Nanoparticles (NPs)-mediated Siglec15 silencing and macrophage repolarization for enhanced cancer immunotherapy

T cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy. Emerging evidence has shown that interferon-gamma (IFNγ) could enhance CXCL9 secretion from macrophages to recruit T cells, but Siglec15 expressed on TAMs can attenuate T cell proliferation. Therefore, targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues. We herein developed reduction-responsive nanoparticles (NPs) made with poly (disulfide amide) (PDSA) and lipid-poly (ethylene glycol) (lipid-PEG) for systemic delivery of Siglec15 siRNA (siSiglec15) and IFNγ for enhanced cancer immunotherapy. After intravenous administration, these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages (TAMs). With the highly concentrated glutathione (GSH) in the cytoplasm to destroy the nanostructure, the loaded IFNγ and siSiglec15 could be rapidly released, which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation, leading to significant inhibition of hepatocellular carcinoma (HCC) growth when combining with the immune checkpoint inhibitor. The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

Hollow copper sulfide nanoparticles carrying ISRIB for the sensitized photothermal therapy of breast cancer and brain metastases through inhibiting stress granule formation and reprogramming tumor-associated macrophages

As known, the benefits of photothermal therapy (PTT) are greatly limited by the heat tolerance of cancer cells resulting from overexpressed heat shock proteins (HSPs). Then HSPs further trigger the formation of stress granules (SGs) that regulate protein expression and cell viability under various stress conditions. Inhibition of SG formation can sensitize tumor cells to PTT. Herein, we developed PEGylated pH (low) insertion peptide (PEG-pHLIP)-modified hollow copper sulfide nanoparticles (HCuS NPs) encapsulating the SG inhibitor ISRIB, with the phase-change material lauric acid (LA) as a gate-keeper, to construct a pH-driven and NIR photo-responsive controlled smart drug delivery system (IL@H-PP). The nanomedicine could specifically target slightly acidic tumor sites. Upon irradiation, IL@H-PP realized PTT, and the light-controlled release of ISRIB could effectively inhibit the formation of PTT-induced SG to sensitize tumor cells to PTT, thereby increasing the antitumor effect and inducing potent immunogenic cell death (ICD). Moreover, IL@H-PP could promote the production of reactive oxygen species (ROS) by tumor-associated macrophages (TAMs), repolarizing them towards the M1 phenotype and remodeling the immunosuppressive microenvironment. In vitro/vivo results revealed the potential of PTT combined with SG inhibitors, which provides a new paradigm for antitumor and anti-metastases.

Study of miR-506 in M2 macrophage polarization and immune intervention in pancreatic cancer mice / 中华肝胆外科杂志

Objective:To analyze the effect of microRNA-506 (miR-506) on M2 macrophages polarization and immune intervention in pancreatic cancer mice.Methods:Macrophages from peripheral blood of healthy volunteers were cultured in vitro, polarized into M1 or M2 type macrophages, and transfected with miR-506 or control sequence (miR-ctrl), respectively. Polarized macrophages from M1+ miR-ctrl group, M1+ miR-506 group, M2+ miR-ctrl group and M2+ miR-506 group were collected. The relative expression of marker genes of M1 and M2 type macrophages of four groups were analyzed by qRT-PCR. The characteristic functions of M1 and M2 type macrophages of four groups were also detected, such as phagocytosis and nitric oxide (NO) synthesis (characteristic function of M1 type macrophages), arginase 1 activity and the secretion of vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), interleukin-10 (IL-10) (characteristic function of M2 type macrophages). Sixty healthy male C57BL/6 mice without specific pathogen, weighing 20-25 g, were randomly divided into miR-ctrl programmed death-1 (PD-1) group, miR-506 PD-1 group, miR-ctrl iso group, and miR-506 iso group. They were injected with miR-506, miR-ctrl, PD-1 antibodies, and isotype control antibodies, with 15 in each group. The tumor volume, tumor weight, Ki-67 and interferon γ expression were analyzed three weeks later. Results:Compared with M2+ miR-ctrl group, the relative expression of M1 type macrophage marker genes increased, and the relative expression of M2 type macrophage marker genes decreased in M2+ miR-506 group, with significant difference (all P<0.05). Compared with M2+ miR-ctrl group, the phagocytic function and NO synthesis of macrophages in M2+ miR-506 group increased, the activity of arginase 1 and the secretion of VEGF, TGF-β and IL-10 decreased, with significant difference (all P<0.05). There was no significant differences in tumor weight, volume, Ki-67, and interferon γ expression between miR-ctrl iso and miR-ctrl PD-1 group (all P>0.05). The tumor weight, tumor volume and Ki-67 in miR-506 PD-1 group were lower than those in miR-ctrl PD-1 group [(0.32±0.13) g vs (0.85±0.24) g; (0.72±0.23) cm 3 vs (2.03±0.21) cm 3; (25.9±10.3)% vs (55.6±12.5)%], while interferon-γ expression was significantly higher than that in miR-ctrl PD-1 group [(122.4±15.3) ng/g vs (82.4±22.2) ng/g] (all P<0.05). Conclusion:miR-506 inhibits the polarization of M2 macrophages and increases the anti PD-1 immunotherapy sensitivity in pancreatic cancer.

El fenómeno de la memoria eléctrica como simulador de isquemia miocárdica

RESUMEN Los trastornos de la repolarización ventricular son manifestaciones comunes de una amplia variedad de situaciones, entre las que se incluye la memoria cardíaca; un fenómeno no reconocido frecuentemente en la práctica diaria. La gravedad de cada una de estas causas es muy variable; sin embargo, el diagnóstico definitivo de cada una de ellas no siempre es evidente. Se presenta el caso de un paciente que acude al servicio de urgencias con dolor torácico y ondas T negativas profundas en el electrocardiograma, que simulan una isquemia miocárdica grave, y que fue definido como memoria eléctrica cardíaca.

ABSTRACT The abnormalities in ventricular repolarization are common manifestations of several conditions, among these, we can include cardiac memory, a frequently unrecognized phenomenon in medical practice. The severity of each of these causes is variable; nonetheless, a definitive diagnosis of each of them is not always evident. We present the case of a patient admitted at the emergency room with chest pain and deeply inverted T waves in the electrocardiogram, mimicking a severe myocardial ischemia, which was defined as cardiac electrical memory.

Electrocardiographic markers of myocardial conduction and repolarization in Boxer dogs / Marcadores eletrocardiográficos de condução e repolarização miocárdica em cães da raça Boxer

ABSTRACT: Electrocardiographic markers have been used in people to classify arrhythmogenic risk. The aims of this study were to investigate electrocardiographic markers of conduction and repolarization in Boxers and non-Boxer dogs, and compare such findings between groups. Ten-lead standard electrocardiograms of Boxer dogs and non-Boxers recorded from 2015 to 2018 were retrospectively reviewed. Dogs >/ 4 years of age and weighing > 20kg were included. Animals with valvular insufficiencies, congenital cardiopathies, cardiac dilation, suspected systolic dysfunction, biphasic T-wave, bundle branch blocks, and those receiving antiarrhythmics were excluded. Electrocardiographic markers of conduction, QRS duration (QRSd) and dispersion (QRSD), and repolarization (corrected QT interval, Tpeak-Tend, JT and JTpeak), as well as derived indices, were measured. Two hundred dogs met the inclusion/exclusion requirements, including 97 Boxers (8.1±2.5 years old; 30±7kg) and 103 non-Boxer (8.8±2.5 years old, 30±8kg). QRSd and QRSD, and repolarization markers in lead II and left precordial lead V4 were considered similar between groups. Dispersion of late repolarization on lead rV2, Tpeak-Tend interval, was considered longer in Boxers (45±8ms vs 38±10ms, P=0.01). The Tpeak-Tend/JTpeak and the JTpeak/JT also differed between groups. Our results indicate that the dispersion of myocardial late repolarization in lead rV2 is slower in Boxers than other dog breeds.(AU)

Marcadores eletrocardiográficos têm sido estudados em seres humanos para estratificação do risco arritmogênico. Os objetivos deste estudo foram investigar os marcadores eletrocardiográficos de condução e repolarização miocárdica em Boxers e em cães de outras raças, e comparar tais resultados entre os grupos. Para tal, a eletrocardiografia convencional de 10 derivações registradas de 2015 a 2018 foram avaliadas de maneira retrospectiva. Cães com idade igual ou superior a 4 anos e pesando > 20kg foram incluídos. Animais com insuficiência valvar, cardiopatias congênitas, dilatação cardíaca, suspeita de disfunção sistólica, onda T bifásica, bloqueio(s) de ramo(s), ou aqueles que recebiam antiarrítmicos foram excluídos. Variáveis eletrocardiográficas de condução, como a duração e dispersão do complexo QRS (QRSd e QRSD, respectivamente), e repolarização (intervalo QT corrigido, Tpico-Tfinal, JT e JTpico), bem como índices derivados, foram mensurados. Duzentos cães que se adequaram aos critérios de inclusão/exclusão foram incluídos, 97 Boxers (8,1±2,5 anos; 30±7kg) e 103 não Boxers (8,8±2,5 anos; 30±8kg). O QRSd e o QRSD, e os marcadores de repolarização nas derivações II e V4 foram similares entre os grupos. O marcador de dispersão da repolarização tardia na derivação rV2, Tpico-Tfinal, foi considerado mais longo no Boxers (45±8ms vs 38±10ms, P=0.01). O Tpico-Tfinal/JTpico e o JTpico/JT também diferiram entre os grupos. Nossos resultados indicam que a dispersão da repolarização miocárdica tardia na derivação precordial direita, rV2, é mais lenta no Boxer do que nas outras raças.(AU)

Effects of hypothermia on the repolarization duration of ventricular myocytes in rats and its mechanism / 中国应用生理学杂志

To observe the effects of hypothermia on the repolarization duration and the expression of Kir2.1 protein of ventricular myocytes in isolated rat heart and explore the role of Kir2.1 protein. Eighteen healthy adult male Sprague-Dawley rats were randomly divided into three groups (n=6 per group): Control group (C group), 35℃ group (H group), 32℃ group (H group). Langendorff isolated heart models were established. After 15 min 37℃ K-H fluid banlanced perfusion, C group continued to perfuse the K-H solution at 37℃ for 30 minutes, H group continued to perfuse the K-H solution at 35℃ for 30 minutes, H group continued to perfuse the K-H solution at 32℃ for 30 minutes. At 15 min of balanced perfusion (T), and 30 min of continuous perfusion (T), the heart rate,and the MAP in the three layers of the left ventricular anterior wall were recorded, the action potential duration at 50% repolarization (MAPD), the action potential duration at 90% repolarization (MAPD) and transmural dispersion of repolarization(TDR) were calculated. At the same time, the occurrence of arrhythmia was recorded. The expression of Kir2.1 protein was measured by Western blot. The average optical density (AOD) and the distribution of Kir2.1 protein were measured by immunohistochemistry in the ventricular tissue measured by electrophysiology. Compared with T, the heart rate was decreased, MAPD and MAPD were prolonged significantly (P＜0.05), and TDR was increased significantly (P＜0.05) in H group, H group at T. Compared with C group, the HR was decreased, the MAPD was prolonged significantly (P＜0.05), TDR was increased significantly (P＜0.05),the expression and the AOD of Kir2.1 protein were decreased significantly (P＜0.05) in Hgroup, Hgroup at T. Compared with H group, the heart rate of H group was decreased significantly (P＜0.05), MAPD and MAPD were prolonged significantly (P＜0.05), and TDR was increased significantly (P＜0.05) at T. The distribution of Kir2.1 protein in group C was normal, while the distribution of Kir2.1 in H group and H group was disordered. Hypothermia prolonged the ventricular duration of repolarization and increased the dispersion of repolarization. The mechanism is related to the down-regulation the expression of Kir2.1 protein and the disorder of the distribution of Kir2.1 protein.

Repolarización ventricular en la terapia oncológica / Ventricular repolarization in cancer therapy

RESUMEN Se discuten los procesos de despolarización y repolarización ventriculares, con su falta de uniformidad y su heterogeneidad, tanto en pacientes con corazón sano como en aquellos enfermos, cuestión de rangos. Se analizan las mediciones que expresan las características de la repolarización ventricular: el intervalo QT y otras mediciones incluso más fidedignas como el intervalo TPICO-TFINAL, su dispersión y otras. Se precisa la existencia del signo y del síndrome de QT largo, así como los tres procesos básicos de la arritmogenia: la heterogeneidad, la alternancia y la dispersión, con las diferencias de los potenciales de acción en las tres zonas del miocardio ventricular. Se precisan los factores de riesgo del QT largo (común con esta terapia), de las arritmias ventriculares (en especial la torsión de puntas, extremadamente rara en estos casos) y se discute la necesidad de valorar datos clínicos, eléctricos, comorbilidades, conflictos agregados y las medidas a tomar en estos pacientes.

ABSTRACT Ventricular depolarization and repolarization processes are discussed, including their differences and heterogeneity both in patients with a healthy/sick heart, a matter of ranges. Measurements expressing the characteristics of ventricular repolarization are analyzed: the QT interval and other even more reliable measurements such as the TPEAK-TEND interval, its dispersion and others. We emphasize on the existence of the long QT syndrome (and sign) and the three basic processes of arrhythmogenesis: heterogeneity, alternation and dispersion, with differences in action potentials in the three zones of the ventricular myocardium. The risk factors of long QT (common in this therapy) and ventricular arrhythmias (especially torsades de pointes, extremely rare in these cases) are highlighted. The need to assess clinical and electrical features, comorbidities, aggregate conflicts, and management of these patients is also discussed.

Regulatory effect of epinephrine on major ion channels in repolarization of ventricular papillary muscle cells / 中国药理学通报

In some states such as myocardial ischemia, heart failure, angina pectoral and myocardial ion channel disease and so on, one person may catch with a rapid cardiac arrhythmia, e-ven a generate ventricular fibrillation or a sudden death, especially in the case of emotional agitation, stress or sympathetic tone increasing abnormally, and exogenous administration of epinephrine , followed by a significant rising of catecholamine. All the above have a relationship with the sympathetic excitatory for ct and p receptors, the regulation of myocardial ion channel function, changing the myocardial action potential, and the myo cardial excitability. From the perspective of myocardial electro-physiology , this paper analyzes the effect of adrenal receptors on the regulation of ion channels, which plays a main action in the myocardial depolarization process, as well as the effect on the action potential duration, aiming to deepen the understanding of the mechanism of catecholamine inducing ventricular arrhythmias.

Anti-arrhythmic effects of taurine-magnesium coordination compound on torsades de pointes / 中国应用生理学杂志

OBJECTIVES@#To investigate the effect of taurine magnesium coordination compound (TMCC) on torsades de pointes (TdP) in isolated guinea pig hearts.@*METHODS@#Healthy male guinea pigs weighting 250~300 g were randomly divided into 4 groups:①TdP model group (=7):Isolated hearts were perfused by normal K-H solution 20 minutes, then perfused by slowly activated delayed rectifier potassium current(IKs) blocker 10mol/L Chromanol 293B under hypokalemic solution(1.8 mmol/L) to establish TdP model;②~④ TdP model + TMCC group (=6):Isolated hearts were perfused by normal K-H solution for 20 minutes, then perfused by IKs blocker 10mol/L Chromanol 293B under hypokalemic solution(1.8 mmol/L) for 60 minutes, at the same time TMCC which concentration was 1, 2, 4 mmol/L was administered respectively by Langendorff retrograde aortic perfusion method. Cardiac surface electrocardiogram of guinea pigs was collected and recorded by Biopac electrophysiological recorder. Incidence of TdP, transmural dispersion of repolarization (TDR), instability of QT interval were acquired from Lead Ⅱ electrocardiograph (ECG) wave forms to describe the effect of TMCC on TdP model. Datas were acquired at the time of 20 min and pre-TdP, in case there was no TdP observed, a value of 60 min was entered for calculation purpose.@*RESULTS@#Incidence of TdP in TdP model group was 6/7. TdP incidence could be decreased significantly by 1, 2, 4 mmol/L TMCC, and was 5/6, 1/6, 0/6 respectively. Compared with the pre-drug, Chromanol 293B under hypokalemic solution in TdP model group increased TDR(corrected) evidently(0.05). Compared with the TdP model group, 2, 4 mmol/L TMCC could evidently decrease the instability of QT interval induced by Chromanol 293B under hypokalemic solution(<0.05). During the establishment of TdP model, P waves in more than one cardiac cycle continuously were disappeared in ECG. However, P wave could always be seen independent in ECG acquired from TdP model + TMCC group.@*CONCLUSIONS@#TMCC can play the role against TdP through decreasing TDR and instability of QT interval, and inhibiting early after depolarization(EAD).

Recurrent ST segment elevations in a patient with asymptomatic early repolarization during head and neck surgery: implications of vasospastic angina

A 57-year-old woman scheduled for cochlear implant removal exhibited preoperative electrocardiographic findings of early repolarization (ER). Four episodes of transient ST segment elevations during surgery raised suspicion for vasospastic angina (VA). In the post-anesthetic care unit, the patient complained of chest discomfort and received sublingual nitroglycerin with uncertain effect. The patient refused to proceed with postoperative invasive coronary angiography, resulting in inconclusive diagnosis. Intraoperative circumstances limit the diagnosis of VA, which emphasizes the need for further testing to confirm the diagnosis. When VA is suspected in patients with underlying ER, it is reasonable to consider invasive examination to establish the diagnosis and prevent recurrence of VA. If ST changes are observed during surgery in patients with preoperative ER, careful monitoring is recommended. Due to general anesthesia, the absence of patient symptoms limits the definitive diagnosis of those with suspected VA. Therefore, additional postoperative surveillance is recommended.

Investigations on effect of taurine-magnesium coordination compound against SQT2 in isolated hearts of guinea pig / 中国药理学通报

Aim To investigate the effect of taurine-magnesium coordination compound (TMCC) on elec-trocardiogram of isolated guinea pig hearts, hoping to describe a primary research on its characteristic of anti-short QT syndrome. Methods The isolated guinea pig heart was retrograde perfused using Langendorff tech-nique. In order to determine the effects of TMCC on QT interval, transmural dispersion of repolarization, effective refractory period, instability of RR interval and instability of QT interval in the presence of potassi-um channel opener pinacidil, the electrocardiogram of isolated guinea pig hearts was recorded using Biopac physiological recorder. Results The shortened QT in-terval and the effective refractory period induced by pinacidil could be prolonged by TMCC; the increased transmural dispersion of repolarization induced by pinacidil could be decreased by TMCC; the increased instability of RR and QT interval induced by pinacidil could be decreased by TMCC. Conclusion TMCC has the effects of anti-SQT2 by prolonging the QT inter-val and the effective refractory period, reducing the transmural dispersion of repolarization and instability.

The role of sex hormones on ion channels of drug-induced long QT syndromes / 天津医药

Female gender is an independent risk factor for the development of torsade de pointes (TdP) arrhythmias not only in congenital long QT syndromes(LQTs)but also in acquired long QT syndromes. Clinical evidences imply that sex steroid hormones appear to play important roles in gender differences by affecting the cardiac repolarization process of action potential. This review summarizes the effects of sex hormones on cardiac ion channel currents and the effects of gender differences on drug-induced long QT syndromes, and reveals the mechanism of sex hormone induced arrhythmia by computer simulation

Effect of down-regulation of IKs repolarization-reserve on ventricular arrhythmogenesis in a guinea pig model of cardiac hypertrophy / 中南大学学报(医学版)

Objective:To observe the changes of rapidly activated delayed rectifier potassium channel (IKs) and slowly activated delayed rectifier potassium channel (IKs) in cardiac hypertrophy and to evaluate the effects of IKs and IKs blocker on the incidence ofventricular arrhythmias in guinea pigs with left ventricular hypertrophy (LVH).Methods:Guinea pigs were divided into a sham operation group and a left ventricular hypertrophy (LVH) group.LVH model was prepared.Whole cell patch-clamp technique was used to record IKr and IKs tail currents in a guinea pig model with LVH.The changes of QTc and the incidence rate of ventricular arrhythmias in LVH guinea pigs were observed by using the IKr and IKs blockers.Results:Compared with cardiac cells in the control group,the interventricular septal thickness at end systole (IVSs),left ventricular posterior wall thickness at end systole (LVPWs),QTc interval and cell capacitance in guinea pigs with LVH were significantly increased (P＜0.05);while IKs densities were significantly reduced [+60 mV:(0.36±0.03) pA/pF vs (0.58±0.05) pA/pF,P＜0.01].However,LVH exerted no significant effect on IKr densities.IKr blocker markedly prolonged the QTc interval (P＜0.01) and increased the incidence of ventricular arrhythmias in guinea pigs with LVH compared with the control guinea pigs.In contrast,IKs blocker produced modest increase in QTc interval in guinea pigs of control group with no increase in LVH animals.IKs blocker did not induce ventricular arrhythmias incidence in either control or LVH animals.Conclusion:The cardiac hypertrophy-induced arrhythmogenesis is due to the down-regulation of IKs.

Profile of the cardiac repolarization in cervical spinal cord injury subjects performing physical exercise / Perfil da repolarização cardíaca de sujeitos com lesão medular cervical submetidos a exercícios físicos

The aim of the study was to compare rest QT interval and QTcorrected intervals of electrocardiogram in trained men with and without cervical spinal cord injury (CSCI) and investigate cardiac electrocardiogram parameters in trained men with CSCI submitted to maximal effort test. Thirty men were separated into three groups: Control without CSCI (CON, 25.3 ± 4.1 yrs, strength training: 3 days week-1; aerobic training 1day week-1; n = 10), high volume exercise (30.5 ± 4.3 yrs, 3 day week-1 rugby specific exercises, 60min. day-1; n = 12) and moderate volume of exercise (33.7 ± 5.9 yrs, 2 days week- 1 specific rugby exercises, 60 min. day-1; n = 8) with incomplete CSCI (C5-C7 cervical vertrebae) more than 12 months. Electrocardiogram was recorded in rest, during and after effort test. QT interval was significantly reduced (p = 0.001) in the high volume exercise group compared to control. Corrected QT interval showed no difference between moderate vs. high volume exercise group (p > 0.05). No changes were observed in QT, corrected QT, PR and QRS intervals of electrocardiogram between rest and post effort (p > 0.05). Thus, effort test does not change electrocardiogram parameters in CSCI subjects. High volume of week exercise promotes abnormalities in cardiac repolarization compared to a moderate training program.

O objetivo do presente estudo foi comparar o perfil dos intervalos QT e QT corrigido (QTc) em homens treinados com e sem lesão medular cervical (LMC) e investigar o perfil eletrocardiográfico de homens treinados com LMC submetidos ao teste de esforço máximo. Trinta homens foram separados em três grupos: controle sem LMC (CON, indivíduos fisicamente ativos; n = 10), LMC praticantes de alto volume de exercícios (praticantes de rugby em cadeira de rodas 180 min. Semana-1; n = 12) e LMC praticantes de moderado volume de exercícios (praticantes de rugby em cadeira de rodas 120 min. Semana-1; n = 8). Todos os participantes do grupo LMC apresentavam lesões incompletas (C5-C7) mais do que 12 meses. Eletrocardiograma foi registrado em repouso, durante e após o teste de esforço. O intervalo QT apresentou redução significativa (p = 0,001) no grupo de alto volume de exercícios quando comparado ao controle. O QTc não mostrou diferença entre os distintos volumes de exercícios (p > 0,05). Ambos os grupos LMC não apresentaram mudanças significativas no intervalo QT, QTc, intervalos PR e QRS entre o repouso e pós-esforço (p > 0,05). Concluimos que o alto volume de exercícios semanais parece promover anormalidades na repolarização cardíaca.

Role of gap junction Cx43 in dexmedetomidine for prevention of reperfusion induced arrhythmias during ischemia-reperfusion in isolated rabbit hearts / 临床麻醉学杂志

Objective To investigate the effect of dexmedetomidine on myocardial repolarization heterogeneity and the expression of Cx43 during ischemia-reperfusion and the role of Cx43 in the dexmedetomidine for inhibition of myocardial repolarization heterogeneity during ischemia-reperfusion in isolated rabbit hearts.Methods Eighteen healthy adult rabbits,weighing (2.0±0.5) kg,were randomly divided into three groups after Langendorff isolated heart perfusion model had been prepared and K-H fluid had been perfused and balanced 15 min.In the control group (group C),37℃ K-H fluid was continuously perfused and balanced for 150 min.In group IR,K-H fluid was stopped after perfusion continue filling for 15 min,and then made the cardiac stop for 60 min with the injection of Thomas solution 10 ml/kg while the heart was protected by the 4℃ Thomas solution around.Following the reperfusion of 4℃ Thomas solution 5 ml/kg was performed for 30 min and the heart was resuscitated by the perfusion of K-H fluid for 60 min.In dexmedetomidine group given (group DEX),dexmedetomidine was added in the K-H fluid and the Thomas solution 25 ng/ml.The other procedures were the same as those of group IR.The heart rate (HR),90% monophasic action potential duration (MAPD90) were recorded at the time of balance perfusion record 15 min (T0),continue perfusion 15 min/balance 30 min (T1),reperfusion 30 min/balance 120 min (T2) and reperfusion 60min/balance 150 min (T3).The transmural dispersion of repolarization (TDR) was calculated.To observe the cardiac reperfusion arrhythmia and rebeating time and recording.Detection expression of Cx43 in the left ventricular myocardial by Western blot and immunohistochemistry at T3.Results Group DEX cardiac resuscitation time was significantly shorter than that of group IR (P<0.05).In group DEX.Compared with T0,HR was significantly decreased and TDR was significantly increased in groups IR and DEX at T2、T3 (P<0.05).Compared with group IR,the TDR of group DEX was significantly decreased at T2、T3 (P<0.05).Compared with group C,the expression of Cx43 was decreased (P<0.05) and the distribution was not uniform in groups IR and DEX.Compared with group IR,the expression of Cx43 was decreased (P<0.05) and the distribution was improved in group DEX.Conclusion Dexmedetomidine could inhibits myocardial repolarization heterogeneity of ischemia-reperfusion injury,and thus play a stable cardiac conduction,reduce reperfusion arrhythmias,and its mechanism may be that dexmedetomidine could inhibits gap junctional uncoupling and inhibits expression and distribution of connexins decreased.

T wave

The T wave in a surface electrocardiogram (ECG) indicates the diastolic phase in the cardiac cycle. Even though the cellular basis of T-wave morphology in surface ECG remains unclear in clinical cardiology, the morphology may be determined by the transmural voltage gradient during the repolarization period that underlies the changes in the T wave and QT interval. The heterogeneous distribution of electrophysiological activity across the heart is essential for normal cardiac function. However, excessive heterogeneity may contribute to arrhythmogenesis and sudden cardiac death. This paper will provide an overview of T wave genesis and the contribution to action potential duration (APD), in which ion channels are involved in the repolarization period, with special emphasis on K+ channels involved in phase 3 repolarization. These channels are primarily Kv11.1 (hERG1), Kv7.1 (KCNQ1), and Kir2.1 (KCNJ2), which are the α-subunits responsible for conducting I(Kr), I(Ks), and I(K1). Changes in the T wave and QT interval that are affected by both functional loss and gain of these currents are associated with various arrhythmogenic diseases. This review also briefly discusses arrhythmogenesis in diseases that are manifested by changes in the T wave and QT interval.

High Prevalence and Clinical Implication of Myocardial Bridging in Patients with Early Repolarization

PURPOSE: Recent evidence suggests that early repolarization (ER) is related with myocardial ischemia. Compression of coronary artery by a myocardial bridging (MB) can be associated with clinical manifestations of myocardial ischemia. This study aimed to evaluate the associations of MB in patients with ER. MATERIALS AND METHODS: In consecutive patients (n=1303, age, 61±12 years) who had undergone coronary angiography, we assessed the prevalence and prognostic implication of MB in those with ER (n=142) and those without ER (n=1161). RESULTS: MB was observed in 54 (38%) and 196 (17%) patients in ER and no-ER groups (p<0.001). In multivariate analysis, MB was independently associated with ER (odd ratio: 2.9, 95% confidence interval: 1.98–4.24, p<0.001). Notched type ER was more frequently observed in MB involving the mid portion of left anterior descending coronary artery (LAD) (69.8% vs. 30.2%, p=0.03). Cardiac event was observed in nine (6.3%) and 22 (1.9%) subjects with and without ER, respectively. MB was more frequently observed in sudden death patients with ER (2 out of 9, 22%) than in those without ER (0 out of 22). CONCLUSION: MB was independently associated with ER in patients without out structural heart disease who underwent coronary angiography. Notched type ER was closely related with MB involving the mid portion of the LAD. Among patients who had experienced cardiac events, a higher prevalence of MB was observed in patients with ER than those without ER. Further prospective studies on the prognosis of MB in ER patients are required.

Voltage sensitive optical mapping used to observe effects of late Na and rapidly activating delayed rectifier K currents on the right and left ventricular electrophysiological heterogeneity / 西安交通大学学报(医学版)

ABSTRACT:Objective To observe the effects of late Na current (INa‐L ) and rapidly activating delayed rectifier K current (IKr ) on ventricular heterogeneity and frequency dependency by using high resolution voltage sensitive optical mapping technology .Methods The model of 12 isolated hearts was constructed in rabbits . Voltage sensitive dye Di‐4‐ANEPPS were perfused into the isolated hearts by Langendorff method .LED source with the wave length of 532 nm was used to record APD80 and APD50 of the left and right ventricles .Experimental groups were divided into 3 groups by perfusion drugs dofetillide (30 nmol/L) ,dofetillide+ATX‐Ⅱ(1 nmol/L) ,and dofetillide +ATX‐Ⅱ +mexiletine (10μmol/L) .The subjects were intervened by the above drugs in order ,and they were self‐compared before dosing .After each drug administration ,the hearts were stimulated respectively with the BCL of 2 000 ms ,1 000 ms ,500 ms ,and 300 ms .Then we observed the changes of APD80 and APD50 in the left and right ventricles before and after the interventions .Results ① In the control group ,APD80 and APD50 of the right ventricle were longer than those of the left ventricle in response to different stimulation , and the differences increased with the decrease of stimulating frequency .② When BCL was 1000 ms ,APD80 and APD50 of the left and right ventricles were prolonged respectively after administration of dofetillide , but the differences in APD80 and APD50 were insignificant between the left and right ventricles (P>0 .05) .ΔAPD80 of the two ventricles increased significantly with the decrease of stimulating frequency . ③ After administration of ATX‐Ⅱ , when BCL was 1000 ms ,APD80 and APD50 of the left and right ventricles increased significantly compared with those in the control group and dofetillide intervention group (P0 .05) .The increase of ΔAPD80 of the two ventricles became milder when the stimulating frequency decreased . Conclusion ① IKr blocked by dofetillide did not affect the heterogeneity between the two ventricles , which showed reverse‐frequency dependence . ② In the context of blocking IKr , ATX‐Ⅱ increased the heterogeneity between the left and right ventricles and enhanced the reverse‐frequency dependence .In contrast ,mexiletine ,the blocker of INa‐L ,decreased the heterogeneity between the two ventricles and reverse‐frequency dependence .

Effects of dexmedetomidine on the monophasic action potential duration and transmural dispersion of re-polarization during ischemia-reperfusion in isolated rabbit hearts / 临床麻醉学杂志

Objective To study the effects of dexmedetomidine on the monophasic action po-tential duration and the transmural dispersion of repolarization during ischemia-reperfusion of isolated rabbit hearts and thus explore its effect on myocardial ischemia-reperfusion electrophysiological char-acteristics.Methods Eighteen healthy adult rabbits,weighing (2.0±0.5)kg,were randomly divided into 3 groups after successful preparation of Langendorff isolated heart perfusion model and 1 5 min perfusion and balance of K-H fluid.In the control group (group C),37 ℃ K-H fluid was continuously perfused and balanced for 1 50 min.In the ischemia/reperfusion group (group IR),K-H fluid was stopped after continuous perfusion and balance for 1 5 min and cardiac arrest was induced for 60 min with the injection of Thomas solution (4 ℃,10 ml/kg)while the heart was protected by the low tem-perature Thomas solution (4 ℃)around it.Reperfusion of Thomas solution (4 ℃,5 ml/kg)was performed for 30 min and the heart was resuscitated by the perfusion of K-H fluid for 60 min.In dexmedetomidine group (group DEX),dexmedetomidine (25 ng/ml)was added in the K-H fluid and the Thomas solution.Other procedures were same as in group IR.Heart rate(HR),monophasic ac-tion potential amplitude (MAPA)of the three layers of heart [endocardium (Endo),myocardium (Mid)and epicardium (Epi)],0 phase maximal increase rate (Vmax),90% monophasic action po-tential duration (MAPD90 )and transmural dispersion of repolarization (TDR)were recorded at the time of continuous balance perfusion 1 5 min(T0 ),continuous perfusion 1 5 min/balance 30 min(T1 ), reperfusion 30 min/balance 120 min(T2 )and reperfusion 60 min/balance 1 50 min(T3 ).Cardiac ar-rhythmia and resuscitation time at cardiac reperfusion were observed,without using drugs to restore normal cardiac rhythm.Results In group DEX,cardiac resuscitation time was significantly shorter (1 6.67±3.78)s than that in group IR (46.33±7.29)s (P <0.05);At T2 ,in group IR,arrhythmia was seen in 6 rabbits and normal cardiac rhythm was restored within 2 min in two rabbits,while in group DEX,arrhythmia was seen in 2 rabbits and normal cardiac rhythm was restored within 2 min in one rabbit,without the use of any drugs.When compared with T0 ,HR was slower at T2 and T3 in group IR and at T1-T3 in group DEX (P <0.05);Compared with T1 ,HR was slower at T2 and T3 in group DEX (P <0.05);Compared with T2 and group C,HR was slower at T3 in group DEX;At T1-T3 ,HR in group DEX were significantly slower than that in group IR (P <0.05).Compared with T0 ,MAPD90 of Mid at T1 and Epi,Mid,Endo at T2 and T3 in group DEX were significantly extend-ed (P <0.05);Compared with T1 ,MAPD90 of Epi,Mid,Endo in group DEX were significantly ex-tended at T3 ;MAPD90 of Mid in group DEX was significantly longer than that in group C at T3 (P <0.05);At T2 and T3 ,MAPD90 of Epi,Mid,Endo in group DEX were longer than that in group IR (P <0.05).Compared with T0 and group C,TDR at T2 and T3 in group IR and at T1-T3 in group DEX significantly increased (P <0.05),while TDR in group DEX were less than that in group IR at T2 and T3 (P <0.05).Conclusion Dexmedetomidine appeared to prolong MAPD and restrain the dis-proportion of resuscitation of myocardial ischemia-reperfusion injury.Dexmedetomidine could have the effect of stabilizing myocardial ischemia-reperfusion electrophysiological characteristics.

Effect of Cardiac Resynchronization Therapy in Patients With Dispersion of Re-polarization and Ventricular Arrhythmia / 中国循环杂志

Objective: To explore the effects of cardiac resynchronization therapy (CRT) in patients with dispersion of re-polarization and ventricular arrhythmia. Methods: A total of 86 consecutive patents with CRT implantation were enrolled. According to weather absolute value of LVEF increased≥10% from baseline at 6 months after CRT implantation, the patients were divided into 2 groups: Response group and Non-response group,n=43 in each group. Dispersion of re-polarization indexes as QRS duration, QTc interval, TpTe interval and the events of ventricular arrhythmia were compared between 2 groups at different time points after CRT. Results:①In Response group, compared with pre-operation, QRS duration and TpTe interval were shorter at 1 year and within 24h after CRT implantation, allP0.05.②During 1 year after CRT implantation, the incidences of PVCs and PVC runs in Response group were much less than those in Non-response group, for lgPVCs: (1.78 ± 0.77) vs (2.73 ± 0.61), for lgPVC runs: (0.64 ± 0.48) vs (1.98 ± 0.72),P Conclusion: CRT ventricular reverse remodeling may reduce dispersion of re-polarization and the risk of ventricular arrhythmia, therefore improve the prognosis in relevant patients; TpTe interval within 24h after CRT had the predictive value for ventricular arrhythmia.