Biomedical subjects

Alan Garny

Publications and source records attributed to Alan Garny.

6 recordsLinked to original sources

PubMed2006

Enabling computer models of the heart for high-performance computers and the grid.

Although it is now feasible to compute multi-cellular models of the heart on a personal desktop or laptop computer, it is not feasible to undertake the detailed sweeps of high-dimensional parameter spaces required if we are to undertake in silico experimentation of the complex processes that constitute heart disease. For this research, modelling requirements move rapidly beyond the limit of commodity computers' resource both in terms of their memory footprint and the speed of calculation, so that multi-processor architectures must be considered. In addition, as such models have become more mature and have been validated against experimental data, there is increasing pressure for experimentalists to be able to make use of these models themselves as a key tool for hypothesis formulation and in planning future experimental studies to test those hypotheses. This paper discusses our initial experiences in a large-scale project (the Integrative Biology (IB) e-Science project) aimed at meeting these dual aims. We begin by putting the research in context by describing in outline the overall aims of the IB project, in particular focusing on the challenge of enabling novice users to make full use of high-performance resources without the need to gain detailed technical expertise in computing. We then discuss our experience of adapting one particular heart modelling package, Cellular Open Resource, and show how the solving engine of this code was dissected from the rest of the package, ported to C++ and parallelized using the Message-Passing Interface. We show that good parallel efficiency and realistic memory reduction can be achieved on simple geometries. We conclude by discussing lessons learnt in this process.

Action Potentials↗

PubMed2006

Mathematical models in physiology.

Computational modelling of biological processes and systems has witnessed a remarkable development in recent years. The search-term (modelling OR modeling) yields over 58000 entries in PubMed, with more than 34000 since the year 2000: thus, almost two-thirds of papers appeared in the last 5-6 years, compared to only about one-third in the preceding 5-6 decades. The development is fuelled both by the continuously improving tools and techniques available for bio-mathematical modelling and by the increasing demand in quantitative assessment of element inter-relations in complex biological systems. This has given rise to a worldwide public domain effort to build a computational framework that provides a comprehensive theoretical representation of integrated biological function-the Physiome. The current and next issues of this journal are devoted to a small sub-set of this initiative and address biocomputation and modelling in physiology, illustrating the breadth and depth of experimental data-based model development in biological research from sub-cellular events to whole organ simulations.

Computer Simulation↗

PubMed2006

Effects of mechanosensitive ion channels on ventricular electrophysiology: experimental and theoretical models.

The heart is an electrically driven mechanical pump, somewhat like an electric motor. Interestingly, like an electric motor in 'dynamo mode', the heart can also convert mechanical stimuli into electrical signals. This feedback from cardiac mechanics to electrical activity involves mechanosensitive ion channels, whose properties and pathophysiological relevance are reviewed in the context of experimental and theoretical modelling of ventricular beat-by-beat electromechanical function.

Animals↗

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

Mechanical induction of arrhythmias during ventricular repolarization: modeling cellular mechanisms and their interaction in two dimensions.

Nonpenetrating mechanical stimulation of the precordial chest is particularly likely to instantaneously induce sustained rhythm disturbances if timed to coincide with ventricular repolarization. A number of possible mechanisms have been proposed, including mechanoelectric feedback acting via stretch-activated ion channels. The cellular effects of such channel activation have been studied and mathematically modeled in great detail. In this study, we investigate their dynamic interaction with the trailing wave of action potential repolarization in a two-dimensional model of ventricular tissue. The model identifies how stretch activation of cation-nonselective ion channels causes ectopic excitation in fully repolarized tissue and functional block of conduction at the intersection of the mechanical stimulus and the repolarization wave end, which may give rise to both trigger and sustaining mechanisms of ventricular arrhythmia. Simulation of stretch activation of K(+)-selective ion channels alone is insufficient in causing instantaneous arrhythmia, although it may, via action potential shortening, contribute to its sustenance.

Arrhythmias, Cardiac↗

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↗