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Millimeter wave (mmWave) wireless networks are envisioned to bring a very high degree of spatial reuse, i.e., multiple links can operate simultaneously without interference. The vision, however, is becoming doubtful, as recent studies found that non-negligible interference exists due to imperfect beam patterns. In this paper, we extensively measure the spatial reuse issue in a dense 60 GHz mmWave network consisting of multiple access points (AP) and users. Our measurement quantifies the impact of interference on network performance and finds that the existing prediction based on interference-resolving approaches are insufficient. Motivated by the findings, we propose MDSR, which enhances the spatial reuse in 60 GHz mmWave networks. Instead of relying on interference prediction, MDSR takes a new measurement principle of building a conflict graph that implicitly takes into account the impact of both beam imperfection and reflections. Using the conflict graph, MDSR improves the spatial reuse from three dimensions: AP association, user scheduling, and beam selection, which can determine the optimal AP-user-beam combination and minimize interference in each scheduling cycle. We prototype and evaluate MDSR on the testbed using commodity mmWave radios. The evaluation results demonstrate that MDSR improves network throughput by multi-folds compared with the state-of-the-art one.

Isorhamnetin, a natural flavonoid, has strong antioxidant and antifibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). The present study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII- and isorhamnetin-treated group. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using atrial tissue and HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Isorhamnetin decreased AF inducibility compared with the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. The findings of the present study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling, highlighting its therapeutic potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.

Perioperative atrial fibrillation is a common postoperative complication. Adverse consequences associated with POAF include hemodynamic instability, increased risk of stroke, extended hospital stays, and increased mortality.To determine the risk factors for POAF and to investigate the outcomes of POAF for patients with cancer, a systematic search of the PubMed and Cochrane Library databases was conducted from inception of the study to 1 September 2021. The inclusion criteria specified studies reporting the prevalence of POAF among patients with cancer. The study excluded articles not written in English, review articles, case reports, letters, commentaries, systematic reviews, meta-analyses, and conference abstracts.The search identified 49 studies with 201,081 patients, and the pooled prevalence of POAF was 13.5% (95% confidence interval [CI], 11.6-15.7%). Meta-analyses showed that the incidence of POAF among patients with cancer was associated with age (mean difference [MD], 4.31; 95%CI, 3.16-5.47), male sex (odds ratio [OR], 1.39; 95% CI, 1.19-1.62), chronic obstructive pulmonary disease (OR, 2.47; 95% CI, 1.71-3.56), hypertension (OR, 1.47; 95% CI, 1.23-1.75), intraoperative blood transfusion (OR, 4.58; 95% CI, 2.31-9.10), and open surgery (OR, 1.51; 95% CI, 1.26-1.81). Patients with POAF had significantly higher in-hospital mortality (OR, 4.25; 95% CI, 2.79-6.45), longer hospital stays (MD, 3.07; 95% CI, 1.63-4.51), and higher incidences of pneumonia (OR, 3.32; 95% CI, 2.85-3.86), stroke (OR, 6.57; 95% CI, 1.56-26.00), and myocardial infarction (OR, 3.00; 95% CI, 1.45-6.20) than those without POAF.For patients with cancer, POAF is associated with an increased burden of comorbidities and worse outcomes.

Historically, a right bundle branch block has been considered a benign finding in asymptomatic individuals. However, this conclusion is based on a few old studies with small sample sizes. We examined the association between a complete right bundle branch block (CRBBB) and subsequent cardiovascular mortality in the general population in Japan. In this large community-based cohort study, data of 90,022 individuals (mean age, 58.5 ± 10.2 years; 66.2% women) who participated in annual community-based health check-ups were assessed. Subjects were followed up from 1993 to the end of 2016. Cox proportional hazards’ models and log-rank tests were used for the data analysis. CRBBB was documented in 1,344 participants (1.5%). Among all included participants, CRBBB was associated with an increased risk of cardiovascular mortality after adjustment for all potential confounders (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.06–1.38). The increased risk of cardiovascular mortality was particularly evident in women aged

Background Ondansetron, a widely prescribed antiemetic, has been implicated in drug-induced long QT syndrome. Recent patch clamp experiments have shown that ondansetron inhibits the apamin-sensitive small conductance calcium-activated potassium current (IKAS). Objective The purpose of this study was to determine whether ondansetron causes action potential duration (APD) prolongation by IKAS inhibition. Methods Optical mapping was performed in rabbit hearts with pacing-induced heart failure (HF) and in normal hearts before and after ondansetron (100 nM) infusion. APD at 80% repolarization (APD80) and arrhythmia inducibility were determined. Additional studies with ondansetron were performed in normal hearts perfused with hypokalemic Tyrode's (2.4 mM) solution before or after apamin administration. Results The corrected QT interval in HF was 326 ms (95% confidence interval [CI] 306–347 ms) at baseline and 364 ms (95% CI 351–378 ms) after ondansetron infusion (P Conclusion Ondansetron is a specific IKAS blocker at therapeutic concentrations. Ondansetron may prolong the QT interval in HF by inhibiting small conductance calcium-activated potassium channels, which increases the vulnerability to ventricular arrhythmias.

Background and Purpose: Isorhamnetin, a natural flavonoid, has strong antioxidant and anti-fibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). This study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Experimental Approach: Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII-and isorhamnetin-treated groups. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Key Results: Isorhamnetin decreased AF inducibility compared to the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. Conclusion and Implications: The findings of this study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling via modulating CaMKII-RyR2 and TRPC-mediated MAPK pathways, highlighting its potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.

Dilated cardiomyopathy (DCM) remains among the most refractory heart diseases because of its complicated pathogenesis, and the key molecules that cause it remain unclear.To elucidate the molecules and upstream pathways critical for DCM pathogenesis, we performed meta-analysis and co-expression analysis of RNA-sequencing (RNA-seq) datasets from publicly available databases. We analyzed three RNA-seq datasets containing comparisons of RNA expression in left ventricles between healthy controls and DCM patients. We extracted differentially expressed genes (DEGs) and clarified upstream regulators of cardiovascular disease-related DEGs by Ingenuity Pathway Analysis (IPA). Weighted Gene Co-expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) analysis were also used to identify the hub gene candidates strongly associated with DCM.In total, 406 samples (184 healthy, 222 DCM) were used in this study. Overall, 391 DEGs [absolute fold change (FC) ≥ 1.5; P 0.01], including 221 upregulated and 170 downregulated ones in DCM, were extracted. Seven common hub genes (LUM, COL1A2, CXCL10, FMOD, COL3A1, ADAMTS4, MRC1) were finally screened. IPA showed several upstream transcriptional regulators, including activating (NFKBIA, TP73, CALR, NFKB1, KLF4) and inhibiting (CEBPA, PPARGC1A) ones. We further validated increased expression of several common hub genes in the transverse aortic constriction-induced heart failure model.In conclusion, meta-analysis and WGCNA using RNA-seq databases of DCM patients identified seven hub genes and seven upstream transcriptional regulators.

To enable accurate indoor localization at low cost, recent research in visible light positioning (VLP) proposed to employ existing ceiling lights as location landmarks, and use smartphone cameras or light sensors to identify the different lights using statistical visual/optical features. Despite the potential, we find such solutions are unreliable: the features are easily corrupted with a slight rotation of the smartphone, and are not discriminative enough for many practical light models with different size/shape/intensity. In this work, we propose Auto-Litell to resolve these critical challenges and make VLP truly robust. Auto-Litell builds a customized deep-learning neural network model to automatically distill the "invisible" visual features from the lights, which are resilient to smartphone orientation and light models. Moreover, Auto-Litell introduces a Light-CycleGAN to generate "fake" light images to augment the training data, so as to relieve human labors in data collection and labeling. We have implemented Auto-Litell as a real-time localization and navigation system on Android. Our experiments demonstrate Auto-Litell's high accuracy in discriminating the lights in the same building, and high reliability across a variety of practical usage scenarios.

Oxidative stress could be a possible mechanism and a therapeutic target of atrial fibrillation (AF). However, the effects of the xanthine oxidase (XO) inhibition for AF remain to be fully elucidated. We investigated the effects of a novel XO inhibitor febuxostat on AF compared with allopurinol in hypertension rat model. Five-week-old Dahl salt-sensitive rats were fed either low-salt (LS) (0.3% NaCl) or high-salt (HS) (8% NaCl) diet. After 4 weeks of diet, HS diet rats were divided into three groups: orally administered to vehicle (HS-C), febuxostat (5 mg/kg/day) (HS-F), or allopurinol (50 mg/kg/day) (HS-A). After 4 weeks of treatment, systolic blood pressure (SBP) was significantly higher in HS-C than LS, and it was slightly but significantly decreased by treatment with each XO inhibitor. AF duration was significantly prolonged in HS-C compared with LS, and significantly suppressed in both HS-F and HS-A (LS; 5.8 ± 3.5 s, HS-C; 33.9 ± 23.7 s, HS-F; 15.0 ± 14.1 s, HS-A; 20.1 ± 11.9 s: P

Background Extended-duration work shifts (EDWSs) might affect the health of physician residents, causing autonomic alteration. Skin sympathetic nerve activity (SKNA) recorded by noninvasive neuro-electrocardiography (neuECG) is used to estimate cardiac sympathetic tone. In this study, we aim to evaluate the impact of EDWSs on nocturnal SKNA assessed in resident doctors. Methods Twenty-four residents working EDWSs and 12 PhD students not working nightshift schedules were prospectively recruited. The neuECG was performed between 12 am and 6 am for 5 consecutive nights. SKNA was filtered from neuECG recorded signals. The questionnaires regarding work stress and sleep quality, blood pressure, and salivary alpha-amylase and cortisol levels were administered. Results The hours of weekly working and sleep opportunities were similar between residents and students, while residents reported more work stress and worse sleep quality. In residents, SKNA at 6 am (SKNA6am) was significantly higher than SKNA2am during the precall night, revealing a dipping pattern. However, the SKNA dipping disappeared during the on-call night and prominently flattened during the first postcall night, the full recovery of which was delayed until the second postcall nights. The morning blood pressure and salivary alpha-amylase and cortisol levels were similar between the precall and postcall days. In contrast, SKNA in students exhibited a constant dipping profile for all recorded nights. Conclusions In healthy young adults, SKNA presents a dip night. The SKNA dip is impaired by working a nightshift, with a delayed recovery. The neuECG might serve as a useful tool to detect subclinical autonomic disturbances in shiftworkers.

Programmed death ligand 2 (PD-L2) is the second ligand of programmed death 1 (PD-1) protein. In autoimmune myocarditis, the protective roles of PD-1 and its first ligand programmed death ligand 1 (PD-L1) have been well documented, however, the role of PD-L2 remains unknown. In this study, we report that PD-L2 deficiency exacerbates myocardial inflammation in mice with experimental autoimmune myocarditis (EAM). EAM was established in wild-type (WT) and PD-L2-deficient mice by immunization with murine cardiac myosin peptide. We found that PD-L2-deficient mice had more serious inflammatory infiltration in the heart and a significantly higher myocarditis severity score than WT mice. PD-L2-deficient dendritic cells (DCs) enhanced CD4+ T cell proliferation in the presence of T cell receptor and CD28 signaling. These data suggest that PD-L2 on DCs protects against autoreactive CD4+ T cell expansion and severe inflammation in mice with EAM.

Background: Isorhamnetin (ISO), a natural flavonoid compound, has been shown to have strong antioxidant and antifibrotic effects in vivo and in vitro; however, no report has been shown on the effect of ISO on arrhythmic disorders. This study aimed to investigate the effect of ISO on angiotensin-II (Ag-II) induced atrial fibrillation (AF) in mice. Methods: Wild-type male mice (C57BL/6J, 8 weeks old) were assigned in 3 groups as follows: control group (Cont), Ag-II group treated with Ag-II and Ag-II & ISO group treated with Ag-II and ISO. Ag-II (1000 ng/kg/min) was continuously administered using an implantable osmotic pump for 2 weeks, and ISO (5 mg/kg) was administered intraperitoneally one week before starting Ag-II administration. We performed AF induction and electrophysiologic study via transvenous electrode catheter and Ca 2+ imaging with isolated cardiomyocyte. We also assessed the gene expression levels of AF-related molecules, and histological examination of atrial fibrosis. Results: Compared with Cont, AF inducibility was dramatically increased by Ag-II and significantly decreased by ISO. AF duration was also remarkably prolonged by Ag-II and significantly reduced by ISO. Atrial effective refractory period (A-ERP) (BCL=150msec) was reduced by Ag-II and recovered by ISO. Incidences of diastolic intracellular Ca 2+ abnormal activities (sarcoplasmic reticulum [SR] Ca 2+ leakage) was observed in Ag-II group; however, ISO treatment eliminated these abnormalities. Ag-II induced elevated expression of fibrosis-related molecules (Col1a1, Tgfb1 and Tgfb2) and Ca 2+ -handling related molecules (Camk2 and Ryr2), those were partially normalized by ISO. Histological examination revealed that cell size and the fibrosis ratio were increased by Ag-II, and significantly attenuated by ISO. Conclusion: These results suggest that ISO prevented against Ag-II induced AF vulnerability through both electrophysiological and structural reverse remodeling.

Aging and obesity are the most prominent risk factors for onset of atrial fibrillation (AF). Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme that catalyzes nicotinamide adenine dinucleotide (NAD) activity. Nampt and NAD are essential for maintenance of cellular redox homeostasis and modulation of cellular metabolism, and their expression levels decrease with aging and obesity. However, a role for Nampt in AF is unknown. The present study aims to test whether there is a role of Nampt/NAD axis in the pathogenesis of obesity-induced AF. Male C57BL/6J (WT) mice and heterozygous Nampt knockout (NKO) mice were fed with a normal chow diet (ND) or a high-fat diet (HFD). Electrophysiological study showed that AF inducibility was significantly increased in WT+HFD, NKO+ND, and NKO+HFD mice compared with WT+ND mice. AF duration was significantly longer in WT+HFD and NKO+ND mice and further prolonged in NKO+HFD mice compared with WT+ND mice and the calcium handling pathway was altered on molecular level. Also, treatment with nicotinamide riboside, a NAD precursor, partially restored the HFD-induced AF perpetuation. Overall, this work demonstrates that partially deletion of Nampt facilitated HFD-induced AF through increased diastolic calcium leaks. The Nampt/NAD axis may be a potent therapeutic target for AF.

Macrophages are fundamental components of inflammation in post‐myocardial infarction (MI) and contribute to adverse cardiac remodelling and heart failure. However, the regulatory mechanisms in macrophage activation have not been fully elucidated. Previous studies showed that myeloid‐associated immunoglobulin–like receptor II (MAIR‐II) is involved in inflammatory responses in macrophages. However, its role in MI is unknown. Thus, this study aimed to determine a novel role and mechanism of MAIR‐II in MI. We first identified that MAIR‐II–positive myeloid cells were abundant from post‐MI days 3 to 5 in infarcted hearts of C57BL/6J (WT) mice induced by permanent left coronary artery ligation. Compared to WT, MAIR‐II–deficient (Cd300c2 −/−) mice had longer survival, ameliorated cardiac remodelling, improved cardiac function and smaller infarct sizes. Moreover, we detected lower pro‐inflammatory cytokine and fibrotic gene expressions in Cd300c2 −/−‐infarcted hearts. These mice also had less infiltrating pro‐inflammatory macrophages following MI. To elucidate a novel molecular mechanism of MAIR‐II, we considered macrophage activation by Toll‐like receptor (TLR) 9–mediated inflammation. In vitro, we observed that Cd300c2 −/− bone marrow–derived macrophages stimulated by a TLR9 agonist expressed less pro‐inflammatory cytokines compared to WT. In conclusion, MAIR‐II may enhance inflammation via TLR9‐mediated macrophage activation in MI, leading to adverse cardiac remodelling and poor prognosis.

Background. Premature ventricular complexes (PVCs) exhibit circadian fluctuation. We determine if PVCs of different origin exhibit specific circadian patterns. Methods. We analyzed Holter recordings from patients with monomorphic PVCs who underwent catheter ablation. PVC circadian patterns were classified as fast-heart rate- (HR-) dependent (F-PVC), slow-HR-dependent (S-PVC), or HR-independent (I-PVC). PVC origins were determined intraprocedurally. Results. In a retrospective cohort of 407 patients, F-PVC and S-PVC typically exhibited diurnal and nocturnal predominance, respectively. Despite decreased circadian fluctuation, I-PVC generally had heavier nocturnal than diurnal burden. PVCs of left anterior fascicle origin were predominantly S-PVC, while those of posterior hemibranch origin were mostly F-PVC. PVCs originating from the aortic sinus of Valsalva (ASV) were predominantly I-PVC, while most PVCs arising from the left ventricular outflow tract (LVOT) were F-PVC. Using a diurnal/nocturnal PVC burden ratio of 0.92 as the cutoff value to distinguish LVOT from ASV origin achieved 97% sensitivity and, as further verification, an accuracy of 89% (16/18) in a prospective cohort of patients with PVCs originating from either ASV or LVOT. In contrast, PVCs originating from right ventricles, such as right ventricular outflow tract, did not show distinct circadian patterns. Conclusions. The circadian patterns exhibit origin specificity for PVCs arising from left ventricles. An analysis of Holter monitoring provides useful information on PVC localization in ablation procedure planning.

KEY POINTS: It is unknown if a sex difference exists in cardiac apamin‐sensitive small conductance Ca(2+)‐activated K(+) (SK) current (I (KAS)). There is no sex difference in I (KAS) in the basal condition. However, there is larger I (KAS) in female rabbit ventricles than in male during isoproterenol infusion. I (KAS) activation by isoproterenol leads to action potential triangulation in females, indicating its abundant activation at early phases of repolarization. I (KAS) activation in females induces negative Ca(2+)–voltage coupling and promotes electromechanically discordant phase 2 repolarization alternans. I (KAS) is important in the mechanisms of ventricular fibrillation in females during sympathetic stimulation. ABSTRACT: Sex has a large influence on cardiac electrophysiological properties. Whether sex differences exist in apamin‐sensitive small conductance Ca(2+)‐activated K(+) (SK) current (I (KAS)) remains unknown. We performed optical mapping, transmembrane potential, patch clamp, western blot and immunostaining in 62 normal rabbit ventricles, including 32 females and 30 males. I (KAS) blockade by apamin only minimally prolonged action potential (AP) duration (APD) in the basal condition for both sexes, but significantly prolonged APD in the presence of isoproterenol in females. Apamin prolonged APD at the level of 25% repolarization (APD(25)) more prominently than APD at the level of 80% repolarization (APD(80)), consequently reversing isoproterenol‐induced AP triangulation in females. In comparison, apamin prolonged APD to a significantly lesser extent in males and failed to restore the AP plateau during isoproterenol infusion. I (KAS) in males did not respond to the L‐type calcium current agonist BayK8644, but was amplified by the casein kinase 2 (CK2) inhibitor 4,5,6,7‐tetrabromobenzotriazole. In addition, whole‐cell outward I (KAS) densities in ventricular cardiomyocytes were significantly larger in females than in males. SK channel subtype 2 (SK2) protein expression was higher and the CK2/SK2 ratio was lower in females than in males. I (KAS) activation in females induced negative intracellular Ca(2+)–voltage coupling, promoted electromechanically discordant phase 2 repolarization alternans and facilitated ventricular fibrillation (VF). Apamin eliminated the negative Ca(2+)–voltage coupling, attenuated alternans and reduced VF inducibility, phase singularities and dominant frequencies in females, but not in males. We conclude that β‐adrenergic stimulation activates ventricular I (KAS) in females to a much greater extent than in males. I (KAS) activation plays an important role in ventricular arrhythmogenesis in females during sympathetic stimulation.

Aging and obesity are the most prominent risk factors for onset of atrial fibrillation (AF). Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme that catalyzes nicotinamide adenine dinucleotide (NAD) activity. Nampt and NAD are essential for maintenance of cellular redox homeostasis and modulation of cellular metabolism, and their expression levels decrease with aging and obesity. However, a role for Nampt in AF is unknown. The present study aims to test whether there is a role of Nampt/NAD axis in the pathogenesis of obesity-induced AF. Male C57BL/6J (WT) mice and heterozygous Nampt knockout (NKO) mice were fed with a normal chow diet (ND) or a high-fat diet (HFD). Electrophysiological study showed that AF inducibility was significantly increased in WT+HFD, NKO+ND, and NKO+HFD mice compared with WT+ND mice. AF duration was significantly longer in WT+HFD and NKO+ND mice and further prolonged in NKO+HFD mice compared with WT+ND mice and the calcium handling pathway was altered on molecular level. Also, treatment with nicotinamide riboside, a NAD precursor, partially restored the HFD-induced AF perpetuation. Overall, this work demonstrates that partially deletion of Nampt facilitated HFD-induced AF through increased diastolic calcium leaks. The Nampt/NAD axis may be a potent therapeutic target for AF.

publication.

Neutrophils are recruited into the heart at an early stage following a myocardial infarction (MI). These secrete several proteases, one of them being neutrophil elastase (NE), which promotes inflammatory responses in several disease models. It has been shown that there is an increase in NE activity in patients with MI, however, the role of NE in MI remains unclear. Therefore, the present study aimed to investigate the role of NE in the pathogenesis of MI in mice. NE expression peaked on day 1 in the infarcted hearts. In addition, NE deficiency improved survival and cardiac function post-MI, limiting fibrosis in the noninfarcted myocardium. Sivelestat, an NE inhibitor, also improved survival and cardiac function post-MI. Flow cytometric analysis showed that the numbers of heart-infiltrating neutrophils and inflammatory macrophages (CD11b+F4/80+CD206low cells) were significantly lower in NE-deficient mice than in wild-type (WT) mice. At the border zone between intact and necrotic areas, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells was lower in NE-deficient mice than in WT mice. Western blot analyses revealed that the expression levels of insulin receptor substrate 1 and phosphorylation of Akt were significantly upregulated in NE-knockout mouse hearts, indicating that NE deficiency might improve cardiac survival by upregulating insulin/Akt signaling post-MI. Thus, NE may enhance myocardial injury by inducing an excessive inflammatory response and suppressing Akt signaling in cardiomyocytes. Inhibition of NE might serve as a novel therapeutic target in the treatment of MI.

AIMS: Phospholamban (PLB) is the key regulator of the cardiac Ca(2+) pump (SERCA2a)-mediated sarcoplasmic reticulum Ca(2+) stores. We recently reported that PLB is highly concentrated in the nuclear envelope (NE) from where it can modulate perinuclear Ca(2+) handling of the cardiomyocytes (CMs). Since inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) mediates nuclear Ca(2+) release, we examined whether the nuclear pool of PLB regulates IP(3)-induced nuclear Ca(2+) handling. METHODS AND RESULTS: Fluo-4 based confocal Ca(2+) imaging was performed to measure Ca(2+) dynamics across both nucleus and cytosol in saponin-permeabilized CMs isolated from wild-type (WT) or PLB-knockout (PLB-KO) mice. At diastolic intracellular Ca(2+) ([Ca(2+)](i)= 100 nM), the Fab fragment of the monoclonal PLB antibody (anti-PLB Fab) facilitated the formation and increased the length of spontaneous Ca(2+) waves (SCWs) originating from the nuclear region in CMs from WT but not from PLB-KO mice. We next examined nuclear Ca(2+) activities at basal condition and after sequential addition of IP(3), anti-PLB Fab, and the IP(3)R inhibitor 2-aminoethoxydiphenyl borate (2-APB) at a series of [Ca(2+)](i). In WT mice, at 10 nM [Ca(2+)](i) where ryanodine receptor (RyR2) based spontaneous Ca(2+) sparks rarely occurred, IP(3) increased fluorescence amplitude (F/F(0)) of overall nuclear region to 1.19 ± 0.02. Subsequent addition of anti-PLB Fab significantly decreased F/F(0) to 1.09 ± 0.02. At 50 nM [Ca(2+)](i), anti-PLB Fab not only decreased the overall nuclear F/F(0) previously elevated by IP(3), but also increased the amplitude and duration of spark-like nuclear Ca(2+) release events. These nuclear Ca(2+) releases were blocked by 2-APB. At 100 nM [Ca(2+)](i), IP(3) induced short SCWs originating from nucleus. Anti-PLB Fab transformed those short waves into long SCWs with propagation from the nucleus into the cytosol. In contrast, neither nuclear nor cytosolic Ca(2+) dynamics was affected by anti-PLB Fab in CMs from PLB-KO mice in all these conditions. Furthermore, in WT CMs pretreated with RyR2 blocker tetracaine, IP(3) and anti-PLB Fab still increased the magnitude of nuclear Ca(2+) release but failed to regenerate SCWs. Finally, anti-PLB Fab increased low Ca(2+) affinity mag-fluo 4 fluorescence intensity in the lumen of NE of nuclei isolated from WT but not in PLB-KO mice. CONCLUSION: PLB regulates nuclear Ca(2+) handling. By increasing Ca(2+) uptake into lumen of the NE and perhaps other perinuclear membranes, the acute reversal of PLB inhibition decreases global Ca(2+) concentration at rest in the nucleoplasm, and increases Ca(2+) release into the nucleus, through mechanisms involving IP(3)R and RyR2 in the vicinity.

Background: Several conducting channels of ventricular tachycardia (VT) can be identified using voltage limit adjustment (VLA) of substrate mapping. However, the sensitivity or specificity to predict a VT isthmus is not high by using VLA alone. This study aimed to evaluate the efficacy of the combined use of VLA and fast-Fourier transform analysis to predict VT isthmuses. Methods and Results: VLA and fast-Fourier transform analyses of local ventricular bipolar electrograms during sinus rhythm were performed in 9 postinfarction patients who underwent catheter ablation for a total of 13 monomorphic VTs. Relatively higher voltage areas on an electroanatomical map were defined as high voltage channels (HVCs), and relatively higher fast-Fourier transform areas were defined as high-frequency channels (HFCs). HVCs were classified into full or partial HVCs (the entire or >30% of HVC can be detectable, respectively). Twelve full HVCs were identified in 7 of 9 patients. HFCs were located on 7 of 12 full HVCs. Five VT isthmuses (71%) were included in the 7 full HVC+/HFC+ sites, whereas no VT isthmus was found in the 5 full HVC+/HFC− sites. HFCs were identical to 9 of 16 partial HVCs. Eight VT isthmuses (89%) were included in the 9 partial HVC+/HFC+ sites, whereas no VT isthmus was found in the 7 partial HVC+/HFC− sites. All HVC+/HFC+ sites predicted VT isthmus with a sensitivity of 100% and a specificity of 80%. Conclusions: Combined use of VLA and fast-Fourier transform analysis may be a useful method to detect VT isthmuses.

BACKGROUND: Apamin-sensitive small conductance calcium-activated K current (I(KAS)) is upregulated during ventricular pacing and masks short-term cardiac memory (CM). OBJECTIVE: To determine the role of I(KAS) in long-term CM. METHODS: CM was created with 3-5 weeks of ventricular pacing and defined by a flat or inverted T-wave off pacing. Epicardial optical mapping was performed in both paced and normal ventricles. Action potential duration (APD(80)) was determined during RA pacing. Ventricular stability was tested before and after I(KAS) blockade. Four paced hearts and 4 normal hearts were used for western blotting and histology. RESULTS: There were no significant differences in either the echocardiographic parameters or in fibrosis levels between groups. Apamin induced more APD(80) prolongation in CM than in normal ventricles (9.6% [8.8%-10.5%] vs 3.1% [1.9%-4.3%], p

Background We investigated the effects of the dipeptidyl peptidase 4 inhibitor teneligliptin on cardiac function and hemodynamics during heart failure in hypertensive model rats. Methods and Results Fifty-five male Dahl salt-sensitive rats were divided into 4 groups: control group (0.3% NaCl chow; n = 13), hypertension (HT) group (8% NaCl chow; n = 20), HT–early TNL group (8% NaCl chow and teneligliptin from 6 weeks; n = 10), and HT–late TNL group (8% NaCl chow and teneligliptin from 10 weeks; n = 12). Hemodynamic measurement and tissue analyses were performed at 18 weeks. In all of the HT groups, systolic blood pressures were similarly elevated (P = .66) and heart weights similarly increased (P = .36) with and without TNL administration. LV end-diastolic dimension was significantly enlarged only in the HT–early TNL group compared with the control group (P = .025). Histologic analysis showed less fibrosis (P = .008) and cardiomyocyte widths (P = .009) in the HT–early TNL group compared with the HT group. On hemodynamic analysis, only the HT group showed significant LV end-diastolic pressure elevation (P = .049) and lung congestion (P Conclusions These results suggest that teneligliptin prevents concentric LV hypertrophy, fibrosis, and development of congestive heart failure in Dahl salt-sensitive rats. Teneligliptin may inhibit pressure-overload hypertrophic adaption and result in LV eccentric hypertrophy with reduced LV ejection fraction.

Background— Ventricular fibrillation (VF) during heart failure is characterized by stable reentrant spiral waves (rotors). Apamin-sensitive small-conductance calcium-activated potassium currents ( I KAS ) are heterogeneously upregulated in failing hearts. We hypothesized that I KAS influences the location and stability of rotors during VF. Methods and Results— Optical mapping was performed on 9 rabbit hearts with pacing-induced heart failure. The epicardial right ventricular and left ventricular surfaces were simultaneously mapped in a Langendorff preparation. At baseline and after apamin (100 nmol/L) infusion, the action potential duration (APD 80 ) was determined, and VF was induced. Areas with a >50% increase in the maximum action potential duration (ΔAPD) after apamin infusion were considered to have a high I KAS distribution. At baseline, the distribution density of phase singularities during VF in high I KAS distribution areas was higher than in other areas (0.0035±0.0011 versus 0.0014±0.0010 phase singularities/pixel; P =0.004). In addition, high dominant frequencies also colocalized to high I KAS distribution areas (26.0 versus 17.9 Hz; P =0.003). These correlations were eliminated during VF after apamin infusion, as the number of phase singularities (17.2 versus 11.0; P =0.009) and dominant frequencies (22.1 versus 16.2 Hz; P =0.022) were all significantly decreased. In addition, reentrant spiral waves became unstable after apamin infusion, and the duration of VF decreased. Conclusions— The I KAS current influences the mechanism of VF in failing hearts as phase singularities, high dominant frequencies, and reentrant spiral waves all correlated to areas of high I KAS . Apamin eliminated this relationship and reduced VF vulnerability.