Publications
346 results found
Nesbitt AD, Cooper PJ, Kohl P, 2001, Commotio cordis - early history of a supposedly modern pathology, Vol: 533, Pages: 37P-37P, ISSN: 0022-3751
Nesbitt AD, Cooper PJ, Kohl P, 2001, Rediscovering commotio cordis, Vol: 357, Pages: 1195-1197, ISSN: 0140-6736
Noble PJ, Lei A, Kohl P, et al., 2001, Mechanisms of murine sino-atrial node pacemaking: the usual suspects, Vol: 536, Pages: 5P-7P, ISSN: 0022-3751
Lei M, Camelliti P, Cooper P, et al., 2001, Stretch-induced whole-cell currents during the action potential of guinea-pig ventricular myocytes, Vol: 533, Pages: 40P-40P, ISSN: 0022-3751
Cheng LX, Lei M, Cooper P, et al., 2001, Stretch-induced afterdepolarizations in rabbit isolated ventricular myocytes, Vol: 80, Pages: 111A-111A, ISSN: 0006-3495
Cooper PJ, Lei M, Kohl P, 2001, Positive chronotropic whole cell current activated byaxial stretch of rabbit sinoatrial pacemaker cells, Vol: 80, Pages: 111A-111A, ISSN: 0006-3495
Hunter PJ, Kohl P, Noble D, 2001, Integrative models of the heart: achievements and limitations (vol 359, pg 1049, 2001), Vol: 359, Pages: 2629-2629, ISSN: 1364-503X
Hunter PJ, Kohl P, Noble D, 2001, Integrative models of the heart: achievements and limitations, Vol: 359, Pages: 1049-1054, ISSN: 1364-503X
The recently completed draft sequence of the human genome provides access to a vast database of information, containing of the order of 30 000-40 000 genes. These are understood to encode some 250 000 proteins. Understanding how the information in the genome is used to create this 'proteome' is a major challenge, not least because predicting: the functionally important three-dimensional structure of proteins from their amino-acid sequences is very difficult. But even these formidable challenges pale into insignificance when we consider the complexity of the next stage: understanding the interactions of tells of thousands of proteins as they generate biological function. This is the task of quantitative analysis of physiological function, which in its entirety is now referred to as the 'physiome' Bioinformatics and computational cell and organ modelling will play an increasingly important role in all these stages of unravelling the way in which the information contained in the genome is 'computed' to create living systems. Here, we address all but a small fragment of the physiome project: the development of integrative models of the heart.
Kohl P, Nesbitt AD, Cooper PJ, et al., 2001, Sudden cardiac death by Commotio cordis: role of mechano-electric feedback, Vol: 50, Pages: 280-289, ISSN: 0008-6363
Moderate pre-cordial mechanical impact can cause sudden cardiac death, even in the absence of morphological damage to the heart. This is the most severe expression of a condition termed, in the 19th century, Commotio cordis. Experimental studies performed in the early 1930s showed that sudden cardiac death after chest impact is brought about by an intrinsic cardiac response to the mechanical stimulus. The precise (sub-)cellular mechanisms of this response are still poorly understood. This article summarises experimental findings on the condition and relates them to the more recently established concept of cardiac mechano-electric feedback. As a result, an explanation of the mechanisms that give rise to sudden cardiac death by Commotio cordis and targets for further research are suggested. (C) 2001 Elsevier Science B.V. All rights reserved.
Nickerson D, Smith N, Kohl P, et al., 2000, Cardiac electro-mechanics: cell and tissue modeling, Annals of Biomedical Engineering, Vol: 28, ISSN: 0090-6964
A model of the coupled electro-mechanics of cardiac tissue is presented. The cell model is incorporated into a 2D tissue model in which the equations of large deformation tissue mechanics are solved by Galerkin finite element techniques and electrical wave propagation is solved with a high resolution finite difference grid based on material points embedded in the mechanically defoming tissue. The extracellular tissue mechanics model includes the nonlinear, anisotropic passive elastic properties based in the underlying connective tissue microstructure.
Kohl P, LeGuennec JY, White E, 2000, Diastolic (dys-)function and electrophysiology., Cardiol Clin, Vol: 18, Pages: 637-xi, ISSN: 0733-8651
Cross-talk between cardiac electrical and mechanical function is a bidirectional process: The origin and spread of electric excitation govern cardiac contraction and relaxation, while the mechanic environment provides feedback information to the heart's electric behavior. The latter tends to be unduly disregarded by the medical community. This article reviews experimental findings on the effects of diastolic mechanics on cardiac electrophysiology, and describes physiological correlates, clinical manifestations, and therapeutic utility of cardiac mechanic stimulation in humans.
Garny A, Zhang H, Noble PJ, et al., 2000, Advanced computational model of central and peripheral rabbit sino-atrial node cells, Vol: 78, Pages: 454A-454A, ISSN: 0006-3495
Cheng LX, Cooper P, Kohl P, 2000, Positive chronotropic response to stretch of isolated spontaneously active rabbit sino-trial node cells, Vol: 78, Pages: 472A-472A, ISSN: 0006-3495
Cooper PJ, Lei M, Cheng LX, et al., 2000, Selected Contribution: Axial stretch increases spontaneous pacemaker activity in rabbit isolated sinoatrial node cells, Vol: 89, Pages: 2099-2104, ISSN: 8750-7587
Isolated, spontaneously beating rabbit sinoatrial node cells were subjected to longitudinal stretch, using carbon fibers attached to both ends of the cell. Their electrical behavior was studied simultaneously in current-clamp or voltage-clamp mode using the perforated patch configuration. Moderate stretch (similar to7%) caused an increase in spontaneous beating rate (by similar to5%) and a reduction in maximum diastolic and systolic potentials (by similar to2.5%), as seen in multicellular preparations. Mathematical modeling of the stretch intervention showed the experimental results to be compatible with stretch activation of cation nonselective ion channels, similar to those found in other cardiac cell populations. Voltage-clamp experiments validated the presence of a stretch-induced current component with a reversal potential near -11 mV. These data confirm, for the first time, that the positive chronotropic response of the heart to stretch is, at least in part, encoded on the level of individual sinoatrial node pacemaker cells; all reported data are in agreement with a major contribution of stretch-activated cation nonselective channels to this response.
Kohl P, Noble D, Winslow RL, et al., 2000, Computational modelling of biological systems: tools and visions, Vol: 358, Pages: 579-610, ISSN: 1364-503X
We are currently witnessing the advent of a revolutionary new tool for biomedical research. Complex biochemically, biophysically and pharmacologically detailed mathematical models of 'living cells' are being arranged in morphologically representative tissue assemblies, and, using large-scale supercomputers, utilized to produce anatomically structured models of integrated tissue and organ function. This provides biomedical sciences with a radical new tool: 'in. silico' organs, organ systems and, ultimately, organisms. In silico models will be a crucial tool for biomedical research and development in the new millennium, extracting knowledge from the vast amount of increasingly detailed data, and integrating this into a comprehensive analytical description of biological function with predictive power: the Physiome. Our review will illustrate this approach using the example of the cardiovascular system, which, along with neurophysiology, has been at, the forefront of analytical bio-mathematical modelling for many years, and which is about to deliver the first anatomico-physiological model of a whole organ. Already, electrophysiologically detailed cardiac cell models have been incorporated into mathematical descriptions of representative ventricular tissue architecture and anatomy, including the coronary vasculature. and assimilated to realistic representation of ventricular active and passive mechanical properties. This is being extended by matching atrial models and linked to an artificial torso to compute the body surface electrocardiogram as a function of sub-cellular activity during various (patho-)physiological conditions. We will illustrate the utility of in silico biological research in the context of refinement and partial replacement of in vivo and in vitro experimental work, show the potential of this approach for devising patient-specific treatment strategies, and try to forecast the impact. of this new technology on biomedical research, health-care, and rela
Kohl P, Cooper P, Cheng LX, et al., 1999, Effects of stretch on heart rhythm: Theory & practice, ISSN: 0589-1019
Effects of stretch on heart rhythm have been known for over a century. They possess considerable clinical importance and range from the increase in heart rate during enhanced venous return to the right atrium (Bainbridge effect) to sudden cardiac death caused by pre-cordial chest thumps (Commotio cordis). The underlying cellular and molecular mechanisms have only recently started to become evident and include stretch-activation of ion channels and mechanical modulation of intracellular calcium handling.
Noble D, Varghese A, Kohl P, et al., 1999, Correction: Improved guinea-pig ventricular cell model incorporating a diadic space, I(Kr) and I(Ks), and length- and tension-dependent processes (The Canadian Journal of Cardiology (1998) 14 (123-134)), Canadian Journal of Cardiology, Vol: 15, ISSN: 0828-282X
Kohl P, LeGrice I, Smaill B, et al., 1999, Connexin45 between myocytes and non-myocytes in rabbit sino-atrial node, Vol: 76, Pages: A220-A220, ISSN: 0006-3495
Noble D, Varghese A, Kohl P, et al., 1999, Improved guinea-pig ventricular cell model incorporating a diadic space, I-kr and I-ka, and length- and tension-dependent processes. (vol 14, pg 123, 1998), Vol: 15, Pages: 127-127, ISSN: 0828-282X
Lei M, Kohl P, Brown H, et al., 1999, Non-muscarinic and non-nicotinic inhibition by the acetylcholine analogue carbachol of the delayed rectifier potassium current, i(K) in rabbit isolated sino-atrial node cells, Vol: 84, Pages: 631-638, ISSN: 0958-0670
The effect of carbachol, an analogue of acetylcholine, on the delayed rectifier potassium current, i(K), was investigated in rabbit isolated sino-atrial node cells using the whole cell patch clamp technique with amphotericin-permeabilized patches. In the presence of 500 nM atropine and 500 nM hexamethonium to block muscarinic and nicotinic receptors, respectively, 500 nM carbachol decreased the amplitude and rate of deactivation of i(K) without, however, affecting the slope of the i(K) activation curve. The same concentration of carbachol decreased the pacemaking rate of spontaneously active sino-atrial node cells by more than 13%. Thus, there is a nonmuscarinic and non-nicotinic pathway for cholinergically induced reduction in the amplitude and rate of deactivation of i(K) that would appear to contribute to negative chronotropy in rabbit sinoatrial node pacemaker cells.
Kohl P, Hunter P, Noble D, 1999, Stretch-induced changes in heart rate and rhythm: clinical observations, experiments and mathematical models, Vol: 71, Pages: 91-138, ISSN: 0079-6107
Clinical and research data indicate that active and passive changes in the mechanical environment of the heart are capable of influencing both the initiation and the spread of cardiac excitation via pathways that are intrinsic to the heart. This direction of the cross-talk between cardiac electrical and mechanical activity is referred to as mechano-electric feedback (MEF). MEF is thought to be involved in the adjustment of heart rate to changes in mechanical load and would help to explain the precise beat-to-beat regulation of cardiac performance as it occurs even in the recently transplanted (and, thus, denervated) heart. Furthermore, there is clinical evidence that MEF may be involved in mechanical initiation of arrhythmias and fibrillation, as well as in the re-setting of disturbed heart rhythm by 'mechanical' first aid procedures. This review will outline the clinical relevance of cardiac MEF, describe cellular correlates to the responses observed in situ, and discuss the role that quantitative mathematical models may play in identifying the involvement of cardiac MEF in the regulation of heart rate and rhythm. (C) 1998 Elsevier Science Ltd. All rights reserved.
Kohl P, Hunter P, 1999, Stretch-induced re-entry of excitation in a 2D electromechanical model of ischaemic ventricular tissue, Vol: 13, Pages: A1075-A1075, ISSN: 0892-6638
Kohl P, 1999, Commotio cordis: early observations, Vol: 82, Pages: 397-397, ISSN: 1355-6037
Ch'en FFT, Garny A, Sakmann BFA, et al., 1999, Incorporation of cellular and genetic characteristics into whole heart computational models, Vol: 13, Pages: A1075-A1075, ISSN: 0892-6638
Kohl P, Day K, Noble D, 1998, Cellular mechanisms of cardiac mechano-electric feedback in a mathematical model, Vol: 14, Pages: 111-119, ISSN: 0828-282X
BACKGROUND: Cardiac mechanical and electrical activity are closely interrelated. While excitation-contraction coupling is rather well characterized, less is known about cellular mechanisms that promote mechanically induced changes in cardiac electrical activity - mechano-electric feedback. OBJECTIVE: To integrate experimental findings on stretch activation of ion channels and length-dependent changes in intracellular calcium handling into a mathematical description of cardiac cellular activity. METHODS: Simulations are based on the cellular OXSOFT HEART v4.8 models of electrical activity of single cardiac cells of different populations and species. Sarcolemmal stretch-activated channels, mechanically induced changes in the affinity of troponin C to calcium, and length-dependent modulation of calcium handling by the sarcoplasmic reticulum were introduced into the models and linked to a description of sarcomere length or isometric tension. RESULTS: Transient or sustained stretch of cardiomyocytes was simulated during electrical systole and diastole. The electrophysiological response observed in the model depended on timing and severity of mechanical stimulation and on the main subcellular target of the intervention. Responses ranged from triggering of premature action potentials, over changes in action potential shape and duration, to length-dependent variations in contractile behaviour. Modelling findings could be related to experimental observations and may help to explain some of the contradictory data in the literature. The model is sufficiently complete to reproduce experimental findings and to help identify causally linked events.
Lei M, Kohl P, 1998, Swelling-induced decrease in spontaneous pacemaker activity of rabbit isolated sino-atrial node cells, Vol: 164, Pages: 1-12, ISSN: 0001-6772
The heart responds to an increase in sino-atrial node wall stress with an augmentation in rate of contraction. It has been suggested that swelling-activated ion channels may play a key role in that response. This paper investigates directly the effects of cell swelling on spontaneous activity of rabbit isolated sino-atrial node pacemaker cells. The main finding is that sino-atrial node cells, studied in current clamp mode using amphotericin-permeabilized patches, decrease their spontaneous pacemaker rate by 24.2 +/- 7.8% (P < 0.01, n = 9) during 75% hyposmotic swelling. This response is opposite to the predicted impact of volume-activation of sarcolemmal ion conductances. Computer modelling (OXSOFT(C) Heart v4.8) suggests that swelling-induced dilution of the cytosol, reduction in intracellular potassium concentration, and decrease in the delayed rectifier potassium current, I-K, are leading mechanisms in the response. This is supported by voltage-clamp data that show a swelling-induced positive shift in the reversal potential of I-K by between 5 and 10 mV(n = 7) and a reduction in amplitude of its rapidly activating component, I-Kr, (n = 6). Thus, spontaneously active sino-atrial node cells reduce pacemaking rate during swelling. This response cannot be explained by the known volume-activated sarcolemmal ion conductances, but appears to be dictated by other mechanisms including dilution of the cytosol and reduction in I-K. The results re-enforce the view that cardiac responses to cell volume changes may be quite different from those to longitudinal stretch.
Kohl P, Fasciano RW, Tung L, et al., 1998, Cardiomyocyte model of mechanical modulation of ion channels and calcium handling. Incorporating 'rate-of-rise' dependence, Vol: 74, Pages: A162-A162, ISSN: 0006-3495
Lei M, Kohl P, Rigg L, et al., 1998, Immunohistochemical staining of minK in rabbit sino-atrial node cells, Vol: 506P, Pages: 39P-40P, ISSN: 0022-3751
Noble D, Varghese A, Kohl P, et al., 1998, Improved guinea-pig ventricular cell model incorporating a diadic space, I-Kr and I-Ks, and length- and tension-dependent processes, Vol: 14, Pages: 123-134, ISSN: 0828-282X
The guinea-pig ventricular cell model, originally developed by Noble et al in 1991, has been greatly extended to include accumulation and depletion of calcium in a diadic space between the sarcolemma and the sarcoplasmic reticulum where, according to contempory understanding, the majority of calcium-induced calcium release is triggered. The calcium in this space is also assumed to play the major role in calcium-induced inactivation of the calcium current. Delayed potassium current equations have been developed to include the rapid (I-Kr) and slow (I-Ks) components of the delayed rectifier current based on the data of of Heath and Terrar, along with data from Sanguinetti and Jurkiewicz. Length- and tension-dependent changes in mechanical and electrophysiological processes have been incorporated as described recently by Kohl et al. Drug receptor interactions have started to be developed, using the sodium channel as the first target. The new model has been tested against experimental data an action potential clamp, and on force-interval and duration-interval relations; it has been found to reliably reproduce experimental observations.
Kohl P, Varghese A, Noble D, 1997, Retrograde conduction in a 2-D cardiac scar model, Vol: 72, Pages: TH130-TH130, ISSN: 0006-3495
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