A model for early afterdepolarizations: induction with the Ca2+ channel agonist Bay K 8644.

January, Craig T.; Riddle, Janet; Salata, Joseph J.

doi:10.1161/01.res.62.3.563

Cited by 225 publications

(134 citation statements)

References 33 publications

(13 reference statements)

Supporting

Mentioning

121

Contrasting

Order By: Relevance

“…The simulation of Fig. 15 provides insight into the ionic mechanism that underlies depolarization of such EADs (January et al 1988;January & Riddle, 1989;Rosen, 1990;Luo & Rudy, 1994b;Viswanathan & Rudy, 2000). APs ( Fig.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Computational biology in the study of cardiac ion channels and cell electrophysiology

Rudy

Silva

2006

Quart. Rev. Biophys.

239

181

View full text Add to dashboard Cite

The cardiac cell is a complex biological system where various processes interact to generate electrical excitation (the action potential, AP) and contraction. During AP generation, membrane ion channels interact nonlinearly with dynamically changing ionic concentrations and varying transmembrane voltage, and are subject to regulatory processes. In recent years, a large body of knowledge has accumulated on the molecular structure of cardiac ion channels, their function, and their modification by genetic mutations that are associated with cardiac arrhythmias and sudden death. However, ion channels are typically studied in isolation (in expression systems or isolated membrane patches), away from the physiological environment of the cell where they interact to generate the AP. A major challenge remains the integration of ion-channel properties into the functioning, complex and highly interactive cell system, with the objective to relate molecular-level processes and their modification by disease to whole-cell function and clinical phenotype. In this article we describe how computational biology can be used to achieve such integration. We explain how mathematical (Markov) models of ion-channel kinetics are incorporated into integrated models of cardiac cells to compute the AP. We provide examples of mathematical (computer) simulations of physiological and pathological phenomena, including AP adaptation to changes in heart rate, genetic mutations in SCN5A and HERG genes that are associated with fatal cardiac arrhythmias, and effects of the CaMKII regulatory pathway and β-adrenergic cascade on the cell electrophysiological function. Prologue'Things should be made as simple as possible, but not any simpler.' Albert EinsteinCardiac muscle can generate propagating electrical impulses (action potentials), a property that classifies it as an excitable tissue similar to skeletal muscle and nerve. At the single-cell level, the electrical action potential (AP) triggers mechanical contraction by inducing a transient rise of intracellular calcium which, in turn, carries the contraction message to the contractile proteins of the cell. This process that couples electrical excitation to mechanical function is termed excitation-contraction coupling. APs are generated by individual cells and are conducted from cell to cell through intercellular gap junctions, forming waves of excitation that activate and synchronize the blood pumping action of the heart. Similar to nerve and skeletal muscle, AP initiation and conduction in cardiac ventricular tissue rely mostly on a single membrane process, namely the flow of sodium ions through sodium-specific ion channels. However, unlike the short-duration APs of skeletal muscle and nerve, the cardiac ventricular AP is characterized by long plateau and repolarization phases that prevent premature arrhythmogenic excitation and provide control of mechanical contraction. In NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript contrast to the 'single-current mechanism' of...

show abstract

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Computational biology in the study of cardiac ion channels and cell electrophysiology

Rudy

Silva

2006

Quart. Rev. Biophys.

239

181

View full text Add to dashboard Cite

show abstract

“…22 Catecholamines potentiate all of the main electrophysiologic phenomena underlying arrhythmogenesis: increased automaticity, triggered activity due to EADs or DADs, and reentry. 25,26 However, increased catecholamine concentrations also increase heart rate, which may decrease the EAD amplitude and thereby suppress PVT. Therefore, although catecholamines can enhance both PVT and MVT, they are more likely to enhance MVT.…”

Section: Mechanism Of Cs-induced Ventricular Arrhythmiasmentioning

confidence: 99%

Baroreflex Sensitivity Predicts the Induction of Ventricular Arrhythmias by Cesium Chloride in Rabbits

Ou¹,

Nakagawa²,

Yonemochi³

et al. 1999

Jpn Circ J

View full text Add to dashboard Cite

“…Figure 8 depicts APs and ionic currents to provide insight into the mechanisms by which enhancement of I NaL indirectly triggers EADs [17]. The APD prolongation (panel A) caused by enhancement of I NaL (panel B) leads to the reactivation of the activation gate d (panel F) of the I CaL , which triggers the EAD, as was suggested by January et al [42]. However, the important contribution of the altered Ca 2+ transient should also be taken into consideration.…”

Section: Arrhythmogenic Effects Of I Nalmentioning

confidence: 76%

Influence of heart failure on nucleolar organization and protein expression in human hearts

Roselló‐Lletí¹,

Rivera²,

Cortés³

et al. 2012

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na + current (I NaL ) is relevant and is currently under investigation. In this study we examined the role of I NaL in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of I NaL . A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human I NaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for I NaL in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca 2+ transient. A mechanistic investigation of intracellular Na + accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na + / K + pump, the Na + /Ca 2+ exchanger and I NaL . The results of the simulations also showed that in failing myocytes, the enhancement of I NaL increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the I NaL prolong APD and alter Ca 2+ transient facilitating the development of early afterdepolarizations. An enhanced I NaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca 2+ ] i homeostasis of failing myocytes.

show abstract

A model for early afterdepolarizations: induction with the Ca2+ channel agonist Bay K 8644.

Cited by 225 publications

References 33 publications

Computational biology in the study of cardiac ion channels and cell electrophysiology

Computational biology in the study of cardiac ion channels and cell electrophysiology

Baroreflex Sensitivity Predicts the Induction of Ventricular Arrhythmias by Cesium Chloride in Rabbits

Influence of heart failure on nucleolar organization and protein expression in human hearts

Contact Info

Product

Resources

About