海葵毒素对心肌钠通道开放模式、动作电位及心电图QT间期的影响

应用膜片箝技术记录游离豚鼠心肌细胞钠通道电流, 细胞内微电极技术记录心室乳头肌的动作电位和心电图机记录豚鼠的心电图。使用与心肌细胞钠通道有高度亲和力的海葵毒素(sea anemone toxin, ATXⅡ)改变钠通道开放的动力过程, 从三个水平来研究钠通道、动作电位、心电图变化的关系, 并试图探讨长QT综合征(long QT syndrome, LQTs)的发病机制。结果显示: ATXⅡ使钠通道的开放频率增加, 钠通道中“长时间开放模式”的开放时间常数增大, 动作电位的持续时间APD50和APD90也分别增加了23%和27%。 ATXⅡ使动物心电图QT间期延长18.6%, QTc (校正的QT间期)增大18.9%。这些结果提示, 钠通道动力过程的变化对动作电位和心电图QT间期有重要影响, 钠通道功能或结构的变异可能是临床上部分长QT综合征产生的原因。     

牛磺酸镁抗豚鼠尖端扭转型室速的作用研究

目的：研究牛磺酸镁配位化合物（TMCC）抗豚鼠心脏尖端扭转型室速（TdP）的作用。方法：取健康、体重250~300 g的成年雄性豚鼠,随机分为4组：① TdP模型组（n=7）：离体心脏以K-H灌流液灌流20 min,然后使用IKs阻滞剂10μmol/L Chromanol 293B合并低钾（钾离子浓度为1.8 mmol/L）进行灌流,建立TdP模型。②~④ TdP模型+TMCC低中高浓度组（n=6）：正常灌流稳定20 min后,在建立TdP模型的同时分别给予1、2、4 mmol/L TMCC。采用Langendorff逆行主动脉灌流法灌流豚鼠离体心脏,利用Biopac电生理记录仪采集并记录豚鼠离体心脏表面心电图。从心电图第Ⅱ导联图形获取各组豚鼠离体心脏TdP发生率、跨室壁复极离散度、QT间期不稳定性,以观察TMCC对TdP的影响。观测指标量取时间分别为：豚鼠离体心脏正常灌流20 min时、TdP发生前及给药60 min时。结果：TdP模型组的TdP发生率为6/7。1、2、4mmol/L TMCC可降低TdP发生率,三组TdP发生率分别为5/6、1/6、0/6。与给药前相比,TdP模型组中Chromanol 293 B合并低钾可使豚鼠离体心脏校正后的跨室壁复极离散度显著增大（P<0.01）;与TdP模型组相比,TdP模型+1、2、4mmol/L TMCC组可明显减弱Chromanol 293B合并低钾导致的豚鼠离体心脏校正后的跨室壁复极离散度增大（P>0.05）。与模型组相比,2、4mmol/L TMCC明显降低Chromanol 293B合并低钾导致的QT间期不稳定增大（P<0.05）。在TdP模型建立过程中,从心电图中可观察到连续多个心动周期的P波消失,而在TdP模型+TMCC组中,心电图始终拥有独立P波。结论：TMCC可通过降低离体心脏跨室壁复极离散度和QT间期不稳定性以及抑制早后除极的发生而发挥抗TdP作用,降低TdP发生率。     

低温对离体大鼠心室肌复极时程的影响及其机制

目的: 观察低温对离体大鼠心室肌复极时程及Kir2.1蛋白表达的影响,探讨Kir2.1蛋白在其中的作用。 方法:18只健康雄性SD大鼠, 随机分为3组(n=6),即正常对照组(C组)、35℃低温组(H₁组)和32℃低温组(H₂组)。制备Langendorff离体心脏灌注模型,37℃ K-H液平衡灌注15 min后,C组继续灌注37℃ K-H液30 min;H₁组继续灌注35℃的K-H液30 min,H₂组继续灌注32℃的K-H液30 min。记录各组平衡灌注15 min(T₁)和继续灌注30 min(T₂)时HR、左心室前壁三层心肌单相动作电位,计算单相动作电位复极50％、90％的时程(MAPD₅₀、MAPD₉₀)和跨室壁复极离散度(TDR),同时记录心律失常发生情况。取测量电生理的心室肌部位组织以Western blot测定Kir2. 1蛋白表达,以免疫组织化学法测量Kir2. 1蛋白的平均光密度值(AOD)及分布情况。结果: 与T₀比较,T₁时H₁组和H₂组HR显著减慢(P＜0.05), MAPD₅₀、MAPD₉₀显著延长(P＜0.05),TDR显著增大(P＜ 0.05);与C组比较,T₁时H₁组和H₂组HR显著减慢(P＜0.05),MAPD₉₀显著延长(P＜0.05),TDR显著增大(P＜ 0.05),Kir2.1蛋白表达显著减少(P＜0.05), AOD值显著减少(P＜0.05)。与H₁组比较,T₁时H₂组心率显著减慢(P＜0.05),MAPD₅₀、MAPD₉₀显著延长(P＜0.05),TDR显著增大(P＜0.05)。C组Kir2.1蛋白分布正常,H₁、H₂组蛋白分布紊乱。结论: 低温会延长心室复极时程,增加复极离散度,其机制与低温下调Kir2.1蛋白表达、改变Kir2.1蛋白分布有关。     

苯肾上腺素对豚鼠和兔离体心室乳头肌的作用

在心得安(1μM)阻断β-受体的情况下,本文通过观察苯肾上腺素(PE)对豚鼠和兔心室乳头肌动作电位及收缩的作用,探讨了心脏α-受体兴奋引起正性变力作用的机制。PE(1—16μM)延长豚鼠心室乳头肌动作电位时程(APD),增加兔和豚鼠心室乳头肌的收缩幅度(AC)。PE 在兔心室乳头肌上表现出的正性变力作用比在豚鼠心室肌上显著得多。FE(16μM)加强兔和豚鼠心室乳头肌收缩力的作用可被α_1-受体阻断剂哌唑嗪(Prazosin)(0.3—0.5μM)所取消。然而,在豚鼠心室乳头肌上被PE延长的APD,仅APD_(30)在哌唑嗪作用下有所缩短,而APD_(90)则不受其影响。在高钾(22mM)除极的心室乳头肌,PE(50μM)使 9个兔标本中的8个、8个豚鼠标本中的2个分别恢复慢反应动作电位。这些慢反应动作电位可被哌唑嗪(1μM)或钙通道阻断剂Mn~( )(1mM)所取消或抑制。以上的结果提示心脏α-肾上腺素能受体兴奋引起正性变力作用可能是由于慢内向电流(I_si)的增加。     

白藜芦醇甙对大鼠心室乳头状肌动作电位的影响及其离子机制(英文)

有研究表明白藜芦醇甙(polydatin)具有抗缺血性心律失常作用,但其电生理学机制尚未明了。本研究旨在应用细胞内记录和全细胞膜片钳方法,探讨白藜芦醇甙对大鼠心室乳头状肌动作电位的影响及其离子机制。结果显示:(1)白藜芦醇甙(50和100μmol/L)可剂量依赖性地缩短正常乳头状肌动作电位复极化50%时间(APD50)和90%时间(APD90)(P<0.01)。白藜芦醇甙对正常乳头状肌静息电位(resting potential,RP)、动作电位幅值(amplitude of action potential,APA)、超射值(overshoot,OS)和0期最大上升速度(Vmax)无影响(P>0.05)。(2)对部分去极化的乳头状肌,白藜芦醇甙(50μmol/L)不但缩短APD50和APD90,而且还降低动作电位OS、APA和Vmax(P<0.05)。(3)ATP敏感钾通道阻断剂格列本脲(10μmol/L)可部分阻断白藜芦醇甙(50μmol/L)的电生理效应。(4)一氧化氮合酶抑制剂L-NAME(1 mmol/L)对白藜芦醇甙的上述效应无影响。(5)白藜芦醇甙(25、50、75、100μmol/L)可浓度依...     

心室不同部位起搏对正常犬和扩张型心肌病心力衰竭犬模型在体心肌跨室壁复极离散的影响

实验以正常犬和扩张型心肌病心力衰竭犬(dilated cardiomyopathy congestive heart failure,DCM-CHF)模型为对象、以心肌跨室壁复极离散的相关参数为指标,研究左心室心外膜起搏、双心室起搏(模拟临床上心室再同步治疗的方法)后的心肌电生理特性变化。实验以快速右心室起搏的方法制备DCM-CHF犬模型;正常犬和DCM-CHF犬均经射频消融希氏束制备三度房室传导阻滞模型;采用同步记录犬体表心电图和内膜下、中层、外膜下三层心肌单相动作电位(monophasic action potentials,MAP)的方法,测定不同部位起搏时的QT间期、Tpeak-Tend(Tp-Te)间期和三层心肌的单相动作电位时程(MAP duration,MAPD)、跨室壁复极离散度(transmural dispersion of repolaization,TDR)。结果显示:在正常犬,左室心外膜与双心室起搏后三层心肌的MAPD均延长,同时TDR增大(左室心外膜起搏47.16 ms、双心室起搏37.54 ms、右室心内膜起搏26.75 ms,P<0.001),体表心电图Tp-Te间期的变化与之平行;在DCM-CHF犬较正常犬已表现出中层心肌MAPD延长(276.30 ms vs 257.35 ms,P<0.0001)和TDR(33.8 ms vs 27.58 ms,P=0.002)增大的基础上,左室心外膜参与起搏后仍进一步使三层心肌的MAPD延长和TDR增大。研究结果提示,左室心外膜起搏和双心室起搏后使内膜下、中层     

银杏苦内酯B对缺血豚鼠心室肌动作电位、L-型钙电流和延迟整流钾电流的作用

目的:研究银杏苦内酯B对正常和缺血心室肌细胞动作电位(action potential,AP),L-型钙电流(L-type calcium current,ICa-L)、延迟整流钾电流(Delayed Rectifier Currennt,IK)的影响.方法:用常规细胞内微电极方法记录豚鼠心室肌细胞动作电位,用全细胞膜片钳技术记录游离心室肌细胞离子流.结果:①在生理条件下,银杏苦内酯B可缩短心室肌细胞动作电位时程 (action potential duration,APD),但对AP其他参数无影响,银杏苦内酯B可增大IK,呈浓度依赖性,但对ICa-L无显著作用;②在缺血条件下,APD50、APD90明显缩短,RP、APA减小,Vmax减慢,而银杏苦内酯B则可延缓和减轻缺血所引起上述参数的变化;3.在缺血条件下,IK和ICa-L均受到抑制,但加入银杏苦内酯B后可逆转缺血所造成这两种离子流的减小.结论:银杏苦内酯B可对抗心肌缺血所引起的心肌电生理的变化,提示银杏苦内酯B可预防心律失常的发生.     

兔右室流出道室速对L型钙通道α1c蛋白表达的影响

目的：通过建立右室流出道室速（RVOT-VT）的动物模型,以L型钙通道α1c蛋白作为观察指标,观察RVOT-VT时对L型钙通道α1c蛋白表达的影响,旨在探讨L型钙通道在RVOT-VT中的作用。方法：健康新西兰大耳白兔30只,随机分三组,分别为对照组（10只）、室速组（10只）、室速加维拉帕米干预组（10只）。采用免疫组织化学的方法对三组实验动物的右室流出道心肌组织进行L型钙通道cdc蛋白表达的检测。结果：1、高频刺激主动脉与肺动脉交界处均诱发了起源于右室流出道部位的室速,且室速持续时间均大于4小时。2、室速组L型钙通道α1c蛋白表达量明显下降;干预组L型钙通道α1cc蛋白的表达下降,但与对照组比较无显著差异。结论：1、室速组的心肌L型钙通道α1c蛋白表达发生了重构。2、维拉帕米可以改善心肌L型钙通道α1c蛋白的重构。3、L型钙通道在RVOT-VT发生、持续中起重要作用。     

2型糖尿病住院患者心脏自主神经病变的影响因素及对夜间AH和夜间VA的影响

摘要 目的：分析2型糖尿病（T2DM）住院患者心脏自主神经病变（CAN）的影响因素,探讨其对夜间无症状低血糖（AH）和夜间室性心律失常（VA）的影响。方法：选取2020年1月～2022年7月肇庆医学高等专科学校附属医院收治的174例T2DM患者,根据是否发生CAN分为CAN组和非CAN组,采用多因素Logistic回归分析T2DM住院患者CAN的影响因素。采用动态血糖监测系统监测夜间AH发生情况,动态心电图监测夜间VA发生情况。结果：174例T2DM患者CAN发生率为37.93%（66/174）。单因素分析显示,CAN组年龄大于非CAN组,病程长于非CAN组,收缩压、舒张压、糖化血红蛋白（HbA1c）、稳态模型评估-胰岛素抵抗（HOMA-IR）、血尿酸和微血管并发症比例高于非CAN组（P＜0.05）。多因素Logistic回归分析显示,年龄增加、病程延长、HOMA-IR升高、血尿酸升高、微血管并发症为T2DM住院患者CAN的独立危险因素（P＜0.05）。与非CAN组比较,CAN组夜间AH、VA发生率增加（P＜0.05）。结论：年龄、病程、HOMA-IR、血尿酸和微血管并发症为T2DM住院患者CAN的影响因素,CAN增加了T2DM住院患者夜间AH和夜间VA的发生率,早期筛查CAN可能有助于降低T2DM住院患者夜间AH和夜间VA的发生风险。     

诱发性2型糖尿病小鼠模型与自发性db/db小鼠特性的比较

目的建立诱发性2型糖尿病小鼠模型,并将其与自发性2型糖尿病小鼠db/db进行比较分析。客观评价两种2型糖尿病小鼠模型,为糖尿病研究中动物模型的选择与实际应用提供实验依据。方法高脂饲料喂养C57BL/6J小鼠4周,腹腔连续3次注射STZ,建立诱发性2型糖尿病小鼠模型。感染后4周,大体肉眼观察小鼠的肝脏、肾脏,测定糖耐量,血清生化指标及血清细胞因子IL-2、IL-4、IL-6、IFN-γ、TNF-α、IL-17、IL-10表达量,将其与同龄的自发性2型糖尿病小鼠db/db进行比较分析。结果肉眼观察发现,两组模型小鼠的肝脏、肾脏与对照组均具有明显差异。糖耐量分析中,两组模型小鼠与对照组小鼠各时间点的血糖值均具有统计学差异（P〈0.05）,耐糖功能低下,两组模型小鼠间血糖值无统计学差异。血液生化指标中,与对照组小鼠相比,两组模型小鼠GLU、CHOL、LDLC明显升高（P〈0.05）;两组模型小鼠相互比较,诱发性2型糖尿病小鼠血脂水平较高（P〈0.05）。免疫指标比较显示：除IL-2外,两组模型小鼠血清中细胞因子水平均较对照组小鼠明显升高（P〈0.05）,而db/db小鼠血清中细胞因子表达较诱发性糖尿病小鼠高,其中IL-6、IFN-γ、TNF-α具有显著性差异（P〈0.05）。结论两组2型糖尿病模型小鼠均在一定程度上模拟了人类糖尿病患者症状,但由于糖尿病产生的原因不同而存在着一定的差异,研究者可根据实际需要参照相关数据进行选择。     

Proteomic analyses of transgenic LQT1 and LQT2 rabbit hearts elucidate an increase in expression and activity of energy producing enzymes

Various biochemical and genomic mechanisms are considered to be a hallmark of metabolic remodeling in the stressed heart, including the hypertrophied and failing heart. In this study, we used quantitative proteomic 2-D Fluorescence Difference In-Gel Electrophoresis (2-D DIGE) in conjunction with mass spectrometry to demonstrate differential protein expression in the hearts of transgenic rabbit models of Long QT Syndrome 1 (LQT1) and Long QT Syndrome 2 (LQT2) as compared to littermate controls (LMC). The results of our proteomic analysis revealed upregulation of key metabolic enzymes involved in all pathways associated with ATP generation, including creatine kinase in both LQT1 and LQT2 rabbit hearts. Additionally, the expression of lamin-A protein was increased in both LQT1 and LQT2 rabbit hearts as was the expression of mitochondrial aldehyde dehydrogenase and desmoplakin in LQT1 and LQT 2 rabbit hearts, respectively. Results of the proteomic analysis also demonstrated down regulation in the expression of protein disulfide-isomerase A3 precuorsor and dynamin-like 120 kDa protein (mitochondrial) in LQT1, and of alpha-actinin 2 in LQT2 rabbit hearts. Up regulation of the expression of the enzymes associated with ATP generation was substantiated by the results of selective enzyme assays in LQT1 and LQT2 hearts, as compared to LMC, which revealed increases in the activities of glycogen phosphorylase (+50%, +65%, respectively), lactate dehydrogenase (+25%, +25%) pyruvate dehydrogenase (+31%, +22%), and succinate dehydrogenase (+32%, +60%). The activity of cytochrome c-oxidase, a marker for the mitochondrial function was also found to be significantly elevated (+80%) in LQT1 rabbit hearts as compared with LMC. Western blot analysis in LQT1 and LQT2 hearts compared to LMC revealed an increase in the expression of very-long chain-specific acyl-CoA dehydrogenase (+35%, +33%), a rate-limiting enzymes in β-oxidation of fatty acids. Collectively, our results demonstrate similar increases in the expression and activities of key ATP-generating enzymes in LQT1 and LQT2 rabbit hearts, suggesting an increased demand, and in turn, increased energy supply across the entire metabolic pathway by virtue of the upregulation of enzymes involved in energy generation.     

Gender disparities in torsade de pointes ventricular tachycardia

Background Gender disparities in the incidence of torsade de pointes (TdP) ventricular tachycardia exist, but the mechanisms in humans are unresolved. We addressed this issue using a mathematical model of a human ventricular cell. MethodsWe implemented gender differences in the Priebe-Beuckelmann model cell by modifying the amplitudes of the L-type Ca²⁺ current (I_Ca,L), transient outward K₊ current (I_to), and rapid component of the delayed rectifier K₊current (I_Kr), according to experimental data from animal male and female hearts. Gender disparities in electrical heterogeneity between transmural layers (subepicardium, midmyocardium, subendocardium) were implemented by modifying various ion currents according to experimental data. ResultsAction potentials in female cells have longer durations and steeper duration versus frequency relationships than male cells. In the female cells, electrical heterogeneity between transmural layers is larger and the susceptibility to early afterdepolarisations is higher than in male cells. ConclusionGender-related differences in I_Ca,L, I_to, and I_Kr may explain the gender disparities in human cardiac electrophysiology. Female cells have an increased susceptibility to early afterdepolarisations following mild reductions in net repolarising forces. Combined with their greater electrical heterogeneity, this renders them more vulnerable to TdP. (Neth Heart J 2007;15:405-11.)     

Increasing I(Ks) corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy

Excessive action potential (AP) prolongation and early afterdepolarizations (EAD) are triggers of malignant ventricular arrhythmias. A slowly activating delayed rectifier K+ current (I(Ks)) is important for repolarization of ventricular AP. We examined the effects of I(Ks) activation by a new benzodiazepine (L3) on the AP of control, dofetilide-treated, and hypertrophied rabbit ventricular myocytes. In both control and hypertrophied myocytes, L3 activated I(Ks) via a negative shift in the voltage dependence of activation and a slowing of deactivation. L3 had no effect on L-type Ca(2+) current or other cardiac K+ currents tested. L3 shortened AP of control, dofetilide-treated, and hypertrophied myocytes more at 0.5 than 2 Hz. Selective activation of I(Ks) by L3 attenuates prolonged AP and eliminated EAD induced by rapidly activating delayed rectifier K+ current inhibition in control myocytes at 0.5 Hz and spontaneous EAD in hypertrophied myocytes at 0.2 Hz. Pharmacological activation of I(Ks) is a promising new strategy to suppress arrhythmias resulting from excessive AP prolongation in patients with certain forms of long QT syndrome or cardiac hypertrophy and failure.     

Dispersions of repolarization and ventricular arrhythmogenesis: Lessons from animal models

Sudden cardiac death resulting from ventricular arrhythmogenesis is a leading cause of mortality in the developed world, accounting for up to 400,000 deaths per year in the US alone. Within the past forty years we have taken considerable leaps forward in our understanding of the causes and mechanisms underlying cardiac arrhythmias, particularly in the setting of inherited and acquired dysfunctions in ionic currents which constitute human long QT syndrome (LQTS). Impaired repolarization seen in LQTS commonly gives rise to an altered dispersion of repolarization, which is considered to provide the functional substrate necessary for the perpetuation of lethal arrhythmias. This review examines the bases for arrhythmias arising from repolarization heterogeneities and explores the applicability of the genetically amenable mouse for the study of arrhythmias arising from such mechanisms.     

Changes in action potentials and intracellular ionic homeostasis in a ventricular cell model related to a persistent sodium current in SCN5A mutations underlying LQT3

In LQT3 patients, SCN5A mutations induce ultraslow inactivation of a small fraction of the hNav1.5 current, i.e. persistent Na⁺ current (I_pNa). We explored the time course of effects of such a change on the intracellular ionic homeostasis in a model of guinea-pig cardiac ventricular cell [Pasek, M., Simurda, J., Orchard, C.H., Christé, G., 2007b. A model of the guinea-pig ventricular cardiomyocyte incorporating a transverse–axial tubular system. Prog. Biophys. Mol. Biol., this issue]. Sudden addition of I_pNa prevented action potential (AP) repolarization when its conductance (g_pNa) exceeded 0.12% of the maximal conductance of fast I_Na (g_Na). With g_pNa at 0.1% g_Na, the AP duration at 90% repolarization (APD₉₀) was initially lengthened to 2.6-fold that in control. Under regular stimulation at 1 Hz it shortened progressively to 1.37-fold control APD₉₀, and intracellular [Na⁺]_i increased by 6% with a time constant of 106 s. Further increasing g_pNa to 0.2% g_Na caused an immediate increase in APD₉₀ to 5.7-fold that in control, which decreased to 2.2-fold that in control in 30 s stimulation at 1 Hz. At this time diastolic [Na⁺]_i and [Ca²⁺]_i were, respectively, 34% and 52% higher than in control and spontaneous erratic SR Ca release occurred.

In the presence of I_pNa causing 46% lengthening of APD₉₀, the model cell displayed arrhythmogenic behaviour when external [K⁺] was lowered to 5 mM from an initial value at 5.4 mM. By contrast, when K⁺ currents I_Kr and I_Ks were lowered in the model cell to produce the same lengthening of APD₉₀, no proarrhythmic behaviour was observed, even when external [K⁺] was lowered to 2.5 mM.     

Gender-related differences in proliferative response of cardiac fibroblasts to hypoxia

Ischemic heart disease is more prevalent in men than in women. The remodeling of extracellular matrix, is a structural correlate of heart failure of ischemic origin and proliferation of cardiac fibroblasts is a key factor in this remodeling. We asked if proliferative response of male and female cardiac fibroblasts is differentially susceptible to hypoxia. DNA synthesis, using 3H-thymidine incorporation was compared under hypoxia (2% O₂) in cardiac fibroblasts obtained from adult, age-matched male and female rat heart. In female cells DNA synthesis remained unchanged under hypoxia and this resistance was dependent on tyrosine kinase activation, as it was abolished in the presence of genistein, a tyrosine kinase inhibitor. Male cells, on the other hand, were susceptible to hypoxia and their DNA synthesis was reduced significantly (70%, (p < 0.0001). This effect was partially reversed by inhibition of tyrosine kinase. Western analysis showed a higher abundance of tyrosine phosphorylated proteins in male cells compared to female cells as well as differences in molecular weight of basal and hypoxia-induced tyrosine-phosphorylated proteins between male and female cells. The presence of estrogen (17- estradiol, 10 nM) altered the response of both cells to hypoxia. In female cells the combined effect of hypoxia and estrogen led to inhibition of DNA synthesis, whereas in male cells estrogen partially reversed the hypoxia-induced inhibition of DNA synthesis (37% (p < 0.01) inhibition in the presence of estrogen vs. 70% (p < 0.0001) inhibition in the absence of estrogen). The effects of estrogen in male and female cells were mediated via estrogen receptors as they were reversed by the pure anti-estrogen, ICI 182,780. Western analysis of cell lysate showed hypoxia-induced increase in the level of estrogen receptor in both male and female cells. Gel shift analysis showed hypoxia-induced increase in cytoplasmic ERE (estrogen response element)-binding activity and decrease in nuclear ERE-binding in male cells. In female cells cytoplasmic and nuclear ERE-binding activities remained unchanged under hypoxia. Together, these data demonstrate that while female cells are resistant to hypoxia-induced inhibition in DNA synthesis, male cells are susceptible; intracellular pathways involving tyrosine phosphorylation are involved in the response of both cells; and estrogen, via estrogen-receptor-dependent mechanisms, differentially alters the response of male and female cells to hypoxia.     

3D current-voltage-time surfaces unveil critical repolarization differences underlying similar cardiac action potentials: A model study

The number of mathematical models of cardiac cellular excitability is rapidly growing, and compact graphical representations of their properties can make new acquisitions available for a broader range of scientists in cardiac field. Particularly, the intrinsic over-determination of the model equations systems when fitted only to action potential (AP) waveform and the fact that they are frequently tuned on data covering only a relatively narrow range of dynamic conditions, often lead modellers to compare very similar AP profiles, which underlie though quite different excitable properties. In this study I discuss a novel compact 3D representation of the cardiac cellular AP, where the third dimension represents the instantaneous current–voltage profile of the membrane, measured as repolarization proceeds. Measurements of this type have been used previously for in vivo experiments, and are adopted here iteratively at a very high time, voltage, current-resolution on (i) the same human ventricular model, endowed with two different parameters sets which generate the same AP waveform, and on (ii) three different models of the same human ventricular cell type. In these 3D representations, the AP waveforms lie at the intersection between instantaneous time–voltage–current surfaces and the zero-current plane. Different surfaces can share the same intersection and therefore the same AP; in these cases, the morphology of the current surface provides a compact view of important differences within corresponding repolarization dynamics.Refractory period, supernormal excitability window, and extent of repolarization reserve can be visualized at once. Two pivotal dynamical properties can be precisely assessed, i.e. all-or-nothing repolarization window and membrane resistance during recovery. I discuss differences in these properties among the membranes under study, and show relevant implications for cardiac cellular repolarization.     

Ventricular repolarization: an overview of (patho)physiology, sympathetic effects and genetic aspects

Most textbook knowledge on ventricular repolarization is based on animal data rather than on data from the in vivo human heart. Yet, these data have been extrapolated to the human heart, often without an appropriate caveat. Here, we review multiple aspects of repolarization, from basic membrane currents to cellular aspects including extrinsic factors such as the effects of the sympathetic nervous system. We critically discuss some mechanistic aspects of the genesis of the T-wave of the ECG in the human heart.

Obviously, the T-wave results from the summation of repolarization all over the heart. The T-wave in a local electrogram ideally reflects local repolarization. The repolarization moment is composed of the moment of local activation plus local action potential duration (APD) at 90% repolarization (APD₉₀). The duration of the latter largely depends on the balance between L-type Ca²⁺ current and the delayed rectifier currents. Generally speaking, there is an inverse relationship between local activation time and local APD₉₀, leading to less dispersion in repolarization moments than in activation moments or in APD₉₀. In transmural direction, the time needed for activation from endocardium toward epicardium has been considered to be overcompensated by shorter APD₉₀ at the epicardium, leading to the earliest repolarization at the subepicardium. In addition, mid-myocardial cells would display the latest repolarization moments. The sparse human data available, however, do not show any transmural dispersion in repolarization moment. Also, the effect of adrenergic stimulation on APD₉₀ has been studied mainly in animals. Again, sparse human data suggest that the effect of adrenergic stimulation is different in the human heart compared to many other mammalian hearts. Finally, aspects of the long QT syndrome are discussed, because this intrinsic genetic disease results from repolarization disorders with extrinsic aspects.     

Presence of Macrovolt T Wave Alternans and Short Coupled PVC Simultaneously in a Patient with Long QT Syndrome

This report presents a patient with macrovolt T wave alternans, PVC with R on T or a long-short sequence followed by torsades de pointes.