scholarly journals Proarrhythmic Effects of Electrolyte Imbalance in Virtual Human Atrial and Ventricular Cardiomyocytes

2020 ◽  
Author(s):  
Sanjay R Kharche
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Calcium Transient ◽  
Additional Treatment ◽  
Electrolyte Imbalance ◽  
Serum Electrolytes ◽  
Model Response ◽  
Arrhythmia Mechanisms ◽  
In Silico Modeling

Dialysis is prescribed to renal failure patients as a long-term chronic treatment. Whereas dialysis therapeutically normalizes serum electrolytes and removes small toxin molecules, it fails to alleviate fibroblast induced structural fibrosis, and unresponsive uremia. The simultaneous presence of altered electrolytes and fibrosis or uremia is thought to be pro-arrhythmogenic. This study explored potential arrhythmogenesis under pre-dialysis (high electrolyte levels) and post-dialysis (low physiological electrolyte levels) in the presence of fibrosis and uremia in human atrial and ventricular model cardiomyocytes.Two validated human cardiomyocyte models were used in this study that permitted simulation of cardiac atrial and ventricular detailed electrophysiology. Pathological conditions simulating active fibrosis and uremia were implemented in both models. Pre- and post-dialysis conditions were simulated using high and low electrolyte levels respectively. Arrythmogenesis was quantified by computing restitution curves that permitted identification of action potential duration and calcium transient alternans instabilities. In comparison to control conditions, fibrosis abbreviated action potential durations while uremia prolonged the same. Under pre-dialysis conditions, an elevation of serum electrolyte levels caused action potential durations to be abbreviated under both fibrosis and uremia. Alternans instability was observed in the ventricular cardiomyocyte model. Under post-dialysis conditions, lower levels of serum electrolytes promoted an abbreviated action potential duration under fibrosis but caused a large increase of the control and uremic action potential durations. Alternans instabilities were observed in the atrial cardiomyocyte model under post-dialysis conditions at physiological heart rates. The calcium transient restitution showed similar alternans instabilities. Co-existing conditions such as fibrosis and uremia in the presence of unphysiological electrolyte levels promote arrhythmogenesis and may require additional treatment to improve dialysis outcomes.Clinical Relevance. Knowledge of model response to clinically relevant conditions permits use of in silico modeling to better understand and dissect underlying arrhythmia mechanisms.

scholarly journals Detachable glass microelectrodes for recording action potentials in active moving organs

2017 ◽  
Vol 312 (6) ◽  
pp. H1248-H1259 ◽  
Author(s):  
Mladen Barbic ◽  
Angel Moreno ◽  
Tim D. Harris ◽  
Matthew W. Kay
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Action Potentials ◽  
Ischemia Reperfusion ◽  
Cellular Level ◽  
High Temporal Resolution ◽  
Physiological Relevance ◽  
Glass Micropipette ◽  
Multiple Cells

Here, we describe new detachable floating glass micropipette electrode devices that provide targeted action potential recordings in active moving organs without requiring constant mechanical constraint or pharmacological inhibition of tissue motion. The technology is based on the concept of a glass micropipette electrode that is held firmly during cell targeting and intracellular insertion, after which a 100-µg glass microelectrode, a “microdevice,” is gently released to remain within the moving organ. The microdevices provide long-term recordings of action potentials, even during millimeter-scale movement of tissue in which the device is embedded. We demonstrate two different glass micropipette electrode holding and detachment designs appropriate for the heart (sharp glass microdevices for cardiac myocytes in rats, guinea pigs, and humans) and the brain (patch glass microdevices for neurons in rats). We explain how microdevices enable measurements of multiple cells within a moving organ that are typically difficult with other technologies. Using sharp microdevices, action potential duration was monitored continuously for 15 min in unconstrained perfused hearts during global ischemia-reperfusion, providing beat-to-beat measurements of changes in action potential duration. Action potentials from neurons in the hippocampus of anesthetized rats were measured with patch microdevices, which provided stable base potentials during long-term recordings. Our results demonstrate that detachable microdevices are an elegant and robust tool to record electrical activity with high temporal resolution and cellular level localization without disturbing the physiological working conditions of the organ. NEW & NOTEWORTHY Cellular action potential measurements within tissue using glass micropipette electrodes usually require tissue immobilization, potentially influencing the physiological relevance of the measurement. Here, we addressed this limitation with novel 100-µg detachable glass microelectrodes that can be precisely positioned to provide long-term measurements of action potential duration during unconstrained tissue movement.

The ex-vivo effects of thyroid status and extracellular calcium concentration on rat atrial and ventricular electrophysiology

1988 ◽  
Vol 66 (1) ◽  
pp. 90-94 ◽  
Author(s):  
R. W. Gristwood ◽  
A. L. Rothaul
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Calcium Concentration ◽  
Ex Vivo ◽  
Additional Treatment ◽  
Extracellular Calcium ◽  
Krebs Solution ◽  
Thyroid Status ◽  
Extracellular Calcium Concentration ◽  
Atrial Electrophysiology

The purpose of this study was to explore the relationship between the thyroid status and both ventricular and atrial electrophysiology in the rat. The study was extended to consider the effects of altering the extracellular calcium concentration. The work was performed in two sections. First, hypothyroid animals were compared with euthyroid (untreated animals); second, hypothyroid animals were compared with hyperthyroid animals. Rats were rendered hypothyroid by pretreatment with the goitrogen methimazole and hyperthyroid by additional treatment with triiodothyronine. Action potential recordings were obtained using standard microelectrode techniques. Action potential measurements were made initially in a Krebs solution to which had been added 2.55 mM calcium (higher Ca Krebs solution) and at the end of each experiment after stabilization with Krebs solution to which had been added 1.28 mM calcium (lower Ca Krebs solution). Assessment of the change in action potential duration on transition from higher to lower Ca Krebs solution revealed that the euthyroid preparations demonstrated less prolongation of action potential duration than the hypothyroid group, and the hyperthyroid group showed hardly any response to reduction in calcium concentration.

scholarly journals The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine hearts

2021 ◽  
Author(s):  
Artur Santos-Miranda ◽  
Julliane V Joviano-Santos ◽  
Taynara Cruz-Nascimento ◽  
Diego Santos Souza ◽  
Leisiane Marques ◽  
...  
Keyword(s):  
Action Potential ◽  
Cardiac Tissue ◽  
Ex Vivo ◽  
Calcium Transient ◽  
Acute Exposure ◽  
Sodium Calcium Exchanger ◽  
Whole Cell Patch Clamp ◽  
Toxicological Studies ◽  
Qt Interval Duration

Tebuconazole (TEB) is an important fungicide that belongs to the triazole family. It is largely applied in agriculture and its use has increased in the last decade. Since TEB is stable in water and soil, long-term exposure of humans to this pesticide is a real threat. Acute toxicological studies to uncover the toxicity of TEB are limited, and there is evidence of an association between long-term exposure to TEB and damage of several biological systems, including hepatotoxicity and cardiotoxicity. In this paper, the effects of acute exposure of cardiomyocytes and murine hearts to TEB were addressed to elucidate its impact on electromechanical properties of the cardiac tissue. In whole-cell patch-clamp records, TEB inhibited both the total outward potassium current (IC50=5.7±1.5 μmol.l−1) and the L-type calcium current (IC50=33.2±7.4 μmol.l−1). Acute exposure to TEB at 30 μmol.l−1 prolonged the action potential duration as well as an induced out-of-pace action potential, and increased the sodium/calcium exchanger current in its forward and reverse modes. Moreover, sarcomere shortening and calcium transient in isolated cardiomyocytes was enhanced when cells were exposed to TEB at 30 μmol.l−1. In ex vivo experiments, TEB 30 μmol.l−1 caused significant electrocardiogram remodeling with prolonged PR, QRS, and QT interval duration. Accordingly, TEB exposure was prone to the appearance of arrhythmias. Combined, our results demonstrate that acute TEB exposure affects the cardiomyocyte's electro-contractile properties and triggers the appearance of ECG abnormalities, including conduction defects and arrhythmias.

scholarly journals Optical Investigation of Action Potential and Calcium Handling Maturation of hiPSC-Cardiomyocytes on Biomimetic Substrates

2019 ◽  
Vol 20 (15) ◽  
pp. 3799 ◽  
Author(s):  
Josè Manuel Pioner ◽  
Lorenzo Santini ◽  
Chiara Palandri ◽  
Daniele Martella ◽  
Flavia Lupi ◽  
...  
Keyword(s):  
Action Potential ◽  
Calcium Transient ◽  
Optical Measurements ◽  
Calcium Handling ◽  
Optical Investigation ◽  
Adrenergic Stimulation ◽  
Ventricular Tissue ◽  
Custom Made ◽  
Induced Pluripotent

Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) are the most promising human source with preserved genetic background of healthy individuals or patients. This study aimed to establish a systematic procedure for exploring development of hiPSC-CM functional output to predict genetic cardiomyopathy outcomes and identify molecular targets for therapy. Biomimetic substrates with microtopography and physiological stiffness can overcome the immaturity of hiPSC-CM function. We have developed a custom-made apparatus for simultaneous optical measurements of hiPSC-CM action potential and calcium transients to correlate these parameters at specific time points (day 60, 75 and 90 post differentiation) and under inotropic interventions. In later-stages, single hiPSC-CMs revealed prolonged action potential duration, increased calcium transient amplitude and shorter duration that closely resembled those of human adult cardiomyocytes from fresh ventricular tissue of patients. Thus, the major contribution of sarcoplasmic reticulum and positive inotropic response to β-adrenergic stimulation are time-dependent events underlying excitation contraction coupling (ECC) maturation of hiPSC-CM; biomimetic substrates can promote calcium-handling regulation towards adult-like kinetics. Simultaneous optical recordings of long-term cultured hiPSC-CMs on biomimetic substrates favor high-throughput electrophysiological analysis aimed at testing (mechanistic hypothesis on) disease progression and pharmacological interventions in patient-derived hiPSC-CMs.

Mechanisms of calcium transient and action potential alternans in cardiac cells and tissues

2008 ◽  
Vol 294 (1) ◽  
pp. H1-H10 ◽  
Author(s):  
William T. Clusin
Keyword(s):  
Action Potential ◽  
Beat Frequency ◽  
Historical Review ◽  
Calcium Transient ◽  
Cardiac Cells ◽  
Time Line ◽  
Arrhythmia Mechanisms ◽  
Diastolic Interval ◽  
Open States ◽  
Hospital Cardiac Arrest

Alternation of cardiac action potential duration (APD) from beat to beat and concurrent alternation of the amplitude of the calcium transient are regarded as important arrhythmia mechanisms. These phenomena are causally interrelated and can be reliably evoked by an increase in beat frequency or by ischemia. The first part of this historical review deals with the physiology of APD alternans. Sections recounting the evolution of knowledge about calcium-activated ion currents and calcium transient alternans are interspersed among sections describing the growth of the so-called “restitution hypothesis,” which involves time-dependent recovery of potassium channels (including their passage through pre-open states) as a function of diastolic interval. Major developments are generally in chronological order, but it is necessary to move back and forth between the two theories to respect the overall time line, which runs from about l965 to the present. The concluding two sections deal with the pathophysiology of calcium transient and APD alternans during ischemia, which may be the basis for out-of-hospital cardiac arrest during the initial stages of acute myocardial infarction.

Preceding Stimulus Frequency-Dependent Potentiation of the Postrest Shortening of the Action Potential Duration in Rabbits.

2000 ◽  
Vol 41 (4) ◽  
pp. 481-492
Author(s):  
Naohiko Takahashi ◽  
Morio Ito ◽  
Shuji Ishida ◽  
Takao Fujino ◽  
Mikiko Nakagawa ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Stimulus Frequency ◽  
Frequency Dependent ◽  
Preceding Stimulus
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