Dataset Information

Slow Delayed Rectifier Current Protects Ventricular Myocytes From Arrhythmic Dynamics Across Multiple Species: A Computational Study.

ABSTRACT: BACKGROUND:The slow and rapid delayed rectifier K+ currents (IKs and IKr, respectively) are responsible for repolarizing the ventricular action potential (AP) and preventing abnormally long APs that may lead to arrhythmias. Although differences in biophysical properties of the 2 currents have been carefully documented, the respective physiological roles of IKr and IKs are less established. In this study, we sought to understand the individual roles of these currents and quantify how effectively each stabilizes the AP and protects cells against arrhythmias across multiple species. METHODS:We compared 10 mathematical models describing ventricular myocytes from human, rabbit, dog, and guinea pig. We examined variability within heterogeneous cell populations, tested the susceptibility of cells to proarrhythmic behavior, and studied how IKs and IKr responded to changes in the AP. RESULTS:We found that (1) models with higher baseline IKs exhibited less cell-to-cell variability in AP duration; (2) models with higher baseline IKs were less susceptible to early afterdepolarizations induced by depolarizing perturbations; (3) as AP duration is lengthened, IKs increases more profoundly than IKr, thereby providing negative feedback that resists excessive AP prolongation; and (4) the increase in IKs that occurs during ?-adrenergic stimulation is critical for protecting cardiac myocytes from early afterdepolarizations under these conditions. CONCLUSIONS:Slow delayed rectifier current is uniformly protective across a variety of cell types. These results suggest that IKs enhancement could potentially be an effective antiarrhythmic strategy.

SUBMITTER: Varshneya M

PROVIDER: S-EPMC6326778 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Slow Delayed Rectifier Current Protects Ventricular Myocytes From Arrhythmic Dynamics Across Multiple Species: A Computational Study.

Varshneya Meera M Devenyi Ryan A RA Sobie Eric A EA

Circulation. Arrhythmia and electrophysiology 20181001 10

<h4>Background</h4>The slow and rapid delayed rectifier K+ currents (IKs and IKr, respectively) are responsible for repolarizing the ventricular action potential (AP) and preventing abnormally long APs that may lead to arrhythmias. Although differences in biophysical properties of the 2 currents have been carefully documented, the respective physiological roles of IKr and IKs are less established. In this study, we sought to understand the i ...[more]

PMID: 30354408

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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.

Project description:Force-frequency relationships of isolated cardiac myocytes show complex behaviors that are thought to be specific to both the species and the conditions associated with the experimental preparation. Ca(2+) signaling plays an important role in shaping the force-frequency relationship, and understanding the properties of the force-frequency relationship in vivo requires an understanding of Ca(2+) dynamics under physiologically relevant conditions. Ca(2+) signaling is itself a complicated process that is best understood on a quantitative level via biophysically based computational simulation. Although a large number of models are available in the literature, the models are often a conglomeration of components parameterized to data of incompatible species and/or experimental conditions. In addition, few models account for modulation of Ca(2+) dynamics via ?-adrenergic and calmodulin-dependent protein kinase II (CaMKII) signaling pathways even though they are hypothesized to play an important regulatory role in vivo. Both protein-kinase-A and CaMKII are known to phosphorylate a variety of targets known to be involved in Ca(2+) signaling, but the effects of these pathways on the frequency- and inotrope-dependence of Ca(2+) dynamics are not currently well understood. In order to better understand Ca(2+) dynamics under physiological conditions relevant to rat, a previous computational model is adapted and re-parameterized to a self-consistent dataset obtained under physiological temperature and pacing frequency and updated to include ?-adrenergic and CaMKII regulatory pathways. The necessity of specific effector mechanisms of these pathways in capturing inotrope- and frequency-dependence of the data is tested by attempting to fit the data while including and/or excluding those effector components. We find that: (1) ?-adrenergic-mediated phosphorylation of the L-type calcium channel (LCC) (and not of phospholamban (PLB)) is sufficient to explain the inotrope-dependence; and (2) that CaMKII-mediated regulation of neither the LCC nor of PLB is required to explain the frequency-dependence of the data.

Dataset Information

Slow Delayed Rectifier Current Protects Ventricular Myocytes From Arrhythmic Dynamics Across Multiple Species: A Computational Study.

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Slow Delayed Rectifier Current Protects Ventricular Myocytes From Arrhythmic Dynamics Across Multiple Species: A Computational Study.

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