scholarly journals Individual Contributions of Cardiac Ion Channels on Atrial Repolarization and Reentrant Waves: A Multiscale In-Silico Study

2022 ◽  
Vol 9 (1) ◽  
pp. 28
Author(s):  
Henry Sutanto
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
In Silico ◽  
Computational Study ◽  
Surrogate Marker ◽  
Cardiac Ion Channels ◽  
Atrial Electrophysiology ◽  
In Silico Study ◽  
In Silico Models ◽  
Atrial Repolarization

The excitation, contraction, and relaxation of an atrial cardiomyocyte are maintained by the activation and inactivation of numerous cardiac ion channels. Their collaborative efforts cause time-dependent changes of membrane potential, generating an action potential (AP), which is a surrogate marker of atrial arrhythmias. Recently, computational models of atrial electrophysiology emerged as a modality to investigate arrhythmia mechanisms and to predict the outcome of antiarrhythmic therapies. However, the individual contribution of atrial ion channels on atrial action potential and reentrant arrhythmia is not yet fully understood. Thus, in this multiscale in-silico study, perturbations of individual atrial ionic currents (INa, Ito, ICaL, IKur, IKr, IKs, IK1, INCX and INaK) in two in-silico models of human atrial cardiomyocyte (i.e., Courtemanche-1998 and Grandi-2011) were performed at both cellular and tissue levels. The results show that the inhibition of ICaL and INCX resulted in AP shortening, while the inhibition of IKur, IKr, IKs, IK1 and INaK prolonged AP duration (APD). Particularly, in-silico perturbations (inhibition and upregulation) of IKr and IKs only minorly affected atrial repolarization in the Grandi model. In contrast, in the Courtemanche model, the inhibition of IKr and IKs significantly prolonged APD and vice versa. Additionally, a 50% reduction of Ito density abbreviated APD in the Courtemanche model, while the same perturbation prolonged APD in the Grandi model. Similarly, a strong model dependence was also observed at tissue scale, with an observable IK1-mediated reentry stabilizing effect in the Courtemanche model but not in the Grandi atrial model. Moreover, the Grandi model was highly sensitive to a change on intracellular Ca2+ concentration, promoting a repolarization failure in ICaL upregulation above 150% and facilitating reentrant spiral waves stabilization by ICaL inhibition. Finally, by incorporating the previously published atrial fibrillation (AF)-associated ionic remodeling in the Courtemanche atrial model, in-silico modeling revealed the antiarrhythmic effect of IKr inhibition in both acute and chronic settings. Overall, our multiscale computational study highlights the strong model-dependent effects of ionic perturbations which could affect the model’s accuracy, interpretability, and prediction. This observation also suggests the need for a careful selection of in-silico models of atrial electrophysiology to achieve specific research aims.

Abstract MP110: Inhibition of the Unfolded Protein Response Reduces Arrhythmic Risk After Myocardial Infarction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Man Liu ◽  
Hong Liu ◽  
Preethy Parthiban ◽  
guangbin shi ◽  
Gyeoung-Jin Kang ◽  
...  
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Ion Channel ◽  
Unfolded Protein Response ◽  
Coronary Artery Ligation ◽  
Unfolded Protein ◽  
Cardiac Ion Channels ◽  
Increased Risk ◽  
The Unfolded Protein Response ◽  
Protein Response

Background: Ischemic cardiomyopathy is associated with an increased risk of sudden death, activation of the unfolded protein response (UPR), and reductions in multiple cardiac ion channels and transporters. When activated, the protein kinase-like ER kinase (PERK) arm of the unfolded protein response (UPR) reduces protein translation and abundance. We hypothesize that inhibition of PERK could prevent cardiac ion channel downregulation and reduce arrhythmic risk after myocardial infarct (MI). Methods: The MI mouse model was induced by a left anterior descending coronary artery ligation. Pharmacological inhibition of PERK was achieved with a specific inhibitor, GSK2606414. Genetic inhibition of PERK was achieved by cardiac-specific PERK knockout in C57BL/6J mice (PERKKO). Echocardiography, telemetry, and electrophysiological measurements were performed to monitor cardiac function and arrhythmias. Results: Three weeks after surgery, the wild type MI mice exhibited decreased ejection fraction (EF%), ventricular tachycardia (VT) and prolonged QTc intervals. The UPR effectors (phospho-PERK, phospho-IRE1, and ATF6N) were elevated significantly (1.7- to 5.9-fold) at protein levels, and all major cardiac ion channels showed decreased protein expression in MI hearts. MI cardiomyocytes showed decreased currents for all major channels (I Na , I CaL , I to , I K1 , and I Kur : 60±6%, 53±9%, 27±6%, 55±7%, and 40±7% of sham, respectively, P<0.05 vs. sham) with significantly prolonged action potential duration (APD 90 : 291±43 ms of MI vs. 100±12 ms of sham, P<0.05) and decreased maximum upstroke velocity (dV/dt max : 95±4 V/s of MI vs. 132±6 ms of sham, P<0.05) of the action potential phase 0. GSK treatment restored I Na and I to , shortened APD, and increased dV/dt max . PERKKO mice exhibited reduced electrical remodeling in response to MI with shortened QTc intervals, less VT episodes, and higher survival rates. Conclusion: PERK is activated during MI and contributes to arrhythmic risk by downregulation of select cardiac ion channels. PERK inhibition prevented these changes and reduced arrhythmic risk. These results suggest that ion channel downregulation during MI is a fundamental arrhythmic mechanism and maintaining ion channel levels is antiarrhythmic.

scholarly journals Lead and Carbon Monoxide Effects on Human Atrial Action Potential. In Silico Study

2017 ◽  
Author(s):  
Catalina Tobon ◽  
Diana C Pachajoa ◽  
Juan P Ugarte ◽  
Andres Orozco-Duque ◽  
Javier Saiz
Keyword(s):  
Carbon Monoxide ◽  
Action Potential ◽  
In Silico ◽  
In Silico Study

Molecular Physiology of Cardiac Repolarization

2005 ◽  
Vol 85 (4) ◽  
pp. 1205-1253 ◽  
Author(s):  
Jeanne M. Nerbonne ◽  
Robert S. Kass
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Action Potentials ◽  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Future Research ◽  
Cardiac Repolarization ◽  
Molecular Physiology ◽  
Cardiac Ion Channels ◽  
Α Subunits

The heart is a rhythmic electromechanical pump, the functioning of which depends on action potential generation and propagation, followed by relaxation and a period of refractoriness until the next impulse is generated. Myocardial action potentials reflect the sequential activation and inactivation of inward (Na+ and Ca2+) and outward (K+) current carrying ion channels. In different regions of the heart, action potential waveforms are distinct, owing to differences in Na+, Ca2+, and K+ channel expression, and these differences contribute to the normal, unidirectional propagation of activity and to the generation of normal cardiac rhythms. Changes in channel functioning, resulting from inherited or acquired disease, affect action potential repolarization and can lead to the generation of life-threatening arrhythmias. There is, therefore, considerable interest in understanding the mechanisms that control cardiac repolarization and rhythm generation. Electrophysiological studies have detailed the properties of the Na+, Ca2+, and K+ currents that generate cardiac action potentials, and molecular cloning has revealed a large number of pore forming (α) and accessory (β, δ, and γ) subunits thought to contribute to the formation of these channels. Considerable progress has been made in defining the functional roles of the various channels and in identifying the α-subunits encoding these channels. Much less is known, however, about the functioning of channel accessory subunits and/or posttranslational processing of the channel proteins. It has also become clear that cardiac ion channels function as components of macromolecular complexes, comprising the α-subunits, one or more accessory subunit, and a variety of other regulatory proteins. In addition, these macromolecular channel protein complexes appear to interact with the actin cytoskeleton and/or the extracellular matrix, suggesting important functional links between channel complexes, as well as between cardiac structure and electrical functioning. Important areas of future research will be the identification of (all of) the molecular components of functional cardiac ion channels and delineation of the molecular mechanisms involved in regulating the expression and the functioning of these channels in the normal and the diseased myocardium.

scholarly journals Polyunsaturated fatty acid analogues differentially affect cardiac NaV, CaV, and KV channels through unique mechanisms

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Briana M Bohannon ◽  
Alicia de la Cruz ◽  
Xiaoan Wu ◽  
Jessica J Jowais ◽  
Marta E Perez ◽  
...  
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Induced Pluripotent Stem Cell ◽  
Voltage Gated ◽  
Kv Channels ◽  
Cardiac Ion Channels ◽  
Induced Pluripotent ◽  
Voltage Gated Ion Channels ◽  
Ventricular Action Potential ◽  
Gated Ion Channels

The cardiac ventricular action potential depends on several voltage-gated ion channels, including NaV, CaV, and KV channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating cardiac ion channels from all three families (NaV, CaV, and KV). In addition, a PUFA analogue selective for the cardiac IKs channel (Kv7.1/KCNE1) is effective in shortening the cardiac action potential in human-induced pluripotent stem cell-derived cardiomyocytes. Our data suggest that PUFA analogues could potentially be developed as therapeutics for LQTS and cardiac arrhythmia.

An In-Silico Study of the Effects of Conductance Variation on the Regionally Based Action Potential Morphology.

2019 ◽  
Author(s):  
Jordan Elliott ◽  
Olaf Doessel ◽  
Axel Loewe ◽  
Luca Mainardi ◽  
Valentina Corino ◽  
...  
Keyword(s):  
Action Potential ◽  
In Silico ◽  
In Silico Study

scholarly journals Carvacrol: An In Silico Approach of a Candidate Drug on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR Receptors in the Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Oscar Herrera-Calderon ◽  
Andres F. Yepes-Pérez ◽  
Jorge Quintero-Saumeth ◽  
Juan Pedro Rojas-Armas ◽  
Miriam Palomino-Pacheco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Dynamic ◽  
Cancer Progression ◽  
In Silico ◽  
Computational Study ◽  
Female Rats ◽  
Ligand Docking ◽  
Dynamic Simulations ◽  
In Silico Study ◽  
Egfr Receptors

Carvacrol is a phenol monoterpene found in aromatic plants specially in Lamiaceae family, which has been evaluated in an experimental model of breast cancer. However, any proposed mechanism based on its antitumor effect has not been reported. In our previous study, carvacrol showed a protective effect on 7,12-dimethylbenz[α]anthracene- (DMBA-) induced breast cancer in female rats. The main objective in this research was to evaluate by using in silico study the carvacrol on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR receptors involved in breast cancer progression by docking analysis, molecular dynamic, and drug-likeness evaluation. A multilevel computational study to evaluate the antitumor potential of carvacrol focusing on the main targets involved in the breast cancer was carried out. The in silico study starts with protein-ligand docking of carvacrol followed by ligand pathway calculations, molecular dynamic simulations, and molecular mechanics energies combined with the Poisson–Boltzmann (MM/PBSA) calculation of the free energy of binding for carvacrol. As result, the in silico study led to the identification of carvacrol with strong binding affinity on mTOR receptor. Additionally, in silico drug-likeness index for carvacrol showed a good predicted therapeutic profile of druggability. Our findings suggest that mTOR signaling pathway could be responsible for its preventive effect in the breast cancer.

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