Yoga for the sinoatrial node: Sarcoplasmic reticulum calcium release confers flexibility

Cummins, Megan; Devenyi, Ryan A.; Sobie, Eric A.

doi:10.1016/j.yjmcc.2013.04.020

Cited by 6 publications

(3 citation statements)

References 37 publications

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“…Parameter sensitivity analysis allows for global and readily interpretable quantification of how these behaviours are influenced by many different model parameters, such as the levels of all ion channels, transporters and pumps. These techniques have been used to quantify the determinants of a variety of crucial aspects of cardiomyocyte physiology, such as Ca 2+ handling (Lee et al 2013;Devenyi & Sobie, 2016), AP morphology (Tondel et al 2011;Mann et al 2012;Britton et al 2013;Heijman et al 2013), arrhythmogenic dynamics (Sarkar & Sobie, 2011;Sadrieh et al 2013;Chang et al 2014;Cummins et al 2014;Sadrieh et al 2014;Zhou et al 2016) and pacemaking in the sinoatrial node (Cummins et al 2013;Maltsev & Lakatta, 2013).…”

Section: Introductionmentioning

confidence: 99%

Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility

Devenyi

Ortega

Groenendaal

et al. 2016

The Journal of Physiology

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Imbalances of ionic currents can destabilize the cardiac action potential and potentially trigger lethal cardiac arrhythmias. In the present study, we combined mathematical modelling with information-rich dynamic clamp experiments to determine the regulation of action potential morphology in guinea pig ventricular myocytes. Parameter sensitivity analysis was used to predict how changes in ionic currents alter action potential duration, and these were tested experimentally using dynamic clamp, a technique that allows for multiple perturbations to be tested in each cell. Surprisingly, we found that a leading mathematical model, developed with traditional approaches, systematically underestimated experimental responses to dynamic clamp perturbations. We then re-parameterized the model using a genetic algorithm, which allowed us to estimate ionic current levels in each of the cells studied. This unbiased model adjustment consistently predicted an increase in the rapid delayed rectifier K current and a drastic decrease in the slow delayed rectifier K current, and this prediction was validated experimentally. Subsequent simulations with the adjusted model generated the clinically relevant prediction that the slow delayed rectifier is better able to stabilize the action potential and suppress pro-arrhythmic events than the rapid delayed rectifier. In summary, iterative coupling of simulations and experiments enabled novel insight into how the balance between cardiac K currents influences ventricular arrhythmia susceptibility.

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Section: Introductionmentioning

confidence: 99%

Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility

Devenyi

Ortega

Groenendaal

et al. 2016

The Journal of Physiology

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“…A modern computational approach to address such problems and to gain broader insights into physiological function is to explore not just a single model of the system, but a large population of models (recently reviewed by Cummins et al (130)). This approach is based on ample computation power of modern computers and tests system behavior within all, or almost all, possible combinations of parameters measured experimentally, i.e.…”

Section: Modern Numerical and Theoretical Approaches To Explore Camentioning

confidence: 99%

“…Thus, in general, this new approach permits identification of physiologically important ranges of parameter combinations to simulate experimental data and to learn how the system robustness and flexibility emerge from the complex interplay of molecules within the coupled-clock system. This approach can be further extended in future studies to provide insights into pathological behaviors, such as sick sinus syndrome or sinus tachycardia (130). …”

Section: Modern Numerical and Theoretical Approaches To Explore Camentioning

confidence: 99%

Modern Perspectives on Numerical Modeling of Cardiac Pacemaker Cell

et al. 2014

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Cardiac pacemaking is a complex phenomenon that is still not completely understood. Together with experimental studies, numerical modeling has been traditionally used to acquire mechanistic insights in this research area. This review summarizes the present state of numerical modeling of the cardiac pacemaker, including approaches to resolve present paradoxes and controversies. Specifically we discuss the requirement for realistic modeling to consider symmetrical importance of both intracellular and cell membrane processes (within a recent “coupled-clock” theory). Promising future developments of the complex pacemaker system models include the introduction of local calcium control, mitochondria function, and biochemical regulation of protein phosphorylation and cAMP production. Modern numerical and theoretical methods such as multi-parameter sensitivity analyses within extended populations of models and bifurcation analyses are also important for the definition of the most realistic parameters that describe a robust, yet simultaneously flexible operation of the coupled-clock pacemaker cell system. The systems approach to exploring cardiac pacemaker function will guide development of new therapies, such as biological pacemakers for treating insufficient cardiac pacemaker function that becomes especially prevalent with advancing age.

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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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Yoga for the sinoatrial node: Sarcoplasmic reticulum calcium release confers flexibility

Cited by 6 publications

References 37 publications

Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility

Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility

Modern Perspectives on Numerical Modeling of Cardiac Pacemaker Cell

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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