabolism in the liver, is produced from tryptophan by the intestinal flora and is ultimately excreted through the kidneys. Hemodialysis helps renal failure patients eliminate many nephrotoxins, except for IS, which leads to a poor prognosis. Although the impacts of IS on cardiac and renal development have been well documented using mouse and rat models, other model organisms, such as zebrafish, have rarely been studied. The zebrafish genome shares at least 70% similarity with the human genome; therefore, zebrafish are ideal model organisms for studying vertebrate development, including renal development. In this study, we aimed to investigate the impact of IS on the development of zebrafish embryos, especially cardiac and renal development. At 24 h postfertilization (hpf), zebrafish were exposed to IS at concentrations ranging from 2.5 to 10 mM. IS reduced survival and the hatching rate, caused cardiac edema, increased mortality, and shortened the body length of zebrafish embryos. In addition, IS decreased heart rates and renal function. IS affected zebrafish development via the ROS and MAPK pathways, which subsequently led to inflammation in the embryos. The results suggest that IS interferes with cardiac and renal development in zebrafish embryos, providing new evidence about the toxicity of IS to aquatic organisms and new insights for the assessment of human health risks. Accordingly, we suggest that zebrafish studies can ideally complement mouse model studies to allow the simultaneous and comprehensive investigation of the physiological impacts of uremic endotheliotoxins, such as IS, on cardiac and renal development.