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.

Clinical Observation of SGLT2 Inhibitor Therapy for Cardiac Arrhythmia and Related Cardiovascular Disease in Diabetic Patients with Controlled Hypertension.

Sodium-glucose transporter 2 (SGLT2) inhibitors are new glucose-lowering agents that have been proven to be beneficial for patients with cardiovascular diseases, heart failure, and sudden cardiac death. However, the possible protective effects of cardiac arrhythmia have not yet been clarified in clinical practice. In this study, we attempted to demonstrate the effects of SGLT2 inhibitors on cardiac arrhythmia by medical records from a single center. This retrospective study included patients diagnosed with type 2 diabetes mellitus (DM) and controlled hypertension who prescribed the indicated glucose-lowering agents based on medical records from 2016 to 2019 from Kaohsiung Medical University Hospital. These patients were divided into two groups. Group one patients were defined as patients with SGLT2 inhibitor therapy, and group two patients were defined as patients without SGLT2 inhibitor therapy. Baseline characteristics were collected from medical records. Univariate, multivariate, and match-paired statistical analyses were performed for the study endpoints. The primary study outcome was the incidence of cardiac arrhythmias, including atrial and ventricular arrhythmias, after SGLT2 inhibitor therapy. The secondary study outcomes were the incidence of stroke, heart failure, and myocardial infarction after SGLT2 inhibitor therapy. From the initial 62,704 medical records, a total of 9609 people who met our experimental design criteria were included. The mean follow-up period was 51.50 ± 4.23 months. Group one included 3203 patients who received SGLT2 inhibitors for treatment, and group two included 6406 patients who received non-SGLT2 inhibitors for treatment. Multivariate analysis showed that group one patients had significantly lower incidences of total cardiac arrhythmia (hazard ratio (HR): 0.58, 95% confidence interval (CI): 0.38-0.89, p = 0.013) and atrial fibrillation (HR: 0.56, 95% CI: 0.35-0.88, p = 0.013) than those of group two patients. The secondary outcome analysis showed that group one patients also had a significantly lower risk of stroke (HR: 0.48, 95% CI: 0.33-0.7; p < 0.001), heart failure (HR: 0.54, 95% CI: 0.41-0.7, p < 0.001), and myocardial infarction (HR: 0.47, 95% CI: 0.31-0.72, p < 0.001). A time-to-event analysis showed that treatment of type 2 DM patients with SGLT2 inhibitors could reduce the probability of total cardiac arrhythmia and related cardiovascular disease, such as atrial fibrillation, stroke, heart failure, or myocardial infarction, by 0.5%~0.8%. This databank analysis showed that SGLT2 inhibitor therapy reduced the incidence of total cardiac arrhythmia and atrial fibrillation in type 2 DM patients and decreased the incidence of related cardiovascular diseases, such as stroke, heart failure, and myocardial infarction. However, additional investigations are needed to confirm this hypothesis.

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.

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.

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.

Effects of Trans, Trans-2,4-decadienal on the Ions Currents of Cardiomyocytes: Possible Mechanisms of Arrhythmogenesis Induced by Cooking-oil Fumes.

Household air pollution has adverse effects on cardiovascular health. One of the major sources of household air pollutants is the combustion of cooking oils during cooking. Trans, trans-2,4-decadienal (tt-DDE) is a type of dienaldehyde that is present in a wide range of food and food products. It is a byproduct of the peroxidation of linoleic acid following the heating of oil during cooking. The mechanisms of the associations between household air pollution and cardiac arrhythmias are currently unclear. The purpose of this study was to determine effects of tt-DDE on the ion currents in H9c2 cells. The IK and ICa,L in H9c2 cells treated with and without tt-DDE were measured using the whole-cell patch clamp method. Expressions of Kv2.1 and Cav1.2 in H9c2 cells treated with and without tt-DDE were measured by western blot analysis. After the H9c2 cells had been exposed to tt-DDE, the IK and ICa,L were significantly decreased. The expression of Kv2.1, unlike that of Cav1.2, was also significantly decreased in these cells. These changes in IK and ICa,L that were induced by tt-DDE may help to explain the association between cardiac arrhythmogenesis and cooking-oil fumes.

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.

Association between adiponectin T94G polymorphism and resistant hypertension in young-onset Taiwanese patients.

Young-onset hypertensives (YOHs) with resistant hypertension (RH) have a greater long-term cardiovascular risk. The present study examined whether a functional adiponectin T94G polymorphism (rs2241766) is associated with RH in YOHs. We analyzed data from the Academia Sinica Collaborative Study on Hypertension Genetics in Taiwanese subjects to compare rs2241766 between YOHs with and without RH (≤50 years of age). RH was defined as the need for at least 3 drugs, including a diuretic to control blood pressure. Genotyping of rs2241766 was performed using TaqMan allelic discrimination. A total of 861 YOHs were enrolled and 54 had RH in enrolled population. For the rs2241766 in the allelic model, the odds ratio (OR) of RH allele frequency was 2.45 (p = 0.008), and there was a linear relationship between allele numbers and the presence of RH (p = 0.005). In multivariate analysis, the rs2241766 (OR = 2.766, p = 0.002), age (OR = 1.103, p = 0.001), uric acid (OR = 1.322, p = 0.001), high-sensitivity C-reactive protein (OR = 2.769, p = 0.001) and aldosterone (OR = 1.004, p = 0.001) were independently associated with the presence of RH. In the Taiwanese population, the adiponectin T94G polymorphism (rs2241766) is associated with RH in YOHs.

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.

Characteristics of diurnal ventricular premature complex variation in right ventricular outflow tract arrhythmias after catheter ablation.

Diurnal variations in ventricular tachyarrhythmias (VAs) have been demonstrated in idiopathic arrhythmogenic heart disease. The electrophysiological characteristics of diurnal variations in idiopathic right ventricular outflow tract (RVOT) VA have not previously been elucidated. Sixty-two consecutive patients undergoing catheter ablation for idiopathic RVOT VA (mean age: 42.8 ±â€Š12.3 years, 35 females) were enrolled. The diurnal variation type (group 1, n = 36) was defined as those patients who had most ventricular premature contractions (VPCs) during the night hours by preprocedure Holter recordings. Group 2 (n = 26) was defined as those patients who did not have significant VPC variations. The baseline characteristics and electrophysiological properties were collected and analyzed, and the rates of recurrence after catheter ablation were compared between the 2 groups. In this study, heart rate variability analysis demonstrated lower low frequency/high frequency ratios in group 1 than in group 2 (3.95 ±â€Š3.08 vs 6.26 ±â€Š5.33; P = 0.042). There were no significant differences in baseline characteristics, echocardiography and electrophysiological characteristics between the 2 groups. During a mean follow-up period of 13.5 ±â€Š11.0 months, a total of 16 patients had VA recurrences, including 13 patients from group 1 and 3 patients from group 2 (36.1% vs 12.5%, P = 0.039). This study demonstrated the effect of the autonomic nervous system in idiopathic RVOT VAs and that the diurnal variation type leads to a higher recurrence rate after catheter ablation.

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.

Hormone replacement therapy and risk of atrial fibrillation in Taiwanese menopause women: A nationwide cohort study.

Hormone replacement therapy (HRT) is associated with risk of vascular disease. The association between atrial fibrillation (AF), vascular events, and different HRTs, including estradiol and conjugated equine estrogens (CEE), has been controversial in previous studies. Thus, we conducted a retrospective cohort study to investigate these associations. Female patients (>45 years old) first diagnosed with menopause were enrolled from National Health Insurance Research Dataset (1998-2008). Cox regression analysis estimated risk of new-onset AF, stroke, and major adverse cardiac events (MACE) after exposure to estradiol or CEE. Of 5489 females (mean age = 55 years) enrolled, 1815 treated with estradiol and 3674 treated with CEE. Incidence per 10(3) person-years of AF, stroke, and MACE in CEE vs estradiol patients was 2.23 vs. 0.92, 14.0 vs. 9.09, and 15.55 vs. 10.47. As compared with patients treated with estradiol, those treated with CEE had a significantly higher incidence of AF, stroke, and MACE. The adjusted hazard ratios for each category were 1.96, 1.30, and 1.26, respectively. The significant results remained similar, even after use of propensity-score-matched strategy. In conclusion, CEE was associated with a higher risk of AF, stroke, and MACE than estradiol in menopausal females. Further exploration of underlying mechanisms is necessary.

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.

Uremic retention solute indoxyl sulfate level is associated with prolonged QTc interval in early CKD patients.

Total mortality and sudden cardiac death is highly prevalent in patients with chronic kidney disease (CKD). In CKD patients, the protein-bound uremic retention solute indoxyl sulfate (IS) is independently associated with cardiovascular disease. However, the underlying mechanisms of this association have yet to be elucidated. The relationship between IS and cardiac electrocardiographic parameters was investigated in a prospective observational study among early CKD patients. IS arrhythmogenic effect was evaluated by in vitro cardiomyocyte electrophysiological study and mathematical computer simulation. In a cohort of 100 early CKD patients, patients with corrected QT (QTc) prolongation had higher IS levels. Furthermore, serum IS level was independently associated with prolonged QTc interval. In vitro, the delay rectifier potassium current (IK) was found to be significantly decreased after the treatment of IS in a dose-dependent manner. The modulation of IS to the IK was through the regulation of the major potassium ion channel protein Kv 2.1 phosphorylation. In a computer simulation, the decrease of IK by IS could prolong the action potential duration (APD) and induce early afterdepolarization, which is known to be a trigger mechanism of lethal ventricular arrhythmias. In conclusion, serum IS level is independently associated with the prolonged QTc interval in early CKD patients. IS down-regulated IK channel protein phosphorylation and the IK current activity that in turn increased the cardiomyocyte APD and QTc interval in vitro and in the computer ORd model. These findings suggest that IS may play a role in the development of arrhythmogenesis in CKD patients.

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.

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.