Modelling and imaging cardiac repolarization abnormalities

Rudy, Yoram

doi:10.1111/j.1365-2796.2005.01586.x

Cited by 12 publications

(6 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This force-frequency dependence arises even in the absence of β-adrenergic stimulation, as evidenced by the observation that in isolated myocytes fast pacing leads to a greater calcium transient (CaT) amplitude and increased force of contraction (Wang et al 1988). The CaMKII signaling cascade is likely to be involved in this process, because it has been shown to interact with the cell machinery that generates the CaT (Maier & Bers, 2002;Hund & Rudy, 2004,2006Zhang et al 2005). Specifically, CaMKII substrates include I Ca(L) , the ryanodine receptor (RyR), the SR Ca 2+ -uptake pump (SERCA2a) and phospholamban (PLB) (Le Peuch et al 1979;Wegener et al 1989;Witcher et al 1991;Toyofuku et al 1994;Yuan & Bers, 1994;Odermatt et al 1996;Hagemann et al 2000).…”

Section: Camkii Regulation Of the Ca 2+ Transientmentioning

confidence: 99%

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

Rudy

Silva

2006

Quart. Rev. Biophys.

241

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: Camkii Regulation Of the Ca 2+ Transientmentioning

confidence: 99%

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

Rudy

Silva

2006

Quart. Rev. Biophys.

241

181

View full text Add to dashboard Cite

show abstract

“…Decreased repolarization reserve results from augmented inward and/or diminished outward currents during the late phase of the AP plateau, so that small increases in inward currents, classically mediated by reactivation of the L-type Ca (I Ca,L ) window current (7,8,27,31,38), can reverse repolarization to create an EAD. EADs are often exacerbated by bradycardia because more complete deactivation of K channels into deeply closed states during diastole further decreases systolic repolarization reserve (23). As such, the role of EADs as triggers of cardiac arrhythmias has received greater emphasis than their potential effects on destabilization of already established reentry.…”

mentioning

confidence: 99%

Effects of early afterdepolarizations on reentry in cardiac tissue: a simulation study

Huffaker

Weiss²,

Kogan³

2007

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Early afterdepolarizations (EADs) are classically generated at slow heart rates when repolarization reserve is reduced by genetic diseases or drugs. However, EADs may also occur at rapid heart rates if repolarization reserve is sufficiently reduced. In this setting, spontaneous diastolic sarcoplasmic reticulum (SR) Ca release can facilitate cellular EAD formation by augmenting inward currents during the action potential plateau, allowing reactivation of the window L-type Ca current to reverse repolarization. Here, we investigated the effects of spontaneous SR Ca release-induced EADs on reentrant wave propagation in simulated one-, two-, and three-dimensional homogeneous cardiac tissue using a version of the Luo-Rudy dynamic ventricular action potential model modified to increase the likelihood of these EADs. We found: 1) during reentry, nonuniformity in spontaneous SR Ca release related to subtle differences in excitation history throughout the tissue created adjacent regions with and without EADs. This allowed EADs to initiate new wavefronts propagating into repolarized tissue; 2) EAD-generated wavefronts could propagate in either the original or opposite direction, as a single new wave or two new waves, depending on the refractoriness of tissue bordering the EAD region; 3) by suddenly prolonging local refractoriness, EADs caused rapid rotor displacement, shifting the electrical axis; and 4) rapid rotor displacement promoted self-termination by collision with tissue borders, but persistent EADs could regenerate single or multiple focal excitations that reinitiated reentry. These findings may explain many features of Torsades des pointes, such as perpetuation by focal excitations, rapidly changing electrical axis, frequent self-termination, and occasional degeneration to fibrillation.

show abstract

“…While EADs are known to occur under conditions of reduced repolarization reserve, such as the various LQT syndromes, they usually require further reduction of repolarization reserve via rate-dependent mechanisms. Under conditions of bradycardia, repolarization reserve is reduced by more complete deactivation of outward K currents during long diastolic intervals [29]. Under conditions of tachycardia, we found that repolarization reserve is reduced by larger Ca-sensitive inward currents during the AP plateau, which in this model is caused by a larger overall Ca i transient when the J spon -triggered release summated with the AP-triggered, I CaL -gated CICR.…”

Section: Discussionmentioning

confidence: 68%

Tachycardia-induced early afterdepolarizations: Insights into potential ionic mechanisms from computer simulations

Huffaker

Samade

Weiss

et al. 2008

Computers in Biology and Medicine

View full text Add to dashboard Cite

Although early afterdepolarizations (EADs) are classically thought to occur at slow heart rates, mounting evidence suggests that EADs may also occur at rapid heart rates produced by tachyarrhythmias, due to Ca overload of the sarcoplasmic reticulum (SR) leading to spontaneous SR Ca release. We hypothesized that the mechanism of tachycardia-induced EADs depends on the spatial and temporal morphology of spontaneous SR Ca release, and tested this hypothesis in computer simulations using a ventricular action potential mathematical model. Using two previously suggested spontaneous release morphologies, we found two distinct tachycardia-induced EAD mechanisms: one mechanistically similar to bradycardia-induced EADs, the other to delayed afterdepolarizations (DADs).

show abstract

Modelling and imaging cardiac repolarization abnormalities

Cited by 12 publications

References 46 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

Effects of early afterdepolarizations on reentry in cardiac tissue: a simulation study

Tachycardia-induced early afterdepolarizations: Insights into potential ionic mechanisms from computer simulations

Contact Info

Product

Resources

About