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Denis Noble

Publications and source records attributed to Denis Noble.

At least 19 recordsLinked to original sources
PubMed2006

From the Hodgkin-Huxley axon to the virtual heart.

Experimentally based models of the heart have been developed since 1960, starting with the discovery and modelling of potassium channels. The early models were based on extensions of the Hodgkin-Huxley nerve impulse equations. The first models including calcium balance and signalling were made in the 1980s and have now reached a high degree of physiological detail. During the 1990s these cell models have been incorporated into anatomically detailed tissue and organ models to create the first virtual organ, the Virtual Heart. With over 40 years of interaction between simulation and experiment, the models are now sufficiently refined to begin to be of use in drug development.

Animals↗
PubMed2006

Modulatory effect of calmodulin-dependent kinase II (CaMKII) on sarcoplasmic reticulum Ca2+ handling and interval-force relations: a modelling study.

We hypothesize that slow inactivation of Ca2+/calmodulin-dependent kinase II (CaMKII) and its modulatory effect on sarcoplasmic reticulum (SR) Ca2+ handling are important for various interval-force (I-F) relations, in particular for the beat interval dependency in transient alternans during the decay of post-extrasystolic potentiation. We have developed a mathematical model of a single cardiomyocyte to integrate various I-F relations, including alternans, by incorporating a conceptual CaMKII kinetics model into the SR Ca2+ handling model. Our model integrates I-F relations, such as the beat interval-dependent twitch force duration, restitution and potentiation, positive staircase phenomenon and alternans. We found that CaMKII affects more or less all I-F relations, and it is a key factor for integration of the various I-F relations in our model. Alternans arises, in the model, out of a steep relation between SR Ca2+ load and release, owing to SR load-dependent changes in the releasability of Ca2+ via the ryanodine receptor. Beat interval-dependent CaMKII activity, owing to its kinetic properties and amplifying effect on SR Ca2+ load dependency of Ca2+ release, replicated the beat interval dependency of alternans, as observed experimentally. Additionally, our model enabled reproduction of the effects of various interventions on alternans, such as the slowing or accelerating of Ca2+ release and/or uptake. We conclude that a slow time-dependent factor, represented in the model by CaMKII, is important for the integration of I-F relations, including alternans, and that our model offers a useful tool for further analysis of the roles of integrative Ca2+ handling in myocardial I-F relations.

Animals↗
PubMed2006

Contributions of inwardly rectifying K+ currents to repolarization assessed using mathematical models of human ventricular myocytes.

Repolarization of the action potential (AP) in cardiac muscle is a major determinant of refractoriness and excitability, and can also strongly modulate excitation-contraction coupling. In clinical cardiac electrophysiology, the Q-T interval, and hence action potential duration, is both an essential marker of normal function and an indicator of risk for arrhythmic events. It is now well known that the termination of the plateau phase of the AP and the repolarization waveform involve a complex interaction of transmembrane ionic currents. These include a slowly inactivating Na+ current, inactivating Ca2+ current, the decline of an electrogenic current due to Na+/Ca2+ exchange and activation of three or four different K+ currents. At present, many of the quantitative aspects of this important physiological and pathophysiological process remain incompletely understood. Recently, three mathematical models of the membrane AP in human ventricle myocyte have been developed and made available on the Internet. In this study, we have implemented these models for the purpose of comparing the K+ currents, which are responsible for terminating the plateau phase of the AP and generating its repolarization. In this paper, our emphasis is on the two highly nonlinear inwardly rectifying potassium currents, (IK1) and (IK,r). A more general goal is to obtain improved understanding of the ionic mechanisms, which underlie all-or-none repolarization and the parameter denoted 'repolarization reserve' in the human ventricle. Further, insights into these fundamental variables can be expected to provide a more rational basis for clinical assessment of the Q-T and Q-TC intervals, and hence provide insights into some of the very substantial efforts in safety pharmacology, which are based on these parameters.

Action Potentials↗
PubMed2006

Modeling cardiac ischemia.

Myocardial ischemia is one of the main causes of sudden cardiac death, with 80% of victims suffering from coronary heart disease. In acute myocardial ischemia, the obstruction of coronary flow leads to the interruption of oxygen flow, glucose, and washout in the affected tissue. Cellular metabolism is impaired and severe electrophysiological changes in ionic currents and concentrations ensue, which favor the development of lethal cardiac arrhythmias such as ventricular fibrillation. Due to the burden imposed by ischemia in our societies, a large body of research has attempted to unravel the mechanisms of initiation, sustenance, and termination of cardiac arrhythmias in acute ischemia, but the rapidity and complexity of ischemia-induced changes as well as the limitations in current experimental techniques have hampered evaluation of ischemia-induced alterations in cardiac electrical activity and understanding of the underlying mechanisms. Over the last decade, computer simulations have demonstrated the ability to provide insight, with high spatiotemporal resolution, into ischemic abnormalities in cardiac electrophysiological behavior from the ionic channel to the whole organ. This article aims to review and summarize the results of these studies and to emphasize the role of computer simulations in improving the understanding of ischemia-related arrhythmias and how to efficiently terminate them.

Action Potentials↗
PubMed2005

Systems biology and the heart.

Understanding the logic of living systems requires knowledge of the mechanisms involved at the levels at which functionality is expressed. This information does not reside in the genome, nor even in the individual proteins that genes code for. No functionality is expressed at these levels. It emerges as the result of interactions between many proteins relating to each other in multiple cascades and in interaction with the cellular environment. There is, therefore, no alternative to copying nature and computing these interactions to determine the logic of healthy and diseased states. The rapid growth in biological databases, models of cells, tissues and organs and the development of powerful computing hardware and algorithms have made it possible to explore functionality in a quantitative manner all the way from the level of genes to the physiological function of whole organs and regulatory systems. I use models of the heart to demonstrate that we can now go all the way from individual genetic information (on mutations, for example) to exploring the consequences at a whole organ level.

Animals↗
PubMed2005

Modelling of calcium handling in airway myocytes.

Airway myocytes are the primary effectors of airway reactivity which modulates airway resistance and hence ventilation. Stimulation of airway myocytes results in an increase in the cytosolic Ca(2+) concentration ([Ca(2+)](i)) and the subsequent activation of the contractile apparatus. Many contractile agonists, including acetylcholine, induce [Ca(2+)](i) increase via Ca(2+) release from the sarcoplasmic reticulum through InsP(3) receptors. Several models have been developed to explain the characteristics of InsP(3)-induced [Ca(2+)](i) responses, in particular Ca(2+) oscillations. The article reviews the modelling of the major structures implicated in intracellular Ca(2+) handling, i.e., InsP(3) receptors, SERCAs, mitochondria and Ca(2+)-binding cytosolic proteins. We developed theoretical models specifically dedicated to the airway myocyte which include the major mechanisms responsible for intracellular Ca(2+) handling identified in these cells. These biocomputations pointed out the importance of the relative proportion of InsP(3) receptor isoforms and the respective role of the different mechanisms responsible for cytosolic Ca(2+) clearance in the pattern of [Ca(2+)](i) variations. We have developed a theoretical model of membrane conductances that predicts the variations in membrane potential and extracellular Ca(2+) influx. Stimulation of this model by simulated increase in [Ca(2+)](i) predicts membrane depolarisation, but not great enough to trigger a significant opening of voltage-dependant Ca(2+) channels. This may explain why airway contraction induced by cholinergic stimulation does not greatly depend on extracellular calcium. The development of such models of airway myocytes is important for the understanding of the cellular mechanisms of airway reactivity and their possible modulation by pharmacological agents.

Acetylcholine↗
PubMed2005

Dimensionality in cardiac modelling.

The development of mathematical models of the heart has been an ongoing concern for many decades. The initial focus of this work was on single cell models that incorporate varyingly detailed descriptions of the mechanisms that give rise to experimentally observed action potential shapes. Clinically relevant heart rhythm disturbances, however, are multicellular phenomena, and there have been many initiatives to develop multidimensional representations of cardiac electromechanical activity. Here, we discuss the merits of dimensionality, from 0D single cell models, to 1D cell strands, 2D planes and 3D volumes, for the simulation of normal and disturbed rhythmicity. We specifically look at models of: (i) the origin and spread of cardiac excitation from the sino-atrial node into atrial tissue, and (ii) stretch-activated channel effects on ventricular cell and tissue activity. Simulation of the spread of normal and disturbed cardiac excitation requires multicellular models. 1D architectures suffer from limitations in neighbouring tissue effects on individual cells, but they can (with some modification) be applied to the simulation of normal spread of excitation or, in ring-like structures, re-entry simulation (colliding wave fronts, tachycardia). 2D models overcome many of the limitations imposed by models of lower dimensionality, and can be applied to the study of complex co-existing re-entry patterns or even fibrillation. 3D implementations are closest to reality, as they allow investigation of scroll waves. Our results suggest that 2D models offer a good compromise between computational resources, complexity of electrophysiological models, and applicability to basic research, and that they should be considered as an important stepping-stone towards anatomically detailed simulations. This highlights the need to identify and use the most appropriate model for any given task. The notion of a single and ultimate model is as useful as the idea of a universal mechanical tool for all possible repairs and servicing requirements in daily life. The ideal model will be as simple as possible and as complex as necessary for the particular question raised.

Animals↗
PubMed2004

Ascending aortic stenosis selectively increases action potential-induced Ca2+ influx in epicardial myocytes of the rat left ventricle.

A decrease of the transient outward potassium current (Ito) has been observed in cardiac hypertrophy and contributes to the altered shape of the action potential (AP) of hypertrophied ventricular myocytes. Since the shape and duration of the ventricular AP are important determinants of the Ca2+ influx during the AP (QCa), we investigated the effect of ascending aortic stenosis (AS) on QCa in endo- and epicardial myocytes of the left ventricular free wall using the AP voltage-clamp technique. In sham-operated animals, QCa was significantly larger in endocardial compared to epicardial myocytes (803 +/- 65 fC pF(-1), n = 27 vs. 167 +/- 32 fC pF(-1), n = 38, P < 0.001). Ascending aortic stenosis significantly increased QCa in epicardial myocytes (368 +/- 54 fC pF(-1), n = 42, P < 0.05), but did not alter QCa in endocardial myocytes (696 +/- 65 fC pF(-1), n = 26). Peak and current-voltage relation of the AP-induced Ca2+ current were unaffected by AS. However, the time course of the current-voltage relation was significantly prolonged in epicardial myocytes of AS animals. Model calculations revealed that the increase in QCa can be ascribed to a prolonged opening of the activation gate, whereas an increase in inactivation prevents an excessive increase in QCa. In conclusion, AS significantly increased AP-induced Ca2+ influx in epicardial but not in endocardial myocytes of the rat left ventricle.

Action Potentials↗
PubMed2004

Requirement of neuronal- and cardiac-type sodium channels for murine sinoatrial node pacemaking.

The majority of Na+ channels in the heart are composed of the tetrodotoxin (TTX)-resistant (KD, 2-6 microm) Nav1.5 isoform; however, recently it has been shown that TTX-sensitive (KD, 1-10 nm) neuronal Na+ channel isoforms (Nav1.1, Nav1.3 and Nav1.6) are also present and functionally important in the myocytes of the ventricles and the sinoatrial (SA) node. In the present study, in mouse SA node pacemaker cells, we investigated Na+ currents under physiological conditions and the expression of cardiac and neuronal Na+ channel isoforms. We identified two distinct Na+ current components, TTX resistant and TTX sensitive. At 37 degrees C, TTX-resistant iNa and TTX-sensitive iNa started to activate at approximately -70 and approximately -60 mV, and peaked at -30 and -10 mV, with a current density of 22 +/- 3 and 18 +/- 1 pA pF(-1), respectively. TTX-sensitive iNa inactivated at more positive potentials as compared to TTX-resistant iNa. Using action potential clamp, TTX-sensitive iNa was observed to activate late during the pacemaker potential. Using immunocytochemistry and confocal microscopy, different distributions of the TTX-resistant cardiac isoform, Nav1.5, and the TTX-sensitive neuronal isoform, Nav1.1, were observed: Nav1.5 was absent from the centre of the SA node, but present in the periphery of the SA node, whereas Nav1.1 was present throughout the SA node. Nanomolar concentrations (10 or 100 nm) of TTX, which block TTX-sensitive iNa, slowed pacemaking in both intact SA node preparations and isolated SA node cells without a significant effect on SA node conduction. In contrast, micromolar concentrations (1-30 microm) of TTX, which block TTX-resistant iNa as well as TTX-sensitive iNa, slowed both pacemaking and SA node conduction. It is concluded that two Na+ channel isoforms are important for the functioning of the SA node: neuronal (putative Nav1.1) and cardiac Nav1.5 isoforms are involved in pacemaking, although the cardiac Nav1.5 isoform alone is involved in the propagation of the action potential from the SA node to the surrounding atrial muscle.

Action Potentials↗
PubMed2004

Editorial: computational modelling of cell & tissue processes & function.

Computational modelling of whole biological systems from cells to organs is gaining momentum in cell biology and disease studies. This pathway is essential for the derivation of explanatory frameworks that will facilitate the development of a predictive capacity for estimating outcomes or risk associated with particular disease processes and therapeutic or stressful treatments. This article introduces a series of invited papers covering a hierarchy of issues and modelling problems, ranging from crucial conceptual considerations of the validity of cellular modelling through to multi-scale modelling up to organ level. The challenges and approaches in cellular modelling are described, including the potential of 'in silico ' modelling applications for receptor-ligand interactions in cell signalling, simulated organ dysfunction (i.e., heart), human and environmental toxicity and the progress of the IUPS Physiome Project. A major challenge now facing biologists is how to translate the wealth of reductionist detail about cells and tissues into a real understanding of how these systems function and are perturbed in disease processes. In biomedicine, simulation models of biological systems now contain sufficient detail, not only to reconstruct normal functions, but also, to reconstruct major disease states. More widely, simulation modelling will aid the targeting of current 'knowledge gaps' and how to fill them; and also provide a research tool for selecting critical factors from multiple simulated experiments for real experimental design. The envisaged longer-term end- product is the creation of simulation models for predicting drug interactions and harmful side-effects; and their use in therapeutic and environmental health risk management. Finally, we take a speculative look at possible future scenarios in cellular modelling, where it is envisioned that integrative biology will move from being largely qualitative and instead become a highly quantitative, computer-intensive discipline.

Cell Physiological Phenomena↗
PubMed2004

Computational physiology and the Physiome Project.

Bioengineering analyses of physiological systems use the computational solution of physical conservation laws on anatomically detailed geometric models to understand the physiological function of intact organs in terms of the properties and behaviour of the cells and tissues within the organ. By linking behaviour in a quantitative, mathematically defined sense across multiple scales of biological organization--from proteins to cells, tissues, organs and organ systems--these methods have the potential to link patient-specific knowledge at the two ends of these spatial scales. A genetic profile linked to cardiac ion channel mutations, for example, can be interpreted in relation to body surface ECG measurements via a mathematical model of the heart and torso, which includes the spatial distribution of cardiac ion channels throughout the myocardium and the individual kinetics for each of the approximately 50 types of ion channel, exchanger or pump known to be present in the heart. Similarly, linking molecular defects such as mutations of chloride ion channels in lung epithelial cells to the integrated function of the intact lung requires models that include the detailed anatomy of the lungs, the physics of air flow, blood flow and gas exchange, together with the large deformation mechanics of breathing. Organizing this large body of knowledge into a coherent framework for modelling requires the development of ontologies, markup languages for encoding models, and web-accessible distributed databases. In this article we review the state of the field at all the relevant levels, and the tools that are being developed to tackle such complexity. Integrative physiology is central to the interpretation of genomic and proteomic data, and is becoming a highly quantitative, computer-intensive discipline.

Biophysical Phenomena↗
PubMed2004

Modeling the heart.

Models of the heart have been developed since 1960, starting with the discovery and modeling of potassium channels. The first models of calcium balance were made in the 1980s and have now reached a high degree of physiological detail. During the 1990s, these cell models were incorporated into anatomically detailed tissue and organ models.

Animals↗
PubMed2003

Will genomics revolutionise pharmaceutical R&D?

The successful identification of drug targets requires an understanding of the high-level functional interactions between the key components of cells, organs and systems, and how these interactions change in disease states. This information does not reside in the genome, or in the individual proteins that genes code for, it is to be found at a higher level. Genomics will succeed in revolutionising pharmaceutical research and development only if these interactions are also understood by determining the logic of healthy and diseased states. The rapid growth in biological databases, models of cells, tissues and organs, and in computing power has made it possible to explore functionality all the way from the level of genes to whole organs and systems. Combined with genomic and proteomic data, in silico simulation technology is set to transform all stages of drug discovery and development. The major obstacle to achieving this will be obtaining the relevant experimental data at levels higher than genomics and proteomics.

Cell Physiological Phenomena↗
PubMed2003

One-dimensional rabbit sinoatrial node models: benefits and limitations.

INTRODUCTION: Cardiac multicellular modeling has traditionally focused on ventricular electromechanics. More recently, models of the atria have started to emerge, and there is much interest in addressing sinoatrial node structure and function. METHODS AND RESULTS: We implemented a variety of one-dimensional sinoatrial models consisting of descriptions of central, transitional, and peripheral sinoatrial node cells, as well as rabbit or human atrial cells. These one-dimensional models were implemented using CMISS on an SGI Origin 2000 supercomputer. Intercellular coupling parameters recorded in experimental studies on sinoatrial node and atrial cell-pairs under-represent the electrotonic interactions that any cardiomyocyte would have in a multidimensional setting. Unsurprisingly, cell-to-cell coupling had to be scaled-up (by a factor of 5) in order to obtain a stable leading pacemaker site in the sinoatrial node center. Further critical parameters include the gradual increase in intercellular coupling from sinoatrial node center to periphery, and the presence of electrotonic interaction with atrial cells. Interestingly, the electrotonic effect of the atrium on sinoatrial node periphery is best described as opposing depolarization, rather than necessarily hyperpolarizing, as often assumed. CONCLUSION: Multicellular one-dimensional models of sinoatrial node and atrium can provide useful insight into the origin and spread of normal cardiac excitation. They require larger than "physiologic" intercellular conductivities in order to make up for a lack of "anatomical" spatial scaling. Multicellular models for more in-depth quantitative studies will require more realistic anatomico-physiologic properties.

Action Potentials↗
PubMed2002

The IUPS human Physiome Project.

The Physiome Project of the International Union of Physiological Sciences (IUPS) is attempting to provide a comprehensive framework for modelling the human body using computational methods which can incorporate the biochemistry, biophysics and anatomy of cells, tissues and organs. A major goal of the project is to use computational modelling to analyse integrative biological function in terms of underlying structure and molecular mechanisms. To support that goal the project is establishing web-accessible physiological databases dealing with model-related data, including bibliographic information, at the cell, tissue, organ and organ system levels. Here we discuss the background and goals of the project, the problems of modelling across multiple spatial and temporal scales, and the development of model ontologies and markup languages at all levels of biological function.

Anatomy↗