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We aimed to investigate the sex-related differences in the clinical course of patients with Atrial Fibrillation (AF) enrolled in the Asia–Pacific-Heart-Rhythm-Society Registry. Logistic regression was utilized to investigate the relationship between sex and oral anticoagulant, rhythm control strategies and the 1-year chance to maintain sinus rhythm. Cox-regression was utilized to assess the 1-year risk of all-cause, and cardiovascular death, thromboembolic events, acute coronary syndrome, heart failure, and major bleeding. In the whole cohort (4121 patients, 69 ± 12 years,34.3% female), females had different cardiovascular risk factors, clinical manifestations, and disease perceptions than men, with more advanced age (72 ± 11 vs 67 ± 12 years, p < 0.001) and dyslipidemia (36.7% vs 41.7%, p = 0.002). Coronary artery disease was more prevalent in males (21.1% vs 16.1%, p < 0.001) as well as the use of antiplatelet drugs. Females had a higher use of oral anticoagulant (84.9% vs 81.3%, p = 0.004) but this difference was non-significant after adjustment for confounders. On multivariable analyses, females were less often treated with rhythm control strategies (Odds Ratio [OR] 0.44,95% Confidence Interval [CI] 0.38–0.51) and were less likely to maintain sinus rhythm (OR 0.27, 95% CI 0.22–0.34) compared to males. Cox-regressions analysis showed no sex-related differences for the risk of death, cardiovascular, and bleeding. The clinical management of Asian AF patients should consider several sex-related differences. [ABSTRACT FROM AUTHOR]

The utilization of FFR remains low. Our study evaluated the per-vessel prognostic value of computational pressure-flow dynamics-derived FFR (caFFR) among patients with stable coronary artery disease. A total of 3329 vessels from 1308 patients were included and analysed. They were stratified into ischaemic (caFFR ≤ 0.8) and non-ischaemic (caFFR > 0.8) cohorts, and the associations between PCI and outcomes were evaluated. The third cohort comprised all included vessels, and the associations between treatment adherent-to-caFFR (PCI in vessels with caFFR ≤ 0.8 and no PCI in vessels with caFFR > 0.8) and outcomes were evaluated. The primary outcome was VOCE, defined as a composite of vessel-related cardiovascular mortality, non-fatal myocardial infarction, and repeat revascularization. PCI was associated with a lower 3-year risk of VOCE in the ischaemic cohort (HR, 0.44; 95% CI, 0.26–0.74; P = 0.002) but not in the non-ischaemic cohort. The risk of VOCE was lower in the adherent-to-caFFR group (n = 2649) (HR, 0.69; 95% CI, 0.48–0.98; P = 0.039). A novel index that uses coronary angiography images to estimate FFR may have substantial clinical value in guiding management among patients with stable coronary artery disease. [ABSTRACT FROM AUTHOR]

Background: The nonuniform benefit of tricuspid annuloplasty may be explained by the proportionality of tricuspid regurgitation (TR) severity to right ventricular (RV) area. The purpose of this study was to delineate distinct morphological phenotypes of functional TR and investigate their prognostic implications in patients undergoing tricuspid annuloplasty during left-sided valvular surgery. Methods: The ratios of pre-procedural effective regurgitant orifice area (EROA) with right ventricular end-diastolic area (RVDA) were retrospectively assessed in 290 patients undergoing tricuspid annuloplasty. Based on optimal thresholds derived from penalized splines and maximally selected rank statistics, patients were stratified into proportionate (EROA/RVDA ratio ≤ 1.74) and disproportionate TR (EROA/RVDA ratio > 1.74). Results: Overall, 59 (20%) and 231 (80%) patients had proportionate and disproportionate TR, respectively. Compared to those with proportionate TR, patients with disproportionate TR were older, had a higher prevalence of atrial fibrillation, lower pulmonary pressures, more impaired RV function, and larger tricuspid leaflet tenting area. Over a median follow-up of 4.1 years, 79 adverse events (47 heart failure hospitalizations and 32 deaths) occurred. Patients with disproportionate TR had higher rates of adverse events than those with proportionate TR (32% vs 10%; P = 0.001) and were independently associated with poor outcomes on multivariate analysis. TR proportionality outperformed guideline-based classification of TR severity in outcome prediction and provided incremental prognostic value to both the EuroSCORE II and STS score (incremental χ2 = 6.757 and 9.094 respectively; both P < 0.05). Conclusions: Disproportionate TR is strongly associated with adverse prognosis and may aid patient selection and risk stratification for tricuspid annuloplasty with left-sided valvular surgery. [ABSTRACT FROM AUTHOR]

Background: Protection of cardiac function following myocardial infarction was largely enhanced by bradykinin-pretreated cardiac-specific c-kit+ (BK-c-kit+) cells, even without significant engraftment, indicating that paracrine actions of BK-c-kit+ cells play a pivotal role in angiogenesis. Nevertheless, the active components of the paracrine actions of BK-c-kit+ cells and the underlying mechanisms remain unknown. This study aimed to define the active components of exosomes from BK-c-kit+ cells and elucidate their underlying protective mechanisms. Methods: Matrigel tube formation assay, cell cycle, and mobility in human umbilical vein endothelial cells (HUVECs) and hindlimb ischemia (HLI) in mice were applied to determine the angiogenic effect of condition medium (CM) and exosomes. Proteome profiler, microRNA sponge, Due-luciferase assay, microRNA-sequencing, qRT-PCR, and Western blot were used to determine the underlying mechanism of the angiogenic effect of exosomes from BK-c-kit+. Results: As a result, BK-c-kit+ CM and exosomes promoted tube formation in HUVECs and the repair of HLI in mice. Angiogenesis-related proteomic profiling and microRNA sequencing revealed highly enriched miR-3059-5p as a key angiogenic component of BK-c-kit+ exosomes. Meanwhile, loss- and gain-of-function experiments revealed that the promotion of angiogenesis by miR-3059-5p was mainly through suppression of TNFSF15-inhibited effects on vascular tube formation, cell proliferation and cell migration. Moreover, enhanced angiogenesis of miR-3059-5p-inhibited TNFSF15 has been associated with Akt/Erk1/2/Smad2/3-modulated signaling pathway. Conclusion: Our results demonstrated a novel finding that BK-c-kit+ cells enrich exosomal miR-3059-5p to suppress TNFSF15 and promote angiogenesis against hindlimb ischemia in mice. [ABSTRACT FROM AUTHOR]

Introduction: Real-world data are needed to understand the effectiveness of new therapeutic options for low-density lipoprotein cholesterol (LDL-C) reduction in Asia–Pacific clinical practice. Description of evolocumab use among adults with establisHed Atherosclerotic cardiovascuLar diseasE or hypercholesterolemia in ASia–Pacific region (HALES) was performed to better understand characteristics of and clinical decision-making for adults with established atherosclerotic cardiovascular disease/hypercholesterolemia after local evolocumab approval.The HALES observational study, conducted at 33 sites (Hong Kong, Thailand, South Korea, Singapore, Taiwan, and Australia) comprised (1) chart review of patients who received evolocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), and (2) physician/patient survey and one-time data collection of patients with high cardiovascular risk initiating evolocumab or initiating/continuing non-PCSK9i lipid-lowering therapy. Patients could only enroll in (1) or (2).Chart review included 724 very high-risk patients initiating evolocumab from regulatory approval to 2021. From median baseline LDL-C of 3.2 mmol/L (123.7 mg/dL), patients had a median percent change in LDL-C of − 60.8% at 1–6 months. Goal achievement increased from 7.9% to 69.8% for < 1.8 mmol/L (< 70 mg/dL) and 4.4% to 57.8% for < 1.4 mmol/L (< 55 mg/dL) from baseline to 12 months. In the one-time data collection, more patients had ≥ 1.8 mmol/L (≥ 70 mg/dL) baseline LDL-C in the evolocumab vs non-PCSK9i group (95.2% and 48.5%, respectively). Surveys found that physicians applied guideline-recommended treatment targets, and patients demonstrated gaps in understanding cardiovascular risk.Real-world, Asia–Pacific data showed that LDL-C reduction after initiating evolocumab was consistent with that observed in other clinical trials and patient populations.Graphical abstract available for this article.·Methods: Real-world data are needed to understand the effectiveness of new therapeutic options for low-density lipoprotein cholesterol (LDL-C) reduction in Asia–Pacific clinical practice. Description of evolocumab use among adults with establisHed Atherosclerotic cardiovascuLar diseasE or hypercholesterolemia in ASia–Pacific region (HALES) was performed to better understand characteristics of and clinical decision-making for adults with established atherosclerotic cardiovascular disease/hypercholesterolemia after local evolocumab approval.The HALES observational study, conducted at 33 sites (Hong Kong, Thailand, South Korea, Singapore, Taiwan, and Australia) comprised (1) chart review of patients who received evolocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), and (2) physician/patient survey and one-time data collection of patients with high cardiovascular risk initiating evolocumab or initiating/continuing non-PCSK9i lipid-lowering therapy. Patients could only enroll in (1) or (2).Chart review included 724 very high-risk patients initiating evolocumab from regulatory approval to 2021. From median baseline LDL-C of 3.2 mmol/L (123.7 mg/dL), patients had a median percent change in LDL-C of − 60.8% at 1–6 months. Goal achievement increased from 7.9% to 69.8% for < 1.8 mmol/L (< 70 mg/dL) and 4.4% to 57.8% for < 1.4 mmol/L (< 55 mg/dL) from baseline to 12 months. In the one-time data collection, more patients had ≥ 1.8 mmol/L (≥ 70 mg/dL) baseline LDL-C in the evolocumab vs non-PCSK9i group (95.2% and 48.5%, respectively). Surveys found that physicians applied guideline-recommended treatment targets, and patients demonstrated gaps in understanding cardiovascular risk.Real-world, Asia–Pacific data showed that LDL-C reduction after initiating evolocumab was consistent with that observed in other clinical trials and patient populations.Graphical abstract available for this article.·Results: Real-world data are needed to understand the effectiveness of new therapeutic options for low-density lipoprotein cholesterol (LDL-C) reduction in Asia–Pacific clinical practice. Description of evolocumab use among adults with establisHed Atherosclerotic cardiovascuLar diseasE or hypercholesterolemia in ASia–Pacific region (HALES) was performed to better understand characteristics of and clinical decision-making for adults with established atherosclerotic cardiovascular disease/hypercholesterolemia after local evolocumab approval.The HALES observational study, conducted at 33 sites (Hong Kong, Thailand, South Korea, Singapore, Taiwan, and Australia) comprised (1) chart review of patients who received evolocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), and (2) physician/patient survey and one-time data collection of patients with high cardiovascular risk initiating evolocumab or initiating/continuing non-PCSK9i lipid-lowering therapy. Patients could only enroll in (1) or (2).Chart review included 724 very high-risk patients initiating evolocumab from regulatory approval to 2021. From median baseline LDL-C of 3.2 mmol/L (123.7 mg/dL), patients had a median percent change in LDL-C of − 60.8% at 1–6 months. Goal achievement increased from 7.9% to 69.8% for < 1.8 mmol/L (< 70 mg/dL) and 4.4% to 57.8% for < 1.4 mmol/L (< 55 mg/dL) from baseline to 12 months. In the one-time data collection, more patients had ≥ 1.8 mmol/L (≥ 70 mg/dL) baseline LDL-C in the evolocumab vs non-PCSK9i group (95.2% and 48.5%, respectively). Surveys found that physicians applied guideline-recommended treatment targets, and patients demonstrated gaps in understanding cardiovascular risk.Real-world, Asia–Pacific data showed that LDL-C reduction after initiating evolocumab was consistent with that observed in other clinical trials and patient populations.Graphical abstract available for this article.·Conclusion: Real-world data are needed to understand the effectiveness of new therapeutic options for low-density lipoprotein cholesterol (LDL-C) reduction in Asia–Pacific clinical practice. Description of evolocumab use among adults with establisHed Atherosclerotic cardiovascuLar diseasE or hypercholesterolemia in ASia–Pacific region (HALES) was performed to better understand characteristics of and clinical decision-making for adults with established atherosclerotic cardiovascular disease/hypercholesterolemia after local evolocumab approval.The HALES observational study, conducted at 33 sites (Hong Kong, Thailand, South Korea, Singapore, Taiwan, and Australia) comprised (1) chart review of patients who received evolocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), and (2) physician/patient survey and one-time data collection of patients with high cardiovascular risk initiating evolocumab or initiating/continuing non-PCSK9i lipid-lowering therapy. Patients could only enroll in (1) or (2).Chart review included 724 very high-risk patients initiating evolocumab from regulatory approval to 2021. From median baseline LDL-C of 3.2 mmol/L (123.7 mg/dL), patients had a median percent change in LDL-C of − 60.8% at 1–6 months. Goal achievement increased from 7.9% to 69.8% for < 1.8 mmol/L (< 70 mg/dL) and 4.4% to 57.8% for < 1.4 mmol/L (< 55 mg/dL) from baseline to 12 months. In the one-time data collection, more patients had ≥ 1.8 mmol/L (≥ 70 mg/dL) baseline LDL-C in the evolocumab vs non-PCSK9i group (95.2% and 48.5%, respectively). Surveys found that physicians applied guideline-recommended treatment targets, and patients demonstrated gaps in understanding cardiovascular risk.Real-world, Asia–Pacific data showed that LDL-C reduction after initiating evolocumab was consistent with that observed in other clinical trials and patient populations.Graphical abstract available for this article.· [ABSTRACT FROM AUTHOR]

We seek to demonstrate whether therapeutic efficacy can be improved by combination of repeated intravenous administration and local transplantation of human induced pluripotential stem cell derived MSCs (hiPSC-MSCs). In this study, mice model of hind-limb ischemia is established by ligation of left femoral artery. hiPSC-MSCs (5 × 105) is intravenously administrated immediately after induction of hind limb ischemia with or without following intravenous administration of hiPSC-MSCs every week or every 3 days. Intramuscular transplantation of hiPSC-MSCs (3 × 106) is performed one week after induction of hind-limb ischemia. We compare the therapeutic efficacy and cell survival of intramuscular transplantation of hiPSC-MSCs with or without a single or repeated intravenous administration of hiPSC-MSCs. Repeated intravenous administration of hiPSC-MSCs can increase splenic regulatory T cells (Tregs) activation, decrease splenic natural killer (NK) cells expression, promote the polarization of M2 macrophages in the ischemic area and improved blood perfusion in the ischemic limbs. The improved therapeutic efficacy of MSC-based therapy is due to both increased engraftment of intramuscular transplanted hiPSC-MSCs and intravenous infused hiPSC-MSCs. In conclusion, our study support a combination of repeated systemic infusion and local transplantation of hiPSC-MSCs for cardiovascular disease. A combination of repeated systemic infusion and local transplantation of hiPSC-MSCs could enhance regenerative therapies for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Concisely, ivabradine use was associated with improved ventricular rate control in symptomatic patients with permanent AF who had prevailing impairment of LVEF, with an effect that was proportional to baseline tachycardia burden. Graph Patients with permanent atrial fibrillation (AF) often suffer from symptomatic tachy-arrhythmia burdens. Findings from our study provided further novel data in permanent AF patients with higher tachycardia burden and symptomatic heart failure with impaired functional status. [Extracted from the article]

Objective: To determine the impact of smoking status in the prediction of stroke using CHADS2 and CHA2DS2-VASc schemes. Methods: Five hundred twenty-eight consecutive patients with arrhythmic symptoms and without any documented arrhythmia from Queen Mary Hospital, Hong Kong, were followed up to determine the incidence of ischemic stroke, new-onset atrial fibrillation (AF), or all-cause mortality. Smoking status was classified into nonsmokers and smokers. The pairwise comparisons of C-statistics for outcomes were performed. Results: During a median follow-up period of 6.2 years, 65 (12.3%) individuals developed ischemic stroke. Smokers experienced higher annual incidence of stroke, a new-onset AF, and all-cause death compare to nonsmokers, with corresponding hazard ratio (HR) of stroke, AF, and all-cause death being 2.51 (95% confidence intervals, CI 1.36als, CIse death bein 1.15a3.24), and 1.95 (95% CI 1.161.95 (95% CIath being 2.51 (95% confidence corr2 and CHA2DS2-VASc for stroke were 0.60 (95% CI 0.51 for stp = 0.09) and 0.59 (95% CI 0.50 (95%, p = 0.15) respectively, whereas the C-statistics of CHADS2 and CHA2DS2-VASc were 0.66 (95% CI 0.61 were 0p = 0.005), 0.75 (95% CI 0.7 CI 0.7p < 0.0001), respectively among nonsmokers. After incorporating smoking, both the CHADS2-smoking and CHA2DS2-VASc-smoking achieved better C-statistics for new-onset ischemic stroke prediction superior to baseline score systems in male groups. Conclusion: Cigarette smoking status has impact on stroke stratification using CHADS2 and CHA2DS2-VASc scheme. The discrimination of the CHADS2 and CHA2DS2-VASc scheme for stroke can be significantly improved if smoking status is additionally considered. [ABSTRACT FROM AUTHOR]

Objective: Patients with axial spondyloarthritis (SpA) are subjected to elevated cardiovascular risks, but assessment of early myocardial damage and clinical risk stratification remained obscure. The aim of this study was to evaluate the prognostic value of speckle-tracking strain analysis and serum high-sensitivity troponin I (hsTnI) in patients with axial SpA. Methods: Two-dimensional speckle-tracking echocardiography was performed to derive longitudinal strain (LS), circumferential strain (CS), and radial strain (RS). Serum hsTnI was measured by validated immunoassay (Architect i1000SR Abbott) as indicator of subclinical myocardial damage. Results: The mean Bath Ankylosing Spondylitis Disease Activity Index and median modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) were 3.8 and 15.5, respectively. Over a median follow-up of 81 months, major adverse cardiovascular events (MACE) occurred in 13% of subjects (n = 116). Univariate Cox regression showed that age, disease duration, Bath Ankylosing Spondylitis Functional Index, modified Schober test, mSASSS, hsTnI, interventricular septal thickness, E/E′, LS, RS, and carotid intima-media thickness were significant predictors of MACE (all P < 0.05). After adjustment for age, sex, and statistically significant disease-related parameters, only subclinically raised hsTnI and impaired LS remained independent predictors for MACE. Kaplan-Meier analysis showed that combined impaired LS ≥ − 17.5% and hsTnI ≥ 3.0 pg/ml significantly predicted MACE (log-rank test P < 0.01; sensitivity 50%; specificity 90%; positive predictive value 43%; negative predictive value 92%). Conclusions: Depressed LS indicating subclinical left ventricular systolic dysfunction and elevated serum hsTnI both independently predicted MACE among young patients with axial SpA. Combined analysis of speckle-tracking-derived strain analysis and serum hsTnI improves risk stratification in these patients. Key Points • Both depressed longitudinal strain (LS) and elevated serum high-sensitivity troponin I (hsTnI) are promising independent predictors for cardiovascular (CV) events in axial SpA. • Importantly, patients with LS ≥ − 17.5% and hsTnI ≥ 3.0 pg/ml had the highest risk of incident MACE. • Axial SpA patients with concomitant impaired LS and raised hsTnI are at a high risk of CV events. [ABSTRACT FROM AUTHOR]

To investigate the safety and midterm outcome of concomitant left atrial appendage (LAA) closure and catheter ablation (CA) as a one-stage hybrid procedure for non-valvular atrial fibrillation (AF) in a multicenter registry. A total of 50 consecutive patients with symptomatic drug-resistant non-valvular AF with CHA2DS2-VASc score ≥ 2 and contraindications for antithrombotic therapy were included in the prospectively established LAA closure registry, and underwent concomitant LAA closure (48 for WATCHMAN and 2 for ACP) and CA procedure (40 for radiofrequency and 10 for cryoballoon CA). Two cardiac tamponades, one peripheral vascular complications and one mild air embolism were observed during perioperative period. After mean follow-up of 20.2 ± 11.5 months, 18 (36%) patients presented with atrial arrhythmia relapse and 45 (91.8%) patients presented with complete sealing; furthermore, there were two transient ischemic attacks and one ischemic stroke under an off-oral anticoagulant situation, respectively. Concomitant CA and LAA closure as a one-stage hybrid procedure might be feasible and potentially decrease costs in patients with symptomatic non-valvular AF with high stroke risk and contraindication to antithrombotic treatment, and as safe as LAA closure procedure only during the perioperative period. However, it was necessary to further validate the mid-term safety. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is associated with increased vascular calcification, although the rate of progress of calcification is uncertain. The aim of the study was to evaluate the progression of and the predictors for calcification in different vascular beds over 10 years. The 10-year actual coronary calcium score (CS) and 10-year predicted coronary CS, based on the pattern of the general population, were compared. Calcification of the coronary and carotid artery and the aorta was assessed by multi-detector computed tomography. Significant CS progression was determined by the difference between the square root of baseline and square root of follow-up calcium score (i.e., SQRT method). The 10-year predicted coronary CS was based on the mathematical formula derived by the Heinz Nixdorf Recall Study. A total of 49 patients (54 ± 11 years, 90% female) had a follow-up scan after 10.0 ± 0.2 years. The CS in all vascular beds was significantly increased; 55% of the patients had a significant progression of CS in the coronary, 29% in the carotid, and 80% in the aorta. Age and systolic blood pressure (SBP) were independently associated with calcification progression in all vascular beds. Importantly, the absolute increase in 10-year actual coronary CS was significantly higher than that predicted. In patients with RA, calcification in all vascular beds significantly increased over 10 years and was independently associated with age and SBP. Importantly, the absolute increase in 10-year actual coronary CS progression was significantly higher than that predicted. [ABSTRACT FROM AUTHOR]

Recent studies have boosted our understanding of long noncoding RNAs (lncRNAs) in numerous biological processes, but few have examined their roles in somatic cell reprogramming. Through expression profiling and functional screening, we have identified that the large intergenic noncoding RNA p21 (lincRNA-p21) impairs reprogramming. Notably, lincRNA-p21 is induced by p53 but does not promote apoptosis or cell senescence in reprogramming. Instead, lincRNA-p21 associates with the H3K9 methyltransferase SETDB1 and the maintenance DNA methyltransferase DNMT1, which is facilitated by the RNA-binding protein HNRNPK. Consequently, lincRNA-p21 prevents reprogramming by sustaining H3K9me3 and/or CpG methylation at pluripotency gene promoters. Our results provide insight into the role of lncRNAs in reprogramming and establish a novel link between p53 and heterochromatin regulation. [ABSTRACT FROM AUTHOR]

Friedreich ataxia (FRDA), a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy, is due to GAA repeat expansions within the first intron of the frataxin ( FXN) gene encoding the mitochondrial protein involved in iron-sulfur cluster biosynthesis. The triplet codon repeats lead to heterochromatin-mediated gene silencing and loss of frataxin. Nevertheless, inadequacy of existing FRDA-cardiac cellular models limited cardiomyopathy studies. We tested the hypothesis that iron homeostasis deregulation accelerates reduction in energy synthesis dynamics which contributes to impaired cardiac calcium homeostasis and contractile force. Silencing of FXN expressions occurred both in somatic FRDA-skin fibroblasts and two of the induced pluripotent stem cells (iPSC) clones; a sign of stress condition was shown in FRDA-iPSC cardiomyocytes with disorganized mitochondrial network and mitochondrial DNA (mtDNA) depletion; hypertrophic cardiac stress responses were observed by an increase in α-actinin-positive cell sizes revealed by FACS analysis as well as elevation in brain natriuretic peptide (BNP) gene expression; the intracellular iron accumulated in FRDA cardiomyocytes might be due to attenuated negative feedback response of transferring receptor (TSFR) expression and positive feedback response of ferritin (FTH1); energy synthesis dynamics, in terms of ATP production rate, was impaired in FRDA-iPSC cardiomyocytes, which were prone to iron overload condition. Energetic insufficiency determined slower Ca transients by retarding calcium reuptake to sarcoplasmic reticulum (SR) and impaired the positive inotropic and chronotropic responses to adrenergic stimulation. Our data showed for the first time that FRDA-iPSCs cardiac derivatives represent promising models to study cardiac stress response due to impaired iron homeostasis condition and mitochondrial damages. The cardiomyopathy phenotype was accelerated in an iron-overloaded condition early in calcium homeostasis aspect. [ABSTRACT FROM AUTHOR]

Prior studies suggest that endomyocardial implantation of autologous bone marrow (BM) mononuclear cell therapy improves symptoms and left ventricular (LV) function in patients with refractory angina; however, the therapeutic efficacy in patients with ischemic cardiomyopathy is unclear. In a randomized, double-blind, placebo-controlled trial, 28 patients with advanced ischemic cardiomyopathy [New York Heart Association III-IV, LV ejection fraction (LVEF) <40 %] were assigned in 2:1 ratio to receive endomyocardial injection of BM cells (100 million, n = 19) or placebo ( n = 9), guided by electroanatomical mapping. After 6 months, there was no significant difference between the two groups in LV ejection fraction (LVEF) and LV end-systolic volume (LVESV), LV infarct volume, and LV peri-infarct ischemic volume as determined by cardiac magnetic resonance imaging or exercise capacity. In conclusion, endomyocardial implantation of autologous BM mononuclear cells did not improve LV function or remodeling in patients with advanced ischemic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Preadipocytes are widely used as an in vitro model to investigate proliferation, adipogenic differentiation, and lipodystrophy; however, cellular physiology and biology are not fully understood in human preadipocytes. The present study was to investigate the expression of transient receptor potential (TRP) channels in human preadipocytes and their potential roles in regulating proliferation and adipogenic differentiation using approaches of confocal microscopy, whole-cell patch voltage-clamp, reverse transcription polymerase chain reaction, Western blot, etc. We found that TRPV2, TRPV4, and TRPM7 channels were abundantly expressed in human preadipocytes. The intracellular Ca transient activated by the TRPV2 activator probenecid was reversed or prevented by ruthenium red, a TRPV2 blocker. The TRPV4 channel activator, 4α-phorbol 12-13-dicaprinate, enhanced intracellular Ca oscillations, and the effect was inhibited by the TRPV4 blocker RN-1734. TRPM7 current was recorded with dialysis of Mg-free pipette solution, which was inhibited by the TRP channel blocker 2-aminoethoxydiphenyl borate and enhanced by acidic extracellular pH. Silencing TRPV2 or TRPM7, but not TRPV4, significantly reduced cell proliferation via inhibiting cyclin D1, cyclin E, and p-ERK1/2. Interestingly, individually silencing these three channels decreased adipogenic differentiation of human preadipocytes by reducing p-Akt kinase. Our results demonstrate for the first time that functional TRPV2, TRPV4, and TRPM7 channels are abundantly expressed in human preadipocytes. TRPV2 and TRPM7, but not TRPV4, regulate cell proliferation via activating cyclin D1, cyclin E, and p-ERK1/2, while they are all involved in adipogenesis in human preadipocytes via phosphorylating Akt kinase. [ABSTRACT FROM AUTHOR]

While human embryonic stem cells (hESCs) can differentiate into functional cardiomyocytes, their immature phenotypes limit their therapeutic application for myocardial regeneration. We sought to determine whether electrical stimulation could enhance the differentiation and maturation of hESC-derived cardiomyocytes. Cardiac differentiation was induced in a HES3 hESC line via embryoid bodies formation treated with a p38 MAP kinase inhibitor. Detailed molecular and functional analysis were performed in those hESC-derived cardiomyocytes cultured for 4 days in the absence or presence of electrical field stimulation (6.6 V/cm, 1 Hz, and 2 ms pulses) using an eight-channel C-Pace stimulator (Ion-Optics Co., MA). Upon electrical stimulation, quantitative polymerase chain reaction demonstrated significant upregulation of cardiac-specific gene expression including HCN1, MLC2V, SCN5A, SERCA, Kv4.3, and GATA4; immunostaining and flow cytometry analysis revealed cellular elongation and an increased proportion of troponin-T positive cells (6.3 ± 1.2 % vs. 15.8 ± 2.1 %; n = 3, P < 0.01). Electrophysiological studies showed an increase in the proportion of ventricular-like hESC-derived cardiomyocytes (48 vs. 29 %, P < 0.05) with lengthening of their action potential duration at 90 % repolarization (387.7 ± 35.35; n = 11 vs. 291.8 ± 20.82; n = 10, P < 0.05) and 50 % repolarization (313.9 ± 27.94; n = 11 vs. 234.0 ± 16.10; n = 10, P < 0.05) after electrical stimulation. Nonetheless, the membrane diastolic potentials and action potential upstrokes of different hESC-derived cardiomyocyte phenotypes, and the overall beating rate remained unchanged (all P > 0.05). Fluorescence confocal imaging revealed that electrical stimulation significantly increased both spontaneous and caffeine-induced calcium flux in the hESC-derived cardiomyocytes (approximately 1.6-fold for both cases; P < 0.01). In conclusion, electrical field stimulation increased the expression of cardiac-specific genes and the yield of differentiation, promoted ventricular-like phenotypes, and improved the calcium handling of hESC-derived cardiomyocytes. [ABSTRACT FROM AUTHOR]

Transient receptor potential (TRP) channels are not well understood in human atrium, and the present study was therefore designed to investigate whether TRPC channels would mediate the nonselective cation current reported previously and are involved in the formation of store-operated Ca entry (SOCE) channels in human atrial myocytes using approaches of whole-cell patch voltage-clamp, RT-PCR, Western blotting, co-immunoprecipitation, and confocal scanning approaches, etc. We found that a nonselective cation current was recorded under K-free conditions in human atrial myocytes, and the current was inhibited by the TRP channel blocker La. Thapsigargin enhanced the current, and its effect was suppressed by La and prevented by pipette inclusion of anti-TRPC1 antibody. Endothlin-1 and angiotensin II enhanced the current that could be inhibited by La. Gene and protein expression of TRPC1 channels were abundant in human atria. In addition, mRNA and protein of STIM1 and Orai1, components of SOCE channels, were abundantly expressed in human atria. Co-immunoprecipitation analysis demonstrated an interaction of TRPC1 with STIM1 and/or Orai1. Ca signaling mediated by SOCE channels was detected by a confocal microscopy technique. These results demonstrate the novel evidence that TRPC1 channels not only mediate the nonselective cation current, but also form SOCE channels in human atria as a component. TRPC1 channels can be activated by endothelin-1 or angiotensin II, which may be involved in the atrial electrical remodeling in patients with atrial fibrillation. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA) is independently associated with endothelial dysfunction, which may be perpetuated by alteration in endothelial repair capacity. Our study evaluates changes in endothelial progenitor cell (EPC) profile in relation to OSA and the role of advanced glycation end-products (AGE) in this relationship. Methods: Consecutive Chinese adults undergoing sleep studies, who had no medical illnesses or regular medications, were enrolled. Subjects with morbid obesity or grossly elevated lipoprotein levels were excluded from analysis. Circulating EPC was measured with flow cytometry analysis. Results: Seventy-two subjects, 64 % with OSA defined by apnea-hypopnea index (AHI) ≥ 5, were analyzed. CD34+ cell counts were positively correlated with oxygen desaturation index (ODI) ( r = 0.250, p = 0.041) and duration of oxygen desaturation <90 % (T90) ( r = 0.261, p = 0.033) and negatively with minimal oxygen saturation ( r = −0.247, p = 0.044) after adjusting for age, glucose, body weight, and smoking status. AGE was positively correlated with indices of OSA severity (AHI, r = 0.249, p = 0.042; ODI, r = 0.244, p = 0.047; T90, r = 0.243, p = 0.047; minimal oxygen saturation, r = −0.251, p = 0.041) and negatively with CD133+ cells ( r = −0.281, p = 0.021). On stepwise multiple linear regression analysis, minimal oxygen saturation ( p = 0.013) and CD133+ cell counts ( p = 0.029) were found to be significant determinants of AGE level ( R = 0.147). Conclusions: Nocturnal hypoxemia in OSA subjects was associated with increase in endothelial cells (CD34+) which may promote vascular repair. Accumulation of AGE in OSA may lead to diminution in early EPC (CD133+) and endothelial repair capacity over time, thus contributing to vascular pathogenesis. [ABSTRACT FROM AUTHOR]

Objetives: To investigate the effects of garlic on endothelial function in patients with ischemic stroke (ISS). Design: Cross-sectional study. Participants: 125 Chinese patients with prior ISS due to athero-thrombotic disease were recruited from the outpatient clinics during July 2005 to December 2006. Measurements: Daily allium vegetable intake (including garlic, onions, Chinese chives and shallots) was ascertained by means of a validated food frequency questionnaire for Chinese and brachial artery flow-mediated dilatation (FMD) was measured using high-resolution ultrasound in all subjects. Results: The mean age of the study population was 65.9±11.1 years and 69% were males. Mean allium vegetable intake and garlic intake of the study population was 7.5±12.7g/day and 2.9±8.8g/day respectively. Their mean FMD was 2.6±2.3%. Daily intake of total allium vegetable (r=0.36, P<0.01) and garlic (r=0.34, P<0.01) significantly correlated with FMD. Using the median daily allium intake as cut-off (3.37g/day), patients with a low allium intake <3.37g/day was noted to have a lower FMD compared to those with a normal allium intake (2.1±2.1% versus 3.0±2.4%, P<0.05). After adjusting for confounding factors, multi-variate analysis identified that daily allium vegetable (B=0.05, 95% confidence interval: 0.02, 0.09, P<0.01) and garlic (B=0.07, 95% confidence interval: 0.02, 0.12, P<0.01) intake, but not onions, Chinese chives and shallots were independent predictors for changes in FMD in patients with ISS. Conclusions: Daily garlic intake is an independent predictor of endothelial function in patients with ISS and may play a role in the secondary prevention of atherosclerotic events. [ABSTRACT FROM AUTHOR]

Background: Early identification of individuals who are at risk of developing atrial fibrillation (AF) and ischemic stroke may enable a closer surveillance and thus prompt initiation of oral anticoagulation for stroke prevention.Objective: This study sought to investigate whether congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke (CHADS2) and CHA2DS2-vascular disease, age 65-74 years, sex category (CHA2DS2-VASc) scores can predict new-onset AF and/or ischemic stroke in patients presenting with arrhythmic symptoms.Methods and Results: We prospectively followed up 528 patients (68.5 ± 10.6 years, male 46.2 %) presented for assessment of arrhythmic symptoms but without any documented arrhythmia, including AF for development of new-onset AF and/or ischemic stroke. Their mean CHADS2 and CHA2DS2-VASc scores on presentation were 1.3 ± 1.3 and 2.3 ± 1.5, respectively. After 6.1 years, 89 patients (16.8 %, 2.77 per 100 patient-years) had documented AF, and 65 patients (12.3 %, 2.0 per 100 patient-years) suffered stroke. Both the CHADS2 (C statistic 0.63, 95 % confidence interval (CI) 0.58-0.67, P < 0.0001, optimal cutoff at 1) and CHA2DS2-VASc (C statistic 0.63, 95 % CI 0.59-0.67, P < 0.0001, optimal cutoff at 2) scores provided similar prediction for the new-onset AF. Similarly, CHADS2 (C statistic 0.69, 95 % CI 0.65-0.73, P < 0.0001, optimal cutoff at 2) and CHA2DS2-VASc (C statistic 0.69, 95 % CI 0.65-0.73, P < 0.0001, optimal cutoff at 2) have compatible efficacy for stroke prediction in this Chinese population.Conclusion: The CHADS2 and CHA2DS2-VASc scores can be used in patients who presented with arrhythmic symptoms to identify those who are at risk with developing new-onset clinical AF and ischemic stroke for close clinical surveillance and early intervention. [ABSTRACT FROM AUTHOR]

Purpose: Epidemiological studies showed that PR prolongation is associated with increased risk of adverse cardiovascular outcomes. We investigated the relations of PR interval with indices of vascular function and endothelial repair as the underlying mechanisms. Methods: The study comprised 348 high-risk patients with prior coronary artery disease, ischemic stroke, and/or diabetes mellitus recruited from medical outpatient clinics and 150 healthy subjects without such a history. PR interval was considered prolonged if >200 ms, as determined from resting 12-lead electrocardiogram. Vascular function was assessed by brachial flow-meditated dilatation (FMD) using high-resolution ultrasound. Circulating CD133/KDR endothelial progenitor cell (EPC) levels were measured by flow cytometry. Results: Among healthy subjects, PR interval was inversely associated with FMD ( R = −0.20, P = 0.015), but not with the level of circulating CD133/KDR EPC ( R = 0.05, P = 0.58). Among high-risk cardiovascular patients, PR prolongation >200 ms was more common compared with healthy subjects (45/348 (13 %) versus 4/150 (3 %), P < 0.001). PR interval was associated inversely with FMD ( R = −0.14, P = 0.01) and positively with circulating CD133/KDR EPC level ( R = +0.14, P = 0.009). Circulating CD133/KDR EPC level was significantly increased in patients with PR prolongation >200 ms (0.87 ± 0.37 versus 0.68 ± 0.42 (log, ×10/ml), P = 0.005). Adjusted for potential confounders, increased PR interval remained independently associated with increased CD133/KDR EPC by +0.002 (95 % confidence interval (CI) 0.000 to 0.004 (log, ×10/ml), P = 0.011) and depressed FMD ( B = −0.014 %, 95 % CI −0.027 to −0.002, P = 0.026). Conclusions: PR prolongation is associated with endothelial dysfunction and evidence of endothelial repair activation in patients with high cardiovascular risk. [ABSTRACT FROM AUTHOR]

Background: Early identification of individuals who are at risk of developing atrial fibrillation (AF) and ischemic stroke may enable a closer surveillance and thus prompt initiation of oral anticoagulation for stroke prevention. Objective: This study sought to investigate whether congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke (CHADS) and CHADS-vascular disease, age 65-74 years, sex category (CHADS-VASc) scores can predict new-onset AF and/or ischemic stroke in patients presenting with arrhythmic symptoms. Methods and results: We prospectively followed up 528 patients (68.5 ± 10.6 years, male 46.2 %) presented for assessment of arrhythmic symptoms but without any documented arrhythmia, including AF for development of new-onset AF and/or ischemic stroke. Their mean CHADS and CHADS-VASc scores on presentation were 1.3 ± 1.3 and 2.3 ± 1.5, respectively. After 6.1 years, 89 patients (16.8 %, 2.77 per 100 patient-years) had documented AF, and 65 patients (12.3 %, 2.0 per 100 patient-years) suffered stroke. Both the CHADS (C statistic 0.63, 95 % confidence interval (CI) 0.58-0.67, P < 0.0001, optimal cutoff at 1) and CHADS-VASc (C statistic 0.63, 95 % CI 0.59-0.67, P < 0.0001, optimal cutoff at 2) scores provided similar prediction for the new-onset AF. Similarly, CHADS (C statistic 0.69, 95 % CI 0.65-0.73, P < 0.0001, optimal cutoff at 2) and CHADS-VASc (C statistic 0.69, 95 % CI 0.65-0.73, P < 0.0001, optimal cutoff at 2) have compatible efficacy for stroke prediction in this Chinese population. Conclusion: The CHADS and CHADS-VASc scores can be used in patients who presented with arrhythmic symptoms to identify those who are at risk with developing new-onset clinical AF and ischemic stroke for close clinical surveillance and early intervention. [ABSTRACT FROM AUTHOR]

Cerebellar hemorrhage is the least common type of intracranial hemorrhage (ICH) encountered in clinical practice, and clinical data concerning the long-term outcomes are limited. This study aimed to investigate the long-term outcomes following spontaneous cerebellar hemorrhage in a cohort of Chinese patients. This single-center observational study was carried out between 1996 and 2010 and included 72 consecutive Chinese patients with a first spontaneous cerebellar hemorrhage. Of 440 patients with primary ICH, 72 (16.4%) had primary cerebellar hemorrhage. The mean age was 67.5 ± 12.3 years and patients were predominantly male (54%). The 30-day mortality was 16.7% with Glasgow coma scale ≤8 as the only predictor. At 6 months, 56.7% of patients who survived the first 30 days had a persistently poor functional status with modified Rankin scale score >2. After a mean follow-up of 4.7 years, 3.3% of patients had recurrent ICH, a recurrence rate of 7.3 per 1,000 patient-years. Ischemic stroke occurred in 12% of patients, an incidence of 25.5 per 1,000 patient-years. This study provided data on the long-term outcome of post-cerebellar hemorrhage in Chinese patients. [ABSTRACT FROM AUTHOR]

Previous experimental studies suggested that mesenchymal stem cell transplantation causes cardiac nerve sprouting; however, whether bone marrow (BM)-derived mononuclear cells (MNC) and endothelial progenitor cells (EPC) can also lead to cardiac nerve sprouting and alter gap junction expression remains unclear. We investigated the effect of electroanatomical mapping-guided direct intramyocardial transplantation of BM-MNC ( n = 8) and CD31EPC ( n = 8) compared with saline control ( n = 8) on cardiac nerve sprouting and gap junction expression in a swine model of chronic ischemic myocardium. At 12 weeks after transplantation, the distribution and density of cardiac nerve sprouting were determined by staining of tyrosine hydroxylase (TH) and growth associated protein 43(GAP-43) and expression of connexin 43 in the targeted ischemic and remote normal myocardium. After 12 weeks, no animal developed sudden death after the transplantation. There were no significant differences in the number of cells with positive staining of TH and GAP-43 in the ischemic and normal myocardium between three groups. Furthermore, expression of connexin 43 was also similar in the ischemic and normal myocardia in each group of animals ( P > 0.05). The results of this study demonstrated that intramyocardial BM-derived MNC or EPC transplantation in a large animal model of chronic myocardial ischemia was not associated with increased cardiac nerve sprouting over the ischemic myocardium. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Although low-density lipoprotein cholesterol (LDL-C) is the primary lipid target for coronary heart disease (CHD) risk reduction, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) have also emerged as CHD risk factors. The objective of this study was to evaluate attainment of lipid goals and normal levels following lipid-modifying therapy (LMT) and its predictors in a representative sample of Chinese patients from Hong Kong. METHODS: Using longitudinal data collected from patient medical records, the study identified 706 patients who initiated LMT from January 2004 to December 2006 and had full lipid panels 12 months before and after therapy. LDL-C goals and normal levels of HDL-C and TG were defined according to the National Cholesterol Education Program Adult Treatment Panel 3 guidelines. Patients with previous CHD, diabetes, and 10-year CHD risk > 20% were classified as high risk. Multiple logistic regressions evaluated predictors of normal lipid-level attainment. RESULTS: Among 706 patients (mean age 64.6 years, 58.6% male), 71.7% had elevated LDL-C, 32.4% had low HDL-C, and 24.9% had elevated TG before LMT. Despite therapy (91.2% statins only), 22.7% had elevated LDL-C, 31.9% had low HDL-C, 12.3% had elevated TG, and 13.9% had multiple abnormal lipid levels. The strongest predictors of attaining >= 2 normal lipid levels included male gender (odds ratio [OR]: 2.11 [1.12 to 4.01]), diabetes (OR: 0.43 [0.23 to 0.78]), obesity (OR: 0.91 [0.86 to 0.97]), and CHD risk > 20% (OR: 0.33 [0.15 to 0.71]). CONCLUSIONS: Current approaches to lipid management in Hong Kong, primarily using statins, considerably improve attainment of LDL-C goal. However, a large proportion of patients do not achieve normal HDL-C levels and control of multiple lipid parameters remains poor. Patients could benefit from a more comprehensive approach to lipid management that treats all three lipid risk factors, as suggested in clinical guidelines. [ABSTRACT FROM AUTHOR]

Background: Whether isoflavone has any effect on recurrent cardiovascular events is unknown. Objective: To investigate the relations between isoflavone intake and the risk of stroke recurrence. Subjects and Methods: We recruited 127 consecutive patients with prior history of atherothrombolic/ hemorrhagic stroke (mean age: 67 ± 11 years, 69% male) and prospectively followed up for a mean duration of 30 months. Stroke recurrence and major adverse cardiovascular events (MACE) were documented. Brachial flow-mediated dilatation (FMD) was measured using high-resolution ultrasound. Isoflavone intake was estimated using a validated food frequency questionnaire. Results: Median isoflavone intake was 6.9 (range: 2.1-14.5) mg/day. Isoflavone intake was independently associated with increased FMD (Pearson R=0.23, p=0.012). At 30 months, there were 10 stroke recurrence and 12 MACE. Kaplan-Meier analysis showed that patients with isoflavone intake higher than median value had significantly longer median stroke recurrence-free survival time (19.0 [range: 10.4-27.6] mth versus 5.0 [range: 4.1-5.9] mth, p=0.021) and MACE-free survival time (19.0 [range: 10.4-27.6] mth versus 4.0 [range: 2.4-5.6] mth, p=0.013). Using multivariate cox regression, higher isoflavone intake was an independent predictor for lower risk of stroke recurrence (hazards ratio 0.18 [95%CI: 0.03-0.95], risk reduction 82%, p=0.043) and MACE (hazards ratio 0.16 [95%CI: 0.03-0.84], risk reduction 84%, p=0.030). Conclusions: Higher isoflavone intake in stroke patients was associated with prolonged recurrence-free survival, and reduced risk of stroke recurrence and MACE, independent of baseline vascular.function. Whether isoflavone may confer clinically significant secondary protection in stroke patients should be further investigated in a randomized controlled trial. [ABSTRACT FROM AUTHOR]

Biventricular pacing (BiV) has been shown to reduce wall stress and workload in regions near the pacing sites. This trial investigated if BiV near the ischemic region would reduce chest pain in patients with refractory angina due to severe coronary artery disease (CAD). Eleven patients were implanted with BiV devices with leads positioned at or adjacent to their ischemic regions as detected by single-photon emission computed tomography (SPECT) and randomized to either pacing turned ON or OFF for 3 months, and then crossed over for 3 months. With pacing turned ON, a Dynamic atrioventricular (AV) delay was set for approximately 90% and 70% of the intrinsic AV delay at the resting heart rate and at the onset of symptoms, respectively. One patient was excluded from the analysis due to a large amount of RV pacing during the OFF periods (24-64%) and due to an inability to properly deliver therapy because of an excessive number of ventricular premature complexes. Overall, with the device ON vs. OFF, the number of angina episodes (0.8 ± 0.4 vs. 1.2 ± 0.7 per week, P = 0.03) and amount of nitroglycerin used (0.2 ± 0.1 vs. 1.0 ± 0.7 per week, P = 0.11) was lower with BiV pacing. Furthermore, the treadmill exercise time to symptoms trended higher (427 ± 65 vs. 408 ± 64 s, P = 0.19), and the sum of fluorodeoxyglucose-positron emission tomography (FDG-PET) scores trended lower (7.9 ± 3.5 vs. 12.0 ± 4.0, P = 0.11) with the device ON vs. OFF. Nevertheless, there were no significant differences in SPECT myocardial perfusion scores, left ventricle ejection fraction, wall motion score index, and quality of life scores with device programmed ON vs. OFF (all P > 0.05). In conclusion, this pilot study demonstrated that BiV-P at or near the ischemic region was feasible and associated with significant reductions in angina in patients with severe CAD. Adequately powered prospective studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Experimental studies have shown that selenium is involved in the synthesis of selenoproteins which might contribute to cardiovascular protection. However, the relationship between selenium deficiency and vascular function in clinical context remains unknown. Objective: To investigate for any relationship between selenium deficiency and systemic arterial function in patients with high risk of vascular events. Design: Cross-sectional study. Setting and Participants: 306 consecutive patients with high risk for cardiovascular events (coronary artery disease 35%, acute/recurrent ischemic stroke 40%, diabetes mellitus 54%) followed up at internal medicine outpatient clinics. Measurements: Non-invasive brachial-ankle pulse wave velocity (PWV) was determined using vascular profiling system (VP-2000). Long-term intake of selenium was determined by a validated food frequency questionnaire. Results: Mean daily selenium intake was 59.5 ± 52.1 mcg/day, and mean PWV was 1782.4 ± 418.4 cm/s. Patients with selenium intake <10th percentile had significantly higher PWV as compared to patients with intake 10th percentile (1968.2 ± 648.9 cm/s versus 1762.2 ± 381.6 cm/s, P=0.010). After adjusting for potential confounders including age, gender, history of hypertension, hyperlipidemia, diabetes and cardiovascular disease, smoking status, use of cardiovascular medications, waist-hip ratio, education/financial status, physical activity, calorie intake and intake of antioxidant vitamins, deficient selenium intake <10th percentile remained independently predictive of increased PWV by +363.4 cm/s [95% CI: 68.1 to 658.6, P=0.016, relative increase 21%]. Conclusions: Selenium deficiency is associated with adverse arterial function in patients with high risk for vascular events. [ABSTRACT FROM AUTHOR]

Rationale: Cardiomyocytes generated from human induced pluripotent stem cells (hiPSCs) are suggested as the most promising candidate to replenish cardiomyocyte loss in regenerative medicine. Little is known about their calcium homeostasis, the key process underlying excitation-contraction coupling. Objective: We investigated the calcium handling properties of hiPSC-derived cardiomyocytes and compared with those from human embryonic stem cells (hESCs). Methods and Results: We differentiated cardiomyocytes from hiPSCs (IMR90 and KS1) and hESCs (H7 and HES3) with established protocols. Beating outgrowths from embryoid bodies were typically observed 2 weeks after induction. Cells in these outgrowths were stained positively for tropomyosin and sarcomeric alpha-actinin. Reverse-transcription polymerase chain reaction studies demonstrated the expressions of cardiac-specific markers in both hiPSC- and hESC-derived cardiomyocytes. Calcium handling properties of 20-day-old hiPSC- and hESC-derived cardiomyocytes were investigated using fluorescence confocal microscopy. Compared with hESC-derived cardiomyocytes, spontaneous calcium transients from both lines of hiPSC-derived cardiomyocytes were of significantly smaller amplitude and with slower maximal upstroke velocity. Better caffeine-induced calcium handling kinetics in hESC-CMs indicates a higher sacroplasmic recticulum calcium store. Furthermore, in contrast with hESC-derived cardiomyocytes, ryanodine did not reduce the amplitudes, maximal upstroke and decay velocity of calcium transients of hiPSC-derived cardiomyocytes. In addition, spatial inhomogeneity in temporal properties of calcium transients across the width of cardiomyocytes was more pronounced in hiPSC-derived cardiomyocytes than their hESC counterpart as revealed line-scan calcium imaging. Expressions of the key calcium-handling proteins including ryanodine recptor-2 (RyR2), sacroplasmic recticulum calcium-ATPase (SERCA), junction (Jun) and triadin (TRDN), were significantly lower in hiPSC than in hESCs. Conclusions: The results indicate the calcium handling properties of hiPSC-derived cardiomyocytes are relatively immature to hESC counterparts. [ABSTRACT FROM AUTHOR]

Aim:To investigate the effects of the cardiotonic steroid, ouabain, on cardiac differentiation of murine embyronic stem cells (mESCs).Methods:Cardiac differentiation of murine ESCs was enhanced by standard hanging drop method in the presence of ouabain (20 μmol/L) for 7 d. The dissociated ES derived cardiomyocytes were examined by flow cytometry, RT-PCR and confocal calcium imaging.Results:Compared with control, mESCs treated with ouabain (20 μmol/L) yielded a significantly higher percentage of cardiomyocytes, and significantly increased expression of a panel of cardiac markers including Nkx 2.5, α-MHC, and β-MHC. The α1 and 2- isoforms Na+/K+-ATPase, on which ouabain acted, were also increased in mESCs during differentiation. Among the three MAPKs involved in the cardiac hypertrophy pathway, ouabain enhanced ERK1/2 activation. Blockage of the Erk1/2 pathway by U0126 (10 μmol/L) inhibited cardiac differentiation while ouabain (20 μmol/L) rescued the effect. Interestingly, the expression of calcium handling proteins, including ryanodine receptor (RyR2) and sacroplasmic recticulum Ca2+ ATPase (SERCA2a) was also upregulated in ouabain-treated mESCs. ESC-derived cardiomyocyes (CM) treated with ouabain appeared to have more mature calcium handling. As demonstrated by confocal Ca2+ imaging, cardiomyocytes isolated from ouabain-treated mESCs exhibited higher maximum upstroke velocity (P<0.01) and maximum decay velocity (P<0.05), as well as a higher amplitude of caffeine induced Ca2+ transient (P<0.05), suggesting more mature sarcoplasmic reticulum (SR).Conclusion:Ouabain induces cardiac differentiation and maturation of mESC-derived cardiomyocytes via activation of Erk1/2 and more mature SR for calcium handling. [ABSTRACT FROM AUTHOR]

The hyperpolarization-activated cyclic nucleotide-modulated channel gene family (HCN1-4) encodes the membrane depolarizing current that underlies pacemaking. Although the topology of HCN resembles K(v) channels, much less is known about their structure-function correlation. Previously, we identified several pore residues in the S5-P linker and P-loop that are externally accessible and/or influence HCN gating, and proposed an evolutionarily conserved pore-to-gate mechanism. Here we sought dynamic evidence by assessing the functional consequences of Cys-scanning substitutions in the unexplored P-S6 linker (residues 352-359), the HCN1-R background (that is, resistant to sulfhydryl-reactive agents). None of A352C, Q353C, A354C, P355C, V356C, S357C, M358C, or S359C produced functional currents; the loss-of-function of Q353C, A354C, S357C, and M358C could be rescued by the reducing agent dithiothreitol. Q353C, A354C, and S357C, but not M358C and HCN1-R, were sensitive to Cd(2+) blockade (IC(50) = 3-12 microM vs. >1 mM). External application of the positively charged covalent sulfhydryl modifier MTSET irreversibly reduced I (-140mV) of Q353C and A354C to 27.9 +/- 3.4% and 58.2 +/- 13.1% of the control, respectively, and caused significant steady-state activation shifts (DeltaV(1/2) = -21.1 +/- 1.6 for Q353C and -10.0 +/- 2.9 mV for A354C). Interestingly, MTSET reactivity was also state dependent. MTSET, however, affected neither S357C nor M358C, indicating site specificity. Collectively, we have identified novel P-S6 residues whose extracellular accessibility was sterically and state dependent and have provided the first functional evidence consistent with a dynamic HCN pore-to-gate model. [ABSTRACT FROM AUTHOR]

An international questionnaire survey was carried out in Asia Pacific, Europe, Latin America and North America to assess the impact of reimbursement on the indications, types of device prescription and waiting time for pacemakers, implantable cardioverter defibrillators (ICD) and radiofrequency ablation therapy for cardiac arrhythmias. The indications for cardiac pacing can be restricted to more symptomatic patients when funding is limited, and new therapy such as cardiac resynchronization therapy (CRT) is restricted in many regions. ICD usage may be limited to secondary prevention candidates because of reimbursement, but referral doctor's ambivalence and knowledge are also important issues independent of the types of health care system. Radiofrequency ablation is generally well accepted, but reimbursement is heterogeneous, with non-fluoroscopic mapping being reimbursed only in a limited way worldwide. Thus with the exception of a well-developed health care system, reimbursement has a major impact on the delivery of arrhythmia management devices and procedures worldwide. [ABSTRACT FROM AUTHOR]

Lowering blood pressure (BP) reduces cardiovascular events, but aggressive BP management may not be advantageous. Optimal BP control (target: <120/80 mm Hg) and conventional BP control (target: <140/90 mm Hg) were compared in patients with hypertension in terms of target-organ damage and tolerability. A total of 23 patients with hypertension were randomly assigned to optimal versus conventional therapy for 6 months. Therapy was initiated with lercanidipine 10 mg/day. For BP control, the dose could be doubled or other drugs added. Three indices of target-organ damage were studied: left ventricular mass (LVM) index, flow-mediated dilatation (FMD) of the brachial artery, and 24-hour urinary albumin excretion. The BP decreased markedly by 21.3+/-3.4/13.2+/-1.7 mm Hg in the conventional therapy group and by 26.6+/-3.6/17.9+/-1.5 mm Hg in the optimal therapy group. Diastolic BP was significantly lower, by 4.7+/-2.3 mm Hg, in the optimal therapy group (P<.05). Ambulatory BP was also decreased in both groups. There was no significant change in LVM or FMD in either group. Baseline LVM index and FMD values were correlated with systolic BP (r=0.51, P=.02; r=0.54, P=.009). In the optimal therapy group, urinary albumin excretion increased significantly (P=.04). Plasma levels of B-type natriuretic peptide (BNP) decreased with antihypertensive therapy (P=.03). Treatment was well tolerated, and none of the patients withdrew from the study. There was no significant difference in adverse events between the 2 groups. Optimization of BP is feasible, safe, and well tolerated; however, a larger study of longer duration may be needed to demonstrate improvements in LVM and endothelial function with conventional versus optimal therapy. [ABSTRACT FROM AUTHOR]

Introduction: Recent studies have demonstrated that premature depolarizations that trigger atrial fibrillation often arise in pulmonary veins. The purpose of this study was to evaluate whether P wave polarity is helpful in distinguishing which of the 4 pulmonary veins is the site of orgin of a premature depolarization. Methods and Results: In 28 patients without structural heart disease who underwent focal ablation of paroxysmal atrial fibrillation, P wave polarity on a 12-lead electrocardiogram (ECG) was analyzed during sinus rhythm, and during pacing at a cycle lengh of 500–600[emsp4 ]ms in the high right atrium and within each of the 4 pulmonary veins. P waves were categorized as positive, negative, biphasic or isoelectric. A negative or biphasic P wave in lead I (sensitivity 85 %, specificity 71 %) or a positive P wave in V1 (sensitivity 85 %, specificity 89 %) were helpful in predicting a pulmonary venous site of origin as opposed to a right atrial site of origin. A positive P wave in lead II and III distinguished superior from inferior pulmonary veins (sensitivity 90 %, specificity 84 %). The sensitivity and specificity of negative or biphasic P waves in lead aVL in distinguishing a left from right pulmonary vein site of origin were 94 % and 42 %, respectively. Conclusions: Analysis of P waves polarity may be helpful in localizing the pulmonary vein that is the site of origin of a premature depolarization. Among the 12 ECG leads, I, II, III, aVL, and V1 are the most helpful in regionalizing premature depolarizations arising in the pulmonary veins. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 74-year-old man with oral mucosal bleeding. As per the case, patient has developed multiple arrhythmias during treatment with oral arsenic trioxide therapy for acute promyelocytic leukemia. The case highlights that medical history of the patient was significant for idiopathic cardiomyopathy and atrial fibrillation.

The use of single lead, atrial synchronous ventricular (VDD) pacing in patients with high grade atrioventricular (AV) block and normal sinus node function is an acceptable alternative to dual chamber (DDD) pacing. Implantation and follow up procedures are simplified, and cost is usually reduced by more than the cost of an additional atrial lead. With the use of either diagonally arranged dipole or closely spaced ring electrodes, reliable atrial sensing can be achieved using differential atrial amplifier and high atrial sensitivity. Also oversensing is infrequently observed using provocation tests and dynamic recordings, clinical undersensing is unusual and minimized by programming to the highest atrial sensitivity. However, as atrial pacing is not possible, loss of AV synchrony and rate response may occur for unrecognized or progressive sinus node disease and lower rate limit. The development of single lead dual chamber pacing system may overcome this limitation. Recent studies have demonstrated that atrial pacing can be effective either with the use of a special pacing lead configuration or via floating atrial electrode with a novel stimulation method. Overlapping Biphasic Impulse (OLBI) can reduce atrial pacing threshold. Early clinical experience suggested that this new pacing method can provide effective and reliable atrial pacing with a relatively low incidence of diaphragmatic pacing. Thus the problem of atrial sensing is solved with a single pass lead but further long term evaluation is required to assess the efficacy and feasibility of new instrumentation for single lead dual chamber pacing. [ABSTRACT FROM AUTHOR]

Inappropriate shock from implantable cardioverter defibrillator (ICD) may result from external electromagnetic interference (EMI), especially for unipolar ventricle sensing. Previous case reports and small in-vitro safety study suggested that endocardial bipolar lead system may be immune from EMI resulting from transcutaneous electrical neuromuscle stimulation (TENS) therapy. This report presents an unusual case of inappropriate discharge in a patient with ICD of endocardial bipolar lead system, receiving TENS from a commercially available device. [ABSTRACT FROM AUTHOR]