Effects of Acute Hypernatremia on the Electrophysiology of Single Human Ventricular Cardiomyocytes: An Study.

Background: Clinical and experimental data on the cardiac effects of acute hypernatremia are scarce and inconsistent. We aimed to determine and understand the effects of different levels of acute hypernatremia on the human ventricular action potential.

Methods: We performed computer simulations using two different, very comprehensive models of the electrical activity of a single human ventricular cardiomyocyte, , the Tomek-Rodriguez model following the O'Hara-Rudy dynamic (ORd) model and the Bartolucci-Passini-Severi model as published in 2020 (known as the ToR-ORd and BPS2020 models, respectively).

Biallelic variants in cause a novel autosomal recessive syndrome presenting with cardiac conduction defects and variable hypertrophic cardiomyopathy.

encodes for the Popeye domain-containing protein 2 which has an important role in cardiac pacemaking and conduction, due in part to its cAMP-dependent binding and regulation of TREK-1 potassium channels. Loss of in mice results in sinus pauses and bradycardia and morpholino knockdown of zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in in 4 families that presented with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects and hypertrophic cardiomyopathy.

The Action Potential Clamp Technique as a Tool for Risk Stratification of Sinus Bradycardia Due to Loss-of-Function Mutations in HCN4: An In Silico Exploration Based on In Vitro and In Vivo Data.

These days, in vitro functional analysis of gene variants is becoming increasingly important for risk stratification of cardiac ion channelopathies. So far, such risk stratification has been applied to , , and gene variants associated with Brugada syndrome and long QT syndrome types 1 and 2, respectively, but risk stratification of gene variants related to sick sinus syndrome has not yet been performed. is the gene responsible for the hyperpolarization-activated 'funny' current I, which is an important modulator of the spontaneous diastolic depolarization underlying the sinus node pacemaker activity.

Human Sinoatrial Node Pacemaker Activity: Role of the Slow Component of the Delayed Rectifier K Current, I.

The pacemaker activity of the sinoatrial node (SAN) has been studied extensively in animal species but is virtually unexplored in humans. Here we assess the role of the slowly activating component of the delayed rectifier K current (I) in human SAN pacemaker activity and its dependence on heart rate and β-adrenergic stimulation. HEK-293 cells were transiently transfected with wild-type and cDNA, encoding the α- and β-subunits of the I channel, respectively.

The Antidepressant Paroxetine Reduces the Cardiac Sodium Current.

A considerable amount of literature has been published on antidepressants and cardiac ion channel dysfunction. The antidepressant paroxetine has been associated with Brugada syndrome and long QT syndrome, albeit on the basis of conflicting findings. The cardiac voltage-gated sodium channel (Na1.

Acetylcholine Reduces L-Type Calcium Current without Major Changes in Repolarization of Canine and Human Purkinje and Ventricular Tissue.

Vagal nerve stimulation (VNS) holds a strong basis as a potentially effective treatment modality for chronic heart failure, which explains why a multicenter VNS study in heart failure with reduced ejection fraction is ongoing. However, more detailed information is required on the effect of acetylcholine (ACh) on repolarization in Purkinje and ventricular cardiac preparations to identify the advantages, risks, and underlying cellular mechanisms of VNS. Here, we studied the effect of ACh on the action potential (AP) of canine Purkinje fibers (PFs) and several human ventricular preparations.

Carbamazepine Increases the Risk of Sudden Cardiac Arrest by a Reduction of the Cardiac Sodium Current.

To assess the risk of sudden cardiac arrest (SCA) associated with the use of carbamazepine (CBZ) and establish the possible underlying cellular electrophysiological mechanisms. The SCA risk association with CBZ was studied in general population cohorts using a case-control design ( = 5,473 SCA cases, 21,866 non-SCA controls). Effects of 1-100 µM CBZ on action potentials (APs) and individual membrane currents were determined in isolated rabbit and human cardiomyocytes using the patch clamp technique.

shRNAs Targeting a Common Variant Could Alleviate Long-QT1 Disease Severity by Inhibiting a Mutant Allele.

Long-QT syndrome type 1 (LQT1) is caused by mutations in . Patients heterozygous for such a mutation co-assemble both mutant and wild-type -encoded subunits into tetrameric Kv7.1 potassium channels.

Acetylcholine Reduces I and Prolongs Action Potentials in Human Ventricular Cardiomyocytes.

Vagal nerve stimulation (VNS) has a meaningful basis as a potentially effective treatment for heart failure with reduced ejection fraction. There is an ongoing VNS randomized study, and four studies are completed. However, relatively little is known about the effect of acetylcholine (ACh) on repolarization in human ventricular cardiomyocytes, as well as the effect of ACh on the rapid component of the delayed rectifier K current (I).

HCN4 current during human sinoatrial node-like action potentials.

Background: Despite the many studies carried out over the past 40 years, the contribution of the HCN4 encoded hyperpolarization-activated 'funny' current (I) to pacemaker activity in the mammalian sinoatrial node (SAN), and the human SAN in particular, is still controversial and not fully established.

Objective: To study the contribution of I to diastolic depolarization of human SAN cells and its dependence on heart rate, cAMP levels, and atrial load.

Methods: HCN4 channels were expressed in human cardiac myocyte progenitor cells (CMPCs) and HCN4 currents assessed using perforated patch-clamp in traditional voltage clamp mode and during action potential clamp with human SAN-like action potential waveforms with 500-1500 ms cycle length, in absence or presence of forskolin to mimic β-adrenergic stimulation and a -15 mV command potential offset to mimic atrial load.

Patch-Clamp Recordings of Action Potentials From Human Atrial Myocytes: Optimization Through Dynamic Clamp.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Consequently, novel therapies are being developed. Ultimately, the impact of compounds on the action potential (AP) needs to be tested in freshly isolated human atrial myocytes.

Toward Biological Pacing by Cellular Delivery of Hcn2/SkM1.

Electronic pacemakers still face major shortcomings that are largely intrinsic to their hardware-based design. Radical improvements can potentially be generated by gene or cell therapy-based biological pacemakers. Our previous work identified adenoviral gene transfer of Hcn2 and SkM1, encoding a "funny current" and skeletal fast sodium current, respectively, as a potent combination to induce short-term biological pacing in dogs with atrioventricular block.

Dynamic Clamp in Electrophysiological Studies on Stem Cell-Derived Cardiomyocytes-Why and How?

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are supposed to be a good human-based model, with virtually unlimited cell source, for studies on mechanisms underlying cardiac development and cardiac diseases, and for identification of drug targets. However, a major drawback of hPSC-CMs as a model system, especially for electrophysiological studies, is their depolarized state and associated spontaneous electrical activity. Various approaches are used to overcome this drawback, including the injection of "synthetic" inward rectifier potassium current (IK1), which is computed in real time, based on the recorded membrane potential ("dynamic clamp").

Ultrarapid Delayed Rectifier K Channelopathies in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. About 5-15% of AF patients have a mutation in a cardiac gene, including mutations in , encoding the K1.5 α-subunit of the ion channel carrying the atrial-specific ultrarapid delayed rectifier K current (I).

Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating.

Homeostatic regulation protects organisms against hazardous physiological changes. However, such regulation is limited in certain organs and associated biological processes. For example, the heart fails to self-restore its normal electrical activity once disturbed, as with sustained arrhythmias.

Aquaporin Channels in the Heart-Physiology and Pathophysiology.

Mammalian aquaporins (AQPs) are transmembrane channels expressed in a large variety of cells and tissues throughout the body. They are known as water channels, but they also facilitate the transport of small solutes, gasses, and monovalent cations. To date, 13 different AQPs, encoded by the genes -, have been identified in mammals, which regulate various important biological functions in kidney, brain, lung, digestive system, eye, and skin.

Cellular Mechanisms of Sinus Node Dysfunction in Carriers of the -E161K Mutation and Role of the H558R Polymorphism.

Carriers of the E161K mutation in the gene, encoding the Na1.5 pore-forming α-subunit of the ion channel carrying the fast sodium current (I), show sinus bradycardia and occasional exit block. Voltage clamp experiments in mammalian expression systems revealed a mutation-induced 2.

Long QT Syndrome and Sinus Bradycardia-A Mini Review.

Congenital long-QT syndrome (LQTS) is an inherited cardiac disorder characterized by the prolongation of ventricular repolarization, susceptibility to Torsades de Pointes (TdP), and a risk for sudden death. Various types of congenital LQTS exist, all due to specific defects in ion channel-related genes. Interestingly, almost all of the ion channels affected by the various types of LQTS gene mutations are also expressed in the human sinoatrial node (SAN).

K4.3 Expression Modulates Na1.5 Sodium Current.

In cardiomyocytes, the voltage-gated transient outward potassium current (I) is responsible for the phase-1 repolarization of the action potential (AP). Gain-of-function mutations in , the gene encoding the I carrying K4.3 channel, have been associated with Brugada syndrome (BrS).

Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations.

The gene encodes the pore-forming α-subunit of the ion channel that carries the cardiac fast sodium current (). The 1795insD mutation in causes sinus bradycardia, with a mean heart rate of 70 beats/min in mutation carriers vs. 77 beats/min in non-carriers from the same family (lowest heart rate 41 vs.

Patch-Clamp Recording from Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Improving Action Potential Characteristics through Dynamic Clamp.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for studying inherited cardiac arrhythmias and developing drug therapies to treat such arrhythmias. Unfortunately, until now, action potential (AP) measurements in hiPSC-CMs have been hampered by the virtual absence of the inward rectifier potassium current () in hiPSC-CMs, resulting in spontaneous activity and altered function of various depolarising and repolarising membrane currents. We assessed whether AP measurements in "ventricular-like" and "atrial-like" hiPSC-CMs could be improved through a simple, highly reproducible dynamic clamp approach to provide these cells with a substantial (computed in real time according to the actual membrane potential and injected through the patch-clamp pipette).