A Simplified Local Control Model of Calcium-Induced Calcium Release in Cardiac Ventricular Myocytes

Hinch, Robert; Greenstein, Joseph L.; Tanskanen, Antti; Li, Xu; Winslow, Raimond L.

doi:10.1529/biophysj.104.049973

Cited by 121 publications

(184 citation statements)

References 52 publications

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“…All channels in a given release site experience the same local [Ca 2ϩ ] (myoplasmic and SR), but these "domain" [Ca 2ϩ ] are heterogenous throughout the cell, i.e., different release sites experience different domain [Ca 2ϩ ]. Similar to previous work by Hinch and colleagues (16,25,26) , and closes with a Ca 2ϩ -independent transition rate:…”

Section: Model Formulationsupporting

confidence: 90%

“…1) is similar to previously published Monte Carlo models of local control (17). The assumptions made here regarding the rapid equilibration of domain Ca 2ϩ are similar to assumptions made in previously published local control models that represent the stochastic dynamics of a large number of Ca 2ϩ -release sites (16,25), but these previous studies have not made a distinction between domain and bulk SR Ca 2ϩ as done in our minimal whole cell model.…”

supporting

confidence: 76%

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Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes

Hartman

Sobie

Smith

2010

American Journal of Physiology-Heart and Circulatory Physiology

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] in the myoplasm or SR can influence the frequency, amplitude, and kinetics of local events. In ventricular myocytes, for instance, propagating Ca 2ϩ waves emerge when spontaneous Ca 2ϩ sparks trigger additional sparks in a regenerative fashion (5). Similarly, changes in channel gating at the level of individual RyRs can immediately affect the production of local events and, over time, influence bulk myoplasmic and SR [Ca 2ϩ ]. An increase in RyR opening will cause a gradual decrease in SR [Ca 2ϩ ] (46), whereas inhibition of RyR opening, over time, will lead to elevated SR [Ca 2ϩ ] (21). This principle has been elegantly demonstrated by Lukyanenko and coworkers (35) in quiescent rat ventricular myocytes treated with caffeine (to sensitize RyRs) or tetracaine (to inhibit RyRs).In heart cells, changes in Ca 2ϩ signaling due to altered RyR activity are currently receiving considerable attention because of close links to disease (13, 48). In particular, catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disorder associated with a dramatic increase in arrhythmia risk, results from mutations in either RyRs or calsequestrin, a SR Ca 2ϩ buffer protein that associates with and modulates RyRs (20,33). Experiments in vitro have shown that CPVT-causing mutations usually increase the open probability of the RyR, resulting in a hyperactive or "leaky" channel (12,28,31). Studies (1, 36) have also suggested that leaky RyRs are characteristic of several experimental heart failure models. Thus, a quantitative understanding of how changes in RyR gating influence local and global Ca 2ϩ responses can provide insights into disease pathophysiology and can potentially suggest novel therapies.The difference in spatial scales between local and global Ca 2ϩ signals, however, creates significant challenges for the development of mechanistic mathematical models. In particular, gating of RyRs depends on both myoplasmic and SR [Ca 2ϩ ] (30), and concentrations within clusters during local events can be dramatically different from the bulk concentrations. In addition, because of the relatively small number of RyRs responsible for Ca 2ϩ sparks (6), the stochastic gating of these channels must be considered when simulating local events. Previous studies (9,27,42,44) have used Monte Carlo simulation methods to investigate the stochastic triggering of Ca 2ϩ sparks, but these have generally treated myoplasmic and bulk SR [Ca 2ϩ ] as fixed boundary conditions. Conversely, modeling studies (4, 10, 40) focusing on cellular Ca 2ϩ transients have usually used representations of SR Ca 2ϩ release that do not account for the stochastic nature of the local events. Attempting to simulate Ca 2ϩ signaling at both spatial scales simultaneously is a daunting prospect because the stochastic behavior of thousands of local events must be considered to determine the effects on the bulk concentrations. As a result, only a few studies (16, 17, 49, 50) have attempted to capture both phenomena.

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Section: Model Formulationsupporting

confidence: 90%

supporting

confidence: 76%

Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes

Hartman

Sobie

Smith

2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…Hinch et al (22) fitted the potential when half of the L-type Ca channels are open (VL) as well as the width of opening potentials (⌬VL) to the current-voltage (I-V) curve of the current (22). However, it is likely that the other 16 parameters also need to be reassessed due to differences between the rat and mouse.…”

Section: Model Derivationmentioning

confidence: 99%

A mathematical model of the murine ventricular myocyte: a data-driven biophysically based approach applied to mice overexpressing the canine NCX isoform

Niederer

Idigo

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Li L, Niederer SA, Idigo W, Zhang YH, Swietach P, Casadei B, Smith NP. A mathematical model of the murine ventricular myocyte: a data-driven biophysically based approach applied to mice overexpressing the canine NCX isoform. Am J Physiol Heart Circ Physiol 299: H1045-H1063, 2010. First published July 23, 2010; doi:10.1152/ajpheart.00219.2010.-Mathematical modeling of Ca 2ϩ dynamics in the heart has the potential to provide an integrated understanding of Ca 2ϩ -handling mechanisms. However, many previous published models used heterogeneous experimental data sources from a variety of animals and temperatures to characterize model parameters and motivate model equations. This methodology limits the direct comparison of these models with any particular experimental data set. To directly address this issue, in this study, we present a biophysically based model of Ca 2ϩ dynamics directly fitted to experimental data collected in left ventricular myocytes isolated from the C57BL/6 mouse, the most commonly used genetic background for genetically modified mice in studies of heart diseases. This Ca 2ϩ dynamics model was then integrated into an existing mouse cardiac electrophysiology model, which was reparameterized using experimental data recorded at consistent and physiological temperatures. The model was validated against the experimentally observed frequency response of Ca 2ϩ dynamics, action potential shape, dependence of action potential duration on cycle length, and electrical restitution. Using this framework, the implications of cardiac Na ϩ / Ca 2ϩ exchanger (NCX) overexpression in transgenic mice were investigated. These simulations showed that heterozygous overexpression of the canine cardiac NCX increases intracellular Ca 2ϩ concentration transient magnitude and sarcoplasmic reticulum Ca 2ϩ loading, in agreement with experimental observations, whereas acute overexpression of the murine cardiac NCX results in a significant loss of Ca 2ϩ from the cell and, hence, depressed sarcoplasmic reticulum Ca 2ϩ load and intracellular Ca 2ϩ concentration transient magnitude. From this analysis, we conclude that these differences are primarily due to the presence of allosteric regulation in the canine cardiac NCX, which has not been observed experimentally in the wild-type mouse heart. calcium transient; C57BL/6 mouse; Na ϩ /Ca 2ϩ exchanger THE RHYTHMIC CONTRACTION of the heart is dependent on tightly regulated intracellular events triggered in a concerted fashion by electrical stimulation. Among a number of regulatory steps, Ca 2ϩ plays, arguably, the most fundamental role in orchestrating the excitation-contraction coupling process. (34, 59). With the large amount of experimental data in the mouse now becoming available, mathematical modeling has the potential power to rationalize the data and provide an integrated understanding of the mouse heart. Previously, Bondarenko and colleagues (6) developed a biophysically based electrophysiology model of murine left ventricular (LV) myocytes. However, several limitations with t...

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“…Stiffness can be eliminated by separation of time scales, for instance by asymptotic approximations (e.g. Hinch et al 2004). Principal component analysis or sensitivity analysis can be used for removal of parameters or model parts to which the output is insensitive (e.g.…”

Section: Model Identification-model Selectionmentioning

confidence: 99%

Cardiac cell modelling: Observations from the heart of the cardiac physiome project

Fink

Niederer

Cherry

et al. 2011

Progress in Biophysics and Molecular Biology

146

136

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In this manuscript we review the state of cardiac cell modelling in the context of international initiatives such as the IUPS Physiome and Virtual Physiological Human Projects, which aim to integrate computational models across scales and physics. In particular we focus on the relationship between experimental data and model parameterisation across a range of model types and cellular physiological systems. Finally, in the context of parameter identification and model reuse within the Cardiac Physiome, we suggest some future priority areas for this field.

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A Simplified Local Control Model of Calcium-Induced Calcium Release in Cardiac Ventricular Myocytes

Cited by 121 publications

References 52 publications

Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes

Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes

A mathematical model of the murine ventricular myocyte: a data-driven biophysically based approach applied to mice overexpressing the canine NCX isoform

Cardiac cell modelling: Observations from the heart of the cardiac physiome project

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A Simplified Local Control Model of Calcium-Induced Calcium Release in Cardiac Ventricular Myocytes

Cited by 121 publications

References 52 publications

Spontaneous Ca2+ sparks and Ca2+ homeostasis in a minimal model of permeabilized ventricular myocytes

Spontaneous Ca2+ sparks and Ca2+ homeostasis in a minimal model of permeabilized ventricular myocytes

A mathematical model of the murine ventricular myocyte: a data-driven biophysically based approach applied to mice overexpressing the canine NCX isoform

Cardiac cell modelling: Observations from the heart of the cardiac physiome project

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Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes

Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes