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Peter Milberg,
Christian Pott,
Gerrit Frommeyer, Martin Fink,
Matthias Ruhe,
Toshio Matsuda,
Akemichi Baba,
Rainer Klocke,
Trong Hung Quang,
Sigrid Nikol,
Jörg Stypmann,
Nani Osada,
Frank U Müller,
Günter Breithardt,
Dennis Noble,
Lars Eckardt
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ABSTRACT: Molecular remodeling in heart failure includes slowing of repolarization, leading to proarrhythmia.
To evaluate the effects of Na(+)/Ca(2+) exchanger (NCX) inhibition on repolarization as a novel antiarrhythmic concept in chronic heart failure (CHF).
CHF was induced by rapid ventricular pacing in rabbits. Left ventricular function was assessed by echocardiography. Monophasic action potentials (MAPs) showed a prolongation of repolarization in CHF after atrioventricular block and stimulation at different cycle lengths. Sotalol (100 μM, n = 13) or veratridine (0.5 μM; n = 15) resulted in a further significant increase in the MAP duration. CHF was associated with an increased dispersion of repolarization, as compared with sotalol-treated (+22 ± 7 ms; P < .05) and veratridine-treated (+20 ± 6 ms; P < .05) sham hearts. In the presence of a low potassium concentration, sotalol and veratridine reproducibly induced early afterdepolarizations (EADs) and polymorphic ventricular tachyarrhythmias (VTs). SEA0400 (1 μM), a pharmacological inhibitor of NCX, significantly shortened the MAP duration (P < .01) and reduced dispersion (P < .05). It suppressed EAD in 6 of 13 sotalol-treated failing hearts and in 9 of 10 veratridine-treated failing hearts, leading to a reduction in VT (60% in sotalol-treated failing hearts and 83% in veratridine-treated failing hearts). Simulations using a mathematical model showed a reduction in the action potential duration and the number of EADs by the NCX block in all subgroups.
In an experimental model of CHF, the acute inhibition of NCX (1) reduces the MAP duration, (2) decreases dispersion of repolarization, and (3) suppresses EAD and VT. Our observations indicate for the first time that pharmacological NCX inhibition increases repolarization reserve and protects against VTs in heart failure.
Heart rhythm: the official journal of the Heart Rhythm Society 11/2011; 9(4):570-8. · 4.56 Impact Factor
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Tongyin Yi,
Johnson Wong,
Eric Feller,
Samantha Sink,
Ouarda Taghli-Lamallem,
Jianyan Wen,
Changsung Kim, Martin Fink,
Wayne Giles,
Walid Soussou,
Huei-Sheng V Chen
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ABSTRACT: Understanding sinoatrial node (SAN) development could help in developing therapies for SAN dysfunction. However, electrophysiological investigation of SAN development remains difficult because mutant mice with SAN dysfunctions are frequently embryonically lethal. Most research on SAN development is therefore limited to immunocytochemical observations without comparable functional studies.
We applied a multielectrode array (MEA) recording system to study SAN development in mouse hearts acutely isolated at embryonic ages (E) 8.5-12.5 days. Physiological heart rates were routinely restored, enabling accurate functional assessment of SAN development. We found that dominant pacemaking activity originated from the left inflow tract (LIFT) region at E8.5, but switched to the right SAN by E12.5. Combining MEA recordings and pharmacological agents, we show that intracellular calcium (Ca(2+))-mediated automaticity develops early and is the major mechanism of pulse generation in the LIFT of E8.5 hearts. Later in development at E12.5, sarcolemmal ion channels develop in the SAN at a time when pacemaker channels are down-regulated in the LIFT, leading to a switch in the dominant pacemaker location. Additionally, low micromolar concentrations of tetrodotoxin (TTX), a sodium channel blocker, minimally affect pacemaker rhythm at E8.5-E12.5, but suppress atrial activation and reveal a TTX-resistant SAN-atrioventricular node (internodal) pathway that mediates internodal conduction in E12.5 hearts.
Using a physiological mapping method, we demonstrate that differential mechanistic development of automaticity between the left and right inflow tract regions confers the pacemaker location switch. Moreover, a TTX-resistant pathway mediates preferential internodal conduction in E12.5 mouse hearts.
Journal of Cardiovascular Electrophysiology 10/2011; 23(3):309-18. · 3.06 Impact Factor
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Cardiovascular research 06/2011; 91(3):376-7. · 5.80 Impact Factor
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ABSTRACT: Ca(2+)-induced delayed afterdepolarizations (DADs) are depolarizations that occur after full repolarization. They have been observed across multiple species and cell types. Experimental results have indicated that the main cause of DADs is Ca(2+) overload. The main hypothesis as to their initiation has been Ca(2+) overflow from the overloaded sarcoplasmic reticulum (SR). Our results using 37 previously published mathematical models provide evidence that Ca(2+)-induced DADs are initiated by the same mechanism as Ca(2+)-induced Ca(2+) release, i.e., the modulation of the opening of ryanodine receptors (RyR) by Ca(2+) in the dyadic subspace; an SR overflow mechanism was not necessary for the induction of DADs in any of the models. The SR Ca(2+) level is better viewed as a modulator of the appearance of DADs and the magnitude of Ca(2+) release. The threshold for the total Ca(2+) level within the cell (not only the SR) at which Ca(2+) oscillations arise in the models is close to their baseline level (∼1- to 3-fold). It is most sensitive to changes in the maximum sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) pump rate (directly proportional), the opening probability of RyRs, and the Ca(2+) diffusion rate from the dyadic subspace into the cytosol (both indirectly proportional), indicating that the appearance of DADs is multifactorial. This shift in emphasis away from SR overload as the trigger for DADs toward a multifactorial analysis could explain why SERCA overexpression has been shown to suppress DADs (while increasing contractility) and why DADs appear during heart failure (at low SR Ca(2+) levels).
AJP Heart and Circulatory Physiology 06/2011; 301(3):H921-35. · 3.71 Impact Factor
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ABSTRACT: 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.
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.
The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.
Cardiovascular research 02/2011; 91(1):53-61. · 5.80 Impact Factor
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ABSTRACT: Interaction between a membrane oscillator generated by voltage-dependent ion channels and an intracellular calcium signal oscillator was present in the earliest models (1984 to 1985) using representations of the sarcoplasmic reticulum. Oscillatory release of calcium is inherent in the calcium-induced calcium release process. Those historical results fully support the synthesis proposed in the articles in this review series. The oscillator mechanisms do not primarily compete with each; they entrain each other. However, there is some asymmetry: the membrane oscillator can continue indefinitely in the absence of the calcium oscillator. The reverse seems to be true only in pathological conditions. Studies from tissue-level work and on the development of the heart also provide valuable insights into the integrative action of the cardiac pacemaker.
Circulation Research 06/2010; 106(12):1791-7. · 9.49 Impact Factor
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Martin Fink,
Steven A Niederer,
Elizabeth M Cherry,
Flavio H Fenton,
Jussi T Koivumäki,
Gunnar Seemann,
Rüdiger Thul,
Henggui Zhang,
Frank B Sachse,
Dan Beard,
Edmund J Crampin,
Nicolas P Smith
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ABSTRACT: In this manuscript we review the state of cardiac cell modelling in the context of international initiatives such as the IUPS Physiome and Virtual Physiological Human Projects, which aim to integrate computational models across scales and physics. In particular we focus on the relationship between experimental data and model parameterisation across a range of model types and cellular physiological systems. Finally, in the context of parameter identification and model reuse within the Cardiac Physiome, we suggest some future priority areas for this field.
Progress in Biophysics and Molecular Biology 03/2010; 104(1-3):2-21. · 3.20 Impact Factor
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ABSTRACT: Cardiovascular disease, and the cardiovascular side effects of drugs, are essentially multifactorial problems involving interactions between many proteins, dependent on highly organized cell, tissue and organ structures. This is one reason why the side effects of drugs are often unanticipated. It is impossible to unravel such problems without using a systems approach, i.e. focussing on processes, not just molecular components. This inevitably involves modelling as the interactions require quantitative analysis. Modelling is a tool of analysis aimed at understanding, first, and predicting, eventually. We illustrate these principles using modelling of the heart. Models of the cardiac myocyte have benefited from several decades of interaction between experimentation and simulation. They are now sufficiently detailed to have been of use in the development of new drug compounds like ranolazine and ivabradine. With the help of cardiac modelling, we have also been able to unravel the mechanisms underlying the beneficial effect of sodium calcium exchange block for long QT syndrome (LQTS) 2 and LQTS3 patients. Detailed models of the interaction between ion channels and blocking agents provide the basis for modelling drug action from basic principles and predict changes in the inhomogeneous tissue of the heart. We demonstrate that mathematical models are beneficial for unravelling the complex interactions of pharmacodynamics in the heart. Embedding these detailed biophysical cellular scale models into anatomically correct models of the ventricle geometry will enable reconstructions of Torsades de Pointes arrhythmias and of fibrillation, providing a mechanism for linking detailed cellular scale experimental data to clinical applications.
Basic & Clinical Pharmacology & Toxicology 03/2010; 106(3):243-9. · 2.18 Impact Factor
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[show abstract]
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ABSTRACT: Cardiovascular disease, and the cardiovascular side effects of drugs, are essentially multifactorial problems involving interactions between many proteins, dependent on highly organized cell, tissue and organ structures. This is one reason why the side effects of drugs are often unanticipated. It is impossible to unravel such problems without using a systems approach, i.e. focussing on processes, not just molecular components. This inevitably involves modelling as the interactions require quantitative analysis. Modelling is a tool of analysis aimed at understanding, first, and predicting, eventually. We illustrate these principles using modelling of the heart. Models of the cardiac myocyte have benefited from several decades of interaction between experimentation and simulation. They are now sufficiently detailed to have been of use in the development of new drug compounds like ranolazine and ivabradine. With the help of cardiac modelling, we have also been able to unravel the mechanisms underlying the beneficial effect of sodium calcium exchange block for long QT syndrome (LQTS) 2 and LQTS3 patients. Detailed models of the interaction between ion channels and blocking agents provide the basis for modelling drug action from basic principles and predict changes in the inhomogeneous tissue of the heart. We demonstrate that mathematical models are beneficial for unravelling the complex interactions of pharmacodynamics in the heart. Embedding these detailed biophysical cellular scale models into anatomically correct models of the ventricle geometry will enable reconstructions of Torsades de Pointes arrhythmias and of fibrillation, providing a mechanism for linking detailed cellular scale experimental data to clinical applications.
Basic & Clinical Pharmacology & Toxicology 02/2010; 106(3):243 - 249. · 2.18 Impact Factor
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ABSTRACT: In the mammalian heart, electrical activity triggers and strongly modulates the contractions. In addition, under both physiological
and pathophysiological conditions the mechanical activity of the heart may change tissue excitability, the action potential
waveform and/or the pattern of conduction. In some cases, this mechanoelectrical feedback can alter the myocardium such that
extrasystoles or rhythm disturbances are observed. It is thought that this sensitivity to mechanical perturbations is due
to stretch-induced activation or alteration of ion channels which are expressed in the sarcolemma of cardiac myocytes. In
the present manuscript, we describe studies on the effects of membrane stretch on the Na+ channel alpha subunit, Nav1.5 (which is predominant in the adult mammalian heart). Three different approaches have been utilized: (i) recordings of
Na+ current from adult rat ventricular myocytes, (ii) studies of currents due to this Na+ channel transcript expressed in a Xenopus laevis oocyte preparation, and (iii) integration of these findings, following appropriate alterations of the descriptors for this
Na+ current in a mathematical model of the human ventricular action potential. The results demonstrate that in both native mammalian
myocytes and in the heterologous expression system, applied stretch causes the Na+ current to activate at more negative membrane potentials. Stretch also significantly increases the Na+ current density. When these effects are incorporated into a mathematical model of the human ventricular action potential,
myocyte excitability is enhanced, and there is also a significant increase in the maximum rate of rise in the action potential.
Thus, in the mammalian heart the effects of stretch on conventional time- and voltage-dependent intrinsic Na+ currents need to be taken into account when attempting to understand either the basis for, or the consequences of mechanoelectrical
feedback.
12/2009: pages 169-184;
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ABSTRACT: Markov models (MMs) represent a generalization of Hodgkin-Huxley models. They provide a versatile structure for modelling single channel data, gating currents, state-dependent drug interaction data, exchanger and pump dynamics, etc. This paper uses examples from cardiac electrophysiology to discuss aspects related to parameter estimation. (i) Parameter unidentifiability (found in 9 out of 13 of the considered models) results in an inability to determine the correct layout of a model, contradicting the idea that model structure and parameters provide insights into underlying molecular processes. (ii) The information content of experimental voltage step clamp data is discussed, and a short but sufficient protocol for parameter estimation is presented. (iii) MMs have been associated with high computational cost (owing to their large number of state variables), presenting an obstacle for multicellular whole organ simulations as well as parameter estimation. It is shown that the stiffness of models increases computation time more than the number of states. (iv) Algorithms and software programs are provided for steady-state analysis, analytical solutions for voltage steps and numerical derivation of parameter identifiability. The results provide a new standard for ion channel modelling to further the automation of model development, the validation process and the predictive power of these models.
Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences 07/2009; 367(1896):2161-79. · 2.77 Impact Factor
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ABSTRACT: The genetic basis of heart development is remarkably conserved from Drosophila to mammals, and insights from flies have greatly informed our understanding of vertebrate heart development. Recent evidence suggests that many aspects of heart function are also conserved and the genes involved in heart development also play roles in adult heart function. We have developed a Drosophila heart preparation and movement analysis algorithm that allows quantification of functional parameters. Our methodology combines high-speed optical recording of beating hearts with a robust, semi-automated analysis to accurately detect and quantify, on a beat-to-beat basis, not only heart rate but also diastolic and systolic intervals, systolic and diastolic diameters, percent fractional shortening, contraction wave velocity, and cardiac arrhythmicity. Here, we present a detailed analysis of hearts from adult Drosophila, 2-3-day-old zebrafish larva, and 8-day-old mouse embryos, indicating that our methodology is potentially applicable to an array of biological models. We detect progressive age-related changes in fly hearts as well as subtle but distinct cardiac deficits in Tbx5 heterozygote mutant zebrafish. Our methodology for quantifying cardiac function in these genetically tractable model systems should provide valuable insights into the genetics of heart function.
BioTechniques 03/2009; 46(2):101-13. · 2.67 Impact Factor
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ABSTRACT: Computational models of cardiac electrophysiology are exemplar demonstrations of the integration of multiple data sets into a consistent biophysical framework. These models encapsulate physiological understanding to provide quantitative predictions of function. The combination or extension of existing models within a common framework allows integrative phenomena in larger systems to be investigated. This methodology is now routinely applied, as demonstrated by the increasing number of studies which use or extend previously developed models. In this study, we present a meta-analysis of this model re-use for two leading models of cardiac electrophysiology in the form of parameter inheritance trees, a sensitivity analysis and a comparison of the functional significance of the sodium potassium pump for defining restitution curves. These results indicate that even though the models aim to represent the same physiological system, both the sources of parameter values and the function of equivalent components are significantly different.
Experimental physiology 02/2009; 94(5):486-95. · 3.17 Impact Factor
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ABSTRACT: We have developed a method for analyzing high speed optical recordings from Drosophila, zebrafish and embryonic mouse hearts (Fink, et. al., 2009). Our Semi-automatic Optical Heartbeat Analysis (SOHA) uses a novel movement detection algorithm that is able to detect cardiac movements associated with individual contractile and relaxation events. The program provides a host of physiologically relevant readouts including systolic and diastolic intervals, heart rate, as well as qualitative and quantitative measures of heartbeat arrhythmicity. The program also calculates heart diameter measurements during both diastole and systole from which fractional shortening and fractional area changes are calculated. Output is provided as a digital file compatible with most spreadsheet programs. Measurements are made for every heartbeat in a record increasing the statistical power of the output. We demonstrate each of the steps where user input is required and show the application of our methodology to the analysis of heart function in all three genetically tractable heart models.
Journal of Visualized Experiments 01/2009;
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ABSTRACT: Long QT syndrome (LQTS) is associated with sudden cardiac death resulting from torsades de pointes (TdP), which are triggered by early afterdepolarizations (EADs). The cardiac Na(+)/Ca(2+) exchanger (NCX) has been suggested to work as a trigger for EADs.
The purpose of this study was to test the hypothesis that inhibition of NCX with a newly developed selective NCX inhibitor (SEA0400) reduces TdP.
In 34 Langendorff-perfused rabbit hearts, the I(Kr)-blocker sotalol (100 microM; n = 18) as well as veratridine (0.5 microM; n = 16), an inhibitor of sodium channel inactivation, led to a significant increase in monophasic action potential (MAP) duration thereby mimicking LQTS2 and LQTS3. In bradycardic hearts, recordings of eight MAPs demonstrated an increased dispersion of repolarization (sotalol: 67%; veratridine: 89%; P <.05). After lowering of potassium concentration, sotalol (56%) and veratridine (63%) induced TdP. Perfusion with SEA0400 (1 microM) suppressed EADs in 15 of 16 sotalol hearts and in seven of 13 veratridine hearts. SEA0400 significantly shortened MAP duration and reduced dispersion of repolarization in both groups (P <.05). This reduced TdP incidence in the sotalol group (100%) and in the veratridine group (77%). To investigate the effects of NCX inhibition on the cellular level, we used a computer model of the rabbit ventricular myocyte. I(Na) and I(Kr) were modified to mimic the effects of veratridine and sotalol, respectively. Consistent with our in vitro experiments, reduction of NCX activity accelerated repolarization of the cellular action potential and prevented EADs.
In an intact rabbit heart model of LQT2 and LQT3 as well as in a computer model of the rabbit cardiac myocyte, inhibition of NCX is effective in preventing TdP due to a suppression of EADs, a reversion of action potential prolongation, and a reduction of dispersion of repolarization. Our observations suggest a therapeutic benefit of selective NCX inhibition in LQTS.
Heart rhythm: the official journal of the Heart Rhythm Society 10/2008; 5(10):1444-52. · 4.56 Impact Factor
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ABSTRACT: In this paper we compare several approaches to identifying certain key respiratory control parameters relying on data normally available from non-invasive measurements. We consider a simple model of the respiratory control system and describe issues related to numerical estimates of key parameters involved in respiratory function such as central and peripheral control gains, transport delay, and lung compartment volumes. The combination of model-specific structure and limited data availability influences the parameter estimation process. Methods for studying how to improve the parameter estimation process are examined including classical and generalized sensitivity analysis, and eigenvalue grouping. These methods are applied and compared in the context of clinically available data. These methods are also compared in conjunction with specialized tests such as the minimally invasive single-breath CO2 test that can improve the estimation, and the enforced fixed breathing test, which opens the control loop in the system. The analysis shows that it is impossible to estimate central and peripheral gain simultaneously without usage of ventilation measurement and a controlled perturbation of the respiratory system, such as the CO2 test. The numerical results are certainly model dependent, but the illustrated methods, the nature of the comparisons, and protocols will carry over to other models and data configurations.
Cardiovascular Engineering 01/2008; 8(2):120-34. · 0.81 Impact Factor
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Scholarpedia. 01/2008; 3:1803.
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Karen Ocorr,
Nick L Reeves,
Robert J Wessells, Martin Fink,
H-S Vincent Chen,
Takeshi Akasaka,
Soichiro Yasuda,
Joseph M Metzger,
Wayne Giles,
James W Posakony,
Rolf Bodmer
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ABSTRACT: Population profiles of industrialized countries show dramatic increases in cardiovascular disease with age, but the molecular and genetic basis of disease progression has been difficult to study because of the lack of suitable model systems. Our studies of Drosophila show a markedly elevated incidence of cardiac dysfunction and arrhythmias in aging fruit fly hearts and a concomitant decrease in the expression of the Drosophila homolog of human KCNQ1-encoded K(+) channel alpha subunits. In humans, this channel is involved in myocardial repolarization, and alterations in the function of this channel are associated with an increased risk for Torsades des Pointes arrhythmias and sudden death. Hearts from young KCNQ1 mutant fruit flies exhibit prolonged contractions and fibrillations reminiscent of Torsades des Pointes arrhythmias, and they exhibit severely increased susceptibility to pacing-induced cardiac dysfunction at young ages, characteristics that are observed only at advanced ages in WT flies. The fibrillations observed in mutant flies correlate with delayed relaxation of the myocardium, as revealed by increases in the duration of phasic contractions, extracellular field potentials, and in the baseline diastolic tension. These results suggest that K(+) currents, mediated by a KCNQ channel, contribute to the repolarization reserve of fly hearts, ensuring normal excitation-contraction coupling and rhythmical contraction. That arrhythmias in both WT and KCNQ1 mutants become worse as flies age suggests that additional factors are also involved.
Proceedings of the National Academy of Sciences 04/2007; 104(10):3943-8. · 9.68 Impact Factor
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ABSTRACT: 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.
Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences 06/2006; 364(1842):1207-22. · 2.77 Impact Factor
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