Role of low-density lipoprotein electronegativity and sexual dimorphism in contributing early ventricular tachyarrhythmias following ST-elevation myocardial infarction.

Background: Early ventricular tachycardia/fibrillation (VT/VF) in patients with ST-elevation myocardial infarction (STEMI) has higher morbidity and mortality. This study examines gender-differentiated risk factors and underlying mechanisms for early onset VT/VF in STEMI. Methods: We analyzed data from 2,964 consecutive STEMI patients between January 1, 2008 and December 31, 2021. Early VT/VF was defined as occurrence of spontaneous VT/VF of ≥30 s or requirement of immediate cardioversion/defibrillation within the first 48 h after symptoms. An ex vivo ischemic-reperfusion experiments were conducted in 8-week-old ApoE-/- mice fed a high-fat diet to explore the underlying mechanisms of early VT/VF. Results: In 255 of out 2,964 STEMI patients who experienced early VT/VF, the age was younger (58.6 ± 13.8 vs. 61.0 ± 13.0 years old, P = 0.008) with a male predominance. The plasma levels of L5, the most electronegative subclass of low-density lipoprotein, was higher in early VT/VF patients compared to those without early VT/VF (n = 21, L5: 14.1 ± 22.6% vs. n = 46, L5: 4.3 ± 9.9%, P = 0.016). In the experimental setup, all male mice (n = 4) developed VT/VF post sham operation, whereas no such incidence was observed in the female mice (n = 3). Significantly, male mice exhibited considerably slower cardiac conduction velocity as compared to their female counterparts in whole heart preparations (25.01 ± 0.93 cm/s vs.42.32 ± 5.70 cm/s, P < 0.001), despite analogous action potential durations. Furthermore, isolated ventricular myocytes from male mice showed a distinctly lower sodium current density (-29.20 ± 3.04 pA/pF, n = 6) in comparison to female mice (-114.05 ± 6.41 pA/pF, n = 6, P < 0.001). This decreased sodium current density was paralleled by a reduced membrane expression of Nav1.5 protein (0.38 ± 0.06 vs. 0.89 ± 0.09 A.U., P < 0.001) and increased cytosolic Nav1.5 levels (0.59 ± 0.06 vs. 0.29 ± 0.04 A.U., P = 0.001) in male mice. Furthermore, it was observed that the overall expressions of sorting nexin 27 (SNX27) and vacuolar protein sorting 26 (VPS26) were significantly diminished in male mice as compared to female littermates (0.91 ± 0.15 vs. 1.70 ± 0.28, P = 0.02 and 0.74 ± 0.09 vs. 1.57 ± 0.13, P < 0.01, respectively). Conclusions: Our findings reveal that male STEMI patients with early VT/VF are associated with elevated L5 levels. The gender-based discrepancy in early VT/VF predisposition might be due to compromised sodium channel trafficking, possibly linked with increased LDL electronegativity.

A rapid and sensitive analytical methodology for the simultaneous biomonitoring of two direct oral anticoagulant drugs and their major metabolites in thromboembolic disordered patients samples for clinical evaluations.

Apixaban and dabigatran are the two major direct oral anticoagulant drugs to treat thromboembolic disordered patients. Increasing the clinical application for the thromboembolic disorder and monitoring the concentrations of apixaban, dabigatran, and their metabolites are essential in most clinical circumstances. In this work, we developed a rapid analytical methodology comprising of vortex-assisted salt-enhanced liquid-liquid microextraction technique coupled with UHPLC-MS/MS for the extraction and simultaneous determination of two major direct oral anticoagulant drugs (apixaban, dabigatran), and their two major metabolites from plasma, serum, and urine samples of patients. The developed method was optimized with various procedural steps and validated to study the analytical merits. The developed method yielded a good detection limit of 0.01 ∼ 0.37 ng/mL, 0.01 ∼ 0.32 ng/ml, and 0.01 ∼ 0.27 ng/mL for four target analytes in the plasma, serum, and urine matrices. Moreover, extraction recoveries ranged from 85.11 - 113.57% (for plasma), 89.63 - 110.47% (for serum), and 87.44 -106.79% (for urine samples) with 8.78% RSD. In addition, the method exhibited good R2 values of 0.999 for all four target analytes, and the specificity and carryover study revealed no carryover effect from the UHPLC-MS/MS system for determining the apixaban, dabigatran, and their metabolites. Due to the above advantages, the developed analytical technique was applied to examine 11 real-time clinical patients' samples, and the observed results were satisfactory for all three different sample matrices. Therefore, this analytical method can be applied for biomonitoring apixaban, dabigatran, and their two major metabolites with high sensitivity in a short time for various clinical applications.

Autonomic Modulation of Atrial Fibrillation.

The autonomic nervous system plays a vital role in cardiac arrhythmias, including atrial fibrillation (AF). Therefore, reducing the sympathetic tone via neuromodulation methods may be helpful in AF control. Myocardial ischemia is associated with increased sympathetic tone and incidence of AF. It is an excellent disease model to understand the neural mechanisms of AF and the effects of neuromodulation. This review summarizes the relationship between autonomic nervous system and AF and reviews methods and mechanisms of neuromodulation. This review proposes that noninvasive or minimally invasive neuromodulation methods will be most useful in the future management of AF.

Enhancing Immunity and Modulating Vaginal Microflora Against Candidal Vaginitis Through Nanoemulsion Supplemented with Porphyra Oligosaccharide as an Intravaginal Vaccine Adjuvant.

Background: Intravaginal vaccination is an encouraging approach to prevent infectious vaginitis, with nanoemulsions showing effectiveness as mucosal adjuvants. Purpose: This study aimed to formulate a nanoemulsion incorporating Porphyra oligosaccharide (PO@NE) and assess its effectiveness as a mucosal adjuvant in intravaginal vaccines against candidal vaginitis. Materials and Methods: PO@NE was prepared, and the stability, immunomodulatory activity and cytotoxicity were screened in vitro. Further, the preventive effect of PO@NE as adjuvants for heat-killed Candida albicans (HK-CA) vaccines was explored in a murine model of candidal vaginitis, in comparison with those supplemented with polysaccharide (PP@NE). The mice were intravaginally vaccinated with 106 HK-CA cells, suspended in 1% NE without or with either PO or PP at a final concentration of 6.5 µg/mL, in a total volume of 20 µL. This vaccination was intravaginally administered once a week for 3 weeks. One week following the final vaccination, the mice underwent an intravaginal challenge with 107 C. albicans cells. One week after the challenge, the mice were euthanized to isolate serum, spleen, vaginal washes, and vaginal tissues for analysis. Results: PP@NE and PO@NE, with diameters approximately around 100 nm, exhibited exceptional stability at 4°C and low cytotoxicity when used at a concentration of 1% (v/v). Intravaginal vaccination with HK-CA adjuvanted with PO@NE effectively protected against candidal vaginitis evidenced by less Candida hyphae colonization, milder mucosal damage and cell infiltration. Moreover, enhanced mucosal antibody production, induction of T helper (Th)1 and Th17-related immune responses, enlarged the population of CD8+ cells, and elevated vaginal microflora diversity were observed in vaccinated mice. Interestingly, the potency was rather attenuated when PO@NE was replaced with PP@NE. Conclusion: These findings indicate PO@NE as a HK-CA vaccine adjuvant for candidal vaginitis prevention via enhancement of both cellular and humoral immunity and modulation of vaginal microflora, emphasizing further intravaginal vaccination development.

Preparation and evaluation of Cordyceps militaris polysaccharide- and sesame oil-loaded nanoemulsion for the treatment of candidal vaginitis in mice.

BACKGROUND: Candida albicans is the most prevalent fungal pathogen, affecting over 75% of women who have experienced candidal vaginitis. Given the identification of drug-resistant C. albicans strains, there is an urgent need to develop therapeutic methods for treating vaginal Candida infection. Polysaccharide is the major bioactive component of Cordyceps militaris, known to modulate immune responses and alleviate inflammation. Sesame oil is known with anti-microbial and anti-inflammatory activities. METHODS: C. militaris polysaccharide was prepared and formulated with sesame oil to prepare emulsion and nanoemulsion, which are ideal mucosal delivery systems for both hydrophobic and hydrophilic compounds concurrently. The physical property and storage stability of these formulations were illustrated, and their effects on ameliorating vaginitis were investigated in a murine model of vaginal Candida infection. RESULTS: C. militaris polysaccharide-containing nanoemulsion showed smaller particle size, lower polydispersity index, higher zeta-potential and better stability than emulsion. Intravaginal administration of C. militaris polysaccharide-containing nanoemulsion significantly attenuated C. militaris colonization and vaginitis. Notably, these formulations exerted distinct effects on modulating cell infiltration and splenic cytokine production. Moreover, different profile of vaginal microflora was observed among the treatment groups, revealing the potential action mechanisms of these formulations to mitigate vaginal Candida infection. CONCLUSION: C. militaris polysaccharide- and sesame oil-containing nanoemulsion is potential to be developed as intravaginal therapeutic strategy for C. albicans-induced vaginitis.

Non-insulin-based insulin resistance indices for predicting all-cause mortality and renal outcomes in patients with stage 1-4 chronic kidney disease: another paradox.

Non-insulin-based insulin resistance (IR) indices serve as the indicators of metabolic syndrome (MetS) but have limited value for predicting clinical outcomes. Whether the obesity paradox affects the predictive value of these indicators in patients with chronic kidney disease (CKD) remains unknown. We investigated whether MetS and non-insulin-based IR indices can predict all-cause mortality and renal outcomes in a prospective observational study with stage 1-4 CKD Asians (N = 2,457). These IR indices were associated with MetS. A Cox regression model including body mass index (BMI) revealed an association between MetS and renal outcomes. Among the IR indices, only high triglyceride-glucose (TyG) index was associated with adverse renal outcomes: the hazard ratio of Q4 quartile of the TyG index was 1.38 (1.12-1.70). All-cause mortality was marginally associated with MetS but not high IR indices. Low TyG and TyG-BMI indices as well as low BMI and triglyceride were paradoxically associated with increased risks of clinical outcomes. The triglyceride-to-high-density lipoprotein cholesterol ratio and metabolic score for IR indices were not associated with clinical outcomes. In conclusion, MetS and TyG index predict renal outcome and obesity paradox affects the prediction of IR indices in patients with stage 1-4 CKD.

Skin sympathetic nerve activity as a potential biomarker for overactive bladder.

PURPOSE: Abnormalities in autonomic function are associated with an overactive bladder (OAB). Heart rate variability is generally used as the sole assessment of autonomic activity; however, we utilized neuECG, a novel method of recording skin electrical signals, to assess autonomic nervous function in healthy controls and patients with OAB before and after treatment. METHODS: The prospective sample included 52 participants: 23 patients newly diagnosed with OAB and 29 controls. Autonomic function was assessed in all participants in the morning using neuECG, which analyzed the average skin sympathetic nerve activity (aSKNA) and electrocardiogram simultaneously. All patients with OAB were administered antimuscarinics; urodynamic parameters were assessed before treatments; autonomic and bladder functions using validated questionnaires for OAB symptoms were evaluated before and after OAB treatment. RESULTS: Patients with OAB had significantly higher baseline aSKNA (p = 0.003), lower standard deviation of the normal-to-normal beat intervals, lower root mean square of the successive differences, lower high-frequency, and higher low-frequency than did controls. Baseline aSKNA had the highest value in predicting OAB (AUROC = 0.783, p < 0.001). The aSKNA was negatively correlated with first desire and normal desire in urodynamic studies (both p = 0.025) and was significantly decreased after treatment at rest, stress, and recovery phases, as compared to those before treatment (p = 0.046, 0.017, and 0.017, respectively). CONCLUSION: Sympathetic activity increased significantly in patients with OAB compared to that in healthy controls, and decreased significantly post-treatment. Higher aSKNA is associated with decreased bladder volume at which voiding is desired. SKNA may be a potential biomarker for diagnosing OAB.

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.

Prognostic Factors of New-Onset Hypertension in New and Traditional Hypertension Definition in a Large Taiwanese Population Follow-up Study.

The aim of this study was to determine the predictors of new-onset hypertension when the definition of hypertension is changed from the traditional definition (140/90 mmHg) to a new definition (130/80 mmHg). Using data from the Taiwan Biobank, a total of 17,072 and 21,293 participants in the new and traditional definition groups were analyzed, respectively. During a mean follow-up period of 3.9 years, 3641 and 3002 participants developed hypertension in the new and traditional definition groups, respectively. After multivariable analysis, older age (OR, 1.035; 95% CI, 1.030 to 1.039; p < 0.001), male sex (OR, 1.332; 95% CI, 1.194 to 1.486; p < 0.001), high systolic blood pressure (SBP) (OR, 1.067; 95% CI, 1.062 to 1.073; p < 0.001), high diastolic blood pressure (DBP) (OR, 1.048; 95% CI, 1.040 to 1.056; p < 0.001), high heart rate (OR, 1.007; 95% CI, 1.002 to 1.012; p = 0.004), high body mass index (BMI) (OR, 1.091; 95% CI, 1.077 to 1.106; p < 0.001), high fasting glucose (OR, 1.004; 95% CI, 1.001 to 1.006; p = 0.002), and high triglycerides (OR, 1.001; 95% CI, 1.000 to 1.001; p = 0.004) were significantly associated with new-onset hypertension in the new definition group. In the traditional definition group, the predictors of new-onset hypertension were older age (OR, 1.038; 95% CI, 1.032 to 1.043; p < 0.001), high SBP (OR, 1.078; 95% CI, 1.072 to 1.084; p < 0.001), high DBP (OR, 1.039; 95% CI, 1.031 to 1.046; p < 0.001), high heart rate (OR, 1.005; 95% CI, 1.000 to 1.010; p = 0.032), high BMI (OR, 1.072; 95% CI, 1.058 to 1.087; p < 0.001), high fasting glucose (OR, 1.003; 95% CI, 1.000 to 1.005; p = 0.020), low cholesterol (OR, 0.998; 95% CI, 0.997 to 0.999; p = 0.004), high triglycerides (OR, 1.001; 95% CI, 1.000 to 1.001; p = 0.001), and low estimated glomerular filtration rate (eGFR) (OR, 0.995; 95% CI, 0.993 to 0.997; p < 0.001). In conclusion, older age, high SBP and DBP, high heart rate, high BMI, high fasting glucose, and high triglycerides were useful predictors of new-onset hypertension in both the new and traditional definition groups. However, male sex was a significant predictor of new-onset hypertension only in the new definition group, and low cholesterol and low eGFR were significant predictors of new-onset hypertension only in the traditional definition group. Hence, changing the diagnostic cut-off value for hypertension may have a significant impact on the association of some clinical and laboratory parameters with new-onset hypertension.

Higher pre-treatment skin sympathetic nerve activity and elevated resting heart rate after chemoradiotherapy predict worse esophageal cancer outcomes.

BACKGROUND: Chemoradiotherapy (CRT), which might affect the autonomic system, is the mainstay therapy for advanced esophageal squamous cell carcinoma (ESCC). Autonomic dysfunction has been found to possibly lead to cancer mortality in those with elevated resting heart rates (RHR). Skin sympathetic nerve activity (SKNA) is a new method of stimulating electrical signals in skin to evaluate autonomic function from sympathetic tone. In this study, we investigated the association between changes in RHR and autonomic function and ESCC mortality. METHODS: Thirty-nine stage II-IV ESCC patients receiving CRT between March 2019 and November 2020 were prospectively enrolled and carefully selected, followed up and received the same meticulous supportive care. Serial RHR was recorded every two weeks from before CRT to eight weeks after CRT and average SKNA were recorded before and four weeks after CRT. All-cause mortality was defined as primary outcome. RESULTS: We found the RHR of ESCC patients to be significantly elevated and peaking at four weeks after CRT (p < 0.001) and then to gradually decrease. Those with an elevated RHR above the cutoff level (18 beat-per-minute) at eight weeks after CRT had worse overall survival. In addition, those with higher baseline sympathetic tone (average SKNA ≥ 0.86 µV) also had poor outcome. CONCLUSIONS: Increased pre-treatment sympathetic tone and elevated RHR after CRT are alarm signs of poor ESCC outcome. Further exploration of the mechanisms underlying these associations could potentially lead to intervention strategies for reducing mortality. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, identifier: NCT03243448.

Tumor Necrosis Factor Receptor Superfamily Member 21 Induces Endothelial-Mesenchymal Transition in Coronary Artery Endothelium of Type 2 Diabetes Mellitus.

Diabetes mellitus (DM) is an increasing threat to human health and regarded as an important public issue. Coronary artery disease is one of the main causes of death in type 2 DM patients. However, the effect of hyperglycemia on coronary artery endothelial cells (CAECs) and the pathophysiologic mechanisms are still not well-explored. This study aims to explore the signal pathway and novel biomarkers of injury of CAECs in DM in understanding the microenvironment changes and mechanisms of diabetic heart disease. Next-generation sequence (NGS) and bioinformatics analysis to analyze the CAECs of one type 2 DM patient and one normal individual was performed, and it was found that tumor necrosis factor receptor superfamily member 21 (TNFRSF21) was a soluble factor in circulating system. Further experiments confirmed that advanced glycation end products (AGEs), the metabolite derived by hyperglycemia, increased the expression of TNFRSF21 in CAECs. TNFRSF21 induced endothelial-mesenchymal transition (EndoMT) in CAECs, resulting in increased permeability of CAECs. In addition, levels of serum TNFRSF21 were higher in type 2 DM patients with left ventricular hypertrophy (LVH) than those without LVH. Serum TNFRSF21 levels were also positively correlated with the LV mass index and negatively with LV systolic function. Serum TNFRSF21 levels were associated with changes in cardiac structure and function in patients with type 2 DM. In conclusion, TNFRSF21 plays a pathogenic role in heart disease of type 2 DM, and can be used as a biomarker of the impairment of cardiac structure and function in type 2 DM patients.

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.

Does COVID-19 Vaccination Cause Storage Lower Urinary Tract Symptoms?

We investigated the storage lower urinary tract symptoms (LUTS) before and after the first dose of coronavirus disease 2019 (COVID-19) vaccine and the association between pre-vaccinated overactive bladder (OAB) and the worsening of storage LUTS following COVID-19 vaccination. This cross-sectional study in a third-level hospital in Taiwan used the validated pre- and post-vaccinated Overactive Bladder Symptom Score (OABSS). Diagnosis of OAB was made using pre-vaccinated OABSS. The deterioration of storage LUTS was assessed as the increased score of OABSS following vaccination. Of 889 subjects, up to 13.4% experienced worsened storage LUTS after vaccination. OAB was significantly associated with an increased risk of worsening urinary urgency (p = 0.030), frequency (p = 0.027), and seeking medical assistance due to urinary adverse events (p < 0.001) after vaccination. The OAB group faced significantly greater changes in OABSS-urgency (p = 0.003), OABSS-frequency (p = 0.025), and total OABSS (p = 0.014) after vaccination compared to those observed in the non-OAB group. Multivariate regression revealed that pre-vaccinated OAB (p = 0.003) was a risk for the deterioration of storage LUTS. In conclusion, storage LUTS may deteriorate after vaccination. OAB was significantly associated with higher risk and greater changes in worsening storage LUTS. Storage LUTS should be closely monitored after COVID-19 vaccination, especially in those OAB patients.

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.

Stability and Transformation of Metabolic Syndrome in Adolescents: A Prospective Assessment in Relation to the Change of Cardiometabolic Risk Factors.

Underlying pathophysiological mechanisms drive excessive clustering of cardiometabolic risk factors, causing metabolic syndrome (MetS). MetS status may transform as adolescents transition to young adulthood. This study investigated the latent clustering structure and its stability for MetS during adolescence, and assessed the anthropometric and clinical metabolic determinants for MetS transformation. A community-based representative adolescent cohort (n = 1516) was evaluated for MetS using four diagnostic criteria, and was followed for 2.2 years to identify new-onset MetS. The clustering structure underlying cardiometabolic parameters was stable across adolescence; both comprised a fat-blood pressure (BP)-glucose three-factor structure (total variance explained: 68.8% and 69.7% at baseline and follow-up, respectively). Among adolescents with MetS-negative at baseline, 3.2-4.4% had incident MetS after 2.2 years. Among adolescents with MetS-positive at baseline, 52.0-61.9% experienced MetS remission, and 38.1-48.0% experienced MetS persistence. Increased systolic BP (SBP) was associated with a high MetS incidence risk, while decreased levels of SBP and glucose were associated with MetS remission. Compared with adolescents with a normal metabolic status at baseline, those with an initial abdominal obesity and increased triglycerides level had a 15.0- and 5.7-fold greater risk for persistent abnormality, respectively. Abdominal obesity and low high-density lipoprotein cholesterol are two abnormal MetS components that highly persist during adolescence, and are the intervention targets for reducing the future risk of cardiometabolic disorders.

Automated ECG classification based on 1D deep learning network.

The standard 12-lead electrocardiogram (ECG) records the heart's electrical activity from electrodes on the skin, and is widely used in screening and diagnosis of the cardiac conditions due to its low price and non-invasive characteristics. Manual examination of ECGs requires professional medical skills, and is strenuous and time consuming. Recently, deep learning methodologies have been successfully applied in the analysis of medical images. In this paper, we present an automated system for the identification of normal and abnormal ECG signals. A multi-channel multi-scale deep neural network (DNN) model is proposed, which is an end-to-end structure to classify the ECG signals without any feature extraction. Convolutional layers are used to extract primary features, and long short-term memory (LSTM) and attention are incorporated to improve the performance of the DNN model. The system was developed with a 12-lead ECG dataset provided by the Kaohsiung Medical University Hospital (KMUH). Experimental results show that the proposed system can yield high recognition rates in classifying normal and abnormal ECG signals.

Usefulness of Upstroke Time per Cardiac Cycle for Cardiovascular and All-Cause Mortality Prediction in Patients with Normal Ankle-Brachial Index.

AIM: Abnormal ankle-brachial index (ABI) is regarded as peripheral artery disease and can be used to predict cardiovascular (CV) outcomes. However, the usefulness of ABI for the prediction of CV outcome in patients with normal ABI is limited. Upstroke time per cardiac cycle (UTCC) is recently reported to be associated with mortality in patients with acute myocardial infarction and the elderly. Therefore, we aimed to evaluate UTCC, left ventricular ejection fraction (LVEF), brachial-ankle pulse wave velocity (baPWV), and ABI for the prediction of mortality in patients with normal ABI. METHODS: Patients arranged for echocardiographic examinations were enrolled, and 1076 patients with normal ABI were included. ABI, baPWV, and UTCC were measured by an ABI-form device. RESULTS: The median follow-up to mortality was 95 months. There were 88 CV and 244 all-cause deaths. After multivariate analysis, UTCC was associated with increased CV and all-cause mortality (P ≤ 0.004). Age, diabetes, heart failure, left ventricular hypertrophy, baPWV, and LVEF were also independent predictors of CV and all-cause mortality, but ABI was not. Furthermore, UTCC had a better additive predictive value than ABI, baPWV, and LVEF for CV mortality ( P ≤ 0.012). It also had a better additive predictive value than ABI and LVEF for all-cause mortality (P ≤ 0.013). CONCLUSIONS: UTCC is an independent predictor for CV and all-cause mortality in patients with normal ABI. It also has a better additive predictive value of CV and all-cause mortality than ABI and LVEF. Therefore, UTCC is a simple, novel, and useful parameter for identifying high-risk patients with normal ABI.

Temporal Clustering of Skin Sympathetic Nerve Activity Bursts in Acute Myocardial Infarction Patients.

Backgrounds: Acute myocardial infarction (AMI) affects the autonomic nervous system (ANS) function. The aim of our study is to detect the particular patterns of ANS regulation in AMI. We hypothesize that altered ANS regulation in AMI patients causes synchronized neural discharge (clustering phenomenon) detected by non-invasive skin sympathetic nerve activity (SKNA). Methods: Forty subjects, including 20 AMI patients and 20 non-AMI controls, participated in the study. The wide-band bioelectrical signals (neuECG) were continuously recorded on the body surface for 5 min. SKNA was signal processed to depict the envelope of SKNA (eSKNA). By labeling the clusters, the AMI subjects were separated into non-AMI, non-cluster appearing (AMINCA), and cluster appearing (AMICA) groups. Results: The average eSKNA was significantly correlated with HRV low-frequency (LF) power (rho = -0.336) and high-frequency power (rho = -0.372). The cross-comparison results demonstrated that eSKNA is a valid surrogate marker to assess ANS in AMI patients. The frequency of cluster occurrence was 0.01-0.03 Hz and the amplitude was about 3 µV. The LF/HF ratio of AMICA (median: 1.877; Q1-Q3: 1.483-2.413) revealed significantly lower than AMINCA (median: 3.959; Q1-Q3: 1.840-6.562). The results suggest that the SKNA clustering is a unique temporal pattern of ANS synchronized discharge, which could indicate the lower sympathetic status (by HRV) in AMI patients. Conclusion: This is the first study to identify SKNA clustering phenomenon in AMI patients. Such a synchronized nerve discharge pattern could be detected with non-invasive SKNA signals. SKNA temporal clustering could be a novel biomarker to classify ANS regulation ability in AMI patients. Clinical and Translational Significance: SKNA is higher in AMI patients than in control and negatively correlates with parasympathetic parameters. SKNA clustering is associated with a lower LF/HF ratio that has been shown to correlate with sudden cardiac death in AMI. The lack of SKNA temporal clustering could indicate poor ANS regulation in AMI patients.

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.