Ion Channel and Structural Remodeling in Obesity-Mediated Atrial Fibrillation

Background: Epidemiological studies have established obesity as an independent risk factor for atrial fibrillation (AF), but the underlying pathophysiological mechanisms remain unclear. Reduced cardiac sodium channel expression is a known causal mechanism in AF. We hypothesized that obesity decreases Nav1.5 expression via enhanced oxidative stress, thus reducing I Na , and enhancing susceptibility to AF. Methods: To elucidate the underlying electrophysiological mechanisms a diet-induced obese mouse model was used. Weight, blood pressure, glucose, F 2 -isoprostanes, NOX2 (NADPH oxidase 2), and PKC (protein kinase C) were measured in obese mice and compared with lean controls. Invasive electrophysiological, immunohistochemistry, Western blotting, and patch clamping of membrane potentials was performed to evaluate the molecular and electrophysiological phenotype of atrial myocytes. Results: Pacing-induced AF in 100% of diet-induced obese mice versus 25% in controls ( P <0.01) with increased AF burden. Cardiac sodium channel expression, I Na and atrial action potential duration were reduced and potassium channel expression (Kv1.5) and current ( I Kur ) and F 2 -isoprostanes, NOX2, and PKC-α/δ expression and atrial fibrosis were significantly increased in diet-induced obese mice as compared with controls. A mitochondrial antioxidant reduced AF burden, restored I Na , I Ca,L , I Kur , action potential duration, and reversed atrial fibrosis in diet-induced obese mice as compared with controls. Conclusions: Inducible AF in obese mice is mediated, in part, by a combined effect of sodium, potassium, and calcium channel remodeling and atrial fibrosis. Mitochondrial antioxidant therapy abrogated the ion channel and structural remodeling and reversed the obesity-induced AF burden. Our findings have important implications for the management of obesity-mediated AF in patients. Graphic Abstract: A graphic abstract is available for this article.

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Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

Cellular Physiology and Biochemistry ◽

10.1159/000492840 ◽

2018 ◽

Vol 49 (1) ◽

pp. 65-77 ◽

Cited By ~ 6

Author(s):

Patrick Lugenbiel ◽

Katharina Govorov ◽

Ann-Kathrin Rahm ◽

Teresa Wieder ◽

Dominik Gramlich ◽

...

Keyword(s):

Action Potential ◽

Ion Channel ◽

Action Potential Duration ◽

Histone Deacetylases ◽

Trichostatin A ◽

Class I ◽

K Channel ◽

Hdac Inhibition ◽

Atrial Cardiomyocytes ◽

Channel Expression

Background/Aims: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes. Methods: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K+ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition. Results: Global HDAC inhibition increased histone acetylation and prolonged APD90 in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K+ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K+ channel remodeling. Conclusion: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation.

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Termination of Action Potential Due to Site Selective Ion Channel Blockers

Fluctuation and Noise Letters ◽

10.1142/s0219477520500157 ◽

2019 ◽

Vol 19 (02) ◽

pp. 2050015

Author(s):

Krishnendu Pal ◽

Gautam Gangopadhyay

Keyword(s):

Action Potential ◽

Ion Channel ◽

Sodium Channel ◽

Action Potential Duration ◽

Ionic Current ◽

Channel Blockers ◽

Quiescent State ◽

Ion Channel Blockers ◽

Different Types ◽

Site Selective

Here, we have provided a qualitative theoretical description about how the action potential generation and its associated intrinsic properties such as ionic current, spiking frequency, action potential duration, gating dynamics, etc. are affected due to site selective ion channel blockers, by suitably adapting Gillespie’s stochastic simulation technique to an extended Hodgkin–Huxley Markov model, representing a very basic type of neuron. Considering different types and degrees of blocking potency of channel blockers to channel proteins, we have found that the nature of action potential termination process and corresponding ionic current profiles are very distinct from each other. With the increasing blocking affinity, the frequency of action potential spiking falls off exponentially in presence of sodium channel only blockers and dual type blockers having more sodium binding potency than potassium blockers, whereas in contrast, for potassium channel only blockers, dual type blockers having equal or higher potassium blocking affinity with respect to sodium blocking, the spiking frequency initially is enhanced followed by a gradual decrease due to the competition between channel number fluctuation and overall sodium and potassium conductances. Sodium channel blockers tend to shorten the action potential duration while the potassium channel blockers broaden it. The channel gating dynamics are also found to be changed drastically for different types of blockers. The final quiescent state arrival time and the quiescent state membrane voltage profiles show distinct features for different types of channel blockers with different applied external stimulus. Finally, we showed how consistent our results are with the existing literature of experimentally observed channel blocking effects in diverse systems and compared the similarities, dissimilarities and advantages of our model with an existing theoretical drug binding model with Langevin description. Our approach provides a qualitative pathway to investigate the effects of many other types of blocking mechanisms such as closed state, inactivated state blocking with desired level of structural and functional details.

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Ion channel expression and electrophysiology of singular human (primary and induced pluripotent stem cell derived) cardiomyocytes

10.1101/2021.03.04.433834 ◽

2021 ◽

Author(s):

Christina Schmid ◽

Najah Abi-Gerges ◽

Dietmar Zellner ◽

Georg Rast

Keyword(s):

Ion Channels ◽

Action Potential ◽

Ion Channel ◽

Single Cell ◽

Action Potential Duration ◽

Drug Effects ◽

Induced Pluripotent Stem Cell ◽

Inward Current ◽

Beat Rate ◽

Channel Expression

SUMMARYHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and primary human cardiomyocytes are used for in vitro cardiac safety testing. hiPSC-CMs have been associated with a vast heterogeneity regarding single-cell morphology, beating behavior and action potential duration, prompting a systematic analysis of single-cell characteristics. Previously published hiPSC-CM studies revealed action potentials with nodal-, atrial- or ventricular-like morphology, although ion channel expression of singular hiPSC-CMs is not fully understood. Other studies used single-cell RNA-sequencing, however, these studies did not extensively focus on expression patterns of cardiac ion channels or failed to detect ion channel transcripts. Thus, the current study used a single-cell patch-clamp-RT-qPCR approach to get insights into single-cell electrophysiology (capacitance, action potential duration at 90% of repolarization, upstroke velocity, spontaneous beat rate, and sodium-driven fast inward current) and ion channel expression (HCN4, CACNA1G, CACNA1D, KCNA5, KCNJ4, SCN5A, KCNJ2, CACNA1D, and KCNH2), the combination of both within individual cells, and their correlations in single cardiomyocytes. We used commercially available hiPSC-CMs (iCell cardiomyocytes, atrial and ventricular Pluricytes) and primary human adult atrial and ventricular cardiomyocytes. Recordings of electrophysiological parameters revealed differences between the cell groups and variation within the hiPSC-CMs groups as well as within primary ventricular cardiomyocytes. Expression analysis on mRNA level showed no-clear-cut discrimination between primary cardiac subtypes and revealed both similarities and differences between all cell groups. Higher expression of atrial-associated ion channels in primary atrial cardiomyocytes and atrial Pluricytes compared to their ventricular counterpart indicates a successful chamber-specific hiPSC differentiation. Interpretation of correlations between the single-cell parameters was challenging, as the total data set is complex, particularly for parameters depending on multiple processes, like the spontaneous beat rate. Yet, for example, expression of SCN5A correlated well with the fast inward current amplitude for all three hiPSC-CM groups. To further enhance our understanding of the physiology and composition of the investigated hiPSC-CMs, we compared beating and non-beating cells and assessed distributions of single-cell data. Investigating the single-cell phenotypes of hiPSC-CMs revealed a combination of attributes which may be interpreted as a mixture of traits of different adult cardiac cell types: (i) nodal-related pacemaking attributes are spontaneous generation of action potentials and high HCN4 expression; and (ii) non-nodal attributes: cells have a prominent INa-driven fast inward current, a fast upstroke velocity and a high expression of SCN5A. In conclusion, the combination of nodal- and non-nodal attributes in single hiPSC-CMs may hamper the interpretation of drug effects on complex electrophysiological parameters like beat rate and action potential duration. However, the proven expression of specific ion channels enables the evaluation of drug effects on ionic currents in a more realistic environment than in recombinant systems.

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Beta-Adrenergic Stimulation Alters Both ion Channel Currents and Functional Refractory Period to Steepen Action Potential Duration Restitution in Persistent Atrial Fibrillation

Biophysical Journal ◽

10.1016/j.bpj.2010.12.2563 ◽

2011 ◽

Vol 100 (3) ◽

pp. 434a-435a

Author(s):

Jason D. Bayer ◽

David E. Krummen ◽

Sanjiv M. Narayan ◽

Natalia Trayanova

Keyword(s):

Atrial Fibrillation ◽

Action Potential ◽

Ion Channel ◽

Action Potential Duration ◽

Refractory Period ◽

Persistent Atrial Fibrillation ◽

Adrenergic Stimulation ◽

Beta Adrenergic ◽

Channel Currents ◽

Action Potential Duration Restitution

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P496Remodeling of atrial action potential duration and atrial chamber deformation: a potential link in the development of atrial fibrillation?

Cardiovascular Research ◽

10.1093/cvr/cvy060.353 ◽

2018 ◽

Vol 114 (suppl_1) ◽

pp. S120-S120

Author(s):

L Sartiani ◽

M Cameli ◽

L Dini ◽

S Modillo ◽

...

Keyword(s):

Atrial Fibrillation ◽

Action Potential ◽

Action Potential Duration ◽

Potential Link

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Faculty Opinions recommendation of Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1105193.561387 ◽

2008 ◽

Author(s):

Hugues Abriel

Keyword(s):

Atrial Fibrillation ◽

Sodium Channel ◽

Cardiac Sodium Channel

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Rare variants in genes encoding the cardiac sodium channel and associated compounds and their impact on outcome of catheter ablation of atrial fibrillation

PLoS ONE ◽

10.1371/journal.pone.0183690 ◽

2017 ◽

Vol 12 (8) ◽

pp. e0183690 ◽

Cited By ~ 2

Author(s):

Daniela Husser ◽

Laura Ueberham ◽

Gerhard Hindricks ◽

Petra Büttner ◽

Christie Ingram ◽

...

Keyword(s):

Atrial Fibrillation ◽

Catheter Ablation ◽

Sodium Channel ◽

Rare Variants ◽

Cardiac Sodium Channel ◽

Genes Encoding

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Frequency- and voltage-dependent effects of disopyramide in canine Purkinje fibers

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y89-115 ◽

1989 ◽

Vol 67 (7) ◽

pp. 710-721 ◽

Cited By ~ 2

Author(s):

Matthew A. Flemming ◽

Betty I. Sasyniuk

Keyword(s):

Potassium Channels ◽

Action Potential ◽

Sodium Channel ◽

Action Potential Duration ◽

Refractory Period ◽

Drug Effect ◽

Effective Refractory Period ◽

Slow Inactivation ◽

Purkinje Fibers ◽

Rate Dependent

The voltage- and frequency-dependent blocking actions of disopyramide were assessed in canine Purkinje fibers within the framework of concentrations, membrane potentials, and heart rates which have relevance to the therapeutic actions of this drug. [Formula: see text] was used to assess the magnitude of sodium channel block. Disopyramide produced a concentration- and rate-dependent increase in the magnitude and kinetics of [Formula: see text] depression. Effects on activation time (used as an estimate of drug effect on conduction) were exactly analogous to effects on [Formula: see text]. A concentration-dependent increase in tonic block was also observed. Despite significant increases in tonic block at more depolarized potentials, rate-dependent block increased only marginally with membrane potential over the range of potentials in which propagated action potentials occur. Increases in extracellular potassium concentration accentuated drug effect on [Formula: see text] but attenuated drug effect on action potential duration. Recovery from rate-dependent block followed two exponential processes with time constants of 689 ± 535 ms and 15.7 ± 2.7 s. The latter component represents dissociation of drug from its binding site and the former probably represents recovery from slow inactivation. A concentration-dependent increase in the amplitude of the first component suggested that disopyramide may promote slow inactivation. There was less than 5% recovery from block during intervals equivalent to clinical diastole. Thus, depression of beats of all degrees of prematurity was similar to that of basic drive beats. Prolongation of action potential duration by therapeutic concentrations of drug following a long quiescent interval was minimal. However, profound lengthening of action potential duration occurred following washout of drug effect at a time when [Formula: see text] depression had reverted to normal, suggesting that binding of disopyramide to potassium channels may not be readily reversed. Variable effects on action potential duration may thus be attributed to a block of the window current flowing during the action potential being partially or over balanced by block of potassium channels. Purkinje fiber refractoriness was prolonged in a frequency-dependent manner. Disopyramide did not significantly alter the effective refractory period of basic beats but did increase the effective refractory period of sequential tightly coupled extra stimuli. The results can account for the antiarrhythmic actions of disopyramide during a rapid tachycardia and prevention of its initiation by programmed electrical stimulation.Key words: action potential duration, effective refractory period, upstroke velocity, conduction, rate of sodium channel unblocking.

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