Parameter Sensitivity Analysis of Stochastic Models Provides Insights into Cardiac Calcium Sparks

Lee, Young-Seon; Liu, Ona Z.; Hwang, Hyun Seok; Knollmann, Björn C.; Sobie, Eric A.

doi:10.1016/j.bpj.2012.12.055

Cited by 47 publications

(60 citation statements)

References 39 publications

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“…While this approach makes use of validated models that highlight specific characteristics of the physiology, such as a spike-and-dome AP morphology, a more comprehensive and less biased approach to understanding the relationships between MEF mechanisms and model characteristics could be achieved through broader reaching approaches to parameter estimation and sensitivity analyses (Britton et al, 2013; Lee et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

An integrative appraisal of mechano-electric feedback mechanisms in the heart

Timmermann

Dejgaard

Haugaa

et al. 2017

Progress in Biophysics and Molecular Biology

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Mechanically-induced alterations in cardiac electrophysiology are referred to as mechano-electric feedback (MEF), and play an important role in electrical regulation of cardiac performance. The influence of mechanical stress and strain on electrophysiology has been investigated at all levels, however the role of MEF in arrhythmia remains poorly understood. During the normal contraction of the heart, mechano-sensitive processes are an implicit component of cardiac activity. Under abnormal mechanical events, stretch-activated mechanisms may contribute to local or global changes in electrophysiology (EP). While such mechanisms have been hypothesised to be involved in mechanically-initiated arrhythmias, the details of these mechanisms and their importance remain elusive. We assess the theoretical role of stretch mechanisms using coupled models of cellular electrophysiology and sarcomere contraction dynamics. Using models of single ventricular myocytes, we first investigated the potential MEF contributions of stretch-activated currents (SAC), and stretch-induced myofilament calcium release, to test how strain and fibrosis may alter cellular electrophysiology. For all models investigated, SACs were alone not sufficient to create a pro-arrhythmic perturbation of the action potential with stretch. However, when combined with stretch-induced myofilament calcium release, the action potential could be shortened depending on the timing of the strain. This effect was highly model dependent, with a canine epicardial EP model being the most sensitive. These model results suggest that known mechanisms of mechano-electric coupling in cardiac myocyte may be sufficient to be pro-arrhythmic, but only in combination and under specific strain patterns.

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Section: Discussionmentioning

confidence: 99%

An integrative appraisal of mechano-electric feedback mechanisms in the heart

Timmermann

Dejgaard

Haugaa

et al. 2017

Progress in Biophysics and Molecular Biology

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“…In addition to the number of RyRs, mathematical modeling studies 17 strongly support the idea that the jSR volume would be an important factor that could interfere with reduce the total amount of Ca 2+ released by CRUs during excitationcontraction coupling. We measured the relative fiber volume occupied by jSR in both WT and R33Q cells ( Table 2, column F) and verified that jSR volume is reduced by ≈30% (P<0.01) in R33Q versus WT (0.33±0.03 versus 0.23±0.02, respectively).…”

Section: Structural and Ultrastructural Features Of R33q Myocytesmentioning

confidence: 93%

Abnormal Propagation of Calcium Waves and Ultrastructural Remodeling in Recessive Catecholaminergic Polymorphic Ventricular Tachycardia

Liu

Denegri

Dun

et al. 2013

Circulation Research

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C atecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by stress-and emotion-induced life-threatening arrhythmias. Mutations in the cardiac ryanodine receptor-2 (RyR2) and cardiac calsequestrin-2 (CASQ2) genes have been associated with the autosomal-dominant and the autosomalrecessive forms of CPVT.1 Knock-in mouse models that carry gain-of-function RyR2 mutations exhibit phenotypes similar to the clinical manifestations observed in patients with CPVT, including the development of bidirectional/polymorphic VT on exposure to catecholamines.2-5 Investigations of knock-in models of dominant CPVT have demonstrated that abnormal Ca 2+ release from mutant RyR2 induces cell-wide Ca 2+ waves, delayed afterdepolarizations (DADs) and triggered activity, all of which are arrhythmogenic. 2,4,6 Recently, attention has turned to the study of the recessive form of CPVT that is caused by homozygous mutations in the CASQ2 gene. Most experimental studies on recessive CPVT have been performed using CASQ2 knockout mice, whereas only few knock-in mouse carriers of human CASQ2 mutations sparks with shortened coupling intervals, suggesting a reduced refractoriness of Ca 2+ release events; (3) have a reduction of the area of membrane contact, of the junctions between junctional sarcoplasmic reticulum and T tubules (couplons), and of junctional sarcoplasmic reticulum volume; (4) have a propensity to develop phase 2 to 4 afterdepolarizations that can elicit triggered beats; and (5) involve viral gene transfer with wild-type cardiac calsequestrin-2 that is able to normalize structural abnormalities and to restore cell-wide calcium wave propagation. Conclusions:Our data show that homozygous cardiac calsequestrin-2-R33Q myocytes develop spontaneous Ca 2+ release events with a broad range of intervals coupled to preceding beats, leading to the formation of early and delayed afterdepolarizations. They also display a major disruption of the Ca 2+ release unit architecture that leads to fragmentation of spontaneous Ca 2+ waves. We propose that these 2 substrates in R33Q myocytes synergize to provide a new arrhythmogenic mechanism for catecholaminergic polymorphic ventricular tachycardia. (Circ Res. 2013;113:142-152.)

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“…“Population-based modeling” methods globally probe complex biological systems by studying a large number of model variants with broadly varied parameters to understand how the component parts work together to generate higher-level behaviors. One common application of this strategy, parameter sensitivity analysis [20–28], can be used to distill the complex underlying model into readily interpretable sensitivity coefficients that quantify how changes in model parameters affect key behaviors.…”

Section: Introductionmentioning

confidence: 99%

There and back again: Iterating between population-based modeling and experiments reveals surprising regulation of calcium transients in rat cardiac myocytes

Devenyi

Sobie

2016

Journal of Molecular and Cellular Cardiology

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While many ion channels and transporters involved in cardiac cellular physiology have been identified and described, the relative importance of each in determining emergent cellular behaviors remains unclear. Here we address this issue with a novel approach that combines population-based mathematical modeling with experimental tests to systematically quantify the relative contributions of different ion channels and transporters to the amplitude of the cellular Ca2+ transient. Sensitivity analysis of a mathematical model of the rat ventricular cardiomyocyte quantified the response of cell behaviors to changes in the level of each ion channel and transporter, and experimental tests of these predictions were performed to validate or invalidate the predictions. The model analysis found that partial inhibition of transient outward current in rat ventricular epicardial myocytes was predicted to have a greater impact on Ca2+ transient amplitude than either: (1) inhibition of the same current in endocardial myocytes, or (2) comparable inhibition of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). Experimental tests confirmed the model predictions qualitatively but showed some quantitative disagreement. This guided us to recalibrate the model by adjusting the relative importance of several Ca2+ fluxes, thereby improving the consistency with experimental data and producing a more predictive model. Analysis of human cardiomyocyte models suggests that the relative importance of outward currents to Ca2+ transporters is generalizable to human atrial cardiomyocytes, but not ventricular cardiomyocytes. Overall, our novel approach of combining population-based mathematical modeling with experimental tests has yielded new insight into the relative importance of different determinants of cell behavior.

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Parameter Sensitivity Analysis of Stochastic Models Provides Insights into Cardiac Calcium Sparks

Cited by 47 publications

References 39 publications

An integrative appraisal of mechano-electric feedback mechanisms in the heart

An integrative appraisal of mechano-electric feedback mechanisms in the heart

Abnormal Propagation of Calcium Waves and Ultrastructural Remodeling in Recessive Catecholaminergic Polymorphic Ventricular Tachycardia

There and back again: Iterating between population-based modeling and experiments reveals surprising regulation of calcium transients in rat cardiac myocytes

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