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R Wilders

Publications and source records attributed to R Wilders.

At least 19 recordsLinked to original sources
PubMed2002

A computationally efficient electrophysiological model of human ventricular cells.

Recent experimental and theoretical results have stressed the importance of modeling studies of reentrant arrhythmias in cardiac tissue and at the whole heart level. We introduce a six-variable model obtained by a reformulation of the Priebe-Beuckelmann model of a single human ventricular cell. The reformulated model is 4.9 times faster for numerical computations and it is more stable than the original model. It retains the action potential shape at various frequencies, restitution of action potential duration, and restitution of conduction velocity. We were able to reproduce the main properties of epicardial, endocardial, and M cells by modifying selected ionic currents. We performed a simulation study of spiral wave behavior in a two-dimensional sheet of human ventricular tissue and showed that spiral waves have a frequency of 3.3 Hz and a linear core of approximately 50-mm diameter that rotates with an average frequency of 0.62 rad/s. Simulation results agreed with experimental data. In conclusion, the proposed model is suitable for efficient and accurate studies of reentrant phenomena in human ventricular tissue.

Action Potentials↗
PubMed2001

Effects of cell-to-cell uncoupling and catecholamines on Purkinje and ventricular action potentials: implications for phase-1b arrhythmias.

OBJECTIVE: The delayed phase of ventricular arrhythmias during acute ischemia (phase-1b arrhythmia) is associated with depletion of catecholamines and cell-to-cell uncoupling between depressed depolarized intramural ischemic region and surviving cells in subepicardium and subendocardium. In the present study we determined the effects of uncoupling and catecholamines on development of proarrhythmic afterdepolarizations. METHODS: Depressed depolarized ischemic region was simulated by a passive electronic circuit with a potential of -73, -53, -33 or -13 mV. Using patch-clamp methodology, single sheep Purkinje and ventricular cells were coupled to the simulated ischemic region via a variable conductance. By varying coupling conductance, we were able to selectively study the effects of various degrees of uncoupling. RESULTS: At strong coupling, cells were inexcitable and depolarized to potentials near those of the simulated ischemic region. Excitability, action potential duration and resting potential increased with progressive uncoupling. In a critical range of uncoupling, ventricular and "high-plateau" Purkinje cells developed early afterdepolarizations when the potential of the simulated ischemic region was -13 mV. Norepinephrine (1 microM) frequently induced early and delayed afterdepolarizations in both ventricular and Purkinje cells, but these afterdepolarizations were only present during uncoupling when the potential of the simulated ischemic region was -33 mV or more positive. CONCLUSIONS: In a critical range of uncoupling, afterdepolarizations were present when the potential of the simulated ischemic region was -33 or -13 mV, suggesting that triggered activity plays a role in phase-1b arrhythmias when surviving layers uncouple from a highly depolarized intramural ischemic region.

Action Potentials↗
PubMed2000

Gap junctions in cardiovascular disease.

Connexins, the protein molecules forming gap junction channels, are reduced in number or redistributed from intercalated disks to lateral cell borders in a variety of cardiac diseases. This "gap junction remodeling" is considered to be arrhythmogenic. Using a simple model of human ventricular myocardium, we found that quantitative remodeling data extracted from the literature gave rise to only small to moderate changes in conduction velocity and the anisotropy ratio. Especially for longitudinal conduction, cytoplasmic resistivity (and thus cellular geometry) is much more important than commonly realized. None of the remodeling data gave rise to slow conduction on the order of a few centimeters per second.

Animals↗
PubMed2000

Effects of anisotropy on the development of cardiac arrhythmias associated with focal activity.

The anisotropy that normally exists in the myocardium may be either enhanced in peri-infarction zones by loss of lateral cell connections or reduced by redistribution of gap junctions. To test how the degree of anisotropy affects the development of ectopic focal activity, we carried out computer simulations in which a model of an ectopic focus is incorporated as the central element of a two-dimensional sheet of ventricular cells. At low values of intercellular coupling conductance (Gc), the focus region is spontaneously active, but the limited intercellular current flow inhibits propagation. At high Gc, automaticity is suppressed by the loading effects of the surrounding cells. At intermediate Gc, the ectopic activity may propagate into the sheet. In the case of isotropic coupling, the minimum size of the focus region for propagation to occur (in terms of number of collaborating cells within the focus) is as small as approximately ten cells, and this number decreases with increasing anisotropy. Thus, the presence of anisotropy facilitates the development of ectopic focal activity. We conclude that the remodeling that occurs in peri-infarction zones may create a substrate that either facilitates (enhanced anisotropy) or inhibits (reduced anisotropy) the development of cardiac arrhythmias associated with ectopic focal activity.

Action Potentials↗
PubMed2000

Injury current modulates afterdepolarizations in single human ventricular cells.

OBJECTIVE: Injury current (I(injury)) and afterdepolarizations are thought to play an important role in arrhythmias that occur during acute ischemia. However, little is known about the effects of I(injury) on afterdepolarizations. The present study was designed to study the effect of I(injury) on afterdepolarizations and action potentials in single human ventricular cells. METHODS: The patch-clamp technique was used to record action potentials and to apply I(injury) to human ventricular cells. In these cells, early and delayed afterdepolarizations (EADs and DADs) were induced by 1 microM norepinephrine. I(injury) was simulated by coupling cells via a variable coupling resistance to a passive resistance circuit with a potential of 0, -20, or -40 mV, mimicking a depolarized ischemic region. RESULTS: At all potentials, I(injury) induced depolarization of the resting membrane potential and action potential shortening. Flowing from 0 mV, I(injury) induced EADs by itself and aggravated the EADs and DADs that were induced by norepinephrine. Flowing from -40 mV, I(injury) abolished the noradrenaline-induced EADs and DADs. CONCLUSIONS: Our results demonstrate that I(injury) may either prevent or promote the occurrence of afterdepolarizations in human ventricle. The latter holds if conduction is slowed to such an extent that it permits flow of current from depolarized ischemic cells at plateau level to cells in phase 3 or phase 4.

Action Potentials↗
PubMed2000

Electrical interactions between a real ventricular cell and an anisotropic two-dimensional sheet of model cells.

We have extended our "coupling clamp" technique, in which we couple a real cell to a real-time simulation of a model cell, to now incorporate a real cardiac cell as the central element of a two-dimensional sheet of model cells, in which the coupling conductances may be different in the x and y directions and a specific region of lack of coupling conductance may serve as a resistive barrier. We stimulated the real cell in the central location and determined the critical size of the real cell for successful activation of the entire sheet. We found that this critical size was decreased when anisotropy was present compared with the isotropic case and was further decreased when the central site of stimulation was close to the resistive barrier. The heart normally has some degree of anisotropy, and it has been shown that the remodeling that occurs in peri-infarction zones produces a particular loss of lateral connections compared with end-to-end connections among heart cells. We propose that the normal existence of anisotropy and enhancement of the degree of anisotropy both by loss of lateral gap junctions and the development of resistive barriers may play a facilitating role in the development of ectopic foci that may lead to cardiac arrhythmias.

Animals↗
PubMed2000

A spontaneously active focus drives a model atrial sheet more easily than a model ventricular sheet.

Tachycardias can be produced when focal activity at ectopic locations in either the atria or the ventricles propagates into the surrounding quiescent myocardium. Isolated rabbit atrioventricular nodal cells were coupled by an electronic circuit to a real-time simulation of an array of cell models. We investigated the critical size of an automatic focus for the activation of two-dimensional arrays made up of either ventricular or atrial model cells. Over a range of coupling conductances for the arrays, the critical size of the focus cell group for successful propagation was smaller for activation of an atrial versus a ventricular array. Failure of activation of the arrays at smaller focus sizes was due to the inhibition of pacing of the nodal cells. At low levels of coupling conductance, the ventricular arrays required larger sizes of the focus due to failure of propagation even when the focus was spontaneously active. The major differences between activation of the atrial and ventricular arrays is due to the higher membrane resistance (lower inward rectifier current) of the atrial cells.

Animals↗
PubMed1999

Effects of ischemia on discontinuous action potential conduction in hybrid pairs of ventricular cells.

BACKGROUND: Acute ischemia often occurs in cardiac tissue that has prior injury, resulting in spatially inhomogeneous distributions of membrane properties and intercellular coupling. Changes in action potential conduction with ischemia, which can be associated with release of catecholamines, may be particularly important in tissue that has discontinuous conduction resulting from prior infarction, hypertrophy, or myopathy. METHODS AND RESULTS: Isolated guinea pig ventricular myocytes were electrically coupled by a coupling-clamp circuit to a comprehensive computer model of a guinea pig ventricular myocyte to assess alterations in the critical value of coupling conductance required for action potential conduction from the real cell to the model cell when the real cell was exposed to a solution that included hypoxia, acidosis, and an elevated extracellular potassium concentration to simulate acute ischemia. The "ischemic" solution increased critical coupling conductance from 6.2+/-0.1 to 7.4+/-0.2 nS and decreased the associated maximum conduction delay from 31+/-1 to 23+/-1 ms (mean+/-SEM, n=11). The ischemic solution plus 1 micromol/L norepinephrine decreased critical coupling conductance from 5.9+/-0.2 to 5.0+/-0.1 nS and increased maximum conduction delay from 31+/-2 to 54+/-4 ms (mean+/-SEM, n=8). CONCLUSIONS: The release of catecholamines with ischemia, in a setting of partially uncoupled cells, may play a major role in producing long conduction delays, which may allow reentrant pathways.

Action Potentials↗
PubMed1999

Electrical interactions among real cardiac cells and cell models in a linear strand.

Previous work with model systems for action potential conduction have been restricted to conduction between two real cells or conduction between a model cell and a real cell. The inclusion of additional elements to make a linear strand has allowed us to investigate the interactions between cells at a higher level of complexity. When, in the simplest case of a linear strand of three elements, the conductance between elements 2 and 3 (GC2) is varied, this affects the success or failure of propagation between elements 1 and 2 (coupled by GC1) as well as the success or failure of propagation between elements 2 and 3. Several major features were illustrated. 1) When GC1 was only slightly greater than the coupling conductance required for successful propagation between a model cell and a real cell, addition of a third element of the strand either prevented conduction from element 1 to element 2 (when GC2 was high) or allowed conduction from element 1 to element 2 but not conduction from element 2 to element 3 (when GC2 was low). 2) For higher levels of GC1, there was an allowable "window" of values of GC2 for successful conduction from element 1 through to element 3. The size of this allowable window of GC2 values increased with increasing values of GC1, and this increase was produced by increases in the upper bound of GC2 values. 3) When the size of the central element of the strand was reduced, this facilitated conduction through the strand, increasing the range of the allowable window of GC2 values. The overall success or failure of conduction through a structure of cells that has a spatially inhomogeneous distribution of coupling conductances cannot be predicted simply by the average or the minimum value of coupling conductance but may depend on the actual spatial distribution of these conductances.

Animals↗
PubMed1999

Contribution of L-type Ca2+ current to electrical activity in sinoatrial nodal myocytes of rabbits.

The role of L-type calcium current (ICa,L) in impulse generation was studied in single sinoatrial nodal myocytes of the rabbit, with the use of the amphotericin-perforated patch-clamp technique. Nifedipine, at a concentration of 5 microM, was used to block ICa,L. At this concentration, nifedipine selectively blocked ICa,L for 81% without affecting the T-type calcium current (ICa,T), the fast sodium current, the delayed rectifier current (IK), and the hyperpolarization-activated inward current. Furthermore, we did not observe the sustained inward current. The selective action of nifedipine on ICa,L enabled us to determine the activation threshold of ICa,L, which was around -60 mV. As nifedipine (5 microM) abolished spontaneous activity, we used a combined voltage- and current-clamp protocol to study the effects of ICa,L blockade on repolarization and diastolic depolarization. This protocol mimics the action potential such that the repolarization and subsequent diastolic depolarization are studied in current-clamp conditions. Nifedipine significantly decreased action potential duration at 50% repolarization and reduced diastolic depolarization rate over the entire diastole. Evidence was found that recovery from inactivation of ICa,L occurs during repolarization, which makes ICa,L available already early in diastole. We conclude that ICa,L contributes significantly to the net inward current during diastole and can modulate the entire diastolic depolarization.

Animals↗
PubMed1998

Quantitative analysis of dual whole-cell voltage-clamp determination of gap junctional conductance.

The dual whole-cell voltage-clamp technique is used widely for determination of kinetics and conductance of gap junctions. The use of this technique may, however, occasion to considerable errors. We have analysed the errors in steady state junctional conductance measurements under different experimental conditions. The errors in measured junctional conductance induced by series resistance alone, and by series resistance in combination with membrane resistance, were quantified both theoretically and experimentally, on equivalent resistive circuits with known resistance values in a dual voltage-clamp setup. We present and analyse a method that accounts for series resistance and membrane resistance in the determination of true junctional conductance. This method requires that series resistance is determined during the experiment, and involves some calculations to determine membrane resistance. We demonstrate that correction for both membrane and series resistance reduces the error in measured junctional conductance to near zero, even when membrane resistances on both sides of the gap junction are as low as 20 MOmega and the (true) junctional conductance is as high as 100 nS.

Computer Simulation↗
PubMed1998

Pacemaker synchronization of electrically coupled rabbit sinoatrial node cells.

The effects of intercellular coupling conductance on the activity of two electrically coupled isolated rabbit sinoatrial nodal cells were investigated. A computer-controlled version of the "coupling clamp" technique was used in which isolated sinoatrial nodal cells, not physically in contact with each other, were electrically coupled at various values of ohmic coupling conductance, mimicking the effects of mutual interaction by electrical coupling through gap junctional channels. We demonstrate the existence of four types of electrical behavior of coupled spontaneously active cells. As the coupling conductance is progressively increased, the cells exhibit: (a) independent pacemaking at low coupling conductances, (b) complex dynamics of activity with mutual interactions, (c) entrainment of action potential frequency at a 1:1 ratio with different action potential waveforms, and (d) entrainment of action potentials at the same frequency of activation and virtually identical action potential waveforms. The critical value of coupling conductance required for 1:1 frequency entrainment was <0.5 nS in each of the five cell pairs studied. The common interbeat interval at a relatively high coupling conductance (10 nS), which is sufficient to produce entrainment of frequency and also identical action potential waveforms, is determined most by the intrinsically faster pacemaker cell and it can be predicted from the diastolic depolarization times of both cells. Evidence is provided that, at low coupling conductances, mutual pacemaker synchronization results mainly from the phase-resetting effects of the action potential of one cell on the depolarization phase of the other. At high coupling conductances, the tonic, diastolic interactions become more important.

Action Potentials↗
PubMed1998

Electrical interactions between a rabbit atrial cell and a nodal cell model.

Atrial activation involves interactions between cells with automaticity and slow-response action potentials with cells that are intrinsically quiescent with fast-response action potentials. Understanding normal and abnormal atrial activity requires an understanding of this process. We studied interactions of a cell with spontaneous activity, represented by a "real-time" simulation of a model of the rabbit sinoatrial (SA) node cell, simultaneously being electrically coupled via our "coupling clamp" circuit to a real, isolated atrial myocyte with variations in coupling conductance (Gc) or stimulus frequency. The atrial cells were able to be driven at a regular rate by a single SA node model (SAN model) cell. Critical Gc for entrainment of the SAN model cell to a nonstimulated atrial cell was 0.55 +/- 0.05 nS (n = 7), and the critical Gc that allowed entrainment when the atrial cell was directly paced at a basic cycle length of 300 ms was 0.32 +/- 0.01 nS (n = 7). For each atrial cell we found periodic phenomena of synchronization other than 1:1 entrainment when Gc was between 0.1 and 0.3 nS, below the value required for frequency entrainment, when the atrial cell was directly driven at a basic cycle length of either 300 or 600 ms. In conclusion, the high input resistance of the atrial cells allows successful entrainment of nodal and atrial cells at low values of Gc, but further uncoupling produces arrhythmic interactions.

Action Potentials↗
PubMed1997

Modulation of propagation from an ectopic focus by electrical load and by extracellular potassium.

We previously developed a technique (R. Kumar, R. Wilders, R. W. Joyner, H. J. Jongsma, E. E. Verheijck, D. A. Golod, A. C. G. van Ginneken, and W. N. Goolsby. Circulation 94: 833-841, 1996) for study of a mathematical model cell with spontaneous activity, viz. a "real-time" simulation of a rabbit sinoatrial node cell (SAN model cell; R. Wilders, H. J. Jongsma, and A. C. van Ginneken. Biophys. J. 60: 1202-1216, 1991) simultaneously being electrically coupled via our "coupling clamp" [H. Sugiura and R. W. Joyner. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1591-H1604, 1992] circuit to a real, isolated ventricular myocyte. We now apply this technique to investigate effects of coupling conductance (Gc), cell size, and the modulation of membrane potential by elevated extracellular potassium concentration on the ability of an ectopic focus, represented by the SAN model cell, to successfully drive a ventricular cell. Values of Gc and the relative sizes of the two cells define three possible outcomes: 1) spontaneous pacing of the SAN model cell but not driving of the ventricular cell, 2) cessation of spontaneous pacing, or 3) pacing of the SAN model cell and driving of the ventricular cell. Below a critical size of the SAN model cell only the first two of these outcomes is possible. Above this critical size there is a range of Gc that allows successful operation of the system as an ectopic focus. Elevation of extracellular potassium concentration from 4 to 8 mM increases both the lower bound and upper bound of Gc for this range. Elevation of extracellular potassium concentration, as commonly observed in myocardial ischemia, may have effects on either inhibiting or releasing from inhibition an ectopic focus.

Animals↗
PubMed1996

Experimental model for an ectopic focus coupled to ventricular cells.

BACKGROUND: We used a mathematical model of a sinoatrial nodal cell (SAN model) electrically coupled to real ventricular cells (VCs) to investigate action potential conduction from an automatic focus. METHODS AND RESULTS: Since input resistance of a VC is less than that of an SAN cell, coupling of the SAN model, with a size factor of 1, to a VC produced either (1) spontaneous pacing at the slower rate of the SAN model but without driving (activation) of the VC for lower values of coupling conductance (Gj) or (2) inhibition of pacing of the SAN model by electrical coupling to the VC for higher values of Gj. When the SAN model was adjusted in size to be 3 to 5 times larger than a sinoatrial nodal cell, thus making effective SAN model capacitance 3 to 5 times larger and input resistance 3 to 5 times smaller, the SAN model propagated activity to the coupled VC for Gj above a critical value. When the VC was paced at 1 Hz, the coupled cell pair demonstrated a stable rhythm of alternating cycle lengths and alternating conduction directions. By increasing pacing frequency to 2 Hz, we converted this rhythm to a regular 2-Hz frequency in which each action potential originated in the VC. More complex periodic interactions were observed at intermediate cycle lengths and lower or higher values of Gj. CONCLUSIONS: The phenomena we observed demonstrate the critical role of the size of an automatic focus as well as the coupling in the propagation of activity from the focus into surrounding myocardium.

Action Potentials↗
PubMed1996

Modulating L-type calcium current affects discontinuous cardiac action potential conduction.

We have used pairs of cardiac cells (i.e., one real guinea pig ventricular cell and a real-time simulation of a numerical model of a guinea pig ventricular cell) to evaluate the effects on action potential conduction of a variable coupling conductance in combination with agents that either increase or decrease the magnitude of the L-type calcium current. For the cell pairs studied, we applied a direct repetitive stimulation to the real cell, making it the "leader" cell of the cell pair. We have demonstrated that significant delays in action potential conduction for a cell pair can occur either with a decreased value of coupling conductance or with an asymmetry in size such that the follower cell is larger than the leader cell. In both conditions we have shown that isoproterenol, applied to the real cell at very low concentrations, can reversibly decrease the critical coupling conductance (below which action potential conduction fails) for a cell pair with fixed cell sizes, or, for a fixed value of coupling conductance, increase the maximum allowable asymmetry in cell size for successful conduction. For either of these effects, we were able to show that treatment of the real cell with BayK 8644, which more specifically increases the magnitude of the L-type calcium current, was able to mimic the actions of isoproterenol. Treatment of the leader cell of the cell pair (the real cell) with nifedipine, which selectively lowers the magnitude of the L-type calcium current, had effects opposite those of isoproterenol or BayK 8644. The actions of nifedipine, isoproterenol, and BayK 8644 are all limited to conditions in which the conduction delay is on the order of 5 ms or more, whether this delay is caused by limited coupling conductance or by asymmetry in size of the cells. This limitation is consistent with the time course of the L-type calcium current and suggests that the effects of calcium channel blockers or beta-adrenergic blocking drugs, in addition to being selective for regions of the heart that depend on the L-type calcium current for the upstroke of the action potential, would also be somewhat selective for regions of the heart that have discontinuous conduction, either normally or because of some pathological condition.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗