The Cardiac Ventricular Action Potential

Rudy, Yoram

doi:10.1002/cphy.cp020113

Cited by 11 publications

(14 citation statements)

References 137 publications

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“…A delicate balance between repolarizing and depolarizing currents provides for precise control of the AP time course (54). Because this balance is modulated by [Ca 2ϩ ] i , it is important to use physiologically detailed models of the cardiac myocyte for studying the interaction between the Ca 2ϩ and electrical subsystems in the study of alternans.…”

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confidence: 99%

Regulation of Ca²⁺and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents

Livshitz¹,

Rudy²

2007

American Journal of Physiology-Heart and Circulatory Physiology

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135

134

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Alternans of cardiac repolarization is associated with arrhythmias and sudden death. At the cellular level, alternans involves beat-to-beat oscillation of the action potential (AP) and possibly Ca(2+) transient (CaT). Because of experimental difficulty in independently controlling the Ca(2+) and electrical subsystems, mathematical modeling provides additional insights into mechanisms and causality. Pacing protocols were conducted in a canine ventricular myocyte model with the following results: 1) CaT alternans results from refractoriness of the sarcoplasmic reticulum Ca(2+) release system; alternation of the L-type calcium current has a negligible effect; 2) CaT-AP coupling during late AP occurs through the sodium-calcium exchanger and underlies AP duration (APD) alternans; 3) increased Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity extends the range of CaT and APD alternans to slower frequencies and increases alternans magnitude; its decrease suppresses CaT and APD alternans, exerting an antiarrhythmic effect; and 4) increase of the rapid delayed rectifier current (I(Kr)) also suppresses APD alternans but without suppressing CaT alternans. Thus CaMKII inhibition eliminates APD alternans by eliminating its cause (CaT alternans) while I(Kr) enhancement does so by weakening CaT-APD coupling. The simulations identify combined CaMKII inhibition and I(Kr) enhancement as a possible antiarrhythmic intervention.

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confidence: 99%

Regulation of Ca²⁺and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents

Livshitz¹,

Rudy²

2007

American Journal of Physiology-Heart and Circulatory Physiology

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135

134

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“…The diverse nature of cardiac myocyte action potentials arises from the non‐linear and finely balanced gating characteristics of many different ionic currents (Carmeliet & Vereecke, 2002; Rudy, 2002; Nerbonne & Kass, 2003; Bondarenko et al 2004; Puglisi, Wang & Bers, 2004). This electrical diversity arises from the combined effects of spatial tissue gradients of gene expression, biophysical channel gating mechanisms, second messenger systems, intracellular Ca 2+ regulatory mechanisms and complex interactions between these multiple systems.…”

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confidence: 99%

“…Different regions of the channel complex may also control inactivation and recovery separately. No proposed Kv4 channel or native phenotypic I to gating model can account for all of these observations (Campbell et al 1993 a , b ; Greenstein et al 2000; Winslow et al 2000; Puglisi & Bers, 2001; Bähring et al 2001 a ; Rudy, 2002; Beck et al 2002; Bondarenko et al 2004; Jerng, Qian & Pfaffinger, 2004; Wang, Puglisi & Bers, 2004; Iyer et al 2004; Winslow et al 2005).…”

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confidence: 99%

Transient outward potassium current, ‘I_to’, phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms

Patel

Campbell

2005

The Journal of Physiology

178

192

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At least two functionally distinct transient outward K + current (I to ) phenotypes can exist across the free wall of the left ventricle (LV). Based upon their voltage-dependent kinetics of recovery from inactivation, these two phenotypes are designated 'I to,fast ' (recovery time constants on the order of tens of milliseconds) and 'I to,slow ' (recovery time constants on the order of thousands of milliseconds). Depending upon species, either I to,fast , I to,slow or both current phenotypes may be expressed in the LV free wall. The expression gradients of these two I to phenotypes across the LV free wall are typically heterogeneous and, depending upon species, may consist of functional phenotypic gradients of both I to,fast and I to,slow and/or density gradients of either phenotype. We review the present evidence (molecular, biophysical, electrophysiological and pharmacological) for Kv4.2/4.3 α subunits underlying LV I to,fast and Kv1.4 α subunits underlying LV I to,slow and speculate upon the potential roles of each of these currents in determining frequency-dependent action potential characteristics of LV subepicardial versus subendocardial myocytes in different species. We also review the possible functional implications of (i) ancillary subunits that regulate Kv1.4 and Kv4.2/4.3 (Kvβ subunits, DPPs), (ii) KChIP2 isoforms, (iii) spider toxin-mediated block of Kv4.2/4.3 (Heteropoda toxins, phrixotoxins), and (iv) potential mechanisms of modulation of I to,fast and I to,slow by cellular redox state, [Ca 2+ ] i and kinase-mediated phosphorylation. I to phenotypic activation and state-dependent gating models and molecular structure-function relationships are also discussed.

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“…The general approach for modelling the AP is the same as described for the dynamic Luo–Rudy (LRd) model of a cardiac ventricular cell [6–8]. For simulating ion channel mutations, a Markov model of the channel is formulated from the single‐channel kinetics [2, 3, 9].…”

Section: Methodsmentioning

confidence: 99%

“… Integrating ion channel kinetics into the whole‐cell model. To relate ion channel properties to whole‐cell function, a Markov model of the channel is introduced into the Luo–Rudy dynamic (LRd) model of a cardiac ventricular cell [6–8]. For simulating HERG mutations [3], the Markovian model of I Kr includes three closed states (C3, C2, C1), an open state (O), and an inactivated state (I).…”

Section: Methodsmentioning

confidence: 99%

Modelling and imaging cardiac repolarization abnormalities

Rudy

2005

Journal of Internal Medicine

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Abstract. Rudy Y (Washington University in St Louis, St Louis, MO, USA). Modelling and imaging cardiac repolarization abnormalities. J Intern Med 2006; 259: 91-106. Repolarization abnormalities, including those induced by the congenital or acquired long QT (LQT) syndrome, provide a substrate for lifethreatening cardiac arrhythmias. In this article, we use computational biology to link HERG mutations mechanistically to the resulting abnormalities of the whole-cell action potential. We study how the kinetic properties of I Ks (the slow delayed rectifier) that are conferred by molecular subunit interactions, facilitate its role in repolarization and 'repolarization reserve'. A new noninvasive imaging modality (electrocardiographic imaging) is shown to image cardiac repolarization on the epicardial surface, suggesting its possible role in risk stratification, diagnosis and treatment of LQT syndrome.

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The Cardiac Ventricular Action Potential

Cited by 11 publications

References 137 publications

Regulation of Ca²⁺and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents

Regulation of Ca²⁺and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents

Transient outward potassium current, ‘I_to’, phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms

Modelling and imaging cardiac repolarization abnormalities

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The Cardiac Ventricular Action Potential

Cited by 11 publications

References 137 publications

Regulation of Ca2+and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents

Regulation of Ca2+and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents

Transient outward potassium current, ‘Ito’, phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms

Modelling and imaging cardiac repolarization abnormalities

Contact Info

Product

Resources

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Regulation of Ca²⁺and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents

Regulation of Ca²⁺and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents

Transient outward potassium current, ‘I_to’, phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms