Increased susceptibility to hypoxia of prolonged action potential duration in ventricular papillary muscles from diabetic rats

Diabetes ◽  
1990 ◽  
Vol 39 (12) ◽  
pp. 1485-1489 ◽  
Author(s):  
M. Aomine ◽  
S. Nobe ◽  
M. Arita
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Diabetic Rats ◽  
Papillary Muscles ◽  
Prolonged Action ◽  
Prolonged Action Potential Duration ◽  
Increased Susceptibility

scholarly journals Human Cardiac Mesenchymal Stem Cells Remodel in Disease and Can Regulate Arrhythmia Substrates

2020 ◽  
Vol 13 (10) ◽  
Author(s):  
Prasongchai Sattayaprasert ◽  
Sunil K. Vasireddi ◽  
Emre Bektik ◽  
Oju Jeon ◽  
Mohammad Hajjiri ◽  
...  
Keyword(s):  
Stem Cells ◽  
Action Potential ◽  
Induced Pluripotent Stem Cells ◽  
Cardiac Myocytes ◽  
Pluripotent Stem Cells ◽  
Action Potential Duration ◽  
Calcium Release ◽  
Prolonged Action ◽  
Induced Pluripotent ◽  
Prolonged Action Potential Duration

Background: The mesenchymal stem cell (MSC), known to remodel in disease and have an extensive secretome, has recently been isolated from the human heart. However, the effects of normal and diseased cardiac MSCs on myocyte electrophysiology remain unclear. We hypothesize that in disease the inflammatory secretome of cardiac human MSCs (hMSCs) remodels and can regulate arrhythmia substrates. Methods: hMSCs were isolated from patients with or without heart failure from tissue attached to extracted device leads and from samples taken from explanted/donor hearts. Failing hMSCs or nonfailing hMSCs were cocultured with normal human cardiac myocytes derived from induced pluripotent stem cells. Using fluorescent indicators, action potential duration, Ca2+ alternans, and spontaneous calcium release (SCR) incidence were determined. Results: Failing and nonfailing hMSCs from both sources exhibited similar trilineage differentiation potential and cell surface marker expression as bone marrow hMSCs. Compared with nonfailing hMSCs, failing hMSCs prolonged action potential duration by 24% ( P <0.001, n=15), increased Ca2+ alternans by 300% ( P <0.001, n=18), and promoted spontaneous calcium release activity (n=14, P <0.013) in human cardiac myocytes derived from induced pluripotent stem cells. Failing hMSCs exhibited increased secretion of inflammatory cytokines IL (interleukin)-1β (98%, P <0.0001) and IL-6 (460%, P <0.02) compared with nonfailing hMSCs. IL-1β or IL-6 in the absence of hMSCs prolonged action potential duration but only IL-6 increased Ca2+ alternans and promoted spontaneous calcium release activity in human cardiac myocytes derived from induced pluripotent stem cells, replicating the effects of failing hMSCs. In contrast, nonfailing hMSCs prevented Ca2+ alternans in human cardiac myocytes derived from induced pluripotent stem cells during oxidative stress. Finally, nonfailing hMSCs exhibited >25× higher secretion of IGF (insulin-like growth factor)-1 compared with failing hMSCs. Importantly, IGF-1 supplementation or anti–IL-6 treatment rescued the arrhythmia substrates induced by failing hMSCs. Conclusions: We identified device leads as a novel source of cardiac hMSCs. Our findings show that cardiac hMSCs can regulate arrhythmia substrates by remodeling their secretome in disease. Importantly, therapy inhibiting (anti–IL-6) or mimicking (IGF-1) the cardiac hMSC secretome can rescue arrhythmia substrates.

scholarly journals Comparative Analysis of Genetic Variations in the Nav1.5 Sodium Channel Subunits that Underlie Brugada Syndrome Using Patient-Specific iPSC-CMs

2020 ◽  
Author(s):  
Yue Zhu ◽  
Linlin Wang ◽  
Chang Cui ◽  
Shaojie Chen ◽  
Hongwu Chen ◽  
...  
Keyword(s):  
Action Potential ◽  
Brugada Syndrome ◽  
Action Potential Duration ◽  
Sodium Current ◽  
Genetic Variations ◽  
Patient Specific ◽  
Control Group ◽  
Prolonged Action ◽  
Ips Cell ◽  
Prolonged Action Potential Duration

Abstract Background: Brugada syndrome (BrS) is an autosomal dominant disorder that causes a high predisposition to sudden cardiac death. Several genes have been reported to be associated with BrS. Considering that the heterogeneity in clinical manifestations may result from genetic variations, the application of patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes (CMs) may help to reveal cell phenotype characteristics resulting from different genetic backgrounds. The present study was to compare the structural and electrophysiological characteristics of sodium channel subunits with different genetic variations and evaluate the safety of quinidine for use with BrS patient-specific iPSC-derived cardiomyocytes.Methods: Two BrS patient-specific iPS cell lines were constructed that carried missense mutations in SCN5A and SCN1B. One iPS cell line from a healthy volunteer was used as a control. The differentiated cardiomyocytes from the three groups were evaluated by flow cytometry, immunofluorescence staining, electron microscopy, as well as calcium transient and patch clamp analyses to assess different pathological phenotypes. Finally, we evaluated the drug responses to varying concentrations of quinidine by measuring the action potential.Results: Compared to the control group, BrS-CMs showed a significant reduction in sodium current, prolonged action potential duration and varying degrees of decreased Vmax, but no structural difference was observed. After applying different concentrations of quinidine, the disease-specific groups and the control group had a downward trend in maximal upstroke velocity, resting membrane potential and action potential amplitude, and exhibited prolonged action potential duration without increasing incidence of arrhythmic events.Conclusion: Both patient-specific iPSC-CMs recapitulated the BrS phenotype at the cellular level. Although the SCN5A variation led to a markedly lower sodium current than what was observed with the SCN1B variation, their responses to quinidine were quite similar. The present study provides an advantageous platform for exploring disease mechanisms and evaluating drug safety in vitro.

scholarly journals Cellular Mechanism of the QT Prolongation Induced by Sulpiride

2009 ◽  
Vol 28 (3) ◽  
pp. 207-212 ◽  
Author(s):  
Hyang-Ae Lee ◽  
Ki-Suk Kim ◽  
Sang-Joon Park ◽  
Eun-Joo Kim
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Plasma Concentrations ◽  
Clinical Signs ◽  
Dependent Manner ◽  
Prolonged Action ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
Severe Arrhythmia ◽  
Prolonged Action Potential Duration

In this study, the authors investigated the electrophysiological effect of sulpiride on cardiac repolarization using conventional microelectrode recording techniques in isolated canine Purkinje fibers and a whole-cell patch clamp technique in transiently transfected cells with the hERG, KCNQ1/KCNE1, KCNJ2, and SCN5A cDNA and in rat cardiac myocytes for ICa. In studies of action potential duration, 10 μM, 100 μM, 300 μM, and 1 mM sulpiride prolonged action potential duration in a concentration-dependent manner. In studies of cardiac ion channels, sulpiride did not significantly affect INa, ICa, IKs, IK1, except for IKr. Sulpiride dose-dependently decreased the hERG tail current. It is considered that the prolonged action potential duration by sulpiride was mainly the result of inhibition of the hERG channel. The data suggest that the clinical use of sulpiride is reasonable within therapeutic plasma concentrations, but all patients taking this drug should be cautiously monitored for clinical signs of long-QT syndrome and severe arrhythmia.

scholarly journals Atrial fibrillation impairs ventricular function by altering excitation-contraction coupling in the human heart

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Pabel ◽  
M Knierim ◽  
F Alebrand ◽  
M Paulus ◽  
J Herting ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Patch Clamp ◽  
Action Potential ◽  
Action Potential Duration ◽  
Negative Impact ◽  
Prolonged Action ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Prolonged Action Potential Duration

Abstract   Atrial fibrillation (AF) often co-exists in patients with heart failure (HF). Recent clinical evidence suggests that the arrhythmic component of AF alone may contribute to ventricular dysfunction. However, the pathophysiological effects of a non-tachycardic AF on the human ventricle are unknown. To investigate the effects of normofrequent AF on the human ventricle we investigated ventricular myocardium from patients with preserved ejection fraction with sinus rhythm (SR) or AF in the absence of HF (compensated hypertrophy, EF&gt;50%, matched clinical characteristics). In histological analysis we detected no difference between SR (n=9) vs. AF (n=6) regarding the amount and distribution of fibrosis. For functional investigation, Ca-handling was studied (Fura-2 AM). While systolic Ca-transient amplitude was in trend reduced in isolated human ventricular AF cardiomyocytes, we found a significantly prolonged Ca-elimination time (n=17–22 cells/4 pat.). Using caffeine application, a decreased SR Ca-load in AF was detected, which may be explained by a significant decrease in SERCA2a activity (ksys-kCaff, n=10–12/4 pat.). Patch-clamp experiments revealed a prolonged action potential duration in AF cardiomyocytes (n=5/15 cells). For the standardized evaluation of the mechanisms of persistent normofrequent arrhythmia, we simulated AF in vitro by using arrhythmic (1 Hz, 40% R-R-variability) or rhythmic (1 Hz) field stimulation. We performed contractility experiments using in-toto isolated human ventricular trabeculae from explanted human hearts. After 8h of pacing, arrhythmically stimulated human trabeculae showed a significantly reduced systolic force, an increase in diastolic tension and a prolonged relaxation (n=11–12 trabeculae/11 pat.). For studying the cellular effects of persistent normofrequent arrhythmia in a model suitable for chronic pacing (up to 7 days), we utilized human iPSC cardiomyocytes (iPSC-CM) from healthy donors (n=6). After 7 days, arrhythmic paced iPSC-CM showed a significantly reduced systolic Ca-transient amplitude, a prolonged Ca-elimination time (n=35/45 cells) as well as a reduced SR Ca-load and a trend towards a lower SERCA2a activity compared to control (n=11 cells). Confocal line-scans (Fluo-4 AM) showed an increased diastolic SR Ca-release, which might also explain the reduced SR Ca-content (n=45/35 cells). Moreover, in irregularly paced iPSC-CM we found significant increased levels of cytosolic Na (n=69 cells each) and in patch-clamp experiments a significantly prolonged action potential duration (n=14/11 cells/3 diff.). This study demonstrates that a normofrequent arrhythmic ventricular excitation as it occurs in AF impairs human ventricular myocardial function by altering cardiomyocyte excitation-contraction coupling. Thus, this study provides the first translational mechanistic characterization and the potential negative impact of isolated AF in the absence of tachycardia on the human ventricle. Funding Acknowledgement Type of funding source: None

Effects of thyroid hormone on action potential and repolarizing currents in rat ventricular myocytes

2000 ◽  
Vol 278 (2) ◽  
pp. E302-E307 ◽  
Author(s):  
Zhuo-Qian Sun ◽  
Kaie Ojamaa ◽  
William A. Coetzee ◽  
Michael Artman ◽  
Irwin Klein
Keyword(s):  
Action Potential ◽  
Cardiac Electrophysiology ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Mechanisms Of Action ◽  
Transient Outward Current ◽  
Prolonged Action ◽  
Electrophysiological Properties ◽  
Whole Cell Patch Clamp ◽  
Prolonged Action Potential Duration

Thyroid hormones play an important role in cardiac electrophysiology through both genomic and nongenomic mechanisms of action. The effects of triiodothyronine (T3) on the electrophysiological properties of ventricular myocytes isolated from euthyroid and hypothyroid rats were studied using whole cell patch clamp techniques. Hypothyroid ventricular myocytes showed significantly prolonged action potential duration (APD90) compared with euthyroid myocytes, APD90 of 151 ± 5 vs. 51 ± 8 ms, respectively. Treatment of hypothyroid ventricular myocytes with T3 (0.1 μM) for 5 min significantly shortened APD by 24% to 115 ± 10 ms. T3 similarly shortened APD in euthyroid ventricular myocytes, but only in the presence of 4-aminopyridine (4-AP), an inhibitor of the transient outward current ( I to), which prolonged the APD by threefold. Transient outward current ( I to) was not affected by the acute application of T3 to either euthyroid or hypothyroid myocytes; however, I to density was significantly reduced in hypothyroid compared with euthyroid ventricular myocytes.

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