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Effects of Na⁺ Current and Mechanogated Channels in Myofibroblasts on Myocyte Excitability and Repolarization.

ABSTRACT: Fibrotic remodeling, characterized by fibroblast phenotype switching, is often associated with atrial fibrillation and heart failure. This study aimed to investigate the effects on electrotonic myofibroblast-myocyte (Mfb-M) coupling on cardiac myocytes excitability and repolarization of the voltage-gated sodium channels (VGSCs) and single mechanogated channels (MGCs) in human atrial Mfbs. Mathematical modeling was developed from a combination of (1) models of the human atrial myocyte (including the stretch activated ion channel current, I_SAC) and Mfb and (2) our formulation of currents through VGSCs (I_{Na_Mfb}) and MGCs (I_{MGC_Mfb}) based upon experimental findings. The effects of changes in the intercellular coupling conductance, the number of coupled Mfbs, and the basic cycle length on the myocyte action potential were simulated. The results demonstrated that the integration of I_SAC, I_{Na_Mfb}, and I_{MGC_Mfb} reduced the amplitude of the myocyte membrane potential (V_max) and the action potential duration (APD), increased the depolarization of the resting myocyte membrane potential (V_rest), and made it easy to trigger spontaneous excitement in myocytes. For Mfbs, significant electrotonic depolarizations were exhibited with the addition of I_{Na_Mfb} and I_{MGC_Mfb}. Our results indicated that I_SAC, I_{Na_Mfb}, and I_{MGC_Mfb} significantly influenced myocytes and Mfbs properties and should be considered in future cardiac pathological mathematical modeling.

SUBMITTER: Zhan H

PROVIDER: S-EPMC5131562 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Effects of Na<sup>+</sup> Current and Mechanogated Channels in Myofibroblasts on Myocyte Excitability and Repolarization.

Zhan Heqing H Zhang Jingtao J Lin Jialun J Han Guilai G

Computational and mathematical methods in medicine 20161117

Fibrotic remodeling, characterized by fibroblast phenotype switching, is often associated with atrial fibrillation and heart failure. This study aimed to investigate the effects on electrotonic myofibroblast-myocyte (Mfb-M) coupling on cardiac myocytes excitability and repolarization of the voltage-gated sodium channels (VGSCs) and single mechanogated channels (MGCs) in human atrial Mfbs. Mathematical modeling was developed from a combination of (1) models of the human atrial myocyte (including ...[more]

PMID: 27980607

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Project description:BACKGROUND:The activation of stretch-activated channels (SACs) in cardiac myocytes, which changes the phases of action potential repolarization, is proven to be highly efficient for the conversion of atrial fibrillation. The expression of Na+ current in myofibroblasts (Mfbs) regenerates myocytes' action potentials, suggesting that Mfbs play an active role in triggering cardiac rhythm disturbances. Moreover, the excitation of mechano-gated channels (MGCs) in Mfbs depolarizes their membrane potential and contributes to the increased risk of post-infarct arrhythmia. Although these electrophysiological mechanisms have been largely known, the roles of these currents in cardiac mechanics are still debated. In this study, we aimed to investigate the mechanical influence of these currents via mathematical modeling. A novel mathematical model was developed by integrating models of human atrial myocyte (including the stretch-activated current, Ca2+-force relation, and mechanical behavior of a single segment) and Mfb (including our formulation of Na+ current and mechano-gated channels' current). The effects of the changes in basic cycle length, number of coupled Mfbs and intercellular coupling conductance on myocyte mechanical properties were compared. RESULTS:Our results indicated that these three currents significantly regulated myocyte mechanical parameters. In isosarcometric contraction, these currents increased segment force by 13.8-36.6% and dropped element length by 12.1-31.5%. In isotonic contraction, there are 2.7-5.9% growth and 0.9-24% reduction. Effects of these currents on the extremum of myocyte mechanical parameters become more significant with the increase of basic cycle length, number of coupled Mfbs and intercellular coupling conductance. CONCLUSIONS:The results demonstrated that stretch-activated current in myocytes and Na+ current and mechano-gated channels' current in Mfbs significantly influenced myocyte mechanical behavior and should be considered in future cardiac mechanical mathematical modeling.

Project description:BACKGROUND:Rapid delayed rectifier K+ current (IKr) and late Na+ current (INaL) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT syndromes associated with malignant ventricular arrhythmias and sudden cardiac death. METHODS:Physiological self AP-clamp was used to measure INaL and IKr during the AP in rabbit and porcine ventricular cardiomyocytes to test our hypothesis that the balance between IKr and INaL affects repolarization stability in health and disease conditions. RESULTS:We found comparable amount of net charge carried by IKr and INaL during the physiological AP, suggesting that outward K+ current via IKr and inward Na+ current via INaL are in balance during physiological repolarization. Remarkably, IKr and INaL integrals in each control myocyte were highly correlated in both healthy rabbit and pig myocytes, despite high overall cell-to-cell variability. This close correlation was lost in heart failure myocytes from both species. Pretreatment with E-4031 to block IKr (mimicking long QT syndrome 2) or with sea anemone toxin II to impair Na+ channel inactivation (mimicking long QT syndrome 3) prolonged AP duration (APD); however, using GS-967 to inhibit INaL sufficiently restored APD to control in both cases. Importantly, INaL inhibition significantly reduced the beat-to-beat and short-term variabilities of APD. Moreover, INaL inhibition also restored APD and repolarization stability in heart failure. Conversely, pretreatment with GS-967 shortened APD (mimicking short QT syndrome), and E-4031 reverted APD shortening. Furthermore, the amplitude of AP alternans occurring at high pacing frequency was decreased by INaL inhibition, increased by IKr inhibition, and restored by combined INaL and IKr inhibitions. CONCLUSIONS:Our data demonstrate that IKr and INaL are counterbalancing currents during the physiological ventricular AP and their integrals covary in individual myocytes. Targeting these ionic currents to normalize their balance may have significant therapeutic potential in heart diseases with repolarization abnormalities. Visual Overview: A visual overview is available for this article.

Dataset Information

Effects of Na⁺ Current and Mechanogated Channels in Myofibroblasts on Myocyte Excitability and Repolarization.

Publications

Effects of Na<sup>+</sup> Current and Mechanogated Channels in Myofibroblasts on Myocyte Excitability and Repolarization.

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Dataset Information

Effects of Na+ Current and Mechanogated Channels in Myofibroblasts on Myocyte Excitability and Repolarization.

Publications

Effects of Na<sup>+</sup> Current and Mechanogated Channels in Myofibroblasts on Myocyte Excitability and Repolarization.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Effects of Na⁺ Current and Mechanogated Channels in Myofibroblasts on Myocyte Excitability and Repolarization.