Background-The mechanisms underlying paroxysmal atrial flutter/atrial fibrillation initiation by ... more Background-The mechanisms underlying paroxysmal atrial flutter/atrial fibrillation initiation by ectopic foci from various locations are unclear. Methods and Results-We used parallel computational techniques to study an anatomically accurate 3-dimensional atrial structure incorporating a detailed ionic-current model of an atrial myocyte. At the single-cell level, upregulation of the L-type Ca 2ϩ current I Ca,L steepened restitution curves of action potential duration and conduction velocity compared with the control. Spontaneous firings of ectopic foci, coupled with sinus activity, produced dynamic spatial dispersions of repolarization, including discordant alternans, which caused conduction block and reentry only for the elevated I Ca,L case. For each foci location, a vulnerable window for atrial flutter/atrial fibrillation induction was identified as a function of the coupling interval and focus cycle length. For ectopic foci in the pulmonary veins and left atrium, the site of conduction block and reentry gradually shifted, as a function of coupling interval, from the right atrium to the interatrial area and finally to the left atrium. The size of the vulnerable window was largest for pulmonary vein foci, becoming markedly smaller for right atrial foci, especially those near the sinoatrial node. Conclusions-These findings suggest that a mechanism of dynamically induced repolarization dispersion, especially discordant alternans, underlies the induction of atrial flutter/atrial fibrillation by atrial ectopic foci. The sites and likelihood of reentry induction varied according to ectopic focus location and timing, with the largest vulnerable window corresponding to the pulmonary vein region.
Medicine Amp Science in Sports Amp Exercise, Nov 1, 1995
Sixteen young, healthy males each performed five to seven randomly assigned, exhaustive exercise ... more Sixteen young, healthy males each performed five to seven randomly assigned, exhaustive exercise bouts on a cycle ergometer, with each bout on a separate day and at a different power, to compare estimates of critical power (PC) and anaerobic work capacity (W') among five different models: t = W'/(Pmax-PC) (two-parameter nonlinear); t = (W'/P-PC))-(W'/(Pmax-PC)) (three-parameter nonlinear); P.t = W' + (PC.t) (linear (P.t)); P = (W'/t) + PC (linear (P)); P = PC + (Pmax-PC)exp(-t/tau) (exponential). The data fit each of the models well (mean R2 = 0.96 through 1.00 for each model). However, significant differences among models were observed for both PC (mean +/- standard deviation (SD) for each model was 195 +/- 29 W through 242 +/- 21 W) and W' (18 +/- 5 kJ through 58 +/- 19 kJ). PC estimates among models were significantly correlated (r = 0.78 through 0.99). For W', between-model correlations ranged from 0.25 to 0.95. For a group of six subjects, the ventilatory threshold for long-term exercise (LTE Tvent; 189 +/- 34 W) was significantly lower than PC for all models except the three-parameter nonlinear (PC = 197 +/- 30 W); PC for each model was, however, positively correlated with LTE Tvent (r = 0.69 through 0.91).(ABSTRACT TRUNCATED AT 250 WORDS)
Attention has recently focused on preventing arrhythmias by controlling sarcoplasmic reticulum (S... more Attention has recently focused on preventing arrhythmias by controlling sarcoplasmic reticulum (SR) Ca 2þ ''leak''. Increased leak in ventricular myocytes is associated with regenerative Ca 2þ waves and delayed afterdepolarizations, leading to arrhythmias. Studies that have measured SR Ca 2þ leak have not examined changes in [Ca 2þ ] SR independent of changes in [Ca 2þ ] i , causing a de-
American Journal of Physiology Heart and Circulatory Physiology, Feb 1, 2001
Generation of wave break is a characteristic feature of cardiac fibrillation. In this study, we i... more Generation of wave break is a characteristic feature of cardiac fibrillation. In this study, we investigated how dynamic factors and fixed electrophysiological heterogeneity interact to promote wave break in simulated two-dimensional cardiac tissue, by using the Luo-Rudy (LR1) ventricular action potential model. The degree of dynamic instability of the action potential model was controlled by varying the maximal amplitude of the slow inward Ca(2+) current to produce spiral waves in homogeneous tissue that were either nearly stable, meandering, hypermeandering, or in breakup regimes. Fixed electrophysiological heterogeneity was modeled by randomly varying action potential duration over different spatial scales to create dispersion of refractoriness. We found that the degree of dispersion of refractoriness required to induce wave break decreased markedly as dynamic instability of the cardiac model increased. These findings suggest that reducing the dynamic instability of cardiac cells by interventions, such as decreasing the steepness of action potential duration restitution, may still have merit as an antifibrillatory strategy.
Physical Review E Statistical Nonlinear and Soft Matter Physics, 2003
We studied spiral wave dynamics in an oscillatory reaction diffusion system. We find a new phenom... more We studied spiral wave dynamics in an oscillatory reaction diffusion system. We find a new phenomenon: without the appearance of any global modulation mode, stable spiral waves break up directly. By investigating the one-dimensional version of the system and the isolated local dynamics, we find that the unstable focus in the local dynamics plays an important role. For different boundary conditions (BCs), we find a transition between spiral waves and traveling waves for periodic BCs and drifting spiral wave for no-flux BC.
Heart failure is a leading cause of death, yet its underlying electrophysiological (EP) mechanism... more Heart failure is a leading cause of death, yet its underlying electrophysiological (EP) mechanisms are not well understood. In this study, we use a multiscale approach to analyze a model of heart failure and connect its results to features of the electrocardiogram (ECG). The heart failure model is derived by modifying a previously validated electrophysiology model for a healthy rabbit heart. Specifically, in accordance with the heart failure literature, we modified the cell EP by changing both membrane currents and calcium handling. At the tissue level, we modeled the increased gap junction lateralization and lower conduction velocity due to downregulation of Connexin 43. At the biventricular level, we reduced the apex-to-base and transmural gradients of action potential duration (APD). The failing cell model was first validated by reproducing the longer action potential, slower and lower calcium transient, and earlier alternans characteristic of heart failure EP. Subsequently, we c...
When cardiac tissue is rapidly paced, spatially discordant APD alternans can emerge, i.e. regions... more When cardiac tissue is rapidly paced, spatially discordant APD alternans can emerge, i.e. regions of long-short APD alternation adjacent to regions with short-long APD alternation. This phenomeon is potentially arrhythmogenic since it leads to the formation of large spatial gradients of APD, which can generate a substrate for wavebreak and reentry. However, the cellular mechanims that cause alternans are still not well established. It has been suggested that alternans can arise from two distinct mechanisms: 1. Steep APD restitution due to recovery kinetics of ion currents that regulate the APD. 2. A dynamical instability of intracellular calcium cycling. Here, we used a mathematical model of intracellular calcium cycling coupled with membrane ion currents to investigate the relationship between cellular voltage-calcium dynamics and spatially discordant alternans at the tissue level. We found that spatially discordant alternans can be induced via three distinct mechanisms: 1. Conduction velocity restitution: If the conduction velocity varies over a wide range of diastolic intervals, spatially discordant alternans is dynamically induced whether the single cell instability is calcium or voltage driven. 2. Spatial heterogeniety: Discordant alternans can be induced by an appropriately timed extrastimulus if fixed spatial gradients in electrophysiological properties are present in the tissue. 3. Calcium-voltage instability: If the cellular instability is due to calcium cycling, then spatially discordant alternans can emerge from a novel dynamical instability when alternans is electromechanically discordant. Furthermore we show that the spatial scale of the interface that separates spatially out-of-phase regions depends sensitively on the cause of the dynamical instability at the single cell level. These findings lead to specific predictions about how optical mapping measurements of the spatial distribution of voltage and calcium can reveal the origin of dynamical instabilities.
We investigated the effect of combined inhibition of oxidative and glycolytic metabolism on L-typ... more We investigated the effect of combined inhibition of oxidative and glycolytic metabolism on L-type Ca 21 channels (LCCs) and Ca 21 spikes in isolated patch-clamped rabbit ventricular myocytes. Metabolic inhibition (MI) reduced LCC open probability, increased null probability, increased first latency, and decreased open time but left conductance unchanged. These results explain the reduction in macroscopic Ca 21 current observed during MI. MI also produced a gradual reduction in action potential duration at 90% repolarization (APD 90 ), a clear decline in spike probability, and an increase in spike latency and variance. These effects are consistent with the changes we observed in LCC activity. MI had no effect on the amplitude or time to peak of Ca 21 spikes until APD 90 reached 10% of control, suggesting preserved sarcoplasmic reticulum Ca 21 stores and ryanodine receptor (RyR) conductance in those couplons that remained functioning. Ca 21 spikes disappeared completely when APD 90 reached ,2% of control, although in two cells, spikes were reactivated in a highly synchronized fashion by very short action potentials. This reactivation is probably due to the increased driving force for Ca 21 entry through a reduced number of LCCs that remain open during early repolarization. The enlarged single channel flux produced by rapid repolarization is apparently sufficient to trigger RyRs whose Ca 21 sensitivity is likely reduced by MI. We suggest that loss of coupling fidelity during MI is explained by loss of LCC activity (possibly mediated by Ca 21 -calmodulin kinase II activity). In addition, the results are consistent with loss of RyR activity, which can be mitigated under conditions likely to enlarge the trigger.
We studied the stability of linear vortex filaments in 3-dimensional (3D) excitable media, using ... more We studied the stability of linear vortex filaments in 3-dimensional (3D) excitable media, using both analytical and numerical methods. We found an intrinsic 3D instability of vortex filaments that is diffusion-induced, and is due to the slower diffusion of the inhibitor. This instability can result either in a single helical filament or in chaotic scroll breakup, depending on the specific kinetic model. When the 2-dimensional dynamics were in the chaotic regime, filament instability occurred via on-off intermittency, a failure of chaos synchronization in the third dimension.
Physical Review E Statistical Physics Plasmas Fluids and Related Interdisciplinary Topics, Nov 1, 1998
We studied the dynamics of a wave propagating around a circular obstacle in a two-dimensional car... more We studied the dynamics of a wave propagating around a circular obstacle in a two-dimensional cardiac tissue model. By starting with a large obstacle and decreasing its radius, a continuous transition was created between the two major types of reentrant cardiac arrhythmias: anatomical reentry (essentially one-dimensional) and functional reentry. As the radius of the obstacle decreases, a sequence of transitions occurs, from periodic motion to a modulated period-2 rhythm, and then to spiral wave breakup. These results may provide a useful basis for refining cardiac ablation techniques currently in use.
American Journal of Physiology Heart and Circulatory Physiology, May 1, 2002
The focal source hypothesis of ventricular fibrillation (VF) posits that rapid activation from a ... more The focal source hypothesis of ventricular fibrillation (VF) posits that rapid activation from a focal source, rather than action potential duration (APD) restitution properties, is responsible for the maintenance of VF. We injected aconitine (100 microg) into normal isolated perfused swine right ventricles (RVs) stained with 4-[beta-[2-(di-n-butylamino)-6-naphthyl]vinyl]pyridinium (di-4-ANEPPS) for optical mapping studies. Within 97 +/- 163 s, aconitine induced ventricular tachycardia (VT) with a mean cycle length 268 +/- 37 ms, which accelerated before converting to VF. Drugs that flatten the APD restitution slope, including diacetyl monoxime (10-20 mM, n = 6), bretylium (10-20 microg/ml, n = 3), and verapamil (2-4 microg/ml, n = 3), reversibly converted VF to VT in all cases. In two RVs, VF persisted despite of the excision of the aconitine site. Simulations in two-dimensional cardiac tissue showed that once VF was initiated, it remained sustained even after the "aconitine" site was eliminated. In this model of focal source VF, the VT-to-VF transition occurred due to a wave break outside the aconitine site, and drugs that flattened the APD restitution slope converted VF to VT despite continuous activation from aconitine site.
CI) between sinus activation and a succeeding PV ectopic beat, and the cycle length (CL) of repet... more CI) between sinus activation and a succeeding PV ectopic beat, and the cycle length (CL) of repetitive beats from that ectopic focus. Results: PV ectopic foci, coupled with sinus activity, produced spatial dispersion of repolarization. For certain CL,CI combinations, such repolarization dispersion caused unidirectional block and reentry. Specifically, for 170ՅCLՅ210 ms (a range for which discordant alternans occurs in a model atrial fiber) and 330ՅCIՅ470 ms, AFL was initiated with as few as 2 PV ectopic beats. Location of conduction block and reentry shifted as a function of CI: right atrium (330ՅCIՅ390 ms), inter-atrial region (410ՅCIՅ430 ms), or left atrium (430ՅCIՅ470 ms). For this CI range, different circuits were found: a) tricuspid annulus (TA) clockwise; b) TA counter-clockwise; c) superior/inferior vena cava; d) inter-atrial region including Bachmann's bundle, atrial septum, fossa ovalis and coronary sinus; e) mitral annulus; f) PVs. Through a "fibrillatory conduction process", in which rapid electrical impulses emanating from flutter circuits interact with functional and/or anatomic obstacles throughout the atria leading to fragmentation and wavelet formation, about 1/3 of AFL spontaneously converted to AF (conversion time: 570Ϯ300 ms), which were characterized by 3-5 wavelets simultaneously meandering in both atria. Conclusions: AFL and AF can be initiated by PV ectopic foci in a realistic 3D atrial model. Atrial reentry initiation resulted from unidirectional conduction block due to dynamic, foci-induced spatial dispersion of repolarization. Conduction block location and flutter circuit was dependent on CI. AFL often converted to AF through fibrillatory conduction.
The collective behaviors of coupled, stochastically excitable elements subjected to global period... more The collective behaviors of coupled, stochastically excitable elements subjected to global periodic forcing are investigated numerically and analytically. We show that the whole system undergoes a period-doubling bifurcation as the driving period decreases, while the individual elements still exhibit random excitations. Using a mean-field representation, we show that this macroscopic bifurcation behavior is caused by interactions between the random excitation, the refractory period, and recruitment (spatial cooperativity) of the excitable elements.
Regional hyperkalemia during acute myocardial ischemia is a major factor promoting electrophysiol... more Regional hyperkalemia during acute myocardial ischemia is a major factor promoting electrophysiological abnormalities leading to ventricular fibrillation (VF). However, steep action potential duration restitution, recently proposed to be a major determinant of VF, is typically decreased rather than increased by hyperkalemia and acute ischemia. To investigate this apparent contradiction, we simulated the effects of regional hyperkalemia and other ischemic components (anoxia and acidosis) on the stability of spiral wave reentry in simulated two-dimensional cardiac tissue by use of the Luo-Rudy ventricular action potential model. We found that the hyperkalemic "ischemic" area promotes wavebreak in the surrounding normal tissue by accelerating the rate of spiral wave reentry, even after the depolarized ischemic area itself has become unexcitable. Furthermore, wavebreak and fibrillation can be prevented if the dynamical instability of the normal tissue is reduced significantly by targeting electrical restitution properties, suggesting a novel therapeutic approach.
Background-The mechanisms underlying paroxysmal atrial flutter/atrial fibrillation initiation by ... more Background-The mechanisms underlying paroxysmal atrial flutter/atrial fibrillation initiation by ectopic foci from various locations are unclear. Methods and Results-We used parallel computational techniques to study an anatomically accurate 3-dimensional atrial structure incorporating a detailed ionic-current model of an atrial myocyte. At the single-cell level, upregulation of the L-type Ca 2ϩ current I Ca,L steepened restitution curves of action potential duration and conduction velocity compared with the control. Spontaneous firings of ectopic foci, coupled with sinus activity, produced dynamic spatial dispersions of repolarization, including discordant alternans, which caused conduction block and reentry only for the elevated I Ca,L case. For each foci location, a vulnerable window for atrial flutter/atrial fibrillation induction was identified as a function of the coupling interval and focus cycle length. For ectopic foci in the pulmonary veins and left atrium, the site of conduction block and reentry gradually shifted, as a function of coupling interval, from the right atrium to the interatrial area and finally to the left atrium. The size of the vulnerable window was largest for pulmonary vein foci, becoming markedly smaller for right atrial foci, especially those near the sinoatrial node. Conclusions-These findings suggest that a mechanism of dynamically induced repolarization dispersion, especially discordant alternans, underlies the induction of atrial flutter/atrial fibrillation by atrial ectopic foci. The sites and likelihood of reentry induction varied according to ectopic focus location and timing, with the largest vulnerable window corresponding to the pulmonary vein region.
Medicine Amp Science in Sports Amp Exercise, Nov 1, 1995
Sixteen young, healthy males each performed five to seven randomly assigned, exhaustive exercise ... more Sixteen young, healthy males each performed five to seven randomly assigned, exhaustive exercise bouts on a cycle ergometer, with each bout on a separate day and at a different power, to compare estimates of critical power (PC) and anaerobic work capacity (W') among five different models: t = W'/(Pmax-PC) (two-parameter nonlinear); t = (W'/P-PC))-(W'/(Pmax-PC)) (three-parameter nonlinear); P.t = W' + (PC.t) (linear (P.t)); P = (W'/t) + PC (linear (P)); P = PC + (Pmax-PC)exp(-t/tau) (exponential). The data fit each of the models well (mean R2 = 0.96 through 1.00 for each model). However, significant differences among models were observed for both PC (mean +/- standard deviation (SD) for each model was 195 +/- 29 W through 242 +/- 21 W) and W' (18 +/- 5 kJ through 58 +/- 19 kJ). PC estimates among models were significantly correlated (r = 0.78 through 0.99). For W', between-model correlations ranged from 0.25 to 0.95. For a group of six subjects, the ventilatory threshold for long-term exercise (LTE Tvent; 189 +/- 34 W) was significantly lower than PC for all models except the three-parameter nonlinear (PC = 197 +/- 30 W); PC for each model was, however, positively correlated with LTE Tvent (r = 0.69 through 0.91).(ABSTRACT TRUNCATED AT 250 WORDS)
Attention has recently focused on preventing arrhythmias by controlling sarcoplasmic reticulum (S... more Attention has recently focused on preventing arrhythmias by controlling sarcoplasmic reticulum (SR) Ca 2þ ''leak''. Increased leak in ventricular myocytes is associated with regenerative Ca 2þ waves and delayed afterdepolarizations, leading to arrhythmias. Studies that have measured SR Ca 2þ leak have not examined changes in [Ca 2þ ] SR independent of changes in [Ca 2þ ] i , causing a de-
American Journal of Physiology Heart and Circulatory Physiology, Feb 1, 2001
Generation of wave break is a characteristic feature of cardiac fibrillation. In this study, we i... more Generation of wave break is a characteristic feature of cardiac fibrillation. In this study, we investigated how dynamic factors and fixed electrophysiological heterogeneity interact to promote wave break in simulated two-dimensional cardiac tissue, by using the Luo-Rudy (LR1) ventricular action potential model. The degree of dynamic instability of the action potential model was controlled by varying the maximal amplitude of the slow inward Ca(2+) current to produce spiral waves in homogeneous tissue that were either nearly stable, meandering, hypermeandering, or in breakup regimes. Fixed electrophysiological heterogeneity was modeled by randomly varying action potential duration over different spatial scales to create dispersion of refractoriness. We found that the degree of dispersion of refractoriness required to induce wave break decreased markedly as dynamic instability of the cardiac model increased. These findings suggest that reducing the dynamic instability of cardiac cells by interventions, such as decreasing the steepness of action potential duration restitution, may still have merit as an antifibrillatory strategy.
Physical Review E Statistical Nonlinear and Soft Matter Physics, 2003
We studied spiral wave dynamics in an oscillatory reaction diffusion system. We find a new phenom... more We studied spiral wave dynamics in an oscillatory reaction diffusion system. We find a new phenomenon: without the appearance of any global modulation mode, stable spiral waves break up directly. By investigating the one-dimensional version of the system and the isolated local dynamics, we find that the unstable focus in the local dynamics plays an important role. For different boundary conditions (BCs), we find a transition between spiral waves and traveling waves for periodic BCs and drifting spiral wave for no-flux BC.
Heart failure is a leading cause of death, yet its underlying electrophysiological (EP) mechanism... more Heart failure is a leading cause of death, yet its underlying electrophysiological (EP) mechanisms are not well understood. In this study, we use a multiscale approach to analyze a model of heart failure and connect its results to features of the electrocardiogram (ECG). The heart failure model is derived by modifying a previously validated electrophysiology model for a healthy rabbit heart. Specifically, in accordance with the heart failure literature, we modified the cell EP by changing both membrane currents and calcium handling. At the tissue level, we modeled the increased gap junction lateralization and lower conduction velocity due to downregulation of Connexin 43. At the biventricular level, we reduced the apex-to-base and transmural gradients of action potential duration (APD). The failing cell model was first validated by reproducing the longer action potential, slower and lower calcium transient, and earlier alternans characteristic of heart failure EP. Subsequently, we c...
When cardiac tissue is rapidly paced, spatially discordant APD alternans can emerge, i.e. regions... more When cardiac tissue is rapidly paced, spatially discordant APD alternans can emerge, i.e. regions of long-short APD alternation adjacent to regions with short-long APD alternation. This phenomeon is potentially arrhythmogenic since it leads to the formation of large spatial gradients of APD, which can generate a substrate for wavebreak and reentry. However, the cellular mechanims that cause alternans are still not well established. It has been suggested that alternans can arise from two distinct mechanisms: 1. Steep APD restitution due to recovery kinetics of ion currents that regulate the APD. 2. A dynamical instability of intracellular calcium cycling. Here, we used a mathematical model of intracellular calcium cycling coupled with membrane ion currents to investigate the relationship between cellular voltage-calcium dynamics and spatially discordant alternans at the tissue level. We found that spatially discordant alternans can be induced via three distinct mechanisms: 1. Conduction velocity restitution: If the conduction velocity varies over a wide range of diastolic intervals, spatially discordant alternans is dynamically induced whether the single cell instability is calcium or voltage driven. 2. Spatial heterogeniety: Discordant alternans can be induced by an appropriately timed extrastimulus if fixed spatial gradients in electrophysiological properties are present in the tissue. 3. Calcium-voltage instability: If the cellular instability is due to calcium cycling, then spatially discordant alternans can emerge from a novel dynamical instability when alternans is electromechanically discordant. Furthermore we show that the spatial scale of the interface that separates spatially out-of-phase regions depends sensitively on the cause of the dynamical instability at the single cell level. These findings lead to specific predictions about how optical mapping measurements of the spatial distribution of voltage and calcium can reveal the origin of dynamical instabilities.
We investigated the effect of combined inhibition of oxidative and glycolytic metabolism on L-typ... more We investigated the effect of combined inhibition of oxidative and glycolytic metabolism on L-type Ca 21 channels (LCCs) and Ca 21 spikes in isolated patch-clamped rabbit ventricular myocytes. Metabolic inhibition (MI) reduced LCC open probability, increased null probability, increased first latency, and decreased open time but left conductance unchanged. These results explain the reduction in macroscopic Ca 21 current observed during MI. MI also produced a gradual reduction in action potential duration at 90% repolarization (APD 90 ), a clear decline in spike probability, and an increase in spike latency and variance. These effects are consistent with the changes we observed in LCC activity. MI had no effect on the amplitude or time to peak of Ca 21 spikes until APD 90 reached 10% of control, suggesting preserved sarcoplasmic reticulum Ca 21 stores and ryanodine receptor (RyR) conductance in those couplons that remained functioning. Ca 21 spikes disappeared completely when APD 90 reached ,2% of control, although in two cells, spikes were reactivated in a highly synchronized fashion by very short action potentials. This reactivation is probably due to the increased driving force for Ca 21 entry through a reduced number of LCCs that remain open during early repolarization. The enlarged single channel flux produced by rapid repolarization is apparently sufficient to trigger RyRs whose Ca 21 sensitivity is likely reduced by MI. We suggest that loss of coupling fidelity during MI is explained by loss of LCC activity (possibly mediated by Ca 21 -calmodulin kinase II activity). In addition, the results are consistent with loss of RyR activity, which can be mitigated under conditions likely to enlarge the trigger.
We studied the stability of linear vortex filaments in 3-dimensional (3D) excitable media, using ... more We studied the stability of linear vortex filaments in 3-dimensional (3D) excitable media, using both analytical and numerical methods. We found an intrinsic 3D instability of vortex filaments that is diffusion-induced, and is due to the slower diffusion of the inhibitor. This instability can result either in a single helical filament or in chaotic scroll breakup, depending on the specific kinetic model. When the 2-dimensional dynamics were in the chaotic regime, filament instability occurred via on-off intermittency, a failure of chaos synchronization in the third dimension.
Physical Review E Statistical Physics Plasmas Fluids and Related Interdisciplinary Topics, Nov 1, 1998
We studied the dynamics of a wave propagating around a circular obstacle in a two-dimensional car... more We studied the dynamics of a wave propagating around a circular obstacle in a two-dimensional cardiac tissue model. By starting with a large obstacle and decreasing its radius, a continuous transition was created between the two major types of reentrant cardiac arrhythmias: anatomical reentry (essentially one-dimensional) and functional reentry. As the radius of the obstacle decreases, a sequence of transitions occurs, from periodic motion to a modulated period-2 rhythm, and then to spiral wave breakup. These results may provide a useful basis for refining cardiac ablation techniques currently in use.
American Journal of Physiology Heart and Circulatory Physiology, May 1, 2002
The focal source hypothesis of ventricular fibrillation (VF) posits that rapid activation from a ... more The focal source hypothesis of ventricular fibrillation (VF) posits that rapid activation from a focal source, rather than action potential duration (APD) restitution properties, is responsible for the maintenance of VF. We injected aconitine (100 microg) into normal isolated perfused swine right ventricles (RVs) stained with 4-[beta-[2-(di-n-butylamino)-6-naphthyl]vinyl]pyridinium (di-4-ANEPPS) for optical mapping studies. Within 97 +/- 163 s, aconitine induced ventricular tachycardia (VT) with a mean cycle length 268 +/- 37 ms, which accelerated before converting to VF. Drugs that flatten the APD restitution slope, including diacetyl monoxime (10-20 mM, n = 6), bretylium (10-20 microg/ml, n = 3), and verapamil (2-4 microg/ml, n = 3), reversibly converted VF to VT in all cases. In two RVs, VF persisted despite of the excision of the aconitine site. Simulations in two-dimensional cardiac tissue showed that once VF was initiated, it remained sustained even after the "aconitine" site was eliminated. In this model of focal source VF, the VT-to-VF transition occurred due to a wave break outside the aconitine site, and drugs that flattened the APD restitution slope converted VF to VT despite continuous activation from aconitine site.
CI) between sinus activation and a succeeding PV ectopic beat, and the cycle length (CL) of repet... more CI) between sinus activation and a succeeding PV ectopic beat, and the cycle length (CL) of repetitive beats from that ectopic focus. Results: PV ectopic foci, coupled with sinus activity, produced spatial dispersion of repolarization. For certain CL,CI combinations, such repolarization dispersion caused unidirectional block and reentry. Specifically, for 170ՅCLՅ210 ms (a range for which discordant alternans occurs in a model atrial fiber) and 330ՅCIՅ470 ms, AFL was initiated with as few as 2 PV ectopic beats. Location of conduction block and reentry shifted as a function of CI: right atrium (330ՅCIՅ390 ms), inter-atrial region (410ՅCIՅ430 ms), or left atrium (430ՅCIՅ470 ms). For this CI range, different circuits were found: a) tricuspid annulus (TA) clockwise; b) TA counter-clockwise; c) superior/inferior vena cava; d) inter-atrial region including Bachmann's bundle, atrial septum, fossa ovalis and coronary sinus; e) mitral annulus; f) PVs. Through a "fibrillatory conduction process", in which rapid electrical impulses emanating from flutter circuits interact with functional and/or anatomic obstacles throughout the atria leading to fragmentation and wavelet formation, about 1/3 of AFL spontaneously converted to AF (conversion time: 570Ϯ300 ms), which were characterized by 3-5 wavelets simultaneously meandering in both atria. Conclusions: AFL and AF can be initiated by PV ectopic foci in a realistic 3D atrial model. Atrial reentry initiation resulted from unidirectional conduction block due to dynamic, foci-induced spatial dispersion of repolarization. Conduction block location and flutter circuit was dependent on CI. AFL often converted to AF through fibrillatory conduction.
The collective behaviors of coupled, stochastically excitable elements subjected to global period... more The collective behaviors of coupled, stochastically excitable elements subjected to global periodic forcing are investigated numerically and analytically. We show that the whole system undergoes a period-doubling bifurcation as the driving period decreases, while the individual elements still exhibit random excitations. Using a mean-field representation, we show that this macroscopic bifurcation behavior is caused by interactions between the random excitation, the refractory period, and recruitment (spatial cooperativity) of the excitable elements.
Regional hyperkalemia during acute myocardial ischemia is a major factor promoting electrophysiol... more Regional hyperkalemia during acute myocardial ischemia is a major factor promoting electrophysiological abnormalities leading to ventricular fibrillation (VF). However, steep action potential duration restitution, recently proposed to be a major determinant of VF, is typically decreased rather than increased by hyperkalemia and acute ischemia. To investigate this apparent contradiction, we simulated the effects of regional hyperkalemia and other ischemic components (anoxia and acidosis) on the stability of spiral wave reentry in simulated two-dimensional cardiac tissue by use of the Luo-Rudy ventricular action potential model. We found that the hyperkalemic "ischemic" area promotes wavebreak in the surrounding normal tissue by accelerating the rate of spiral wave reentry, even after the depolarized ischemic area itself has become unexcitable. Furthermore, wavebreak and fibrillation can be prevented if the dynamical instability of the normal tissue is reduced significantly by targeting electrical restitution properties, suggesting a novel therapeutic approach.
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Papers by alan garfinkel