Quantitative mapping of force-pCa curves to whole-heart contraction and relaxation.

The force-pCa (F-pCa) curve is used to characterize steady-state contractile properties of cardiac muscle cells in different physiological, pathological and pharmacological conditions. This provides a reduced preparation in which to isolate sarcomere mechanisms. However, it is unclear how changes in the F-pCa curve impact emergent whole-heart mechanics quantitatively. We study the link between sarcomere and whole-heart function using a multiscale mathematical model of rat biventricular mechanics that describes sarcomere, tissue, anatomy, preload and afterload properties quantitatively. We first map individual cell-level changes in sarcomere-regulating parameters to organ-level changes in the left ventricular function described by pressure-volume loop characteristics (e.g. end-diastolic and end-systolic volumes, ejection fraction and isovolumetric relaxation time). We next map changes in the sarcomere-regulating parameters to changes in the F-pCa curve. We demonstrate that a change in the F-pCa curve can be caused by multiple different changes in sarcomere properties. We demonstrate that changes in sarcomere properties cause non-linear and, importantly, non-monotonic changes in left ventricular function. As a result, a change in sarcomere properties yielding changes in the F-pCa curve that improve contractility does not guarantee an improvement in whole-heart function. Likewise, a desired change in whole-heart function (i.e. ejection fraction or relaxation time) is not caused by a unique shift in the F-pCa curve. Changes in the F-pCa curve alone cannot be used to predict the impact of a compound on whole-heart function. KEY POINTS: The force-pCa (F-pCa) curve is used to assess myofilament calcium sensitivity after pharmacological modulation and to infer pharmacological effects on whole-heart function. We demonstrate that there is a non-unique mapping from changes in F-pCa curves to changes in left ventricular (LV) function. The effect of changes in F-pCa on LV function depend on the state of the heart and could be different for different pathological conditions. Screening of compounds to impact whole-heart function by F-pCa should be combined with active tension and calcium transient measurements to predict better how changes in muscle function will impact whole-heart physiology.

In silico identification of potential calcium dynamics and sarcomere targets for recovering left ventricular function in rat heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a complex disease associated with multiple co-morbidities, where impaired cardiac mechanics are often the end effect. At the cellular level, cardiac mechanics can be pharmacologically manipulated by altering calcium signalling and the sarcomere. However, the link between cellular level modulations and whole organ pump function is incompletely understood. Our goal is to develop and use a multi-scale computational cardiac mechanics model of the obese ZSF1 HFpEF rat to identify important biomechanical mechanisms that underpin impaired cardiac function and to predict how whole-heart mechanical function can be recovered through altering cellular calcium dynamics and/or cellular contraction. The rat heart was modelled using a 3D biventricular biomechanics model. Biomechanics were described by 16 parameters, corresponding to intracellular calcium transient, sarcomere dynamics, cardiac tissue and hemodynamics properties. The model simulated left ventricular (LV) pressure-volume loops that were described by 14 scalar features. We trained a Gaussian process emulator to map the 16 input parameters to each of the 14 outputs. A global sensitivity analysis was performed, and identified calcium dynamics and thin and thick filament kinetics as key determinants of the organ scale pump function. We employed Bayesian history matching to build a model of the ZSF1 rat heart. Next, we recovered the LV function, described by ejection fraction, peak pressure, maximum rate of pressure rise and isovolumetric relaxation time constant. We found that by manipulating calcium, thin and thick filament properties we can recover 34%, 28% and 24% of the LV function in the ZSF1 rat heart, respectively, and 39% if we manipulate all of them together. We demonstrated how a combination of biophysically based models and their derived emulators can be used to identify potential pharmacological targets. We predicted that cardiac function can be best recovered in ZSF1 rats by desensitising the myofilament and reducing the affinity to intracellular calcium concentration and overall prolonging the sarcomere staying in the active force generating state.

A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability.

There is an inherent tension in Quantitative Systems Pharmacology (QSP) between the need to incorporate mathematical descriptions of complex physiology and drug targets with the necessity of developing robust, predictive and well-constrained models. In addition to this, there is no "gold standard" for model development and assessment in QSP. Moreover, there can be confusion over terminology such as model and parameter identifiability; complex and simple models; virtual populations; and other concepts, which leads to potential miscommunication and misapplication of methodologies within modeling communities, both the QSP community and related disciplines. This perspective article highlights the pros and cons of using simple (often identifiable) vs. complex (more physiologically detailed but often non-identifiable) models, as well as aspects of parameter identifiability, sensitivity and inference methodologies for model development and analysis. The paper distills the central themes of the issue of identifiability and optimal model size and discusses open challenges.

Quantitative analysis of variability in an integrated model of human ventricular electrophysiology and ß-adrenergic signaling.

In ventricular myocytes, stimulation of ß-adrenergic receptors activates critical cardiac signaling pathways, leading to shorter action potentials and increased contraction strength during the "fight-or-flight" response. These changes primarily result, at the cellular level, from the coordinated phosphorylation of multiple targets by protein kinase A. Although mathematical models of the intracellular signaling downstream of ß-adrenergic receptor activation have previously been described, only a limited number of studies have explored quantitative interactions between intracellular signaling and electrophysiology in human ventricular myocytes. Accordingly, our objective was to develop an integrative mathematical model of ß-adrenergic receptor signaling, electrophysiology, and intracellular calcium (Ca2+) handling in the healthy human ventricular myocyte. We combined published mathematical models of intracellular signaling and electrophysiology, then calibrated the model results against voltage clamp data and physiological changes occurring after stimulation of ß-adrenergic receptors with isoproterenol. We subsequently: (1) explored how molecular variability in different categories of model parameters translated into phenotypic variability; (2) identified the most important parameters determining physiological cellular outputs in the model before and after ß-adrenergic receptor stimulation; and (3) investigated which molecular level alterations can produce a phenotype indicative of heart failure with preserved ejection fraction (HFpEF). Major results included: (1) variability in parameters that controlled intracellular signaling caused qualitatively different behavior than variability in parameters controlling ion transport pathways; (2) the most important model parameters determining action potential duration and intracellular Ca2+ transient amplitude were generally consistent before and after ß-adrenergic receptor stimulation, except for a shift in the importance of K+ currents in determining action potential duration; and (3) decreased Ca2+ uptake into the sarcoplasmic reticulum, increased Ca2+ extrusion through Na+/Ca2+ exchanger and decreased Ca2+ leak from the sarcoplasmic reticulum may contribute to HFpEF. Overall, this study provided novel insight into the phenotypic consequences of molecular variability, and our integrated model may be useful in the design and interpretation of future experimental studies of interactions between ß-adrenergic signaling and cellular physiology in human ventricular myocytes.

Regeneration of Salicaceae riparian forests in the Northern Hemisphere: A new framework and management tool.

Human activities on floodplains have severely disrupted the regeneration of foundation riparian shrub and tree species of the Salicaceae family (Populus and Salix spp.) throughout the Northern Hemisphere. Restoration ecologists initially tackled this problem from a terrestrial perspective that emphasized planting. More recently, floodplain restoration activities have embraced an aquatic perspective, inspired by the expanding practice of managing river flows to improve river health (environmental flows). However, riparian Salicaceae species occupy floodplain and riparian areas, which lie at the interface of both terrestrial and aquatic ecosystems along watercourses. Thus, their regeneration depends on a complex interaction of hydrologic and geomorphic processes that have shaped key life-cycle requirements for seedling establishment. Ultimately, restoration needs to integrate these concepts to succeed. However, while regeneration of Salicaceae is now reasonably well-understood, the literature reporting restoration actions on Salicaceae regeneration is sparse, and a specific theoretical framework is still missing. Here, we have reviewed 105 peer-reviewed published experiences in restoration of Salicaceae forests, including 91 projects in 10 world regions, to construct a decision tree to inform restoration planning through explicit links between the well-studied biophysical requirements of Salicaceae regeneration and 17 specific restoration actions, the most popular being planting (in 55% of the projects), land contouring (30%), removal of competing vegetation (30%), site selection (26%), and irrigation (24%). We also identified research gaps related to Salicaceae forest restoration and discuss alternative, innovative and feasible approaches that incorporate the human component.

Vegetation response to invasive Tamarix control in southwestern U.S. rivers: a collaborative study including 416 sites.

Most studies assessing vegetation response following control of invasive Tamarix trees along southwestern U.S. rivers have been small in scale (e.g., river reach), or at a regional scale but with poor spatial-temporal replication, and most have not included testing the effects of a now widely used biological control. We monitored plant composition following Tamarix control along hydrologic, soil, and climatic gradients in 244 treated and 172 reference sites across six U.S. states. This represents the largest comprehensive assessment to date on the vegetation response to the four most common Tamarix control treatments. Biocontrol by a defoliating beetle (treatment 1) reduced the abundance of Tamarix less than active removal by mechanically using hand and chain-saws (2), heavy machinery (3) or burning (4). Tamarix abundance also decreased with lower temperatures, higher precipitation, and follow-up treatments for Tamarix resprouting. Native cover generally increased over time in active Tamarix removal sites, however, the increases observed were small and was not consistently increased by active revegetation. Overall, native cover was correlated to permanent stream flow, lower grazing pressure, lower soil salinity and temperatures, and higher precipitation. Species diversity also increased where Tamarix was removed. However, Tamarix treatments, especially those generating the highest disturbance (burning and heavy machinery), also often promoted secondary invasions of exotic forbs. The abundance of hydrophytic species was much lower in treated than in reference sites, suggesting that management of southwestern U.S. rivers has focused too much on weed control, overlooking restoration of fluvial processes that provide habitat for hydrophytic and floodplain vegetation. These results can help inform future management of Tamarix-infested rivers to restore hydrogeomorphic processes, increase native biodiversity and reduce abundance of noxious species.

Long-term shifts in the phenology of rare and endemic Rocky Mountain plants.

UNLABELLED: • PREMISE OF THE STUDY: Mountainous regions support high plant productivity, diversity, and endemism, yet are highly vulnerable to climate change. Historical records and model predictions show increasing temperatures across high elevation regions including the Southern Rocky Mountains, which can have a strong influence on the performance and distribution of montane plant species. Rare plant species can be particularly vulnerable to climate change because of their limited abundance and distribution.• METHODS: We tracked the phenology of rare and endemic species, which are identified as imperiled, across three different habitat types with herbarium records to determine if flowering time has changed over the last century, and if phenological change was related to shifts in climate.• KEY RESULTS: We found that the flowering date of rare species has accelerated 3.1 d every decade (42 d total) since the late 1800s, with plants in sagebrush interbasins showing the strongest accelerations in phenology. High winter temperatures were associated with the acceleration of phenology in low elevation sagebrush and barren river habitats, whereas high spring temperatures explained accelerated phenology in the high elevation alpine habitat. In contrast, high spring temperatures delayed the phenology of plant species in the two low-elevation habitats and precipitation had mixed effects depending on the season.• CONCLUSIONS: These results provide evidence for large shifts in the phenology of rare Rocky Mountain plants related to climate, which can have strong effects on plant fitness, the abundance of associated wildlife, and the future of plant conservation in mountainous regions.

Restoration of riparian vegetation: A global review of implementation and evaluation approaches in the international, peer-reviewed literature.

We examined how restoration of riparian vegetation has been implemented and evaluated in the scientific literature during the past 25 years. A total of 169 papers were read systematically to extract information about the following: 1) restoration strategies applied, 2) scale of monitoring and use of reference sites, 3) metrics used for evaluation, and 4) drivers of success. Hydro-geomorphic approaches (e.g., dam operations, controlled floods, landform reconfiguration) were the most frequent, followed by active plant introduction, exotic species control, natural floodplain conversion and grazing and herbivory control. Our review revealed noteworthy limitations in the spatio-temporal approaches chosen for evaluation. Evaluations were mostly from one single project and frequently ignored the multi-dimensional nature of rivers: landscape spatial patterns were rarely assessed, and most projects were assessed locally (i.e., ≤meander scale). Monitoring rarely lasted for more than six years and the projects evaluated were usually not more than six years old. The impact of the restoration was most often (43%) assessed by tracking change over time rather than by comparing restored sites to unrestored and reference sites (12%), and few projects (30%) did both. Among the ways which restoration success was evaluated, vegetation structure (e.g., abundance, density, etc.) was assessed more often (152 papers) than vegetation processes (e.g., biomass accumulation, survival, etc.) (112 papers) and vegetation diversity (78 papers). Success was attributed to hydro-geomorphic factors in 63% of the projects. Future evaluations would benefit from incorporating emerging concepts in ecology such as functional traits to assess recovery of functionality, more rigorous experimental designs, enhanced comparisons among projects, longer term monitoring and reporting failure.

Pool size measurements improve precision of flux estimates but increase sensitivity to unmodeled reactions outside the core network in isotopically nonstationary metabolic flux analysis (INST-MFA).

Metabolic flux analysis (MFA) involves model-based estimation of metabolic reaction rates (i.e., fluxes) and, in some cases, metabolite content (i.e., pool sizes) from experimental measurements. Applying MFA to biological data helps determine the fate of substrates and the activity of specific pathways within metabolic networks. However, reliably estimating fluxes by using simplified "core" models to predict the dynamics of larger metabolic networks remains a challenge. One point of uncertainty relates to the advantages and potential pitfalls of including pool size measurements as experimental inputs for isotopically nonstationary MFA (INST-MFA). Here, we directly assessed the role of pool sizes using various core models and simulated datasets. To investigate the effects of pool size measurements on INST-MFA, we assessed the accuracy and precision of flux estimates obtained using different subsets of data (e.g., with or without pool size measurements) and simple network models that either matched or differed from the true network. The inclusion of pool size measurements provided incremental improvements to the precision of the flux estimates. However, adding pool size measurements increased the sensitivity of the flux solution to unmodeled reactions outside the core network. These results were confirmed using a large Escherichia coli model that is representative of realistic metabolic networks examined in MFA studies. Our findings indicate that accurate flux estimates can be obtained in the absence of pool size measurements, even when using core models that lack full network coverage. Addition of pool size measurements to INST-MFA datasets may reveal the activity of non-core reactions that influence the labeling dynamics and therefore necessitate network expansion in order to reconcile all available data to the model. Our findings also emphasize the key role that goodness-of-fit testing plays in assessing the quality of model fits obtained with INST-MFA.

AMPK activation is sufficient to increase skeletal muscle glucose uptake and glycogen synthesis but is not required for contraction-mediated increases in glucose metabolism.

The AMP-activated protein kinase (AMPK) is a cellular sensor of energetics and when activated in skeletal muscle during contraction can impart changes in skeletal muscle metabolism. Therapeutics that selectively activate AMPK have been developed to lower glucose levels through increased glucose disposal rates as an approach to abrogate the hyperglycemic state of diabetes; however, the metabolic fate of glucose following AMPK activation remains unclear. We have used a combination of in vivo evaluation of glucose homeostasis and ex vivo skeletal muscle incubation to systematically evaluate metabolism following pharmacological activation of AMPK with PF-739, comparing this with AMPK activation through sustained intermittent electrical stimulation of contraction. These methods to activate AMPK result in increased glucose uptake but divergent metabolism of glucose: pharmacological activation results in increased glycogen accumulation while contraction-induced glucose uptake results in increased lactate formation and glucose oxidation. These results provide additional evidence to support a role for AMPK in control of skeletal muscle metabolism and additional insight into the potential for AMPK stimulation with small molecule direct activators.

A Prototype QSP Model of the Immune Response to SARS-CoV-2 for Community Development.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires the rapid development of efficacious treatments for patients with life-threatening coronavirus disease 2019 (COVID-19). Quantitative systems pharmacology (QSP) models are mathematical representations of pathophysiology for simulating and predicting the effects of existing or putative therapies. The application of model-based approaches, including QSP, have accelerated the development of some novel therapeutics. Nevertheless, the development of disease-scale mechanistic models can be a slow process, often taking years to be validated and considered mature. Furthermore, emerging data may make any QSP model quickly obsolete. We present a prototype QSP model to facilitate further development by the scientific community. The model accounts for the interactions between viral dynamics, the major host immune response mediators and tissue damage and regeneration. The immune response is determined by viral activation of innate and adaptive immune processes that regulate viral clearance and cell damage. The prototype model captures two physiologically relevant outcomes following infection: a "healthy" immune response that appropriately defends against the virus, and an uncontrolled alveolar inflammatory response that is characteristic of acute respiratory distress syndrome. We aim to significantly shorten the typical QSP model development and validation timeline by encouraging community use, testing, and refinement of this prototype model. It is our expectation that the model will be further advanced in an open science approach (i.e., by multiple contributions toward a validated quantitative platform in an open forum), with the ultimate goal of informing and accelerating the development of safe and effective treatment options for patients.

The role of the Na+/Ca2+ exchangers in Ca2+ dynamics in ventricular myocytes.

The role of the Na+/Ca2+ exchanger (NCX) as the main pathway for Ca2+ extrusion from ventricular myocytes is well established. However, both the role of the Ca2+ entry mode of NCX in regulating local Ca2+ dynamics and the role of the Ca2+ exit mode during the majority of the physiological action potential (AP) are subjects of controversy. The functional significance of NCXs location in T-tubules and potential co-localization with ryanodine receptors was examined using a local Ca2+ control model of low computational cost. Our simulations demonstrate that under physiological conditions local Ca2+ and Na+ gradients are critical in calculating the driving force for NCX and hence in predicting the effect of NCX on AP. Under physiological conditions when 60% of NCXs are located on T-tubules, NCX may be transiently inward within the first 100 ms of an AP and then transiently outward during the AP plateau phase. Thus, during an AP NCX current (INCX) has three reversal points rather than just one. This provides a resolution to experimental observations where Ca2+ entry via NCX during an AP is inconsistent with the time at which INCX is thought to become inward. A more complex than previously believed dynamic regulation of INCX during AP under physiological conditions allows us to interpret apparently contradictory experimental data in a consistent conceptual framework. Our modelling results support the claim that NCX regulates the local control of Ca2+ and provide a powerful tool for future investigations of the control of sarcoplasmic reticulum (SR) Ca2+ release under pathological conditions.

Predicting critical drug concentrations and torsadogenic risk using a multiscale exposure-response simulator.

Torsades de pointes is a serious side effect of many drugs that can trigger sudden cardiac death, even in patients with structurally normal hearts. Torsadogenic risk has traditionally been correlated with the blockage of a specific potassium channel and a prolonged recovery period in the electrocardiogram. However, the precise mechanisms by which single channel block translates into heart rhythm disorders remain incompletely understood. Here we establish a multiscale exposure-response simulator that converts block-concentration characteristics from single cell recordings into three-dimensional excitation profiles and electrocardiograms to rapidly assess torsadogenic risk. For the drug dofetilide, we characterize the QT interval and heart rate at different drug concentrations and identify the critical concentration at the onset of torsades de pointes: For dofetilide concentrations of 2x, 3x, and 4x, as multiples of the free plasma concentration Cmax = 2.1 nM, the QT interval increased by +62.0%, +71.2%, and +82.3% compared to baseline, and the heart rate changed by -21.7%, -23.3%, and +88.3%. The last number indicates that, at the critical concentration of 4x, the heart spontaneously developed an episode of a torsades-like arrhythmia. Strikingly, this critical drug concentration is higher than the concentration estimated from early afterdepolarizations in single cells and lower than in one-dimensional cable models. Our results highlight the importance of whole heart modeling and explain, at least in part, why current regulatory paradigms often fail to accurately quantify the pro-arrhythmic potential of a drug. Our exposure-response simulator could provide a more mechanistic assessment of pro-arrhythmic risk and help establish science-based guidelines to reduce rhythm disorders, design safer drugs, and accelerate drug development.

Functional significance of Na+/Ca2+ exchangers co-localization with ryanodine receptors.

Co-localization of Na+/Ca2+ exchangers (NCX) with ryanodine receptors (RyRs) is debated. We incorporate local NCX current in a biophysically detailed model of L-type Ca2+ channels (LCCs) and RyRs and study the effect of NCX on the regulation of Ca2+-induced Ca2+ release and the shape of the action potential. In canine ventricular cells, under pathological conditions, e.g., impaired LCCs, local NCXs become an enhancer of sarcoplasmic reticulum release. Under such conditions incorporation of local NCXs is critical to accurately capture mechanisms of excitation-contraction coupling.

Competition between Native Populus deltoides and Invasive Tamarix ramosissima and the Implications for Reestablishing Flooding Disturbance.

Changes in historical disturbance regimes have been shown to facilitate non-native plant invasions, but reinstatement of disturbance can be successful only if native colonizers are able to outcompete colonizing invasives. Reintroduction of flooding in the southwestern United States is being promoted as a means of reestablishing Populus deltoides subsp. wislizenii, but flooding can also promote establishment of an introduced, invasive species, Tamarix ramosissima. We investigated competition between Populus and Tamarix at the seedling stage to aid in characterizing the process by which Tamarix may invade and to determine the potential ability of Populus to establish itself with competitive pressure from Tamarix. We planted seedlings of Tamarix and Populus in five ratios at three densities for a total of 15 treatments. The growth response of each species was measured in terms of height, above-ground biomass, and tissue concentrations of nitrogen and phosphorous. These measurements across treatments were modeled as three-dimensional response surfaces. For both species, Populus density was more important than Tamarix density for determining growth response. Both species were negatively affected by increasing numbers of Populus seedlings. Due to the larger size of the native Populus, we predict that its superior competitive ability can lead to its dominance when conditions allow native establishment. Our results suggest that even in the presence of an invader that positively responds to disturbance, reestablishment of historical flooding regimes and post-flood hydrology can restore this ecosystem by promoting its dominant plant species.

RESUMEN: Los cambios en los regímenes históricos de perturbaciones han mostrado que facilitan invasiones de plantas no nativas; sin embargo, la reinstauración de la perturbación solo puede ser exitosa si los colonizadores nativos son capaces de competir y desplazar a las especies invasoras. La reintroducción de las inundaciones en el sudoeste de los Estados Unidos está siendo promovida como una forma de restablecer Populus deltoides subespecie wislizenii, pero las inundaciones pueden promover también el establecimiento de una especie invasora, Tamarix ramosissima. Investigamos la competencia entre Populus y Tamarix al estado de plántula para ayudar a caracterizar el proceso por el cual Tamarix puede invadir y para determinar la habilidad potencial de Populus para establecer presión competitiva contra Tamarix. Sembramos plántulas de Tamarix y Populus en 5 diferentes radios y densidades para un total de 15 tratamientos. La respuesta en crecimiento de cada especie fue medida en forma de altura, biomasa sobre el suelo y concentraciones de nitrógeno y fósforo en tejido. Estas mediciones en los tratamientos fueron modeladas en superficies de respuesta tridimensionales. La densidad de Populus fue más importante para la determinación del crecimiento que la densidad de Tamarix. Ambas especies estuvieron negativamente afectadas por el incremento en el número de plántulas de Populus. Debido al mayor tamaño de la nativa Populus, nosotros predecimos que su superior habilidad competitiva puede conducir a su dominación cuando las condiciones permiten el establecimiento nativo. Nuestros resultados sugieren que aún en presencia de una especie invasora que responde positivamente a las perturbaciones, el restablecimiento de los regímenes históricos de inundaciones y de la hidrología post-inundación puede restaurar este ecosistema al promover a sus especies de plantas dominantes.

Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk.

AIMS: The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC(50)) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk. METHODS AND RESULTS: We collected multiple ion channel data (hERG, Na, L-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC(50) values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers. CONCLUSION: The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.

Multistability property in cardiac ionic models of mammalian and human ventricular cells.

The underlying mechanisms of irregular cardiac rhythms are still poorly understood. Many experimental and modeling studies are aimed at identifying factors which cause cardiac arrhythmias. However, a lack of understanding of heart rhythm dynamical properties makes it difficult to uncover precise mechanisms of electrical instabilities, and hence to predict the onset of heart rhythm disorders. We review and compare the existing methods of studying cardiac dynamics, including restitution protocol (S1-S2), dynamic restitution protocol and multistability test protocol (S1-CI-S2). We focus on cardiac cell dynamics to elucidate regularities of heart rhythm. We demonstrate the advantages of our newly proposed systematic approach of analysis of cardiac cell dynamics using mammalian Luo Rudy 1991 and human ventricular Ten Tusscher 2006 single cell models under healthy and diseased conditions such as altered K(+) or Ca(2+) related currents. We investigate the role of ionic properties and the shape of an action potential on the nonlinear dynamics of electrical processes in periodically stimulated cardiac cells. We show the existence of multistability property for human ventricular cells. Moreover, the multistability is proposed to be an intrinsic property of cardiac cells, and is also suggested to be one of the mechanisms which could underlie the sudden triggering of life-threatening ventricular arrhythmias in the human heart.

A global sensitivity tool for cardiac cell modeling: Application to ionic current balance and hypertrophic signaling.

Cardiovascular diseases are the major cause of death in the developed countries. Identifying key cellular processes involved in generation of the electrical signal and in regulation of signal transduction pathways is essential for unraveling the underlying mechanisms of heart rhythm behavior. Computational cardiac models provide important insights into cardiovascular function and disease. Sensitivity analysis presents a key tool for exploring the large parameter space of such models, in order to determine the key factors determining and controlling the underlying physiological processes. We developed a new global sensitivity analysis tool which implements the Morris method, a global sensitivity screening algorithm, onto a Nimrod platform, which is a distributed resources software toolkit. The newly developed tool has been validated using the model of IP3-calcineurin signal transduction pathway model which has 30 parameters. The key driving factors of the IP3 transient behaviour have been calculated and confirmed to agree with previously published data. We next demonstrated the use of this method as an assessment tool for characterizing the structure of cardiac ionic models. In three latest human ventricular myocyte models, we examined the contribution of transmembrane currents to the shape of the electrical signal (i.e. on the action potential duration). The resulting profiles of the ionic current balance demonstrated the highly nonlinear nature of cardiac ionic models and identified key players in different models. Such profiling suggests new avenues for development of methodologies to predict drug action effects in cardiac cells.