Publications
346 results found
Solovyova OE, Vikulova NA, Konovalov PV, et al., 2004, Mathematical modelling of mechano-electric feedback in cardiomyocytes, Vol: 19, Pages: 331-351, ISSN: 0927-6467
We earlier developed the mathematical model of electrical and mechanical activity in myocardium, which takes into account both direct coupling and feedback between excitation and contraction. In this paper, in the framework of the model we found conditions under which both the abrupt shortening and stretch of cardiac preparation can cause extra action potentials and hence anomalous deformations can be arrhythmia sources. In the framework of the model, we establish possible mechanisms underlying the Anrep phenomenon that reflects a relationship between myocardium contraction and vascular resistance in the intact heart.
Garny A, Kohl P, Hunter PJ, et al., 2003, One-dimensional rabbit sinoatrial node models: benefits and limitations., J Cardiovasc Electrophysiol, Vol: 14, Pages: S121-S132, ISSN: 1045-3873
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.
Kohl P, Cooper PJ, Holloway H, 2003, Effects of acute ventricular volume manipulation on in situ cardiomyocyte cell membrane configuration, Vol: 82, Pages: 221-227, ISSN: 0079-6107
Effects of mechanical stimulation on cardiac electrical activity, gene expression, protein synthesis, and tissue remodelling have received increasing attention in recent years, as reviewed in this issue of PBMB. Little is known, though, about how changes in ventricular filling affect the cell configuration of cardiomyocytes in the ventricular wall. Here, we present first electron-microscopic insight into changes in cardiomyocyte cell structure in situ during acute ventricular volume manipulation. Apart from confirming the anticipated ventricular volume-related changes in cardiornyocyte sarcomere length, there is evidence of (i) unfolding of 'slack' membrane, primarily from sarcolemmal invaginations near the Z-lines, and (ii) stretch-induced incorporation of sub-membrane caveolae into the surface membrane. The functional relevance of these changes in cardiornyocyte membrane configuration-other than to cater for the length-dependent modulation of the cell surface to cell volume ratio-remains to be elucidated. (C) 2003 Elsevier Science Ltd. All rights reserved.
Lei M, Lancaster M, Jones SA, et al., 2003, Electrophysiological features of murine sino-atrial node in relation to the role of i(Na), Vol: 84, Pages: 555A-555A, ISSN: 0006-3495
Markhasin VS, Solovyova O, Katsnelson LB, et al., 2003, Mechano-electric interactions in heterogeneous myocardium: development of fundamental experimental and theoretical models, Vol: 82, Pages: 207-220, ISSN: 0079-6107
The heart is structurally and functionally a highly non-homogenous organ, yet its main function as a pump can only be achieved by the co-ordinated contraction of millions of ventricular cells. This apparent contradiction gives rise to the hypothesis that 'well-organised' inhomogeneity may be a pre-requisite for normal cardiac function. Here, we present a set of novel experimental and theoretical tools for the study of this concept. Heterogeneity, in its most condensed form, can be simulated using two individually controlled, mechanically interacting elements (duplex). We have developed and characterised three different types of duplexes: (i) biological duplex, consisting of two individually perfused biological samples (like thin papillary muscles or a trabeculae), (ii) virtual duplex, made-up of two interacting- mathematical models of cardiac muscle, and (iii) hybrid duplex, containing a biological sample that interacts in real-time with a virtual muscle. In all three duplex types,. in-series or in-parallel mechanical interaction of elements can be studied during externally isotonic, externally isometric, and auxotonic modes of contraction and relaxation. Duplex models, therefore, mimic (patho-)physiological mechano-electric interactions in heterogeneous myocardium at the multicellular level, and in an environment that allows one to control mechanical, electrical and pharmacological parameters. Results obtained. using the duplex method show that: (i) contractile elements in heterogeneous myocardium are not 'independent' generators of tension/shortening, as their ino- and lusitropic characteristics change dynamically during mechanical interaction-potentially matching microscopic contractility to macroscopic demand, (ii) mechanical heterogeneity contributes differently to action potential duration (APD) changes, depending on whether mechanical coupling of elements is in-parallel or in-series, which may play a role in mechanical tuning of distant tissue regions, (iii)
Solovyova O, Vikulova N, Katsnelson LB, et al., 2003, Mechanical interaction of heterogeneous cardiac muscle segments in silico: Effects on Ca2+ handling and action potential, Vol: 13, Pages: 3757-3782, ISSN: 0218-1274
Effects of cardiac mechanical heterogeneity on the electrical function of the heart are difficult to assess experimentally, yet they pose a serious (patho-) physiological challenge. Here, we present an in silico study of the effects of mechanical heterogeneity on action potential duration (APD) in mechanically interacting muscle regions and consequent effects on the dispersion of repolarization, a well-established determinant of cardiac arrhythmogenesis. Using a novel mathematical description of ventricular electromechanical activity (virtual muscle), we first assessed how differences in intrinsic contractile properties affect the electrical behavior of cardiac muscle representations. In spite of identical electrophysiological model descriptions in virtual muscle samples, faster muscle models show shorter APD than their slower counterparts. This is a consequence of Ca2+-mediated feedback from mechanical to electrical activity in the individual muscle models. This mechano-electric feedback (MEF) is, of course, significantly more complex in native cardiac tissue, as the heterogeneous muscle elements interact both mechanically and electrically. Cardiac mechanical heterogeneity, in its most reduced form, can be represented by a duplex consisting of two mechanically interacting muscle segments. Our in silico model of heterogeneous myocardium therefore consists of two individual virtual muscles that are mechanically interconnected in-series to form a virtual heterogeneous duplex. During isometric contraction of the duplex (i.e. at constant external length), internal mechanical interactions affect Ca2+ handling and APD of muscle elements, resulting in an increased dispersion of repolarization beyond the intrinsic APD differences. Duplex electromechanical activity is strongly affected by the activation sequence of its elements. Late activation of the faster (subepicardial type) duplex element, postponed by time-lags that correspond to normal transmural activation delays, op
Solovyova O, Vikulova N, Markhasin VS, et al., 2003, A novel method for quantifying the contribution of different intracellular mechanisms to mechanically induced changes in action potential characteristics, Functional Imaging and Modeling of the Heart, Proceedings, Editors: Magnin, Clarysse, Katila, Montagnat, Nenonen, Pages: 8-17, ISBN: 3-540-40262-4
We introduce the Difference-Current Integral (DCI) method as a tool for quantitative assessment of contributions by individual model components to dynamic responses at the system's level. Using a detailed model of cardiac electrophysiology and mechanics, we assess the relative effects of mechano-sensitive ion channels and intracellular calcium handling to stretch-induced changes in action potential (AP) characteristics. DCI supports the hypothesis that some of the experimentally observed variability in cardiac AP responses to mechanical stimulation may be caused by differences in activation of underlying mechanisms, rather than solely species or technical differences. In particular, the model suggests that systems with a pronounced reverse mode Na+-Ca2+ exchange during the AP will respond to mechanical interventions that affect primarily cellular Ca2+ handling with AP shortening, whereas a predominant contribution of mechano-sensitive ion channels, in particular cation nonselective ones, may cause late AP prolongation and cross-over of repolarisation.
Camelliti P, Kohl P, Green C, 2003, Functional coupling of fibroblasts in rabbit sino-atrial node, Biophysical Journal, Pages: 96A-96A, ISSN: 0006-3495
Cooper PJ, Garny A, Kohl P, 2003, Cardiac electrophysiology: Theoretical considerations of a potential target for weak electromagnetic field effects, Vol: 106, Pages: 363-368, ISSN: 0144-8420
With the widespread introduction of extra high voltage power transmission lines in the 1960s, and subsequent to early reports from Soviet Union scientists about health risks for transformer station personnel((1)), public concern regarding the effects of electromagnetic fields (EMFs) on biological function has given rise to a large number of investigations and legislation to limit domestic and occupational exposure to EMFs. The underlying rationale for concern is related to the fact that living cells are electrically active, which makes them potentially vulnerable to electromagnetic interference. In the heart, electrical activity is crucial in coordinating the contraction of millions of cardiac cells, and disturbances in cardiac electrical activity, also known as arrhythmias, are often life threatening. Electrical fields induced in the heart by weak external EMFs (such as those encountered in a domestic setting) are understood to be at least 2 orders of magnitude smaller (<1%) than those that occur naturally as an intrinsic consequence of cardiac activity. Using quantitative models of cardiac cellular electrophysiology, the effect of weak (1 %) manipulation of key current mechanisms that give rise to the electrical activity of the heart is therefore assessed.
Cooper PJ, Kohl P, 2003, Influence of diastolic mechanics on cardiac electrophysiology: effects on sino-atrial node function, ISBN: 88-470-0235-4
Garny A, Dobrzynski H, Boyett M, et al., 2003, Anatomico-physiological model of rabbit sino-atrial node implemented using cellular open resource (COR), Vol: 84, Pages: 406A-407A, ISSN: 0006-3495
Garny A, Hunter PJ, Noble D, et al., 2003, Rabbit sino-atrial node modeling: from single cell to tissue structure, Proceedings of the 25th Annual International Conference of the Ieee Engineering in Medicine and Biology Society, Vols 1-4: A New Beginning for Human Health, Pages: 28-31, ISBN: 0-7803-7789-3
Multicellular models of atrial structure and function have recently started to emerge, but still lack the level of anatomical and electrophysiological detail of their ventricular counterparts. This discrepancy needs to be addressed in order to approach whole heart modeling, including implementation of viable models of intrinsic cardiac pacemaking in the sino-atrial node (SAN). We addressed this issue by developing 1D, 2D and, more recently, 3D SAN-atrial models. Electrophysiological descriptions are based on published single cell models of rabbit SAN and atrial myocytes. Electrotonic interaction is via gap junctions, which are modeled based on experimental data from isolated rabbit SAN and -atrial cell pairs. In 1D simulations, intercellular conductivities need to be scaled up beyond the levels observed in isolated cell pairs to achieve normal sinus rhythm. This is not required in models of higher spatial dimensionality. Implementation of detailed anatomical information in 2D SAN models allows reproduction of the spread of excitation from the central SAN towards the Crista terminalis, rather than the atrial septum. This level of structural detail will also be required in 3D models, as otherwise non-physiological conduction patterns are observed. Thus, dimensionality and cell distribution information are critical for normal origin and spread of SAN excitation.
Garny A, Kohl P, Hunter PJ, et al., 2003, One-dimensional rabbit sinoatrial node models: Benefits and limitations, Vol: 14, Pages: S121-S132, ISSN: 1045-3873
One-Dimensional Rabbit Sinoatrial Node Models. 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(R) Origin(R) 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.
Garny A, Kohl P, Noble D, 2003, Cellular Open Resource (COR): A public CellML based environment for modeling biological function, Vol: 13, Pages: 3579-3590, ISSN: 0218-1274
Computer models have proved to be invaluable to experimental and theoretical research in cardiac electrophysiology, and several environments have been designed to aim at easing the development of such models. Recent advances in computing have made the development of graphical user interfaces much simpler, which has lead to the arrival of new software packages that are used primarily for teaching, not research. Here, we introduce Cellular Open Resource (COR), a modeling environment that runs under Microsoft Windows(R) and that can be used for both research and teaching. It is built around CellML(TM), which provides COR with "out of the box" access to an increasing database of single cell models. Though COR was initially developed to handle cardiac modeling, it may also be applied to other types of reaction (and diffusion) problems. The interface is designed with user friendliness in mind (e.g. an equation viewer can be used to graphically visualize an equation as it would appear in a publication). All the cell models used in a single cell or a multicellular problem are checked for correctness, before being dynamically compiled and converted into machine code, in order to maximize computing efficiency. The computation of a problem is both interactive and event-driven. One can, thus, modify the properties of a problem at any point in time and/or subject to a particular condition. COR is freely available for academic use from http://COR.physiol.ox.ac.uk/.
Kohl P, 2003, Heterogeneous cell coupling in the heart - An electrophysiological role for fibroblasts, Vol: 93, Pages: 381-383, ISSN: 0009-7330
Kohl P, Ravens U, 2003, Cardiac mechano-electric feedback: past, present, and prospect, Vol: 82, Pages: 3-9, ISSN: 0079-6107
Mechanical effects on heart rhythm have been known to. the clinical community for well over a century, and documented cases include both arrhythmogenic and pro-rhythmic consequences of mechanical stimulation. The intracardiac pathway that leads from changes in the cardiac mechanical environment to altered electrical activity is referred to as mechano-electric feedback (MEF). Fundamental research into the mechanisms underlying cardiac MEF is 'engineering-intensive', and much of the current insight would have been impossible without the introduction of novel techniques for the study of isolated cardiac cells. Clinical and basic research into MEF have developed over different time scales, often uninformed of each other, and utilizing disparate concepts and terminology. Bridging the gap between the two domains is not straightforward, as physicians and scientists tend to publish in different journals and attend different meetings. There is, however, a growing interest in 're-uniting' the clinic and basic MEF research, as witnessed by an increasing number of dedicated journal issues and international meetings, including events hosted by major European and American professional organisations such as the ESC and NASPE. Last year alone saw an international workshop on Cardiac MEF & Arrhythmias at Oxford, as well as dedicated sessions at NASPE's 23rd annual meeting in San Diego, CardioStim 2002 in Nice, and the UK Physiological Society meeting in Leeds. This volume of Progress in Biophysics and Molecular Biology incorporates clinical and basic science results, and it is,fitting that its publication coincides with a special session on cardiac MEF at the 2003 meeting of NASPE. (C) 2003 Elsevier Science Ltd. All rights reserved.
Konovalov P, Solovyova O, Markhasin VS, et al., 2003, Local contractility matching to global demand in heterogeneous myocardium: Role of mechanical interaction, Vol: 84, Pages: 240A-240A, ISSN: 0006-3495
Lei M, Cooper P, Kohl P, 2002, Mechanisms of murine sino-atrial node pacemaking: a role for the fast sodium current, iNa?, Vol: 29, Pages: A75-A76, ISSN: 0305-1870
Li WH, Eason JC, Kohl P, et al., 2002, The influence of stretch-activated channels on defibrillation, Second Joint Embs-Bmes Conference 2002, Vols 1-3, Conference Proceedings: Bioengineering - Integrative Methodologies, New Technologies, Pages: 1434-1435, ISBN: 0-7803-7612-9
Passive filling of the ventricles during fibrillation could engage stretch-activated ionic channels, which, in their turn, may alter the dynamics of fibrillation or defibrillation. We quantify the electrophysiological changes in myocardial tissue associated with the recruitment of stretch-activated channels and assess their effects on termination of a reentrant wavefront in a computational model. Our analysis reveals that stretch-activated channels elevate the resting potential, shorten the refractory period, increase propagation velocity, and alter the efficacy of shocks in terminating an arrhythmia. Most importantly, the involvement of stretch-activated channels causes the defibrillation dose-response curve to flatten; weak shocks are slightly more likely to succeed while strong shocks are more likely to fail.
Vikulova N, Solovyova O, Markhasin V, et al., 2002, Modelling cross-talk of mechano-dependent Ca2+ handling and stretch-activated currents in cardiac mechanoelectric feedback, Vol: 544, Pages: 63P-63P, ISSN: 0022-3751
Lei M, Cooper PJ, Camelliti P, et al., 2002, Role of the 293b-sensitive, slowly activating delayed rectifier potassium current, i(Ks), in pacemaker activity of rabbit isolated sino-atrial node cells, Vol: 53, Pages: 68-79, ISSN: 0008-6363
Objectives: (i) to characterize the electrophysiological properties of the slowly activating delayed rectifier potassium current, i,,, defined as the 293b-sensitive current, during tire action potential (AP) of rabbit sino-atrial node (,SAN) pacemaker cells:, (ii) to evaluate the contribution of i,, to the pacemaker AP under physiological conditions and during P-adrenergic stimulation. Methods: Rabbit SAN pacemaker cells were studied using the perforated patch clamp technique in voltage-, AP- and current-clamp modes. Results: Voltage-clamp findings.Block of i(Kb) by 293b is dose-dependent, with an IC50(half block) in rabbit SAN cells of 1.35 muM and an IC80 (sub-maximal block) of 5 muM. Sub-maximal concentrations of 293b have no significant effect, oil long-lasting and transient inward calcium cur-rents, i(CR.L) and i(Ca.r) inward hyperpolarization activated current, i(r), and transient outward current, i(to). AP-clamp experiments. The 293b-sensitive current activates near the peak of the SAN pacemaker action potential, reaches a mean maximal current density of 1.0 +/- 0.3 pA/pF (n=8, cell capacitances 27 to 62 pF, mean 35 +/- 4.0 pF) during late repolarization, and inactivates towards the end of repolarization. Additionally, in two smaller cells (cell capacitances 15 and 23 pF), no discernible 293b-sensitive cur-rent component was detected. Current-clamp data. In spontaneously beating SAN cells under control conditions, sub-maximal block of i,, by 5 NI 293b has negligible effects on action potential characteristics and does not change average cycle length (n =11). In contrast, after pre-treatment with 1 0 nM isoprenaline to mimic beta-adrenergic stimulation, cells showed a 293b-induced dcpolarization of maximum diastolic potential by 2.2 +/- 1%, a decrease in diastolic depolarization rate by 9.9 +/- 4%, and a slowing of late action potential repolarization by 28.7 +/- 10.2%, resulting in a prolongation of spontaneous cycle length by 9.8 +/- 3.0% (P<0.05, n = 10;
Garny AF, Hunter PJ, Kohl P, et al., 2002, Anatomically and biophysically detailed computer model of rabbit sino-atrial node pacemaking, Vol: 82, Pages: 93A-94A, ISSN: 0006-3495
Camelliti P, Kohl P, Green C, 2002, Myocyte/non-myocyte interactions in the heart: clues to an alternative mechanosensor for cardiac MEF, Journal of Physiology-London, Pages: 21S-21S, ISSN: 0022-3751
Lei M, Cooper PJ, Camelliti P, et al., 2002, Contribution of the fast sodium inward current, iNa, to murine sino-atrial node pacemaking, Vol: 82, Pages: 609A-609A, ISSN: 0006-3495
Garny A, Noble PJ, Kohl P, et al., 2002, Cellular open resource (COR): a new environment for cellular and multicellular modelling of cardiac electrophysiology, Vol: 544, Pages: 1P-2P, ISSN: 0022-3751
Garny A, Noble PJ, Kohl P, et al., 2002, Comparative study of rabbit sino-atrial node cell models, Vol: 13, Pages: 1623-1630, ISSN: 0960-0779
This paper compares recent mathematical models of rabbit sino-atrial node pacemaker cell activity [Cellular and Neuronal Oscillators, Dekker, New York, 1989, p. 59; Am. J. Physiol. 266 (1994) C832; J. Theor. Biol. 181 (1996) 245; Am. J. Physiol. 279 (2000) H397] and evaluates them with the perspective of developing detailed multicellular models of the right atrium. (i) All evaluated models reproduce control action potential shapes, which have been recorded experimentally (although one of them (Dokos et al., loc. cit.) shows an unusually long spontaneous diastolic depolarisation phase, probably more compatible with room-temperature rather than body-temperature conditions). This is achieved on the basis of implementing sarcolemmal ion fluxes as a function of (computed) internal and (computed/ fixed) external ion concentrations. Also, all models address, to some extent, intracellular calcium handling processes. (ii) Application of the various models to simulated experimental interventions (such as block of selected ion currents) reveals a wide range of responses (partially outside patho-physiologically plausible ranges) and inconsistencies between simulated and experimental data, thus defining the need for further model improvement. (iii) The heterogeneity of cell parameters within the sino-atrial node is addressed only by one of the models (Zhang et al., loc. cit.). (iv) Computation time differs greatly between the various models, with a ratio of 1:6 between the slowest and the fastest models. We conclude that, out of the currently available set, the Zhang et al. (loc. cit.) model is best suited for application to multicellular modelling of the right atrium. (C) 2002 Published by Elsevier Science Ltd.
Camelliti P, Kohl P, Green C, 2002, Gap junction coupling of cardiac fibroblasts in situ, Vol: 82, Pages: 632A-632A, ISSN: 0006-3495
Kohl P, Noble D, Hunter PJ, 2001, The integrated heart: modelling cardiac structure and function - Preface, Vol: 359, Pages: 1047-1047, ISSN: 1364-503X
Kohl P, Sachs F, 2001, Mechanoelectric feedback in cardiac cells, Vol: 359, Pages: 1173-1185, ISSN: 1364-503X
Cardiac electrophysiology is affected by cardiac mechanics. The input from the heart's mechanical environment to its electrical behaviour has been termed mechano-electric feedback (MEF) and is well documented by more than a century of clinical observations on mechanical modulation of heart rate and rhythm. The mechanisms underlying cardiac MEF have been investigated for only a few decades and include stretch activation of ion channels and mechanical. modulation of cellular Ca(2+) handling. This review briefly outlines the scope and limitations of current experimental insight and its implementation in mathematical models of cardiac cellular activity.
Lei M, Cooper P, Kohl P, 2001, Role of slowly activating delayed rectifier current, IKs, in pacemaker activity of rabbit sino-atrial node cells, Vol: 80, Pages: 640A-640A, ISSN: 0006-3495
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