Molecular Remodeling of Kv4.3 Potassium Channels in Human Atrial Fibrillation

Grammer, Joachim B.; Bosch, Ralph F.; Kühlkamp, Volker; Seipel, L

doi:10.1111/j.1540-8167.2000.tb00024.x

Cited by 94 publications

(62 citation statements)

References 26 publications

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“…In some cases, more significant rate adaptation can be observed at the shortest CLs (Kim et al, 2002;Dobrev and Ravens, 2003). Similar alterations to those given by Courtemanche et al (1999) have been observed in other experiments as well (Dobrev and Ravens, 2003), including substantial reductions in I Ca,L (Bosch et al, 1999;Van Wagoner et al, 1999;Skasa et al, 2001;Workman et al, 2001) and I to (Van Wagoner et al, 1997;Bosch et al, 1999;Brandt et al, 2000;Grammer et al, 2000;Workman et al, 2001). The reduction in I Kur proposed by Courtemanche et al (1999) has been found in some studies (Van Wagoner et al, 1997;Brandt et al, 2000) but not in others (Grammer et al, 2000;Workman et al, 2001).…”

Section: Atrial Fibrillation-induced Changes In Rate Dependence and Msupporting

confidence: 83%

Dynamics of human atrial cell models: Restitution, memory, and intracellular calcium dynamics in single cells

Cherry

Hastings

Evans

2008

Progress in Biophysics and Molecular Biology

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Mathematical models of cardiac cells have become important tools for investigating the electrophysiological properties and behavior of the heart. As the number of published models increases, it becomes more difficult to choose a model appropriate for the conditions to be studied, especially when multiple models describing the species and region of the heart of interest are available. In this paper, we will review and compare two detailed ionic models of human atrial myocytes, the Nygren et al. model (NM) and the Courtemanche et al. model (CM). Although both models include the same transmembrane currents and are largely based on the same experimental data from human atrial cells, the two models exhibit vastly different properties, especially in their dynamical behavior, including restitution and memory effects. The CM produces pronounced rate adaptation of action potential duration (APD) with limited memory effects, while the NM exhibits strong rate dependence of resting membrane potential (RMP), limited APD restitution, and stronger memory, as well as delayed afterdepolarizations and auto-oscillatory behavior upon cessation of rapid pacing. Channel conductance modifications based on experimentally measured changes during atrial fibrillation modify rate adaptation and memory in both models, but do not change the primary rate-dependent properties of APD and RMP for the CM and NM, respectively. Two sets of proposed changes to the NM that yield a spike-and-dome action potential morphology qualitatively similar to the CM at slow pacing rates similarly do not change the underlying dynamics of the model. Moreover, interchanging the formulations of all transmembrane currents between the two models while leaving calcium handling and ionic concentrations intact indicates that the currents strongly influence memory and the rate adaptation of RMP, while intracellular calcium dynamics primarily determine APD rate adaptation. Our results suggest that differences in intracellular calcium handling between the two human atrial myocyte models are responsible for marked dynamical differences and may prevent reconciliation between the models by straightforward channel conductance modifications.

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Section: Atrial Fibrillation-induced Changes In Rate Dependence and Msupporting

confidence: 83%

Dynamics of human atrial cell models: Restitution, memory, and intracellular calcium dynamics in single cells

Cherry

Hastings

Evans

2008

Progress in Biophysics and Molecular Biology

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“…Of note, other studies using larger species have reported good correlations between protein and gene expression of the Kv4.3 potassium channel (encoded by Kcnd3; Figure 7A), and down-regulation of this channel was associated with AF in humans and dogs. [51][52][53][54] PI3K(p110␣) has also been reported to differentially regulate metabolism genes in ventricular tissue. 55 Further studies are required to examine the functional consequence of these alterations in gene expression.…”

Section: Discussionmentioning

confidence: 99%

Reduced Phosphoinositide 3-Kinase (p110α) Activation Increases the Susceptibility to Atrial Fibrillation

Pretorius

Woodcock

et al. 2009

The American Journal of Pathology

160

133

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Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments. A limited understanding of the molecular mechanisms responsible for the development of AF has hindered treatment strategies. The purpose of this study was to assess whether reduced activation of phosphoinositide 3-kinase (PI3K, p110␣) makes the compromised heart susceptible to AF. Risk factors for AF, including aging, obesity, and diabetes, have been associated with insulin resistance that leads to depressed/defective PI3K signaling. However, to date, there has been no link between PI3K(p110␣) and AF. To address this question, we crossed a cardiac-specific transgenic mouse model of dilated cardiomyopathy (DCM) with a cardiac-specific transgenic mouse expressing a dominant negative mutant of PI3K (dnPI3K; reduces PI3K activity). Adult (ϳ4.5 months) double-transgenic (dnPI3K-DCM), single-transgenic (DCM-Tg, dnPI3K-Tg), and nontransgenic mice were subjected to morphological, functional/ECG, microarray, and biochemical analyses. dnPI3K-DCM mice developed AF and had depressed cardiac function as well as greater atrial enlargement and fibrosis than DCM-Tg mice. AF was not detected in other groups. Aged DCM-Tg mice (ϳ15 months) with a similar phenotype to dnPI3K-DCM mice (4.5 months) did not develop AF , suggesting loss of PI3K activity directly contributed to the AF phenotype. Furthermore, increasing PI3K activity reduced atrial fibrosis and improved cardiac conduction in DCM-Tg mice. Finally, in atrial appendages from patients with AF, PI3K activation was lower compared with tissue from patients in sinus rhythm. These results suggest a link between PI3K(p110␣) and AF. (Am J Pathol

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“…11 In experimental reports from animal models in which tachycardia lasted several hours to several months, there was down-regulation of the L-type calcium current (IcaL) 12,13 associated with excessive intracellular calcium loading, and down-regulation in the ultrarapid delayed rectifier potassium current (Ikur), 14 transient outward potassium current (Ito), 13 sodium current (INa) 15 and slow-type delayed rectifier potassium current (Iks) 16 as an up-regulation of ion channels. In human atrial muscle that has been converted to permanent AF, down-regulation of ion channels such as the L-type calcium current (IcaL) 17 and transient outward potassium current (Ito), 18 and up-regulation of the inward potassium current (Ikl) and acetylcholine-activated potassium current (IKach) 17 have been reported, whereas neither the ultrarapid delayed rectifier potassium current (Ikur) 18 nor rapid delayed rectifier potassium current (Ikr) 19 showed any changes. Those changes in the ion channels result in a shortened effective refractory period of atrial muscle and shortened excitable wave lengths according to the reduction of conduction velocity.…”

Section: Discussionmentioning

confidence: 99%

Randomized Crossover Study of the Long-Term Effects of Pilsicainide and Cibenzoline in Preventing Recurrence of Symptomatic Paroxysmal Atrial Fibrillation Influence of the Duration of Arrhythmia Before Therapy

Kubo

Satō

Tachibana

et al. 2006

Circ J

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Molecular Remodeling of Kv4.3 Potassium Channels in Human Atrial Fibrillation

Abstract: Chronic AF in humans reduces Ito by transcriptional down-regulation of the Kv4.3 potassium channel. Altered gene expression is an important component of the electrical remodeling process and may contribute to repolarization abnormalities in AF.

Cited by 94 publications

References 26 publications

Dynamics of human atrial cell models: Restitution, memory, and intracellular calcium dynamics in single cells

Dynamics of human atrial cell models: Restitution, memory, and intracellular calcium dynamics in single cells

Reduced Phosphoinositide 3-Kinase (p110α) Activation Increases the Susceptibility to Atrial Fibrillation

Randomized Crossover Study of the Long-Term Effects of Pilsicainide and Cibenzoline in Preventing Recurrence of Symptomatic Paroxysmal Atrial Fibrillation Influence of the Duration of Arrhythmia Before Therapy

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