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Background: Sodium-glucose cotransporter-2 inhibitors, such as empagliflozin, are pivotal therapies for heart failure. However, the effect of empagliflozin on doxorubicin-related cardiac dysfunction remains unclear. Methods: Human induced pluripotent stem cell- and embryonic stem cell-derived cardiomyocytes were used to investigate the direct effect of empagliflozin on human cardiomyocytes. Then, the c-Jun amino-terminal kinases (JNK) inhibitor SP600125 was administered to the doxorubicin cardiotoxicity model in vitro and in vivo to investigate the role of JNK in empagliflozin. Results: In human stem cell-derived cardiomyocytes, pretreatment with empagliflozin attenuated doxorubicin-induced cleavage of caspase 3 and other apoptosis markers. Empagliflozin significantly attenuated doxorubicin-induced phosphorylation of JNK and p38. Inhibiting the phosphorylation of JNK (SP600125) or STAT3 attenuated doxorubicin-induced apoptosis, but inhibiting the phosphorylation of p38 did not. SP600125 inhibits the phosphorylation of STAT3 (S727), and a STAT3 (Y705) inhibitor also inhibits the phosphorylation of JNK. Empagliflozin and SP600125 attenuated doxorubicin-induced increases in reactive oxygen species (ROS) and decreases in oxidized nicotinamide adenine dinucleotide (NAD+). In animal studies, empagliflozin and SP600125 attenuated doxorubicin-induced cardiac dysfunction and fibrosis. Conclusions: Empagliflozin attenuated doxorubicin-induced apoptosis by inhibiting the phosphorylation of JNK and its downstream signaling pathways, including ROS and NAD+.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly common liver disease worldwide. MAFLD is diagnosed based on the presence of steatosis on images, histological findings, or serum marker levels as well as the presence of at least one of the three metabolic features: overweight/obesity, type 2 diabetes mellitus, and metabolic risk factors. MAFLD is not only a liver disease but also a factor contributing to or related to cardiovascular diseases (CVD), which is the major etiology responsible for morbidity and mortality in patients with MAFLD. Hence, understanding the association between MAFLD and CVD, surveillance and risk stratification of MAFLD in patients with CVD, and assessment of the current status of MAFLD management are urgent requirements for both hepatologists and cardiologists. This Taiwan position statement reviews the literature and provides suggestions regarding the epidemiology, etiology, risk factors, risk stratification, nonpharmacological interventions, and potential drug treatments of MAFLD, focusing on its association with CVD.

The molecular and genetic mechanisms underlying left atrial (LA) enlargement and atrial fibrosis following right ventricular (RV) dependent pacing remain unclear. Our objective was to investigate genetic expressions in the LA of pigs subjected to RV pacing for atrioventricular block (AVB), as well as to identify the differential gene expressions affected by biventricular (BiV) pacing. We established an AVB pig model and divided the subjects into three groups: a sham control group, an RV pacing group, and a BiV pacing group. Differential expression genes (DEGs) analyses conducted through next-generation sequencing (NGS) and enrichment analyses were employed to identify genes with altered expression in the LA myocardium. The RV pacing group showed a significant increase in extracellular fibrosis in the LA myocardium compared to the control group. NGS analysis revealed suppressed expression of the sirtuin signaling pathway in the RV pacing group. Among the DEGs within this pathway, GADD45G was found to be downregulated in the RV pacing group and upregulated in the BiV pacing group. Remarkably, the BiV pacing group exhibited elevated levels of GADD45G protein. In our study, we observed significant downregulation of SIRT1 and GADD45G genes, which are associated with the sirtuin signaling pathway, in the LA myocardium of the RV pacing group when compared to the control group. Moreover, these genes, which were downregulated in the RV pacing group, displayed a noteworthy upregulation in the BiV pacing group when compared to the RV pacing group.

Abstract Background The second-and third-generation drug-eluting stents (DESs) in-stent restenosis (ISR) genetic risk score (GRS) model has been previously validated. However, the model has not been validated in geriatric patients. Therefore, we conducted this study to test the feasibility of the DES-ISR GRS model in geriatric patients with coronary artery disease (CAD) in Taiwan. Methods We conducted a retrospective, single-center cohort study and included geriatric patients (age ≥ 65 years) with CAD and second-or third-generation DES(s) deployment. Patients undergoing maintenance dialysis were excluded. ISR was defined as ≥ 50% luminal narrowing on the follow-up coronary arteriography. The DES-ISR GRS model included five selected exonic single-nucleotide polymorphisms (SNPs): CAMLG, GALNT2, C11orf84, THOC5, and SAMD11. The GRS was defined as the sum of the five selected SNPs for the risk allele. Results We enrolled 298 geriatric patients from January 2010 and December 2019 in this study. After propensity score matching, there were 192 geriatric patients with CAD in the final analysis, of which 32 patients had ISR. Patients were divided into two groups based on their GRS values: low (0–2) and high (≥ 3) GRS. A high GRS was significantly associated with DES-ISR in geriatric patients. Conclusion Those geriatric patients with a high GRS had significantly higher second-or third-generation DES ISR rates. The five SNP-derived DES-ISR GRS model could provide genetic information for interventional cardiologists to treat geriatric patients with CAD. Trial registration The primary study protocol was registered with clinicaltrials.org. with registration number: NCT03877614; on March 15, 2019. ( http://clinicaltrials.gov/ct2/show/NCT03877614 )

Diabetes, dyslipidemia, obesity, and cardiac dysfunction are the hallmarks of the cardiometabolic syndrome. Pathogens include hypercoagulability, inflammation, endothelial dysfunction, and oxidative stress. Increased white fat, nonalcoholic fatty liver disease, diabetes, and cardiovascular disease are caused by obesity. Depression increases the risk of future obesity, a surprising link between obesity and neuropathology. High glucose levels, abnormal lipids, and metabolic syndrome are the root causes of CVD associated with diabetes. Diets high in fat induce insulin resistance and liver fat. Inflammation, diminished insulin signaling, and ectopic lipid accumulation are the causes of ectopic lipid accumulation. Polyunsaturated fatty acids with eicosapentaenoic acid and docohexasonoic acid inhibit the synthesis of triglycerides and increase their clearance. Omega-3 regulates the nervous system, blood pressure, hematic clotting, glucose tolerance, and inflammation. However, anxiety and depression can cause cardiovascular disease. It has been shown that PUFAs found in fish oil can improve glucose and lipid metabolism, cardiac membrane composition, and inflammation in the body. By repairing the dysregulation of metabolic syndrome, fish oil is a potential therapeutic target for cardiovascular diseases.

Abstract Renal denervation (RDN) suppresses the activity of the renin–angiotensin–aldosterone system and inflammatory cytokines, leading to the prevention of cardiac remodeling. Limited studies have reported the effects of renal denervation on ventricular electrophysiology. We aimed to use optical mapping to evaluate the effect of RDN on ventricular structural and electrical remodeling in a tachycardia-induced cardiomyopathy rabbit model. Eighteen rabbits were randomized into 4 groups: sham control group (n = 5), renal denervation group receiving RDN (n = 5), heart failure group receiving rapid ventricular pacing for 1 month (n = 4), and RDN-heart failure group (n = 4). Rabbit hearts were harvested for optical mapping. Different cycle lengths were paced (400, 300, 250, 200, and 150 ms), and the results were analyzed. In optical mapping, the heart failure group had a significantly slower epicardial ventricular conduction velocity than the other three groups. The RDN-heart failure, sham control, and RDN groups had similar velocities. We then analyzed the 80% action potential duration at different pacing cycle lengths, which showed a shorter action potential duration as cycle length decreased (P for trend

Abstract Background Vitamin K antagonists and different direct oral anticoagulants (DOACs) have different renal clearance rates. However, the impact of different stages of chronic renal impairment on the efficacy and safety of warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban in atrial fibrillation (AF) patients remains unclear. Methods This study enrolled AF patients from the Chang Gung Research Database. The study endpoints included thromboembolic events, major/fatal bleeding, gastrointestinal (GI) bleeding and intracranial hemorrhage (ICH). The risks of time to study endpoints between groups were compared using a Cox proportional hazards regression model with adjustment. Results This study enrolled 3525 patients with moderate renal impairment (30 ≤ creatinine clearance (CrCl)

Background/Purpose: Pharmacogenetics is a potential driver of the “East Asian paradox,” in which East Asian acute coronary syndrome (ACS) patients receiving dual antiplatelet therapy (DAPT) with clopidogrel following percutaneous coronary intervention (PCI) demonstrate higher levels of platelet reactivity on treatment than Western patients, yet have lower ischemic risk and higher bleeding risk at comparable doses. However, the impact of pharmacogenetics, particularly regarding CYP2C19 genotype, on the pharmacodynamics of P2Y12 inhibitors has not been extensively studied in Taiwanese ACS patients as yet. Methods: CYP2C19 genotyping and pharmacogenetic analysis was conducted on 102 subjects from the Switch Study, a multicenter, single-arm, open-label intervention study that examined the effects on platelet activity and clinical outcomes of switching from clopidogrel (75 mg daily) to low-dose prasugrel (3.75 mg daily) for maintenance DAPT after PCI in 203 Taiwanese ACS patients. Results: Genotyping results revealed that 43.1% were CYP2C19 extensive metabolizers (EM), while 56.9% were reduced metabolizers (RM). After switching to prasugrel, mean P2Y12 reaction units (PRU) values were significantly reduced in both EM and RM populations, while the proportion of high on-treatment platelet reactivity (HPR) patients significantly declined in RM patients. No increase in bleeding risk after switching was observed during follow-up. Multivariate analysis indicated that for RM patients, low estimated glomerular filtration rate (eGFR) and low hemoglobin were associated with greater HPR risk on clopidogrel, but not after switching to prasugrel. Conclusion: Switching to low-dose prasugrel from clopidogrel reduced mean PRU levels and proportion of HPR patients, with more significant reduction in RM patients.

Abstract Tumor endothelial marker 1 (TEM1) is a transmembrane glycoprotein that appears on mesenchymal lineage-derived cells during embryogenesis, but its expression greatly reduces after birth. Re-upregulation of TEM1 is found in tumor angiogenesis, organ fibrosis and wound healing indicating its potential role in tissue remodeling and repair. The expression level and function of TEM1 in adult heart are unknown. In explanted hearts from heart failure (HF) patients received cardiac transplantation, immunofluorescence staining showed TEM1 was expressed in cardiomyocytes (CMs) and cardiac fibroblasts. Bioinformatics analysis showed TEM1 upregulation in mouse heart after coronary ligation. Cardiac TEM1 expression was reconfirmed in mouse HF induced by coronary ligation or doxorubicin injection. TEM1 expression increased in cultured CMs stimulated with mechanical stretch, doxorubicin and hypoxia. Further studies showed recombinant TEM1 (rTEM1) was a functional protein that influenced cell behaviors of CMs. It directly activated Erk and Akt through interaction with PDGF receptor. TEM1lacZ/lacZ mice had less collagen deposition and worse cardiac function than wild type mice. These results indicate that TEM1 expression increases in the heart after cardiac injury and works as a functional protein that participates in cardiac remodeling.

Abstract This meta-analysis compared the outcomes of transradial access (TRA) and transfemoral access (TFA) in chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in recent decades. We searched multiple databases for articles published between January 1, 2015, and December 31, 2020. Six observational studies with 11,736 patients were analyzed. Data included baseline demographics, Japan-chronic total occlusion (J-CTO) score, sheath size, PCI vessel, retrograde method, procedural time, fluoroscopy time, and contrast volume. The more prevalent target CTO vessel was the left coronary artery in the TRA group and the right coronary artery in the TFA group. Higher J-CTO score, longer procedural time, and more contrast volume were seen in the TFA group. In comparison, the TRA group had better procedural success rate (odds ratio (OR), 0.846; 95% confidence interval (CI) 0.749–0.956) and less vascular complications (OR, 0.323; 95% CI 0.203–0.515), but similar retrograde success rate (OR, 0.965; 95% CI 0.382–2.435). In-hospital death (OR, 0.527; 95% CI 0.187–1.489) and major adverse cardiovascular events (OR, 0.729; 95% CI 0.504–1.054) did not differ between the groups. Overall, fewer vascular complications and higher procedural success rates were noted in the TRA CTO PCI population. However, similar retrograde success rates and clinical outcomes were noted between the groups.

Background High burden of premature ventricular complex (PVC) leads to increased cardiovascular mortality. A recent nationwide population‐based study demonstrated that PVC is associated with an increased risk of atrial fibrillation (AF). However, the relationship between PVC burden and new‐onset AF has not been investigated. The purpose of the study is to elucidate whether PVC burden is associated with new‐onset AF. Methods and Results We designed a single‐center, retrospective, large population‐based cohort study to evaluate the role of PVC burden and new‐onset AF in Taiwan. Patients who were AF naïve with PVC were divided into the low burden group (

Background: Hepatocellular carcinoma (HCC) patients suffer varying degrees of heart dysfunction after tyrosine kinase inhibitor (TKI) treatment. Interestingly, HCC patients often have higher levels of pentraxin 3 (PTX3), and PTX3 inhibition was found to improve left ventricular dysfunction in animal models. Objectives: We sought to assess the therapeutic potential of PTX3 inhibition on TKI-associated cardiotoxicity. Methods: We used a human embryonic stem cell line, RUES2, to generate cardiomyocyte cultures (RUES2-CM) for functional testing. We also assessed heart function and PTX3 expression levels in 16 HCC patients who received TKI treatment, 3 HCC patients who did not receive TKIs, and 7 healthy volunteers. Results: Significantly higher PTX3 expression was noted in HCC patients with TKI treatment versus those without, and 38% of male and 33% of female patients had QTc prolongation after TKI treatment. Treatment of cardiomyocyte cultures with sorafenib also increased PTX3 expression and induced cytoskeletal remodelling, contraction reduction, sodium current inhibition, and mitochondrial respiratory dysfunction. PTX3 colocalised with CD44 in cardiomyocytes, and cardiomyocyte contraction, mitochondrial respiratory function, and regular cytoskeletal and apoptotic protein expression were restored with PTX3 inhibition. CD44 knockdown confirmed PTX3/CD44 signalling. These results suggest a possible mechanism in which sorafenib treatment increases PTX3 expression, thereby resulting in reduced extracellular signal-regulated kinase (ERK) 1/2 expression that affects cardiomyocyte contraction, while also activating c-Jun N-terminal kinase (JNK) downstream pathways to disrupt mitochondrial respiration and trigger apoptosis. Conclusions: TKI-induced cardiotoxicity may be partly mediated by the upregulation of PTX3, and thus PTX3 inhibition has potential as a therapeutic strategy.

Abstract Objective Long-term oral anticoagulant should be considered or recommended in patients with atrial fibrillation (AF) and CHA2DS2VASc score ≥ 1 for stroke prevention. Warfarin and different direct oral anticoagulants (DOACs) are metabolized differently by the kidney. The impact on renal function after long-term use of anticoagulants in the patients with AF remains unclear. This study aimed to compare DOACs and warfarin’s impact on the decline in renal function from a large cohort with AF. Methods This study included patients with nonvalvular AF from 2000 to 2018, mainly through the medical history (ICD code) of the Chang Gung Research Database. Baseline estimated glomerular filtration rate (eGFR), follow-up eGFR and the change in eGFR between 2-year eGFR and baseline eGFR were compared between different DOACs and warfarin after propensity score matching. The primary study endpoint was acute kidney injury (AKI). Results 3657 patients were enrolled in this study and the mean observation time was 3.3 ± 0.9 years. During the observation period, there was a significantly higher incidence of AKI during follow-up in the warfarin group than in the different DOAC groups before and after propensity score matching (before: warfarin vs. DOAC: 9.2% vs. 5.2%, p

Type 2 diabetes is a major threat to human health in the 21st century. More than half a billion people may suffer from this pandemic disease in 2030, leading to a huge burden of cardiovascular complications. Recently, 2 novel antidiabetic agents, glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, reduced cardiovascular complications in a number of randomized control trials. To integrate new information and to achieve a streamlined process for better patient care, a working group was appointed by the Taiwan Society of Cardiology to formulate a stepwise consensus pathway for these therapies to reduce cardiovascular events in patients with type 2 diabetes. This consensus pathway is complementary to clinical guidelines, acting as a reference to improve patient care.

Tyrosine kinase inhibitors (TKIs) are widely used in cancer treatment due to their effectiveness in cancer cell killing. However, an off-target of this agent limits its success. Cardiotoxicity-associated TKIs have been widely reported. Tyrosine kinase is involved in many regulatory processes in a cell, and it is involved in cancer formation. Recent evidence suggests the role of tyrosine kinase in cardiovascular calcification, specifically, the calcification of heart vessels and valves. Herein, we summarized the accumulating evidence of the crucial role of receptor tyrosine kinase (RTK) in cardiovascular calcification and provided the potential clinical implication of TKIs-related ectopic calcification. We found that RTKs, depending on the ligand and tissue, can induce or suppress cardiovascular calcification. Therefore, RTKs may have varying effects on ectopic calcification. Additionally, in the context of cardiovascular calcification, TKIs do not always relate to an unfavored outcome—they might offer benefits in some cases.

Abstract Premature atrial complexes (PACs) have been suggested to increase the risk of adverse events. The distribution of PAC burden and its dose–response effects on all-cause mortality and cardiovascular death had not been elucidated clearly. We analyzed 15,893 patients in a medical referral center from July 1st, 2011, to December 31st, 2018. Multivariate regression driven by ln PAC (beats per 24 h plus 1) or quartiles of PAC burden were examined. Older group had higher PAC burden than younger group (p for trend

Background Multidisciplinary rounds (MDRs) are scheduled, patient-focused communication mechanisms among multidisciplinary providers in the intensive care unit (ICU). Objectivei-Dashboard is a custom-developed visualization dashboard that supports (1) key information retrieval and reorganization, (2) time-series data, and (3) display on large touch screens during MDRs. This study aimed to evaluate the performance, including the efficiency of prerounding data gathering, communication accuracy, and information exchange, and clinical satisfaction of integrating i-Dashboard as a platform to facilitate MDRs. MethodsA cluster-randomized controlled trial was performed in 2 surgical ICUs at a university hospital. Study participants included all multidisciplinary care team members. The performance and clinical satisfaction of i-Dashboard during MDRs were compared with those of the established electronic medical record (EMR) through direct observation and questionnaire surveys. ResultsBetween April 26 and July 18, 2021, a total of 78 and 91 MDRs were performed with the established EMR and i-Dashboard, respectively. For prerounding data gathering, the median time was 10.4 (IQR 9.1-11.8) and 4.6 (IQR 3.5-5.8) minutes using the established EMR and i-Dashboard (P

Abstract Left ventricular (LV) global peak systolic longitudinal strain (GLS) is a sensitive measurement for detecting subtle LV systolic dysfunction and a powerful prognostic predictor. However, the clinical implication of LV GLS in lymphoma patients receiving cancer therapy remains unknown. We prospectively enrolled 74 lymphoma patients (57.9 ± 17.0 years old, 57% male). We performed echocardiographic studies after the 3rd and 6th cycles and 1 year after chemotherapy and a cardiopulmonary exercise test upon completion of 3 cycles of anticancer therapy. Cancer therapy-related cardiac dysfunction (CTRCD) was defined as a ≥ 15% relative reduction in GLS value from baseline. The primary outcome was a composite of all-cause mortality and heart failure events. Thirty-six patients (49%) had CTRCD (LV GLS: baseline vs. after 3rd cycle of therapy: 20.1 ± 2.6 vs. 17.5 ± 2.3%, p

Abstract Although some studies have assessed the cost-effectiveness of percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI), there has been a lack of nationwide real-world studies estimating life expectancy (LE), loss-of-LE, life-years saved, and lifetime medical costs. We evaluated the cost-effectiveness of PCI versus non-PCI therapy by integrating a survival function and mean-cost function over a lifelong horizon to obtain the estimations for AMI patients without major comorbidities. We constructed a longitudinal AMI cohort based on the claim database of Taiwan's National Health Insurance during 1999–2015. Taiwan's National Mortality Registry Database was linked to derive a survival function to estimate LE, loss-of-LE, life-years saved, and lifetime medical costs in both therapies. This study enrolled a total of 38,441 AMI patients; AMI patients receiving PCI showed a fewer loss-of-LE (3.6 versus 5.2 years), and more lifetime medical costs (US$ 49,112 versus US$ 43,532). The incremental cost-effectiveness ratio (ICER) was US$ 3488 per life-year saved. After stratification by age, the AMI patients aged 50–59 years receiving PCI was shown to be cost-saving. From the perspective of Taiwan's National Health Insurance, PCI is cost-effective in AMI patients without major comorbidities. Notably, for patients aged 50–59 years, PCI is cost-saving.

BackgroundVentricular premature complex (VPC) is one of the most common ventricular arrhythmias. The presence of VPC is associated with an increased risk of heart failure (HF).MethodWe designed a single-center, retrospective, and large population-based cohort to clarify the role of VPC burden in long-term prognosis in Taiwan. We analyzed the database from the National Cheng Kung University Hospital-Electronic Medical Record (NCKUH-EMR) and NCKUH-Holter (NCKUH-Holter). A total of 19,527 patients who underwent 24-h Holter ECG monitoring due to palpitation, syncope, and clinical suspicion of arrhythmias were enrolled in this study.ResultsThe clinical outcome of interests involved 5.65% noncardiovascular death and 1.53% cardiovascular-specific deaths between 2011 and 2018. Multivariate Cox regression analysis, Fine and Gray's competing risk model, and propensity score matching demonstrated that both moderate (1,000–10,000/day) and high (>10,000/day) VPC burdens contributed to cardiovascular death in comparison with a low VPC burden (

AimsPremature atrial complexes (PACs) have been reported to increase the risk of adverse cardiovascular outcomes. Beta blockers at low dosages may help to reduce PAC symptoms, but it is unclear whether they can improve long-term outcomes.MethodsPatients enrolled from a Holter cohort in a medical referral center were stratified into high-burden (≥100 beats/24 h) and low-burden (

Heterotopic ossification (HO) in patients with spinal cord injury could lead to local tissue swelling and sometimes mimic the clinical presentation of deep vein thrombosis. Recognition and effective management is critical. We report the case of a bedridden patient with spinal cord injury presenting with diffuse right lower limb swelling caused by external venous compression from HO. The patient underwent surgery and local radiation therapy. Postoperative venography disclosed a marked improvement in the blood flow, and symptoms were alleviated. We discuss the role of venography in the diagnosis and treatment of venous compression in the setting of HO.

Objective. A target of low-density lipoprotein cholesterol (LDL-C)

Objective. Conduction disorders with a widened QRS are associated with poor prognosis in patients with acute coronary syndrome (ACS). Conduction disorders include left bundle branch block (LBBB), right bundle branch block (RBBB), and nonspecific intraventricular conduction delay (NICD). Previous studies did not have conflicting results regarding the type of bundle branch block (BBB) with the worst prognosis, and few studies have focused on the prognosis of patients with NICD. Methods. Patients with ACS were enrolled between January 2005 and December 2019, and their medical history (International Classification of Diseases codes) was obtained from the Chang Gung Research Database. Age, sex, comorbidities, left ventricular ejection fraction (LVEF), and drug use were compared between the patients with and without conduction disorders. The following clinical outcomes were compared between patients with and without conduction disorders: heart failure (HF) hospitalization, cardiovascular (CV) mortality, and all-cause mortality. After propensity score matching, the Kaplan–Meier curve analysis for HF hospitalization, CV mortality, and all-cause mortality were compared among patients with LBBB, RBBB, and NICD. Results. This study enrolled a total of 33970 participants and involved 3392 and 30578 patients with and without conduction disorders, respectively. Older age and a higher prevalence of comorbidities were noted in patients with conduction disorders. Lower mean LVEF was exhibited in the patients with conduction disorders (with vs. without; 44.64 ± 20.73% vs. 49.85 ± 20.63%; p

Background: Age affects the efficacy of pharmacological treatment for atrial fibrillation (AF). Catheter ablation, including radiofrequency (RF) or cryoballoon ablation, is an effective strategy for symptomatic AF. This meta-analysis aimed to analyze the efficacy and safety of AF ablation in elderly patients with AF compared to non-elderly patients with AF.Methods: We searched several databases for articles published between January 1, 2008 and March 31, 2020. Eighteen observational studies with 21,039 patients were analyzed. Data including recurrence of AF or atrial tachyarrhythmia (ATA), complications, procedural time, and fluoroscopic time were compared between the elderly and non-elderly groups.Results: The elderly patients had significantly higher incidences of recurrent AF or ATA after AF ablation compared to the non-elderly patients (

Summary: The new generation, i.e., second- and third-generation, drug-eluting stents (DESs) remain a risk of in-stent restenosis (ISR). We evaluated the power of a genetic risk score (GRS) model to identify high-risk populations for new generation DES ISR. We enrolled patients with coronary artery disease (CAD) treated with new generations DESs by a single-center cohort study in Taiwan and evaluated their genetic profile. After propensity score matching, there were 343 patients and 153 patients in the derivation and validation cohorts, respectively. Five selected single-nucleotide polymorphisms (SNPs), i.e., SNPs in CAMLG, GALNT2, C11orf84, THOC5, and SAMD11, were included to calculate the GRS for new generation DES ISR. In the derivation and the validation cohorts, patients with a GRS greater than or equal to 3 had significantly higher new generation DES ISR rates. We provide biological information for interventional cardiologists prior to percutaneous coronary intervention by specific five SNP-derived GRS.

Mitral regurgitation (MR), the disruption of the mitral valve, contributes to heart failure (HF). Under conditions of volume overload, excess mineralocorticoids promote cardiac fibrosis. The mineralocorticoid receptor antagonist spironolactone is a potassium-sparing diuretic and a guideline-recommended therapy for HF, but whether it can ameliorate degenerative MR remains unknown. Herein, we investigate the efficacy of spironolactone in improving cardiac remodeling in MR-induced HF compared with that of a loop diuretic, furosemide. Using a novel and mini-invasive technique, we established a rat model of MR. We treated the rats with spironolactone or furosemide for twelve weeks. The levels of cardiac fibrosis, apoptosis, and stress-associated proteins were then measured. In parallel, we compared the cardiac remodeling of 165 patients with degenerative MR receiving either spironolactone or furosemide. Echocardiography was performed at baseline and at six months. In MR rats treated with spironolactone, left ventricular function—especially when strained—and the pressure volume relationship significantly improved compared to those of rats treated with furosemide. Spironolactone treatment demonstrated significant attenuation of cardiac fibrosis and apoptosis in left ventricular tissue compared to furosemide. Further, spironolactone suppressed the expression of apoptosis-, NADPH oxidase 4 (NOX4)- and inducible nitric oxide synthase (iNOS)-associated proteins. Similarly, compared with MR patients receiving furosemide those prescribed spironolactone demonstrated a trend toward reduction in MR severity and showed improvement in left ventricular function. Collectively, MR-induced cardiovascular dysfunction, including fibrosis and apoptosis, was effectively attenuated by spironolactone treatment. Our findings suggest a potential therapeutic option for degenerative MR-induced HF.

Background: Atrial fibrillation (AF) is associated with an increased risk of heart failure, death and thromboembolism. AF is prevalent in patients with cancer. Although current guidelines suggest the application of oral anticoagulants (OACs) for thromboembolic event prevention in high-risk AF patients, owing to the high thromboembolic and bleeding risks of active-cancer patients, there is no consensus on the use of OACs in such a population. Therefore, we conducted this retrospective cohort study to investigate the applicability of the CHA2DS2-VASc score and to evaluate the efficacy and safety outcomes of OAC therapy in active-cancer patients with AF. Methods: This retrospective cohort study enrolled patients diagnosed with cancer at National Cheng Kung University Hospital between November 2012 and August 2019. The primary outcomes included all-cause mortality, thromboembolic events (stroke/transient ischemic attack and systemic emboli), acute myocardial infarction (AMI), hospitalization for HF and major bleeding events. Results: We enrolled 2429 patients with active cancer. Among these patients, 1060 patients (43.6%) had AF. After 1:2 propensity score matching, 690 cancer patients with AF were enrolled for the final analysis, grouped as follows: 225 patients taking OACs and 465 patients without OAC treatment. The OAC-treated group had lower all-cause mortality than the patients without OAC treatment (all-cause mortality rate in OAC treatment vs. non-OAC treatment: 24.4% vs. 37.4%, hazard ratio 0.58 [95% confidence interval (CI) 0.43–0.78], p < 0.001). However, there was no difference in thromboembolic events, myocardial infarction or heart failure hospitalization between the OAC-treated and non-OAC-treated groups. Importantly, the risk of major bleeding composition (i.e., major gastrointestinal bleeding and intracranial hemorrhage) was similar between these two groups. Moreover, the CHA2DS2-VASc score could not predict thromboembolic events in the enrolled active-cancer patients with AF (OR 1.23, 95% CI 0.98–1.56). Conclusions: OAC treatment may significantly reduce the risk of death, without safety concerns, in active-cancer patients with AF. OAC treatment may not prevent thromboembolic events in patients with active cancer and AF. However, we found that OAC treatment is associated with improved prognosis without increasing the risks of major bleeding, despite several limitations in this study. Further studies are required to determine the optimal use of anticoagulation therapy in this high-risk population.

Remdesivir (RDV, GS-5734), a broad-spectrum antiviral drug in the class of nucleotide analogs, has been particularly tailored for treatment of coronavirus infections. However, to which extent RDV is able to modify various types of membrane ion currents remains largely uncertain. In this study, we hence intended to explore the possible perturbations of RDV on ionic currents endogenous in pituitary GH3 cells and Jurkat T-lymphocytes. The whole-cell current recordings of ours disclosed that upon membrane depolarization in GH3 cells the exposure to RDV concentration-dependently depressed the peak or late components of IK(DR) elicitation with effective IC50 values of 10.1 or 2.8 μM, respectively; meanwhile, the value of dissociation constant of RDV-induced blockage of IK(DR) on the basis of the first-order reaction was yielded to be 3.04 μM. Upon the existence of RDV, the steady-state inactivation curve of IK(DR) was established in the RDV presence; moreover, the recovery became slowed. However, RDV-induced blockage of IK(DR) failed to be overcome by further addition of either α,β-methylene ATP or cyclopentyl-1,3-dipropylxanthine. The RDV addition also lessened the strength of M-type K+ current with the IC50 value of 2.5 μM. The magnitude of voltage hysteresis of IK(M) elicited by long-lasting triangular ramp pulse was diminished by adding RDV. Membrane electroporation-induced current in response to large hyperpolarization was enhanced, with an EC50 value of 5.8 μM. Likewise, in Jurkat T-lymphocytes, adding RDV declined IK(DR) amplitude concomitantly with the raised rate of current inactivation applied by step depolarization. Therefore, in terms of the RDV molecule, there appears to be an unintended activity of the prodrug on ion channels. Its inhibition of both IK(DR) and IK(M) occurring in a non-genomic fashion might provide additional but important mechanisms through which in vivo cellular functions are seriously perturbed.

Atherosclerosis is a chronic multifactorial disease characterized by mainly changes of blood lipids profile and inflammation in vessel wall. The cardiovascular disease based on atherosclerosis is currently the leading cause of mortality in developed countries. Therefore, timely prevention and therapy of atherosclerosis are able to reduce the risk of the development of its clinical manifestations. Anti-atherosclerotic activity of medicinal plants mainly appears in their multiple effects such as anti-inflammatory, antioxidant, anti-atherogenic, hypotensive, lipid-lowering, anti-thrombotic. Moreover, most of medicinal plants are characterized by their pleiotropic anti-atherosclerotic action. In addition, the medicinal plants-derived pharmacological substances and/or compounds are characterized by relative safety and fewer side effects that allows considering them as one of potential anti-atherosclerotic effective agents. The direct anti-atherosclerotic effect of some medicinal plants was confirmed in clinical trials of carotid Intima-media thickness (IMT) progression during long-term medication with medicinal plants. This review attempted to determine the current status of the databases PubMed and Scopus (until November, 2019) to investigate the medicinal plants possessing anti-atherosclerotic activity in experimental and clinical studies.

Chronic kidney disease (CKD) is normally related to proteinuria, a common finding in a compromised glomerular filtration barrier (GFB). GFB is a structure composed of glomerular endothelial cells, the basement membrane, and the podocytes. CKD with podocyte damage may be associated with actin cytoskeleton reorganization, resulting in podocyte effacement. Gelsolin plays a critical role in several diseases, including cardiovascular diseases and cancer. Our current study aimed to determine the connection between gelsolin and podocyte, and thus the mechanism underlying podocyte injury in CKD. Experiments were carried out on Drosophila to demonstrate whether gelsolin had a physiological role in maintaining podocyte. Furthermore, the survival rate of gelsolin-knocked down Drosophila larvae was extensively reduced after AgNO3 exposure. Secondly, the in vitro podocytes treated with puromycin aminonucleoside (PAN) enhanced the gelsolin protein expression, as well as small GTPase RhoA and Rac1, which also regulated actin dynamic expression incrementally with the PAN concentrations. Thirdly, we further demonstrated in vivo that GSN was highly expressed inside the glomeruli with mitochondrial dysfunction in a CKD mouse model. Our findings suggest that an excess of gelsolin may contribute to podocytes damage in glomeruli.

Glycosylation is an important step in post-translational protein modification. Altered glycosylation results in an abnormality that causes diseases such as malignancy and cardiovascular diseases. Recent emerging evidence highlights the importance of glycosylation in vascular calcification. Two major types of glycosylation, N-glycosylation and O-glycosylation, are involved in vascular calcification. Other glycosylation mechanisms, which polymerize the glycosaminoglycan (GAG) chain onto protein, resulting in proteoglycan (PG), also have an impact on vascular calcification. This paper discusses the role of glycosylation in vascular calcification.

In Taiwan, the prevalence of hyperlipidemia increased due to lifestyle and dietary habit changes. Low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) are all significant predicting factors of coronary artery disease in Taiwan. We recognized that lipid control is especially important in patients with existed atherosclerotic cardiovascular diseases (ASCVD), including coronary artery disease (CAD), ischemic stroke and peripheral arterial disease (PAD). Because the risk of ASCVD is high in patients with diabetes mellitus (DM), chronic kidney disease (CKD) and familial hypercholesterolemia (FH), lipid control is also necessary in these patients. Lifestyle modification is the first step to control lipid. Weight reduction, regular physical exercise and limitation of alcohol intake all reduce triglyceride (TG) levels. Lipid-lowering drugs include HMG-CoA reductase inhibitors (statins), cholesterol absorption inhibitors (ezetimibe), proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, nicotinic acids (niacin), fibric acids derivatives (fibrates), and long-chain omega-3 fatty acids. Statin is usually the first line therapy. Combination therapy with statin and other lipid-lowering agents may be considered in some clinical settings. For patients with acute coronary syndrome (ACS) and stable CAD, LDL-C < 70 mg/dL is the major target. A lower target of LDL-C 40 in men and >50 mg/dL in women in DM. LDL-C increased CV risk in patients with CKD. In adults with glomerular filtration rate (GFR) < 60 mL/min/1.73m2 without chronic dialysis (CKD stage 3–5), statin therapy should be initiated if LDL-C ≥ 100 mg/dL. Ezetimibe can be added to statin to consolidate the CV protection in CKD patients. Mutations in LDL receptor, apolipoprotein B and PCSK9 genes are the common causes of FH. Diagnosis of FH usually depends on family history, clinical history of premature CAD, physical findings of xanthoma or corneal arcus and high levels of LDL-C. In addition to conventional lipid lowering therapies, adjunctive treatment with mipomersen, lomitapide, or PCSK9 inhibitors become necessary to further reduce LDL-C in patients with FH. Overall, these recommendations are to help the health care professionals in Taiwan to treat hyperlipidemia with current scientific evidences. We hope the prescription rate of lipid lowering drugs and control rate of hyperlipidemia in high risk patients could be increased by implementation of the clinical guidelines. The major purpose is to improve clinical outcomes of these high risk patients through the control of hyperlipidemia.

Carfilzomib (CFZ, Kyprolis®) is widely recognized as an irreversible inhibitor of proteasome activity; however, its actions on ion currents in electrically excitable cells are largely unresolved. The possible actions of CFZ on ionic currents and membrane potential in pituitary GH3, A7r5 vascular smooth muscle, and heart-derived H9c2 cells were extensively investigated in this study. The presence of CFZ suppressed the amplitude of delayed-rectifier K+ current (IK(DR)) in a time-, state-, and concentration-dependent manner in pituitary GH3 cells. Based on minimal reaction scheme, the value of dissociation constant for CFZ-induced open-channel block of IK(DR) in these cells was 0.33 µM, which is similar to the IC50 value (0.32 µM) used for its efficacy on inhibition of IK(DR) amplitude. Recovery from IK(DR) block by CFZ (0.3 µM and 1 µM) could be well fitted by single exponential with 447 and 645 ms, respectively. The M-type K+ current, another type of K+ current elicited by low-threshold potential, was slightly suppressed by CFZ (1 µM). Under current-clamp condition, addition of CFZ depolarized GH3 cells, broadened the duration of action potentials as well as raised the firing frequency. In A7r5 vascular smooth muscle cells or H9c2 cardiac cells, the CFZ-induced inhibition of IK(DR) remained efficacious. Therefore, our study led us to reflect that CFZ or other structurally similar compounds should somehow act on the activity of membrane KV channels through which they influence the functional activities in different types of electrically excitable cells such as endocrine, neuroendocrine cells, smooth muscle cells, or heart cells, if similar in vivo findings occur.

Verteporfin (VP), a benzoporphyrin derivative, has been clinically tailored as a photosensitizer and recently known to suppress YAP-TEAD complex accompanied by suppression of the growth in an array of neoplastic cells. However, the detailed information is little available regarding possible modifications of it and its related compounds on transmembrane ionic currents, despite its growing use in clinical settings. In this study, from whole cell recordings, VP (0.3–100 μM) increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) in pituitary tumor (GH3) cells in a concentration-dependent manner with an EC50 value of 2.4 μM. VP-stimulated IK(Ca) in these cells was suppressed by further addition of either paxilline, iberiotoxin, or dithiothreitol, but not by that of tobultamide or TRAM-39. VP at a concentration of 10 μM mildly suppressed the amplitude of delayed-rectifier K+ current; however, it had minimal effects on M-type K+ current. In cell-attached current recordings, addition of VP to the recording medium enhanced the activity of large-conductance Ca2+-activated K+ (BKCa) channels. In the presence of VP, additional illumination with light intensity of 5.5 mW/cm2 raised the probability of BKCa-channel openings further. Addition of VP decreased the peak amplitude of L-type Ca2+ current together with slowed inactivation time course of the current; however, it failed to modify voltage-gated Na+ current. Illumination of GH3 cells in continued presence of VP also induced a non-selective cation current. Additionally, VP increased the activity of BKCa channels in human 13-06-MG glioma cells with an EC50 value of 1.9 μM. Therefore, the effects of VP on ionic currents described herein tend to be upstream of its inhibition of YAP-TEAD complex and they are conceivably likely to contribute to the underlying mechanisms through which it and its structurally similar compounds effect the modifications in functional activities of pituitary or glial neoplastic cells, if the in vivo findings occur.

Pentagalloyglucose (PGG, penta-O-galloyl-β-d-glucose; 1,2,3,4,6-pentagalloyl glucose), a pentagallic acid ester of glucose, is recognized to possess anti-bacterial, anti-oxidative and anti-neoplastic activities. However, to what extent PGG or other polyphenolic compounds can perturb the magnitude and/or gating of different types of plasmalemmal ionic currents remains largely uncertain. In pituitary tumor (GH3) cells, we found out that PGG was effective at suppressing the density of delayed-rectifier K+ current (IK(DR)) concentration-dependently. The addition of PGG could suppress the density of proton-activated Cl− current (IPAC) observed in GH3 cells. The IC50 value required for the inhibitory action of PGG on IK(DR) or IPAC observed in GH3 cells was estimated to be 3.6 or 12.2 μM, respectively, while PGG (10 μM) mildly inhibited the density of the erg-mediated K+ current or voltage-gated Na+ current. The presence of neither chlorotoxin, hesperetin, kaempferol, morin nor iberiotoxin had any effects on IPAC density, whereas hydroxychloroquine or 4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5yl)oxy] butanoic acid suppressed current density effectively. The application of PGG also led to a decrease in the area of voltage-dependent hysteresis of IPAC elicited by long-lasting isosceles-triangular ramp voltage command, suggesting that hysteretic strength was lessened in its presence. In human cardiac myocytes, the exposure to PGG also resulted in a reduction of ramp-induced IK(DR) density. Taken literally, PGG-perturbed adjustment of ionic currents could be direct and appears to be independent of its anti-oxidative property.

Cardiovascular disease is the leading cause of deaths worldwide, claiming an estimated total of 17.9 million lives each year, of which one-third of the people are under the age of 70 years. Since adult cardiomyocytes fail to regenerate, the heart loses the ability to repair itself after an injury, making patients with heart disease suffer from poor prognosis. Pluripotent stem cells have the ability to differentiate into cardiomyocytes in vitro through a well-established process, which is a new advancement in cardiac regeneration therapy. However, pluripotent stem cell-derived cardiomyocytes have certain drawbacks, such as the risk of arrhythmia and immune incompatibility. Thus, amniotic fluid stem cells (AFSCs), a relatively novel source of stem cells, have been exploited for their ability of pluripotent differentiation. In addition, since AFSCs are weakly positive for the major histocompatibility class II molecules, they may have high immune tolerance. In summary, the possibility of development of cardiomyocytes from AFSCs, as well as their transplantation in host cells to produce mechanical contraction, has been discussed. Thus, this review article highlights the progress of AFSC therapy and its application in the treatment of heart diseases in recent years.

FTY720 (fingolimod), a modulator of sphingosine-1-phosphate receptors, is known to produce the immunomodulatory actions and to be beneficial for treating the relapsing multiple sclerosis. However, whether it exerts any effects on membrane ion currents in immune cells remains largely unknown. Herein, the effects of FTY720 on ionic currents in Jurkat T-lymphocytes were investigated. Cell exposure to FTY720 suppressed the amplitude of delayed-rectifier K+ current (IK(DR)) in a time- and concentration-dependent manner with an IC50 value of 1.51 μM. Increasing the FTY720 concentration not only decreased the IK(DR) amplitude but also accelerated the inactivation time course of the current. By using the minimal reaction scheme, the effect of FTY720 on IK(DR) inactivation was estimated with a dissociation constant of 3.14 μM. FTY720 also shifted the inactivation curve of IK(DR) to a hyperpolarized potential with no change in the slope factor, and recovery from IK(DR) became slow during the exposure to this compound. Cumulative inactivation for IK(DR) in response to repetitive depolarizations was enhanced in the presence of FTY720. In SEW2871-treated cells, FTY720-induced inhibition of IK(DR) was attenuated. This compound also exerted a stimulatory action on the activity of intermediate-conductance Ca2+-activated K+ channels in Jurkat T-lymphocytes. However, in NSC-34 neuronal cells, FTY720 did not modify the inactivation kinetics of KV3.1-encoded IK(DR), although it suppressed IK(DR) amplitude in these cells. Collectively, the perturbations by FTY720 on different types of K+ channels may contribute to the functional activities of immune cells, if similar findings appear in vivo.

Aim: Immunological checkpoint therapy is considered a powerful method for cancer therapy and acts by re-activating autologous T cells to kill the cancer cell. Myocarditis cases have been reported in cancer patients after immunological therapy; for example, nivolumab treatment is a monoclonal antibody that blocks programmed cell death-1/programmed cell death ligand-1 ligand interaction. This project provided insight into the inflammatory response as a benchmark to investigate the potential cardiotoxic effect of T cell response to the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis in regulating cardiomyocyte injury in vitro. Methods and Results: We investigated cardiomyopathy resulted from the PD-1/PD-L1 axis blockade using the anti-PD-1 antibody in Rockefeller University embryonic stem cells-derived cardiomyocytes (RUES2-CMs) and a melanoma tumor-bearing murine model. We found that nivolumab alone did not induce inflammatory-related proteins, including PD-L1 expression, and did not induce apoptosis, which was contrary to doxorubicin, a cardiotoxic chemotherapy drug. However, nivolumab was able to exacerbate the immune response by increasing cytokine and inflammatory gene expression in RUES2-CMs when co-cultured with CD4+ T lymphocytes and induced apoptosis. This effect was not observed when RUES2-CMs were co-cultured with CD8+ T lymphocytes. The in vivo model showed that the heart function of tumor-bearing mice was decreased after treatment with anti-PD-1 antibody and demonstrated a dilated left ventricle histological examination. The dilated left ventricle was associated with an infiltration of CD4+ and CD8+ T lymphocytes into the myocardium. PD-L1 and inflammatory-associated gene expression were significantly increased in anti-PD-1-treated tumor-bearing mice. Cleaved caspase-3 and mouse plasma cardiac troponin I expressions were increased significantly. Conclusion: PD-L1 expression on cardiomyocytes suppressed T-cell function. Blockade of PD-1 by nivolumab enhanced cardiomyocyte inflammation and apoptosis through the enhancement of T-cell response towards cardiomyocytes.

Mature mammalian hearts possess very limited regenerative potential. The irreversible cardiomyocyte loss after heart injury can lead to heart failure and death. Pluripotent stem cells (PSCs) can differentiate into cardiomyocytes for cardiac repair, but there are obstacles to their clinical application. Among these obstacles is their potential for post-transplant rejection. Although human amniotic fluid-derived stem cells (hAFSCs) are immune privileged, they cannot induce cardiac differentiation. Thus, we generated hAFSC-derived induced PSCs (hAFSC-iPSCs) and used a Wnt-modulating differentiation protocol for the cardiac differentiation of hAFSC-iPSCs. In vitro studies using flow cytometry, immunofluorescence staining, and patch-clamp electrophysiological study, were performed to identify the characteristics of hAFSC-iPSC-derived cardiomyocytes (hAFSC-iPSC-CMs). We injected hAFSC-iPSC-CMs intramuscularly into rat infarcted hearts to evaluate the therapeutic potential of hAFSC-iPSC-CM transplantation. At day 21 of differentiation, the hAFSC-iPSC-CMs expressed cardiac-specific marker (cardiac troponin T), presented cardiomyocyte-specific electrophysiological properties, and contracted spontaneously. Importantly, these hAFSC-iPSC-CMs demonstrated low major histocompatibility complex (MHC) class I antigen expression and the absence of MHC class II antigens, indicating their low immunogenicity. The intramyocardial transplantation of hAFSC-iPSC-CMs restored cardiac function, partially remuscularized the injured region, and reduced fibrosis in the rat infarcted hearts. Therefore, hAFSC-iPSCs are potential candidates for the repair of infarcted myocardium.

Lapatinib (LAP) and sorafenib (SOR) are multitargeted tyrosine kinase inhibitors (TKIs) with antineoplastic properties. In clinical observations, LAP and SOR may contribute to QTc prolongation, but the detailed mechanism for this has been largely unexplored. In this study, we investigated whether LAP and SOR affect the activities of membrane ion channels. Using a small animal model and primary cardiomyocytes, we studied the impact of LAP and SOR on Na+ and K+ currents. We found that LAP-induced QTc prolongation in mice was reversed by isoproterenol. LAP or SOR suppressed the amplitude of the slowly activating delayed-rectifier K+ current (IK(S)) in H9c2 cells in a time- and concentration-dependent fashion. The LAP-mediated inhibition of IK(S) was reversed by adding isoproterenol or meclofenamic acid, but not by adding diazoxide. The steady-state activation curve of IK(S) during exposure to LAP or SOR was shifted toward a less negative potential, with no change in the gating charge required to activate the current. LAP shortened the recovery from IK(S) deactivation. As rapid repetitive stimuli, the IK(S) amplitude decreased; however; the LAP-induced inhibition of IK(S) remained effective. LAP or SOR alone also suppressed inwardly rectifying K+ and voltage-gated Na+ current in neonatal rat ventricular myocytes. The inhibition of ionic currents during exposure to TKIs could be an important mechanism underlying changes in QTc intervals.

Oxaliplatin (OXAL) is regarded as a platinum-based anti-neoplastic agent. However, its perturbations on membrane ionic currents in neurons and neuroendocrine or endocrine cells are largely unclear, though peripheral neuropathy has been noted during its long-term administration. In this study, we investigated how the presence of OXAL and other related compounds can interact with two types of inward currents; namely, hyperpolarization-activated cation current (Ih) and membrane electroporation-induced current (IMEP). OXAL increased the amplitude or activation rate constant of Ih in a concentration-dependent manner with effective EC50 or KD values of 3.2 or 6.4 μM, respectively, in pituitary GH3 cells. The stimulation by this agent of Ih could be attenuated by subsequent addition of ivabradine, protopine, or dexmedetomidine. Cell exposure to OXAL (3 μM) resulted in an approximately 11 mV rightward shift in Ih activation along the voltage axis with minimal changes in the gating charge of the curve. The exposure to OXAL also effected an elevation in area of the voltage-dependent hysteresis elicited by long-lasting triangular ramp. Additionally, its application resulted in an increase in the amplitude of IMEP elicited by large hyperpolarization in GH3 cells with an EC50 value of 1.3 μM. However, in the continued presence of OXAL, further addition of ivabradine, protopine, or dexmedetomidine always resulted in failure to attenuate the OXAL-induced increase of IMEP amplitude effectively. Averaged current-voltage relation of membrane electroporation-induced current (IMEP) was altered in the presence of OXAL. In pituitary R1220 cells, OXAL-stimulated Ih remained effective. In Rolf B1.T olfactory sensory neurons, this agent was also observed to increase IMEP in a concentration-dependent manner. In light of the findings from this study, OXAL-mediated increases of Ih and IMEP may coincide and then synergistically act to increase the amplitude of inward currents, raising the membrane excitability of electrically excitable cells, if similar in vivo findings occur.

Gastrodigenin (HBA) and gastrodin (GAS) are phenolic ingredients found in Gastrodia elata Blume (GEB), a traditional Chinese herbal medicine. These compounds have been previously used to treat cognitive dysfunction, convulsion, and dizziness. However, at present, there is no available information regarding their potential ionic effects in electrically excitable cells. In the current study, the possible effects of HBA and GAS on different ionic currents in pituitary GH3 cells and hippocampal mHippoE-14 neurons were investigated using the patch-clamp technique. The addition of HBA or GAS resulted in the differential inhibition of the M-type K+ current (IK(M)) density in a concentration-dependent manner in GH3 cells. HBA resulted in a slowing of the activation time course of IK(M), while GAS elevated it. HBA also mildly suppressed the density of erg-mediated or the delayed-rectifier K+ current in GH3 cells. Neither GAS nor HBA (10 µM) modified the voltage-gated Na+ current density, although they suppressed the L-type Ca2+ current density at the same concentration. In hippocampal mHippoE-14 neurons, HBA was effective at inhibiting IK(M) density as well as slowing the activation time course. Taken together, the present study provided the first evidence that HBA or GAS could act on cellular mechanisms, and could therefore potentially have a functional influence in various neurologic disorders.

BackgroundMany patients with coronary artery heart disease are unable to access traditional psychosocial rehabilitation conducted face to face due to excessive travel distance. Therefore, this study developed and assessed the feasibility and acceptability of an 8-week Internet-based cognitive-behavior group therapy program, described the patterns of use and measured change in risk factors.MethodsThis study adopted an online video conference system, JointNet, to maintain group interaction functions similar to face to face groups online, and also built an self-learning platform to deliver psychoeducation content and cognitive-behavior therapy related materials and homework. Forty-three out-patients were recruited in the pilot study, who then chose to participate in either the Internet-based cognitive-behavior group therapy or face to face group based on their preference. Fourteen patients were assigned to the waiting-list control.ResultsSeventeen participants (17/43 = 39.5%) chose the Internet-based cognitive-behavior group therapy program. Among them, thirteen participants (13/17 = 76.5%) finished the program and were more male (92.3% vs. 50%), employed (53.8% vs. 35.3%), and had longer education duration (13.9 vs. 12.5 years) than the counterparts of the face to face group. Furthermore, they were highly motivated with average number of log-ins (66.5 time), website surfing time (950.94 min), reading frequency (78.15 time) and reading time (355.90 min) for the self-learning platform during eight weeks; and also highly satisfied (97%) with visiting the self-learning platform and video conferences. The treatment effectiveness of Internet-based cognitive-behavior group therapy was comparable with face to face one in reducing anxiety, hostility, respiration rate, and in improving vasodilation but not depression compared with the waiting-list control.ConclusionThese results indicated that the Internet-based group therapy program using video conference is feasible and acceptable for the psychosocial rehabilitation of patients with coronary artery heart disease, and provides an alternative for patients who are unable to obtain conventional psychosocial rehabilitation conducted face to face.

BACKGROUND:Right ventricular (RV) function has been found to be a major factor of exercise capacity in patients with heart failure. However, the role of RV function in exercise capacity in healthy subjects has not been well studied. This study aims to validate the role of RV strain derived from speckle tracking echocardiography for exercise capacity for health check-up subjects. METHODS:This study prospectively recruited subjects from a routine health examination. All of them were symptom free. RV function represented by RV strain was derived from speckle tracking echocardiography in addition to traditional echocardiography parameters. Functional capacity was determined by a symptom limited treadmill exercise test with the Bruce protocol. RESULTS:Among 164 recruited subjects (age 52.2 ±9.2 years, 66.4% male), 32 subjects represented impaired functional capacity (MET