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.

Up-regulated small-conductance calcium-activated potassium currents contribute to atrial arrhythmogenesis in high-fat feeding mice.

AIMS: Metabolic syndrome (MetS) is associated with arrhythmias and cardiovascular mortality. Arrhythmogenesis in MetS results from atrial structural and electrical remodelling. The small-conductance Ca2+-activated K+ (SK) currents modulate atrial repolarization and may influence atrial arrhythmogenicity. This study investigated the regulation of SK current perturbed by a high-fat diet (HFD) to mimic MetS. METHODS AND RESULTS: Thirty mice were divided into two groups that were fed with normal chow (CTL) and HFD for 4 months. Electrocardiography and echocardiography were used to detect cardiac electrical and structure remodelling. Atrial action potential duration (APD) and calcium transient duration (CaTD) were measured by optical mapping of Langendorff-perfused mice hearts. Atrial fibrillation (AF) inducibility and duration were assessed by burst pacing. Whole-cell patch clamp was performed in primarily isolated atrial myocytes for SK current density. The SK current density is higher in atrial myocytes from HFD than in CTL mice (P ≤ 0.037). The RNA and protein expression of SK channels are increased in HFD mice (P ≤ 0.041 and P ≤ 0.011, respectively). Action potential duration is shortened in HFD compared with CTL (P ≤ 0.015). The shortening of the atrial APD in HFD is reversed by the application of 100 nM apamin (P ≤ 0.043). Compared with CTL, CaTD is greater in HFD atria (P ≤ 0.029). Calcium transient decay (Tau) is significantly higher in HFD than in CTL (P = 0.001). Both APD and CaTD alternans thresholds were higher in HFD (P ≤ 0.043), along with higher inducibility and longer duration of AF in HFD (P ≤ 0.023). CONCLUSION: Up-regulation of apamin-sensitive SK currents plays a partial role in the atrial arrhythmogenicity of HFD mice.

Skin sympathetic nerve activity and ventricular arrhythmias in acute coronary syndrome.

BACKGROUND: Acute coronary syndrome (ACS) is major cause of ventricular arrhythmias (VAs) and sudden death. neuECG is a noninvasive method to simultaneously record skin sympathetic nerve activity (SKNA) and electrocardiogram. OBJECTIVE: The purpose of this study was to test the hypotheses that (1) ACS increases average SKNA (aSKNA), (2) the magnitude of aSKNA elevation is associated with VAs during ACS, and (3) there is a gender difference in aSKNA between patients without and with ACS. METHODS: We prospectively studied 128 ACS and 165 control participants. The neuECG was recorded with electrodes at Lead I configuration at baseline, during mental math stress, and during recovery (5 minutes for each phase). All recordings were done in the morning. RESULTS: In the control group, women have higher aSKNA than do men at baseline (0.82 ± 0.25 µV vs 0.73 ± 0.20 µV; P = .009) but not during mental stress (1.21 ± 0.36 µV vs 1.16 ± 0.36 µV; P = .394), suggesting women had lower sympathetic reserve. In comparison, ACS is associated with equally elevated aSKNA in women vs men at baseline (1.14 ± 0.33 µV vs 1.04 ± 0.35 µV; P = .531), during mental stress (1.46 ± 0.32 µV vs 1.33 ± 0.37 µV; P = .113), and during recovery (1.30 ± 0.33 µV vs 1.11 ± 0.30 µV; P = .075). After adjusting for age and gender, the adjusted odds ratio for VAs including ventricular tachycardia and ventricular fibrillation is 1.23 (95% confidence interval 1.05-1.44) for each 0.1 µV aSKNA elevation. aSKNA is positively correlated with plasma norepinephrine level. CONCLUSION: ACS is associated with elevated aSKNA, and the magnitude of aSKNA elevation is associated with the occurrence of VAs. Women have higher aSKNA and lower SKNA reserve than do men among controls but not among patients with ACS.

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.

High Skin Sympathetic Nerve Activity in Patients with Recurrent Syncope.

(1) Background: The autonomic imbalance plays a role in vasovagal syncope (VVS) diagnosed by head-up tilting test (HUT). neuECG is a new method of recording skin electrical signals to simultaneously analyze skin sympathetic nerve activity (SKNA) and electrocardiogram. We hypothesize that SKNA is higher in subjects with tilt-positive than tilt-negative and the SKNA surges before syncope. (2) Methods: We recorded neuECG in 41 subjects who received HUT (according to the "Italian protocol"), including rest, tilt-up, provocation and recovery phases. Data were analyzed to determine the average SKNA (aSKNA, µV) per digitized sample. Electrocardiogram was used to calculate standard deviation of normal-to-normal beat intervals (SDNN). The "SKNA-SDNN index" was calculated by rest aSKNA multiplied by the ratio of tilt-up to rest SDNN. (3) Results: 16 of 41 (39%) subjects developed syncope. The aSKNA at rest phase is significantly higher in the tilt-positive (1.21 ± 0.27 µV) than tilt-negative subjects (1.02 ± 0.29 µV) (p = 0.034). There are significant surges and withdraw of aSKNA 30 s before and after syncope (both p ≤ 0.006). SKNA-SDNN index is able to predict syncope (p < 0.001). (4) Conclusion: Higher SKNA at rest phase is associated with positive HUT. The SKNA-SDNN index is a novel marker to predict syncope during HUT.

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.

Shorter Leukocyte Telomere Length Is Associated With Atrial Remodeling and Predicts Recurrence in Younger Patients With Paroxysmal Atrial Fibrillation After Radiofrequency Ablation.

BACKGROUND: Telomere length is a biologic aging marker. This study investigated leukocyte telomere length (LTL) as a new biomarker to predict recurrence after paroxysmal atrial fibrillation (PAF) ablation.Methods and Results:A total of 131 participants (26 healthy individuals and 105 symptomatic PAF patients) were enrolled. PAF patients (54.1±10.8 years) who received catheter ablation therapy were divided into 2 groups: recurrent AF (n=25) and no recurrent AF after catheter ablation (n=80). Peripheral blood mononuclear cells were collected from all subjects to measure LTL. Under 50 years old, LTL in healthy individuals (n=17) was longer than in PAF patients (n=31; 7.34±0.58 kbp vs. 6.44±0.91 kbp, P=0.01). In PAF patients, LTL was positively correlated with left atrial bipolar voltage (R=0.497, P<0.001), and negatively correlated with biatrial scar area (R=-0.570, P<0.001) and left atrial diameter (R=-0.214, P=0.028). LTL was shorter in the patients with recurrent AF than in those without recurrent AF after catheter ablation (5.68±0.82 kbp vs. 6.66±0.71 kbp; P<0.001). On receiver operating characteristic curve analysis, LTL cut-off <6.14 kbp had a specificity of 0.68 and sensitivity of 0.79 to predict recurrent AF after catheter ablation. CONCLUSIONS: Young PAF patients (≤50 years) had shorter LTL. Shorter LTL was associated with a degenerative atrial substrate and recurrence after catheter ablation in younger PAF patients.

The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats.

BACKGROUND: Sodium glucose co-transporter 2 inhibitor (SGLT2i), a new class of anti-diabetic drugs acting on inhibiting glucose resorption by kidneys, is shown beneficial in reduction of heart failure hospitalization and cardiovascular mortality. The mechanisms remain unclear. We hypothesized that SGLT2i, empagliflozin can improve cardiac hemodynamics in non-diabetic hypertensive heart failure. METHODS AND RESULTS: The hypertensive heart failure model had been created by feeding spontaneous hypertensive rats (SHR) with high fat diet for 32 weeks (total n = 13). Half SHRs were randomized to be administered with SGLT2i, empagliflozin at 20 mg/kg/day for 12 weeks. After evaluation of electrocardiography and echocardiography, invasive hemodynamic study was performed and followed by blood sample collection and tissue analyses. Empagliflozin exhibited cardiac (improved atrial and ventricular remodeling) and renal protection, while plasma glucose level was not affected. Empagliflozin normalized both end-systolic and end-diastolic volume in SHR, in parallel with parameters in echocardiographic evaluation. Empagliflozin also normalized systolic dysfunction, in terms of the reduced maximal velocity of pressure incline and the slope of end-systolic pressure volume relationship in SHR. In histological analysis, empagliflozin significantly attenuated cardiac fibrosis in both atrial and ventricular tissues. The upregulation of atrial and ventricular expression of PPARα, ACADM, natriuretic peptides (NPPA and NPPB), and TNF-α in SHR, was all restored by treatment of empagliflozin. CONCLUSIONS: Empagliflozin improves hemodynamics in our hypertensive heart failure rat model, associated with renal protection, attenuated cardiac fibrosis, and normalization of HF genes. Our results contribute some understanding of the pleiotropic effects of empagliflozin on improving heart function.

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.

Electronegative Low-Density Lipoprotein L5 Induces Adipose Tissue Inflammation Associated With Metabolic Syndrome.

Context: Electronegative low-density lipoprotein (LDL) L5 is a naturally occurring, atherogenic entity found at elevated levels in the plasma of patients with metabolic syndrome (MetS) in the absence of elevated plasma LDL levels. Objective: To investigate the role of L5 in the mechanism of adipose tissue inflammation associated with MetS. Patients/Setting: Plasma LDL isolated from patients with MetS (n = 29) and controls (n = 29) with similar plasma LDL levels was separated into five subfractions, L1 to L5, with increasing electronegativity. Design: We examined the invivo effects of L5 on adipose tissue in mice and the in vitro effects of L5 on adipocytokine signaling and monocytes. Results: Tail-vein injection of human L5 but not L1 into C57BL/6 mice induced the accumulation of F4/80+ and CD11c+ M1 macrophages. The effects of L5 were attenuated in mice deficient for L5's receptor, lectin-like oxidized LDL receptor 1 (LOX-1). L5 but not L1 induced human adipocytes to release inflammatory adipocytokines. Incubating human THP-1 monocytes with LDL-free culture media from L5-treated adipocytes enhanced the migration of monocytes by 300-fold (P < 0.001 vs L1-treated adipocyte media)-effects that were attenuated by LOX-1 neutralizing antibody. Migrated cells were positive for mature macrophage marker PM-2K, indicating the transformation of monocytes into macrophages. The infiltration of M1 macrophages in adipose tissue was also observed in a previously established hamster model of endogenously elevated L5. Conclusions: L5 induces adipose inflammation through LOX-1 by promoting macrophage maturation and infiltration into adipose tissue. Elevated plasma L5 levels may be a novel etiology of adipose tissue inflammation in patients with MetS.

A novel noninvasive surface ECG analysis using interlead QRS dispersion in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: This study investigated the feasibility of using the precordial surface ECG lead interlead QRS dispersion (IQRSD) in the identification of abnormal ventricular substrate in arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS: Seventy-one consecutive patients were enrolled and reclassified into 4 groups: definite ARVC with epicardial ablation (Group 1), ARVC with ventricular tachycardia (VT, Group 2), idiopathic right ventricular outflow tract VT without ARVC (Group 3), and controls without VT (Group 4). IQRSD was quantified by the angular difference between the reconstruction vectors obtained from the QRS-loop decomposition, based on a principal component analysis (PCA). Electroanatomic mapping and simulated ECGs were used to investigate the relationship between QRS dispersion and abnormal substrate. RESULTS: The percentage of the QRS loop area in the Group 1-2 was smaller than the controls (P = 0.01). The IQRSD between V1-V2 could differentiate all VTs from control (P<0.01). Group 1-2 had a greater IQRSD than the Group 3-4 (V4-V5,P = 0.001), and Group 1 had a greater IQRSD than Group 3-4 (V6-Lead I, P<0.001). Both real and simulated data had a positive correlation between the maximal IQRSD (γ = 0.62) and the extent of corresponding abnormal substrate (γ = 0.71, both P<0.001). CONCLUSIONS: The IQRSD of the surface ECG precordial leads successfully differentiated ARVC from controls, and could be used as a noninvasive marker to identify the abnormal substrate and the status of ARVC patients who can benefit from epicardial ablation.

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.

Ablation of ventricular arrhythmia originating at the papillary muscle using an automatic pacemapping module.

BACKGROUND: Ventricular arrhythmia originating from the papillary muscle (VA-PM) is characterized by multiple exits and morphologic alternations. The conventional ablation strategy relies on activation mapping, but the results might be suboptimal. OBJECTIVE: The purpose of this study was to propose a novel pacemapping strategy aimed at multiple exits using high-output software as a complementary approach to the conventional strategy. METHODS: A consecutive 13 patients with VA-PM were enrolled in this study. Novel pacemapping based on an automatic matching algorithm and integrated electroanatomic mapping was used to quantify the morphology variation in these patients and to identify the potential exits of VA-PM. Complementary ablation targeting at the best matching site of each morphology was performed. RESULTS: Twelve of 13 patients (92%) experienced morphologic alternation, and a total of 34 morphologies were detected (2.6 ± 1.0 per patient). A total of 23 (68%) morphologies were detected as spontaneous pleomorphic ventricular premature complexes (VPCs) before procedure, and 4 morphologies (12%) were induced under isoproterenol infusion. Another 7 of 34 morphologies (21%) could be found only after radiofrequency ablation attempts. Exits with a high pacemapping correlation index for corresponding morphology would be mapped, so preferential exits could be identified. Mean interexit distance was 15.1 ± 5.9 mm. Acute success rate was 100%. During mean follow-up of 12.2 ± 6.9 months, only 1 case recurred with ventricular tachycardia. Although 3 cases recurred with different VPC morphologies, the VPC burden decreased from 16.3% ± 8.8% to 2.6% ± 1.7%. CONCLUSION: This novel pacemapping strategy could effectively eliminate multiple exits as a complementary approach to the conventional strategy.

Periesophageal vagal plexus injury is a favorable outcome predictor after catheter ablation of atrial fibrillation.

BACKGROUND: Collateral damage to periesophageal vagal plexus associated with symptomatic gastric hypomotility and associated symptoms are not uncommon after catheter ablation of atrial fibrillation (AF). The injury may indicate transmural ablation lesions. OBJECTIVE: The purpose of this study was to evaluate the periesophageal vagal plexus injury (PNI) and long-term outcome after catheter ablation of AF. METHODS: A total of 441 consecutive patients with AF (mean age 54.71 ± 10.52 years; 134 women) who underwent catheter ablation (paroxysmal AF, n = 312; persistent AF, n = 129) were retrospectively enrolled from 2011 to 2013; group 1 was defined as patients with PNI and associated symptoms (n = 88), and group 2 was defined as patients without PNI or associated symptoms (n = 353). Baseline characteristics and electrophysiological properties were collected to analyze the relationship between PNI and clinical outcome. The association of AF recurrence after catheter ablation and PNI symptoms was also investigated. RESULTS: During a mean follow-up period of 37.3 ± 0.94 months, group 1 had longer AF-freedom days in sinus rhythm after AF ablation and had less recurrence after the blanking period compared with group 2 (mean recurrence days, 1254.22 ± 45.26 days vs 1065.21 ± 33.35 days; P < .01). Multivariate analysis also revealed that PNI was an independently protective predictor of AF recurrence (hazard ratio 0.527; 95% confidence interval 0.289-0.959; P = .036). There was no difference in baseline characteristics, CHA2DS2-VASc score, or echocardiography follow-up duration. CONCLUSION: PNI and associated symptoms are not uncommon after catheter ablation of AF. A better long-term outcome is thereby independently predicted, suggesting transmural ablation lesions during pulmonary vein isolation.

Statin Dose and the Risk of Intracerebral Hemorrhage: A Population-Based Longitudinal Study in Taiwan.

BACKGROUND: In the last 15 years, there has been considerable interest in statin use as a means to reduce the likelihood of vascular events. Several clinical trials have shown that high-dose statin (HDS) treatment could reduce vascular events. In high-risk populations, lipid treatment guidelines have generally suggested prescribing statin up to the highest recommended dosage. However, there remains concern about the risk of intracerebral hemorrhage (ICH) with HDS treatment. METHODS: This was a national population-based cohort study from the National Health Insurance Research Database of Taiwan extending from July 2001 to December 2008. Patients with cerebrovascular or cardiovascular disease were enrolled. The HDS group was defined as those patients receiving more than 420 mg per year of atorvastatin or an equivalent potency statin. Moderate dose statin group (MDS) was defined as those patients receiving atorvastatin in amounts between 196-420 mg per year or an equivalent potency statin. Low dose statin (LDS) group was defined as those receiving less than 196 mg per year of atorvastatin or an equivalent statin. The primary endpoint is ICH. The secondary endpoints are myocardial infarction (MI), ischemic stroke (IS) and new-onset DM (NDM). RESULTS: A total of 5459 patients were enrolled in our study, with study participant ages ranging from 62.91 ± 11.85 years and a mean follow-up time of 2039 ± 6 days. After adjusting for age, gender, diabetes and hypertension, Cox regression analysis found ICH risk was lower in HDS and MDS groups compared with LDS (HR 0.49, 95% CI 0.26-0.91, p = 0.0246 and HR 0.45, 95% CI 0.24-0.86, p = 0.0157). The risk of IS is lower in patients with HDS treatment (HR 0.68, 95% CI 0.55-0.83, p < 0.01). However, the risk of MI and NDM incidence are not statistically significant between the different dose groups. CONCLUSIONS: In the real-world data provided by Taiwan's National Health Insurance research database, it was shown that patients who received a higher dose of statin had a reduced and not elevated risk of intracerebral hemorrhage. KEY WORDS: High-dose statin; Hyperlipidemia; Intracerebral hemorrhage; Ischemic stroke; New-onset DM.

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.