scholarly journals Co-expression of calcium channels and delayed rectifier potassium channels protects the heart from proarrhythmic events

2019 ◽  
Author(s):  
Sara Ballouz ◽  
Melissa M Mangala ◽  
Matthew D Perry ◽  
Stewart Heitmann ◽  
Jesse A Gillis ◽  
...  
Keyword(s):  
Ion Channel ◽  
Cardiac Electrophysiology ◽  
Meta Analysis ◽  
Surrogate Marker ◽  
Induced Pluripotent Stem Cell ◽  
Delayed Rectifier ◽  
Cardiac Electrical Activity ◽  
Channel Expression ◽  
Induced Pluripotent ◽  
Electrical Signaling

AbstractCardiac electrical activity is controlled by the carefully orchestrated activity of more than a dozen different ion conductances. Yet, there is considerable variability in cardiac ion channel expression levels both within and between subjects. In this study we tested the hypothesis that variations in ion channel expression between individuals are not random but rather there are modules of co-expressed genes and that these modules make electrical signaling in the heart more robust.Meta-analysis of 3653 public RNA-Seq datasets identified a strong correlation between expression of CACNA1C (L-type calcium current, ICaL) and KCNH2 (rapid delayed rectifier K+ current, IKr), which was verified in mRNA extracted from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). In silico modeling, validated with functional measurements in hiPSC-CM, indicates that the co-expression of CACNA1C and KCNH2 limits the variability in action potential duration and reduces susceptibility to early afterdepolarizations, a surrogate marker for pro-arrhythmia.Impact StatementCoexpressed levels of potassium and calcium ion channel genes in the heart encode more robust cardiac electrophysiology and provide insights into genetic basis of arrhythmic risk

scholarly journals Ion Channel Expression and Characterization in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Zhihan Zhao ◽  
Huan Lan ◽  
Ibrahim El-Battrawy ◽  
Xin Li ◽  
Fanis Buljubasic ◽  
...  
Keyword(s):  
Stem Cell ◽  
Ion Channels ◽  
Ion Channel ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Biological Study ◽  
Adrenergic Stimulation ◽  
Cell Therapies ◽  
Channel Expression ◽  
Induced Pluripotent

Background. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are providing new possibilities for the biological study, cell therapies, and drug discovery. However, the ion channel expression and functions as well as regulations in hiPSC-CMs still need to be fully characterized. Methods. Cardiomyocytes were derived from hiPS cells that were generated from two healthy donors. qPCR and patch clamp techniques were used for the study. Results. In addition to the reported ion channels, INa, ICa-L, ICa-T, If, INCX, IK1, Ito, IKr, IKs IKATP, IK-pH, ISK1–3, and ISK4, we detected both the expression and currents of ACh-activated (KACh) and Na+-activated (KNa) K+, volume-regulated and calcium-activated (Cl-Ca) Cl−, and TRPV channels. All the detected ion currents except IK1, IKACh, ISK, IKNa, and TRPV1 currents contribute to AP duration. Isoprenaline increased ICa-L, If, and IKs but reduced INa and INCX, without an effect on Ito, IK1, ISK1–3, IKATP, IKr, ISK4, IKNa, ICl-Ca, and ITRPV1. Carbachol alone showed no effect on the tested ion channel currents. Conclusion. Our data demonstrate that most ion channels, which are present in healthy or diseased cardiomyocytes, exist in hiPSC-CMs. Some of them contribute to action potential performance and are regulated by adrenergic stimulation.

scholarly journals Co-expression of calcium and hERG potassium channels reduces the incidence of proarrhythmic events

2020 ◽  
Author(s):  
Sara Ballouz ◽  
Melissa M Mangala ◽  
Matthew D Perry ◽  
Stewart Heitmann ◽  
Jesse A Gillis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Electrical Activity ◽  
Ion Channel ◽  
In Silico ◽  
Large Scale ◽  
Heart Function ◽  
Surrogate Marker ◽  
Heart Tissue ◽  
Delayed Rectifier ◽  
Cardiac Electrical Activity

Abstract Aims Cardiac electrical activity is extraordinarily robust. However, when it goes wrong it can have fatal consequences. Electrical activity in the heart is controlled by the carefully orchestrated activity of more than a dozen different ion conductances. While there is considerable variability in cardiac ion channel expression levels between individuals, studies in rodents have indicated that there are modules of ion channels whose expression co-vary. The aim of this study was to investigate whether meta-analytic co-expression analysis of large-scale gene expression datasets could identify modules of co-expressed cardiac ion channel genes in human hearts that are of functional importance. Methods and results Meta-analysis of 3653 public human RNA-seq datasets identified a strong correlation between expression of CACNA1C (L-type calcium current, ICaL) and KCNH2 (rapid delayed rectifier K+ current, IKr), which was also observed in human adult heart tissue samples. In silico modelling suggested that co-expression of CACNA1C and KCNH2 would limit the variability in action potential duration seen with variations in expression of ion channel genes and reduce susceptibility to early afterdepolarizations, a surrogate marker for proarrhythmia. We also found that levels of KCNH2 and CACNA1C expression are correlated in human-induced pluripotent stem cell-derived cardiac myocytes and the levels of CACNA1C and KCNH2 expression were inversely correlated with the magnitude of changes in repolarization duration following inhibition of IKr. Conclusion Meta-analytic approaches of multiple independent human gene expression datasets can be used to identify gene modules that are important for regulating heart function. Specifically, we have verified that there is co-expression of CACNA1C and KCNH2 ion channel genes in human heart tissue, and in silico analyses suggest that CACNA1C–KCNH2 co-expression increases the robustness of cardiac electrical activity.

Hormones and sex differences: changes in cardiac electrophysiology with pregnancy

2016 ◽  
Vol 130 (10) ◽  
pp. 747-759 ◽  
Author(s):  
Glenna C.L. Bett
Keyword(s):  
Postpartum Period ◽  
Cardiac Electrophysiology ◽  
Delayed Rectifier ◽  
Hormonal Changes ◽  
Large Variability ◽  
Early Symptom ◽  
Cardiac Electrical Activity ◽  
Channel Expression ◽  
Electrocardiogram Ecg ◽  
Ionic Basis

Disruption of cardiac electrical activity resulting in palpitations and syncope is often an early symptom of pregnancy. Pregnancy is a time of dramatic and dynamic physiological and hormonal changes during which numerous demands are placed on the heart. These changes result in electrical remodelling which can be detected as changes in the electrocardiogram (ECG). This gestational remodelling is a very under-researched area. There are no systematic large studies powered to determine changes in the ECG from pre-pregnancy, through gestation, and into the postpartum period. The large variability between patients and the dynamic nature of pregnancy hampers interpretation of smaller studies, but some facts are consistent. Gestational cardiac hypertrophy and a physical shift of the heart contribute to changes in the ECG. There are also electrical changes such as an increased heart rate and lengthening of the QT interval. There is an increased susceptibility to arrhythmias during pregnancy and the postpartum period. Some changes in the ECG are clearly the result of changes in ion channel expression and behaviour, but little is known about the ionic basis for this electrical remodelling. Most information comes from animal models, and implicates changes in the delayed-rectifier channels. However, it is likely that there are additional roles for sodium channels as well as changes in calcium homoeostasis. The changes in the electrical profile of the heart during pregnancy and the postpartum period have clear implications for the safety of pregnant women, but the field remains relatively undeveloped.

scholarly journals Contribution of two-pore K+ channels to cardiac ventricular action potential revealed using human iPSC-derived cardiomyocytes

2017 ◽  
Vol 312 (6) ◽  
pp. H1144-H1153 ◽  
Author(s):  
Sam Chai ◽  
Xiaoping Wan ◽  
Drew M. Nassal ◽  
Haiyan Liu ◽  
Christine S. Moravec ◽  
...  
Keyword(s):  
Action Potential ◽  
Expression Profile ◽  
Cardiac Electrophysiology ◽  
Human Heart ◽  
Induced Pluripotent Stem Cell ◽  
Heart Tissue ◽  
Induced Pluripotent ◽  
Interfering Rna ◽  
Human Ipsc ◽  
Physiological Systems

Two-pore K+ (K2p) channels have been described in modulating background conductance as leak channels in different physiological systems. In the heart, the expression of K2p channels is heterogeneous with equivocation regarding their functional role. Our objective was to determine the K2p expression profile and their physiological and pathophysiological contribution to cardiac electrophysiology. Induced pluripotent stem cells (iPSCs) generated from humans were differentiated into cardiomyocytes (iPSC-CMs). mRNA was isolated from these cells, commercial iPSC-CM (iCells), control human heart ventricular tissue (cHVT), and ischemic (iHF) and nonischemic heart failure tissues (niHF). We detected 10 K2p channels in the heart. Comparing quantitative PCR expression of K2p channels between human heart tissue and iPSC-CMs revealed K2p1.1, K2p2.1, K2p5.1, and K2p17.1 to be higher expressed in cHVT, whereas K2p3.1 and K2p13.1 were higher in iPSC-CMs. Notably, K2p17.1 was significantly lower in niHF tissues compared with cHVT. Action potential recordings in iCells after K2p small interfering RNA knockdown revealed prolongations in action potential depolarization at 90% repolarization for K2p2.1, K2p3.1, K2p6.1, and K2p17.1. Here, we report the expression level of 10 human K2p channels in iPSC-CMs and how they compared with cHVT. Importantly, our functional electrophysiological data in human iPSC-CMs revealed a prominent role in cardiac ventricular repolarization for four of these channels. Finally, we also identified K2p17.1 as significantly reduced in niHF tissues and K2p4.1 as reduced in niHF compared with iHF. Thus, we advance the notion that K2p channels are emerging as novel players in cardiac ventricular electrophysiology that could also be remodeled in cardiac pathology and therefore contribute to arrhythmias. NEW & NOTEWORTHY Two-pore K+ (K2p) channels are traditionally regarded as merely background leak channels in myriad physiological systems. Here, we describe the expression profile of K2p channels in human-induced pluripotent stem cell-derived cardiomyocytes and outline a salient role in cardiac repolarization and pathology for multiple K2p channels.

scholarly journals Cardiac Transmembrane Ion Channels and Action Potentials: Cellular Physiology and Arrhythmogenic Behavior

2020 ◽  
Author(s):  
András Varró ◽  
Jakub Tomek ◽  
Norbert Nagy ◽  
Laszlo Virag ◽  
Elisa Passini ◽  
...  
Keyword(s):  
Ion Channel ◽  
Action Potentials ◽  
Cardiac Electrophysiology ◽  
Current Knowledge ◽  
Animal Experiments ◽  
Cardiac Cells ◽  
Cellular Mechanisms ◽  
Electrophysiological Properties ◽  
Channel Expression ◽  
Ionic Mechanisms

Cardiac arrhythmias are among the leading causes of mortality. They often arise from alterations in the electrophysiological properties of cardiac cells, and their underlying ionic mechanisms. It is therefore critical to further unravel the patho-physiology of the ionic basis of human cardiac electrophysiology in health and disease. In the first part of this review, current knowledge on the differences in ion channel expression and properties of the ionic processes that determine the morphology and properties of cardiac action potentials and calcium dynamics from cardiomyocytes in different regions of the heart are described. Then the cellular mechanisms promoting arrhythmias in congenital or acquired conditions of ion channel function (electrical remodelling) are discussed. The focus is human relevant findings obtained with clinical, experimental and computational studies, given that interspecies differences make the extrapolation from animal experiments to the human clinical settings difficult. Deepening the understanding of the diverse patholophysiology of human cellular electrophysiology will help developing novel and effective antiarrhythmic strategies for specific subpopulations and disease conditions.

Chronic heart rate reduction remodels ion channel transcripts in the mouse sinoatrial node but not in the ventricle

2006 ◽  
Vol 24 (1) ◽  
pp. 4-12 ◽  
Author(s):  
Anne-Laure Leoni ◽  
Céline Marionneau ◽  
Sophie Demolombe ◽  
Sabrina Le Bouter ◽  
Matteo E. Mangoni ◽  
...  
Keyword(s):  
Heart Rate ◽  
Ion Channel ◽  
Clustering Analysis ◽  
Connexin 43 ◽  
Sinoatrial Node ◽  
Rt Pcr ◽  
Cardiac Electrical Activity ◽  
Channel Expression ◽  
Freely Moving ◽  
Α Subunits

We investigated the effects of chronic and moderate heart rate (HR) reduction on ion channel expression in the mouse sinoatrial node (SAN) and ventricle. Ten-week-old male C57BL/6 mice were treated twice daily with either vehicle or ivabradine at 5 mg/kg given orally during 3 wk. The effects of HR reduction on cardiac electrical activity were investigated in anesthetized mice with serial ECGs and in freely moving mice with telemetric recordings. With the use of high-throughput real-time RT-PCR, the expression of 68 ion channel subunits was evaluated in the SAN and ventricle at the end of the treatment period. In conscious mice, ivabradine induced a mean 16% HR reduction over a 24-h period that was sustained over the 3-wk administration. Other ECG parameters were not modified. Two-way hierarchical clustering analysis of gene expression revealed a separation of ventricles from SANs but no discrimination between treated and untreated ventricles, indicating that HR reduction per se induced limited remodeling in this tissue. In contrast, SAN samples clustered in two groups depending on the treatment. In the SAN from ivabradine-treated mice, the expression of nine ion channel subunits, including Navβ1 (−25%), Cav3.1 (−29%), Kir6.1 (−28%), Kvβ2 (−41%), and Kvβ3 (−30%), was significantly decreased. Eight genes were significantly upregulated, including K+ channel α-subunits (Kv1.1, +30%; Kir2.1, +29%; Kir3.1, +41%), hyperpolarization-activated cation channels (HCN2, +24%; HCN4, +52%), and connexin 43 (+26%). We conclude that reducing HR induces a complex remodeling of ion channel expression in the SAN but has little impact on ion channel transcripts in the ventricle.

scholarly journals Potential Consequences of the Red Blood Cell Storage Lesion on Cardiac Electrophysiology

2020 ◽  
Vol 9 (21) ◽  
Author(s):  
Marissa Reilly ◽  
Chantal D. Bruno ◽  
Tomas M. Prudencio ◽  
Nina Ciccarelli ◽  
Devon Guerrelli ◽  
...  
Keyword(s):  
Stem Cell ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Cardiac Electrophysiology ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Cardiac Complications ◽  
Blood Products ◽  
Storage Lesion ◽  
Induced Pluripotent

Background The red blood cell (RBC) storage lesion is a series of morphological, functional, and metabolic changes that RBCs undergo following collection, processing, and refrigerated storage for clinical use. Since the biochemical attributes of the RBC unit shifts with time, transfusion of older blood products may contribute to cardiac complications, including hyperkalemia and cardiac arrest. We measured the direct effect of storage age on cardiac electrophysiology and compared it with hyperkalemia, a prominent biomarker of storage lesion severity. Methods and Results Donor RBCs were processed using standard blood‐banking techniques. The supernatant was collected from RBC units, 7 to 50 days after donor collection, for evaluation using Langendorff‐heart preparations (rat) or human induced pluripotent stem cell–derived cardiomyocytes. Cardiac parameters remained stable following exposure to “fresh” supernatant from red blood cell units (day 7: 5.8±0.2 mM K + ), but older blood products (day 40: 9.3±0.3 mM K + ) caused bradycardia (baseline: 279±5 versus day 40: 216±18 beats per minute), delayed sinus node recovery (baseline: 243±8 versus day 40: 354±23 ms), and increased the effective refractory period of the atrioventricular node (baseline: 77±2 versus day 40: 93±7 ms) and ventricle (baseline: 50±3 versus day 40: 98±10 ms) in perfused hearts. Beating rate was also slowed in human induced pluripotent stem cell–derived cardiomyocytes after exposure to older supernatant from red blood cell units (−75±9%, day 40 versus control). Similar effects on automaticity and electrical conduction were observed with hyperkalemia (10–12 mM K + ). Conclusions This is the first study to demonstrate that “older” blood products directly impact cardiac electrophysiology, using experimental models. These effects are likely caused by biochemical alterations in the supernatant from red blood cell units that occur over time, including, but not limited to hyperkalemia. Patients receiving large volume and/or rapid transfusions may be sensitive to these effects.

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