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Y Rudy

Publications and source records attributed to Y Rudy.

At least 55 records · Page 3Linked to original sources
PubMed1997

Electrophysiologic effects of acute myocardial ischemia: a theoretical study of altered cell excitability and action potential duration.

OBJECTIVE: To study the ionic mechanisms of electrophysiologic changes in cell excitability and action potential duration during the acute phase of myocardial ischemia. METHODS: Using an ionic-based theoretical model of the cardiac ventricular cell, the dynamic LRd model, we have simulated the three major component conditions of acute ischemia (elevated [K]o, acidosis and anoxia) at the level of individual ionic currents and ionic concentrations. The conditions were applied individually and in combination to identify ionic mechanisms responsible for reduced excitability at rest potentials, delayed recovery of excitability, and shortened action potential duration. RESULTS: Increased extracellular potassium ([K]o) had the major effect on cell excitability by depolarizing resting membrane potential (Vrest), causing reduction in sodium channel availability. Acidosis caused a [K]o-independent reduction in maximum upstroke velocity, (dVm/dt)max. A transition from sodium-current dominated to calcium-current dominated upstroke occurred, and calcium current alone was able to sustain the upstroke, but only after sodium channels were almost completely (97%) inactivated. Acidic conditions prevented the transition to calcium dominated upstroke by acidic reduction of both sodium and calcium currents. Anoxia, simulated by lowering [ATP]i and activating the APT-dependent potassium current, IK(ATP), was the only process that could decrease action potential duration by more than 50% and reproduce AP shape changes that are observed experimentally. Acidic or anoxic depression of the L-type calcium current could not reproduce the observed action potential shape changes and APD shortening. Delayed recovery of excitability, known as 'post-repolarization refractoriness', was determined by the voltage-dependent kinetics of sodium channel recovery; Vrest depolarization caused by elevated [K]o increased the time constant of (dVm/dt)max recovery from tau = 10.3 ms at [K]o = 4.5 mM to tau = 81.4 ms at [K]o = 12 mM, reflecting major slowing of sodium-channel recovery. Anoxia and acidosis had little affect on tau. CONCLUSIONS: The major conditions of acute ischemia, namely elevated [K]o, acidosis and anoxia, applied at the ionic channel level are sufficient to simulate the major electrical changes associated with ischemia. Depression of membrane excitability and delayed recovery of excitability in the single, unloaded cell are caused by elevated [K]o with additional excitability depression by acidosis. Major changes in action potential duration and shape can only be accounted for by anoxia-dependent opening of IK(ATP).

Acidosis↗
PubMed1997

Regional regularization of the electrocardiographic inverse problem: a model study using spherical geometry.

This study examines the use of a new regularization scheme, called regional regularization, for solving the electrocardiographic inverse problem. Previous work has shown that different time frames in the cardiac cycle require varying degrees of regularization. This reflects differences in potential magnitudes, gradients, signal-to-noise ratio (SNR), and locations of electrical activity. One might expect, therefore, that a single regularization parameter and a uniform level of regularization may also be insufficient for a single potential map of a single time frame because in one map there are regions of high and low potentials and potential gradients. Regional regularization is a class of methods that subdivides a given potential map into functional "regions" based on the spatial characteristics of the potential ("spatial frequencies"). These individual regions are regularized separately and recombined into a complete map. This paper examines the hypothesis that such regionally regularized maps are more accurate than if all regions were taken together and solved with an averaged level of regularization. In a homogeneous concentric spheres model, Legendre polynomials are used to decompose a torso potential map into a set of submaps, each with a different degree of spatial variation. The original torso map is contaminated with data noise, or geometrical error or both, and regional regularization improves the epicardial potential reconstruction by up to 25% [relative error (RE)]. Regional regularization also improves the reconstructed location of peaks. A practical goal is to extend the application of this method to the realistic torso geometry, but because Legendre decomposition is limited to geometries with spherical symmetry, other methods of map decomposition must be found. Singular value decomposition (SVD) is used to decompose the maps into component parts. Its individual submaps also have different levels of spatial variation; moreover, it is generalizable to any vector, does not require spherical symmetry, and is extremely efficient numerically. Using SVD decomposition for regional regularization, significant improvement was achieved in the map quality in the presence of data noise.

Artifacts↗
PubMed1997

Noncontact endocardial mapping: reconstruction of electrograms and isochrones from intracavitary probe potentials.

INTRODUCTION: Mapping endocardial activation and repolarization processes is critical to the study of arrhythmias and selection of therapeutic procedures. Previously, we developed methodology for reconstructing endocardial potentials from potentials measured with a noncontact, intracavitary probe. This study further develops and evaluates the ability of the approach to provide detailed information on the spatiotemporal characteristics of the activation process. Specifically, we reconstructed endocardial electrograms and isochrones throughout the activation process over the entire endocardium during a single beat. METHODS AND RESULTS: Cavity potentials were measured with a 65-electrode probe placed inside an isolated canine left ventricle. Endocardial potentials were measured simultaneously using 52 electrodes. Potentials were acquired during subendocardial pacing from different locations. Computed electrograms at various sites closely resemble the measured electrograms (correlation coefficient > 0.9 at 60% of the electrodes). Computed isochrones locate subendocardial pacing sites with 10-mm accuracy. Two pacing sites, 17 mm apart, were resolved. Critical regions, such as areas of isochrone crowding, were accurately reconstructed. CONCLUSIONS: Results indicate the applicability of the approach to mapping the cardiac excitation process on a beat-by-beat basis without occluding the ventricle. The ability of locating electrical events (e.g., single or multiple initiation sites) is demonstrated. Importantly, the method is shown to be capable of reconstructing electrograms over the entire endocardium and determining nonuniformities of activation spread (e.g., areas of slow conduction). These capabilities are important to clinical application in the electrophysiology laboratory and experimental studies of arrhythmias in the intact animal.

Animals↗
PubMed1997

Role of passive electrical properties during action potential restitution in intact heart.

Action potential duration (APD) restitution is classically attributed to membrane ionic currents; however, the role of cell-to-cell coupling in restitution is poorly understood. To test the hypothesis that passive electrical properties of multicellular preparations influence restitution, spatial gradients of transmembrane voltage were measured with high spatial (0.83 mm), voltage (1 mV), and temporal (0.5 ms) resolutions using voltage-sensitive dye in Langendorff-perfused guinea pig ventricle. At short premature coupling intervals, APD failed to shorten in cells located near (< 3 mm) the site of pacing corresponding to the site of earliest repolarization, deviating from classical restitution. In contrast, APD shortened exponentially with increasing stimulus prematurity when pacing was remote from the identical recording site. The mechanism responsible for nonexponential restitution was investigated in a one-dimensional propagation model using the dynamic Luo-Rudy formulation of the ventricular cell and was found to be attributable to depolarizing axial current present in regions of steep repolarization gradients. Moreover, axial current loading attenuated spatial gradients of repolarization that were prominent in the absence of cell-to-cell coupling. These data demonstrate that 1) in contrast to restitution in isolated cells, restitution in multicellular tissue is influenced by axial current from neighboring cells, and 2) in normal myocardium, axial current between cells attenuates dispersion of repolarization during premature stimulation of the heart.

Action Potentials↗
PubMed1997

Electrophysiologic effects of acute myocardial ischemia. A mechanistic investigation of action potential conduction and conduction failure.

A multicellular ventricular fiber model was used to determine mechanisms of slowed conduction and conduction failure during acute ischemia. We simulated the three major pathophysiological component conditions of acute ischemia: elevated [K+]o, acidosis, and anoxia. Elevated [K+]o was the major determinant of conduction, causing supernormal conduction, depressed conduction, and conduction block as [K+]o was gradually increased from 4.5 to 14.4 mmol/L. Only elevated [K+]o caused conduction failure when varied within the range reported for acute ischemia. Before block, depressed upstrokes consisted of two distinct components: the first to the fast Na+ current (INa) and the second to the L-type Ca2+ current (ICa(L)). Even in highly depressed conduction, excitability was maintained by INa, with conduction block occurring at 95% INa inactivation. However, because ICa(L) supported the later phase of the depressed upstroke, ICa(L) enhanced conduction and delayed block by increasing the electrotonic source current. At [K+]o = 18 mmol/L, slow action potentials generated by ICa(L) were obtained with 10% ICa(L) augmentation. However, in the presence of acidosis and anoxia, significantly larger (120%) ICa(L) augmentation was required. The depressant effect was due mostly to anoxic activation of outward ATP-sensitive K+ current, which counteracts inward ICa(L) and, by lowering the action potential amplitude, decreases the electrotonic current available to depolarize downstream cells. The simulations highlight the interactive nature of electrophysiological ischemic changes during propagation and demonstrate that both membrane changes and load factors (by downstream fiber) must be considered.

Action Potentials↗
PubMed1997

Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling.

In cardiac tissue, reduced membrane excitability and reduced gap junction coupling both slow conduction velocity of the action potential. However, the ionic mechanisms of slow conduction for the two conditions are very different. We explored, using a multicellular theoretical fiber, the ionic mechanisms and functional role of the fast sodium current, INa, and the L-type calcium current, ICa(L), during conduction slowing for the two fiber conditions. A safety factor for conduction (SF) was formulated and computed for each condition. Reduced excitability caused a lower SF as conduction velocity decreased. In contrast, reduced gap junction coupling caused a paradoxical increase in SF as conduction velocity decreased. The opposite effect of the two conditions on SF was reflected in the minimum attainable conduction velocity before failure: decreased excitability could reduce velocity to only one third of control (from 54 to 17 cm/s) before failure occurred, whereas decreased coupling could reduce velocity to as low as 0.26 cm/s before block. Under normal conditions and conditions of reduced excitability, ICa(L) had a minimal effect on SF and on conduction. However, ICa(L) played a major role in sustaining conduction when intercellular coupling was reduced. This phenomenon demonstrates that structural, nonmembrane factors can cause a switch of intrinsic membrane processes that support conduction. High intracellular calcium concentration, [Ca]i, lowered propagation safety and caused earlier block when intercellular coupling was reduced. [Ca]i affected conduction via calcium-dependent inactivation of ICa(L). The increase of safety factor during reduced coupling suggests a major involvement of uncoupling in stable slow conduction in infarcted myocardium, making microreentry possible. Reliance on ICa(L) for this type of conduction suggests ICa(L) as a possible target for antiarrhythmic drug therapy.

Animals↗
PubMed1995

Reconstruction of endocardial potentials and activation sequences from intracavitary probe measurements. Localization of pacing sites and effects of myocardial structure.

BACKGROUND: Mapping of endocardial activation is an important procedure for diagnosing cardiac arrhythmias and locating the arrhythmogenic site before treatment. The objective of the present study was to develop and test a mathematical method to reconstruct the endocardial potentials and activation sequences (isochrones) from potential data measured with a noncontact, intracavitary multielectrode probe (the "inverse problem"). METHODS AND RESULTS: A boundary element based mathematical method, combined with a numeric regularization technique, was developed for computing the inverse solution. Endocardial potentials were computed from intracavitary potentials measured with a multielectrode probe placed in the cavity of an isolated, perfused canine left ventricle. Data were acquired during rhythms induced by electrical stimuli applied at different locations and varying depths within the myocardium. Endocardial potentials were measured using intramural needles to evaluate the accuracy of the inverse solutions by direct comparison. Inversely computed endocardial potentials, from measured probe potentials, reconstruct with good accuracy the major features (potential maxima and minima, regions of negative and positive potentials) compared with the measured endocardial potentials. During early activation, the computed endocardial potentials exhibit a potential minimum in close proximity to the pacing site, determining the location of the stimulus with good accuracy (within 10-mm error). Multiple stimuli, as close as 10 to 20 mm to each other, can be distinguished and localized to their sites of origin by the inverse reconstruction. Similar to the measured endocardial potentials, the spatial distribution of the computed endocardial potentials reflects the underlying cardiac fiber direction, and dynamic changes of the computed endocardial potentials reflect the rotation of fibers with intramural depth. Maps of isochrones show good correspondence between the isochrones determined from the computed endocardial potentials and those determined directly from the measured endocardial potentials. CONCLUSIONS: Compared with actual, measured endocardial potentials and activation sequences, endocardial potential patterns and activation sequences can be reconstructed on a beat-by-beat basis from cavitary potentials measured with a multielectrode, noncontact probe. The approach presented here is shown to reconstruct, with 10-mm accuracy and resolution of 10 to 20 mm, local events of cardiac excitation (eg, pacing sites). In addition, the reconstructed endocardial potentials correctly reflect the underlying fibrous structure of the myocardium. These results demonstrate the feasibility of the approach. In the experiments, the probe position and endocardial geometry were determined invasively. To be clinically applicable, the reconstruction method should be combined with a noninvasive method for determining the probe-cavity geometry in the catheterization laboratory. It could then be developed into a catheter-based technique for locating arrhythmogenic sites and for studying and diagnosing conduction abnormalities, reentrant activity, and the effects of drugs and other interventions on cardiac activation and arrhythmias.

Animals↗
PubMed1995

Model studies of cellular excitation.

A mathematical model of the cardiac ventricular cell is used to describe ionic currents and dynamic concentration changes during a normal action potential. The model is also used to study arrhythmogenic activity of the single cell including early afterdepolarizations, delayed afterdepolarizations and rhythmic (spontaneous and triggered) activity under various degrees of calcium overload.

Action Potentials↗
PubMed1995

Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence.

A model of the cardiac ventricular action potential that accounts for dynamic changes in ionic concentrations was used to study the mechanism, characteristics, and rate dependence of early after depolarizations (EADs). A simulation approach to the study of the effects of pharmacological agents on cellular processes was introduced. The simulation results are qualitatively consistent with experimental observations and help resolve contradictory conclusions in the literature regarding the mechanism of EADs. Our results demonstrate that: 1) the L-type calcium current, ICa, is necessary as a depolarizing charge carrier during an EAD; 2) recovery and reactivation of ICa is the mechanism of EAD formation, independent of the intervention used to induce the EADs (cesium, Bay K 8644, or isoproterenol were used in our simulations, following similar published experimental protocols); 3) high [Ca2+]i is not required for EADs to develop and calcium release by the sarcoplasmic reticulum does not occur during the EAD; 4) although the primary mechanism of EAD formation is recovery of ICa, other plateau currents can modulate EAD formation by affecting the balance of currents during a conditional phase before the EAD take-off; and 5) EADs are present at drive cycle lengths longer than 1000 ms. Because of the very long activation time constant of the delayed rectifier potassium current, IK, the activation gate of IK does not deactivate completely between consecutive stimuli at fast rates (drive cycle length < 1000 ms). As a result, IK plays a key role in determining the rate dependence of EADs.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1995

Reentry: insights from theoretical simulations in a fixed pathway.

This review article summarizes theoretical insights into the principles and mechanisms associated with reentrant activity in cardiac tissue. A mathematical ring model is used in computer simulations to investigate, at the cellular level, mechanistic aspects of initiation, perpetuation, and termination of reentry. Taking advantage of the ability to compute membrane processes in this model, we relate dynamic properties of the reentrant action potential (e.g., beat-to-beat alternans) to the underlying kinetics of membrane ionic channels. Effects on reentry of inhomogeneities in refractoriness, excitability, cellular coupling at gap junctions, and fiber cross-section are also studied.

Action Potentials↗
PubMed1995

The vulnerable window for unidirectional block in cardiac tissue: characterization and dependence on membrane excitability and intercellular coupling.

INTRODUCTION: Unidirectional block is a requisite event in the initiation of reentry in cardiac tissue, but its initiation and behavior in the presence of tissue pathologies remain poorly understood. Previous experimental and theoretical reports on vulnerability to unidirectional block under conditions of reduced cellular coupling and reduced membrane excitability have varied due to differences in experimental and simulation protocols. METHODS AND RESULTS: We have addressed the issue of vulnerability to unidirectional block using the recent Luo-Rudy membrane model and computer simulations of propagation in a one-dimensional cardiac fiber. The vulnerable window (VW) of unidirectional block from premature stimulation is expressed in units of time, VWtime, and as a range of membrane potentials at the stimulus site, VWpot. VWpot and VWtime were quantified over a range of membrane excitability and gap junction resistances (intercellular coupling). With normal membrane excitability and intercellular coupling, VWpot and VWtime were small (VWpot = 0.44 mV, VWtime = 0.39 msec). A uniform reduction (0.25x) in the degree of intercellular coupling increased VWtime and VWpot by factors of 3.6 and 4.7, respectively, whereas a uniform decrease (0.25x) in membrane excitability (same resulting velocity) increased VWtime by only a factor of 0.4 and decreased VWpot to negligible levels. When inhomogeneities in fiber properties were introduced (intercellular coupling and membrane excitability), VWtime increased more due to inhomogeneity in membrane excitability (VWtime = 4.5 msec) than to inhomogeneity in intercellular coupling (VWtime = 1.5 msec). The simulations also clarify the dependence of the VW on the dimensions of the stimulating electrode. The length of the stimulating electrode added a factor, equal to the propagation time across the electrode length, to the intrinsic VW of the fiber. CONCLUSIONS: VWpot and VWtime are both important parameters for quantifying vulnerability to unidirectional block. In an environment with uniform distribution of fiber and membrane properties, reduced intercellular coupling has a greater effect on the VW than reduced membrane excitability. Inhomogeneous reduction of membrane excitability can significantly enhance vulnerability to unidirectional block, much more so than inhomogeneous reduction of intercellular coupling. Theoretically, stimulation at a point should be used to define the VW. Finite electrode dimensions introduce a geometrical factor that affects the measurement of the VW.

Arrhythmias, Cardiac↗
PubMed1995

Two components of the delayed rectifier K+ current in ventricular myocytes of the guinea pig type. Theoretical formulation and their role in repolarization.

Two distinct delayed rectifier K+ currents, IKr and IKs, were found recently in ventricular cells. We formulated these currents theoretically and investigated their roles in action potential repolarization and the restitution of action potential duration (APD). The Luo-Rudy (L-R) model of the ventricular action potential was used in the simulations. The single delayed rectifier K+ current in the model was replaced by IKr and IKs. Our results show that IKs is the major outward current during the plateau repolarization. A specific block of either IKr or IKs can effectively prolong APD to the same degree. Therefore, either channel provides a target for class III antiarrhythmic drugs. In the simulated guinea pig ventricular cell, complete block of IKr does not result in early afterdepolarizations (EADs). In contrast, > 80% block of IKs results in abnormal repolarization and EADs. This behavior reflects the high IKs-to-IKr density ratio (approximately 8:1) in this cell and can be reversed (ie, IKr block can cause EADs) by reducing the ratio of IKs to IKr. The computed APD restitution curve is consistent with the experimental behavior, displaying fast APD variation at short diastolic intervals (DIs) and downward shift at longer DIs with the decrease of basic drive cycle length (BCL). Examining the ionic currents and their underlying kinetic processes, we found that activation of both IKr and IKs is the primary determinant of the APD restitution at shorter DIs, with Ca2+ current through L-type channels (ICa) playing a minor role. The rate of APD change depends on the relative densities of IKr and IKs; it increases when the IKr-to-IKs density ratio is large. The BCL-dependent shift of restitution at longer DIs is primarily attributed to long-lasting changes in [Ca2+]i. This in turn causes different degrees of Ca(2+)-dependent inactivation of ICa and different degrees of Ca(2+)-dependent conductance of IKs at very long DIs (> 5 s) for different BCLs. This BCL dependence of ICa and IKs that is secondary to long-lasting changes in [Ca2+]i is responsible for APD changes at long DIs and can be viewed as a "memory property" of cardiac cells.

Action Potentials↗
PubMed1994

Mathematical model of acetylcholine kinetics in neuroeffector junctions.

Acetylcholine (ACh) kinetics in neuroeffector junctions (NEJ) of the sinus node plays a key role in vagal control of heart rate. Prior studies have shown that the concentration of ACh ([ACh]) in NEJ appears to follow first-order linear kinetics. To find out the reason why, we examine mathematically diffusion, degradation, and receptor binding of ACh in NEJ. We identify seven conditions that potentially influence ACh kinetics. Because these conditions are satisfied for NEJ in the sinus node, 1) the nonlinearity of ACh binding to muscarinic receptors has little effect on [ACh]; 2) [ACh] does not depend on the distribution of acetylcholinesterase between the interstitial space and the pacemaker cells; 3) the interval from trough to subsequent peak [ACh] at the pacemaker cells is negligible; 4) the mean [ACh] at the pacemaker cells is proportional to the frequency of vagal activity multiplied by the amount of ACh released per vagal stimulus and divided by the rate coefficient of ACh degradation; and 5) [ACh] at pacemaker cells nearly follows first-order linear kinetics but does not at other sites in the NEJ. We conclude that earlier studies showed that [ACh] follows first-order linear kinetics, because they predicted [ACh] only at pacemaker cells. ACh kinetics at other sites in the NEJ, such as at nerve endings, is different.

Acetylcholine↗
PubMed1994

Mechanism of interruption of atrial flutter by moricizine. Electrophysiological and multiplexing studies in the canine sterile pericarditis model of atrial flutter.

BACKGROUND: Moricizine is said to have potent effects on cardiac conduction but little or no effect on cardiac refractoriness. METHODS AND RESULTS: The effects of moricizine (2 mg/kg IV) on induced atrial flutter were studied 2 to 4 days after the creation of sterile pericarditis in 11 dogs. Ten episodes of stable atrial flutter before and after the administration of moricizine were studied in 9 dogs in the conscious, nonsedated state, and 7 episodes were studied in 6 dogs in the anesthetized, open chest state. In the conscious state, the effects of moricizine on atrial excitability, atrial effective refractory period, and intra-atrial conduction times were studied by recording during overdrive pacing of sinus rhythm from epicardial electrodes placed at selected atrial sites. Moricizine prolonged the atrial flutter cycle length in all the episodes, from a mean of 133 +/- 9 to 172 +/- 27 milliseconds (P < .001), and then terminated 7 of the 10 episodes. Moricizine increased the atrial threshold of excitability from a mean of 2.3 +/- 1.4 to 3.3 +/- 2.2 mA (P < .01) and prolonged intra-atrial conduction times (measured from the sulcus terminalis to the posteroinferior left atrium) from a mean of 58 +/- 6 to 64 +/- 5 milliseconds (P < .005). Prolongation of the atrial effective refractory period from 166 +/- 20 to 174 +/- 24 milliseconds (P < .05) was observed only at the sulcus terminalis site. In the open chest studies, administration of moricizine prolonged the atrial flutter cycle length from a mean of 150 +/- 15 to 216 +/- 30 milliseconds (P < .001) and then terminated the atrial flutter in all 7 episodes. As demonstrated by simultaneous multisite mapping from 95 bipolar sites on the right atrial free wall, the atrial flutter cycle length prolongation was either due to further slowing of conduction in an area of slow conduction in the reentrant circuit of the atrial flutter (5 episodes) or further slowing of conduction in an area of slow conduction plus the development of a second area of slow conduction (2 episodes). The change in conduction times in the rest of the reentrant circuit was negligible (10.9 +/- 8.7% of the total change). In all 7 episodes, the last circulating reentrant wave front blocked in an area of slow conduction. CONCLUSIONS: Moricizine (1) prolongs the atrial flutter cycle length, primarily by slowing conduction in an area of slow conduction in the reentrant circuit, (2) terminates atrial flutter by causing block of the circulating reentrant wave front in an area of slow conduction of the reentrant circuit, and (3) effectively interrupts otherwise stable atrial flutter in this canine model. The reason for these effects of moricizine are not readily explained by its effects on global atrial conduction times and refractoriness studied during sinus rhythm. Local changes in conduction in an area(s) of slow conduction are responsible for both cycle length prolongation and atrial flutter termination rather than the traditional wavelength concept of head-tail interaction.

Animals↗
PubMed1994

Characterization of the excitable gap in a functionally determined reentrant circuit. Studies in the sterile pericarditis model of atrial flutter.

BACKGROUND: Single premature beats were introduced in the reentrant circuit during stable atrial flutter in the canine sterile pericarditis model to test the hypotheses that (1) despite the fact that the reentrant circuit is functionally determined, there is a fully excitable gap; (2) the excitable gap in the reentrant circuit is not uniform; and (3) inhomogeneities of conduction in the reentrant circuit explain the effects of premature beats. METHODS AND RESULTS: A multiplexing system was used to record 190 unipolar electrograms from the right atrial free wall during 18 atrial flutter episodes in 9 dogs. In all 18 episodes, premature stimuli captured the atrial flutter reentrant circuit. At the longest coupling intervals, the return cycle at the site closest to the pacing site did not prolong. As the coupling interval of the premature stimulus decreased, the return cycle then progressively increased, associated with changes in conduction in the reentrant circuit that were not uniform. The result was that coupling intervals associated with introduction of the premature beat also were not constant. The mean duration of the total (ie, fully plus partially) excitable gap was 12 +/- 4 ms in areas of slow conduction, and it was always shorter than the total excitable gap in other areas (22 +/- 6 ms, P < .001). The mean duration of the fully excitable gap based on analysis of the return cycle was 4 +/- 1 ms in the reentrant circuit. In 13 of 18 atrial flutter episodes, a premature stimulus terminated atrial flutter by causing block of the orthodromic wave front of the premature beat in an area of slow conduction. The mean coupling interval that caused orthodromic block was 113 +/- 5 ms (recorded at the site just proximal to the area of block), and it was always longer than the delivered stimulus coupling interval at the pacing site (96 +/- 8 ms, P < .001). CONCLUSIONS: We conclude that in this functionally determined atrial flutter reentrant circuit in the canine sterile pericarditis model, (1) a fully excitable gap is present in at least part of the reentrant circuit; (2) the duration of the excitable gap in the reentrant circuit is shortest in areas of slow conduction; and (3) when a premature beat encounters the partially excitable gap of the reentrant circuit, it results in changes in conduction such that the coupling intervals are not uniform throughout in the reentrant circuit.

Animals↗
PubMed1994

Mapping the conversion of atrial flutter to atrial fibrillation and atrial fibrillation to atrial flutter. Insights into mechanisms.

It is not generally believed that there is a relation between atrial flutter, thought to be due to a single reentrant circuit, and atrial fibrillation, thought to be due to simultaneously circulating multiple-reentrant wave fronts. However, there are many reasons to suggest that these rhythms are more closely related than previously thought. To test the hypothesis that the length of an area of functional block in the right atrial free wall is critical to the conversion of atrial flutter to atrial fibrillation and of atrial fibrillation to atrial flutter, we studied spontaneous and ATP-induced conversion of stable atrial flutter to sustained atrial fibrillation and spontaneous conversion of sustained atrial fibrillation to stable atrial flutter. We studied 13 episodes of the conversion of stable atrial flutter to sustained atrial fibrillation and sustained atrial fibrillation to stable atrial flutter in seven dogs with sterile pericarditis. Six episodes were spontaneous and seven were ATP related. All episodes were studied by using a multisite mapping system to record 190 unipolar electrograms (converted in the software to 95 bipolar electrograms) from the right atrial free wall along with ECG lead II. Atrial flutter induction was attempted by atrial stimulation (S1S2 or S1S2S3) or by rapid atrial pacing for > or = 20 beats from selected sites at selected rates. For both the spontaneous and the ATP-related episodes, stable atrial flutter was defined as any episode of > or = 5 minutes, and sustained atrial fibrillation was any episode of > or = 1 minute. During all the episodes of stable atrial flutter, a line of functional block with a mean length of 24 +/- 4 mm was localized on the right atrial free wall. When the previously stable line of functional block decreased to a mean of 16 +/- 3 mm (P < .05), either spontaneously or after ATP administration (40 mg i.v.), the new line of functional block was not long enough to maintain stable atrial flutter, and conversion to atrial fibrillation resulted. This shortened line of functional block continued to change and migrate over the right atrial free wall throughout sustained atrial fibrillation. These observations were similar for both spontaneous and ATP-induced conversions. When sustained atrial fibrillation evolved to stable atrial flutter, there was reformation of a long line of functional block, long enough (> or = prior length) to create a stable reentrant circuit, which then captured the right atrial free wall and subsequently both atria.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1994

A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes.

A mathematical model of the cardiac ventricular action potential is presented. In our previous work, the membrane Na+ current and K+ currents were formulated. The present article focuses on processes that regulate intracellular Ca2+ and depend on its concentration. The model presented here for the mammalian ventricular action potential is based mostly on the guinea pig ventricular cell. However, it provides the framework for modeling other types of ventricular cells with appropriate modifications made to account for species differences. The following processes are formulated: Ca2+ current through the L-type channel (ICa), the Na(+)-Ca2+ exchanger, Ca2+ release and uptake by the sarcoplasmic reticulum (SR), buffering of Ca2+ in the SR and in the myoplasm, a Ca2+ pump in the sarcolemma, the Na(+)-K+ pump, and a nonspecific Ca(2+)-activated membrane current. Activation of ICa is an order of magnitude faster than in previous models. Inactivation of ICa depends on both the membrane voltage and [Ca2+]i. SR is divided into two subcompartments, a network SR (NSR) and a junctional SR (JSR). Functionally, Ca2+ enters the NSR and translocates to the JSR following a monoexponential function. Release of Ca2+ occurs at JSR and can be triggered by two different mechanisms, Ca(2+)-induced Ca2+ release and spontaneous release. The model provides the basis for the study of arrhythmogenic activity of the single myocyte including afterdepolarizations and triggered activity. It can simulate cellular responses under different degrees of Ca2+ overload. Such simulations are presented in our accompanying article in this issue of Circulation Research.

Action Potentials↗