Reflected reentry, delayed conduction, and electrotonic inhibition in segmentally depressed atrial tissues

Reflection is a subclass of reentrant cardiac arrhythmias in which reexcitation of the heart occurs as a result of to and fro electrotonically mediated transmission of impulses across a narrow zone of impaired conductivity. Although relatively well characterized in ventricular tissues, the reflection mechanism has not been studied in atrial tissues. In this study we examine the possibility of reflected reentry in segmentally depressed atrial tissues and evaluate conduction characteristics in these preparations. Narrow strips of atrial pectinate muscle or crista terminalis (canine and calf) were placed in a three-chambered bath and the central segment was superfused with an isotonic sucrose solution or an "ischemic" Tyrode's solution. Proximal to distal conduction across the 1.0- to 1.2-mm wide ischemic gap showed step delays as long as 210 ms. Reflected reentry was readily demonstrable when prominent step delays occurred during anterograde conduction of the impulse across the gap. Progressive acceleration of the stimulation rate resulted in progressively greater impairment of anterograde conduction until complete block occurred. The incidence and patterns of reflected reentry were therefore a sensitive function of the stimulation rate. Other features exhibited by these preparations include a slow recovery of excitability following the action potential, postrepolarization refractoriness, and electrotonic inhibition and summation. Our data suggest that the characteristics of conduction and reflection in segmentally depressed atrial tissues are qualitatively similar to those in ventricular tissues. The presence of electrotonic inhibition in atrial may also help to explain the functionally inexcitable zone seen in the vortex of the leading circle model of atrial flutter.     

High-density mapping of pulmonary veins and left atrium during ibutilide administration in a canine model of sustained atrial fibrillation

Ibutilide can prolong refractory period and terminate reentry. Whether ibutilide has the same effects on pulmonary vein (PV) focal discharge (FD) is unclear. We induced sustained atrial fibrillation (AF) in seven dogs by rapid left atrial (LA) pacing for 74 +/- 46 days. Ibutilide was repeatedly infused until it terminated AF (0.02 +/- 0.01 mg/kg) or when a cumulative dose was reached (0.04 mg/kg). High-resolution computerized epicardial mapping was performed. We found intermittent FD at the PVs and reentry at the PV-LA junction during AF. Ibutilide increased the cycle length of consecutive reentry from 97 +/- 13 to 112 +/- 18 ms and increased FD from 96 +/- 7 to 113 +/- 9 ms. In four dogs with both FD and reentry at the PVs, the incidence of reentry decreased from 3.5 +/- 1.9/s at baseline to 2.2 +/- 1.8/s after ibutilide administration. However, the incidence of FD remained unchanged. The conducted wave fronts between PV and LA were significantly reduced by ibutilide (10.4 +/- 2.0/s vs. 8.0 +/- 1.6/s). The ibutilide dose needed to terminate AF correlated negatively with the baseline effective refractory period of PV and LA. We conclude that ibutilide reduces reentrant wave fronts but not PV FD in a canine model of pacing-induced sustained AF. These findings suggest that the PV FD during AF is due to nonreentrant mechanisms. High doses of ibutilide may completely terminate all reentrant activity, converting AF to PV tachycardia before the resumption of sinus rhythm.     

Effects of electrical and structural remodeling on atrial fibrillation maintenance: a simulation study

Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength--electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely.     

Mechanisms of Transition from Normal to Reentrant Electrical Activity in a Model of Rabbit Atrial Tissue: Interaction of Tissue Heterogeneity and Anisotropy

Experimental evidence suggests that regional differences in action potential (AP) morphology can provide a substrate for initiation and maintenance of reentrant arrhythmias in the right atrium (RA), but the relationships between the complex electrophysiological and anatomical organization of the RA and the genesis of reentry are unclear. In this study, a biophysically detailed three-dimensional computer model of the right atrial tissue was constructed to study the role of tissue heterogeneity and anisotropy in arrhythmogenesis. The model of Lindblad et al. for a rabbit atrial cell was modified to incorporate experimental data on regional differences in several ionic currents (primarily, I_Na, I_CaL, I_K1, I_to, and I_sus) between the crista terminalis and pectinate muscle cells. The modified model was validated by its ability to reproduce the AP properties measured experimentally. The anatomical model of the rabbit RA (including tissue geometry and fiber orientation) was based on a recent histological reconstruction. Simulations with the resultant electrophysiologically and anatomically detailed three-dimensional model show that complex organization of the RA tissue causes breakdown of regular AP conduction patterns at high pacing rates (>11.75 Hz): as the AP in the crista terminalis cells is longer, and electrotonic coupling transverse to fibers of the crista terminalis is weak, high-frequency pacing at the border between the crista terminalis and pectinate muscles results in a unidirectional conduction block toward the crista terminalis and generation of reentry. Contributions of the tissue heterogeneity and anisotropy to reentry initiation mechanisms are quantified by measuring action potential duration (APD) gradients at the border between the crista terminalis and pectinate muscles: the APD gradients are high in areas where both heterogeneity and anisotropy are high, such that intrinsic APD differences are not diminished by electrotonic interactions. Thus, our detailed computer model reconstructs complex electrical activity in the RA, and provides new insights into the mechanisms of transition from focal atrial tachycardia into reentry.     

Computer simulation of microreentry in the sinoatrial node

We have studied the dynamics of reentry inside the sinoatrial node (SAN). We have found that reentry is unstable at high intercellular conductance. Rotating reentry induces a slow migrating crescent-shaped functional block near the SAN boundary. Abnormal conduction from atrial tissue into the SAN occurs after decay of the reentry. Acetylcholine increases the lifespan of reentry in the SAN.     

Electrophysiological mechanisms of atrial flutter

Atrial flutter (AFL) is a common arrhythmia in clinical practice. Several experimental models such as tricuspid regurgitation model, tricuspid ring model, sterile pericarditis model and atrial crush injury model have provided important information about reentrant circuit and can test the effect of antiarrhythmic drugs. Human atrial flutter has typical and atypical forms. Typical atrial flutter rotates around tricuspid annulus and uses the crista terminalis and sometimes sinus venosa as the boundary. The IVC-tricuspid isthmus is a slow conduction zone and the target of radiofrequency ablation. Atypical atrial flutter may arise from the right or left atrium. Right atrial flutter includes upper loop reentry, free wall reentry and figure of eight reentry. Left atrial flutter includes mitral annular atrial flutter, pulmonary vein-related atrial flutter and left septal atrial flutter. Radiofrequency ablation of the isthmus between the boundaries can eliminate these arrhythmias.     

Nonreentrant focal activations in pulmonary veins in canine model of sustained atrial fibrillation

Repetitive rapid activities are present in the pulmonary veins (PVs) in dogs with pacing-induced sustained atrial fibrillation (AF). The mechanisms are unclear. We induced sustained (>48 h) AF by rapidly pacing the left atrium (LA) in six dogs. High-density computerized mapping was done in the PVs and atria. Results show repetitive focal activations in all dogs and in 12 of 18 mapped PVs. Activation originated from the middle of the PV and then propagated to the LA and distal PV with conduction blocks. The right atrium (RA) was usually activated by a single large wavefront. Mean AF cycle length in the PVs (left superior, 82 +/- 6 ms; left inferior, 83 +/- 6 ms; right inferior, 83 +/- 4 ms) and LA posterior wall (87 +/- 5 ms) were significantly (P < 0.05) shorter than those in the LA anterior wall (92 +/- 4 ms) and RA (107 +/- 5 ms). PVs in normal dogs did not have focal activations during induced AF. No reentrant wavefronts were demonstrated in the PVs. We conclude that nonreentrant focal activations are present in the PVs in a canine model of pacing-induced sustained AF.     

The pinwheel experiment revisited: effects of cellular electrophysiological properties on vulnerability to cardiac reentry

In normal heart, ventricular fibrillation can be induced by a single properly timed strong electrical or mechanical stimulus. A mechanism first proposed by Winfree and coined the "pinwheel experiment" emphasizes the timing and strength of the stimulus in inducing figure-of-eight reentry. However, the effects of cellular electrophysiological properties on vulnerability to reentry in the pinwheel scenario have not been investigated. In this study, we extend Winfree's pinwheel experiment to show how the vulnerability to reentry is affected by the graded action potential responses induced by a strong premature stimulus, action potential duration (APD), and APD restitution in simulated monodomain homogeneous two-dimensional tissue. We find that a larger graded response, longer APD, or steeper APD restitution slope reduces the vulnerable window of reentry. Strong graded responses and long APD promote tip-tip interactions at long coupling intervals, causing the two initiated spiral wave tips to annihilate. Steep APD restitution promotes wave front-wave back interaction, causing conduction block in the central common pathway of figure-of-eight reentry. We derive an analytical treatment that shows good agreement with numerical simulation results.     

Transitions among atrial fibrillation, atrial flutter, and sinus rhythm during procainamide infusion and vagal stimulation in dogs with sterile pericarditis

The mechanism of atrial flutter and fibrillation induced by rapid pacing in 22 dogs with 3-day-old sterile pericarditis was investigated by computerized epicardial mapping of atrial activation before and after administration of agents known to modify atrial electrophysiologic properties: procainamide, isoproterenol, and electrical stimulation of the vagosympathetic trunks. Before the administration of any of these agents, a total of 30 episodes of sustained atrial flutter (greater than 1 min duration, monomorphic; regular cycle length, 127 +/- 12 ms, mean +/- SD) was induced in 15 out of 22 dogs and 9 episodes of unstable atrial flutter (duration, less than 1 min; cycle length, 129 +/- 34 ms; monomorphic, alternating with fibrillation) were induced in the remaining 7 preparations. In the latter, administration of procainamide transformed unstable atrial flutter and atrial fibrillation to sustained atrial flutter (cycle length, 142 +/- 33 ms; n = 9 episodes). During control atrial flutter, atrial maps displayed circus movement of excitation in the right atrial free wall with faster conduction parallel to the orientation of intra-atrial myocardial bundles. Vagal stimulation changed atrial flutter to atrial fibrillation in 32 of 73 trials; this was associated with acceleration of conduction in the lower right atrium, leading to fragmentation of the major wave front. Isoproterenol produced a 6-25% increase of the atrial rate in 6 out of 14 trials of atrial flutter and induced atrial fibrillation in 4. After procainamide, the reentrant pathway was lengthened and conduction was slowed further in the right atrium. Maps obtained during unstable atrial flutter showed incomplete circuits involving the right atrium. Following procainamide infusion, the area of functional dissociation or block was enlarged and a stable circus movement pattern, which was similar to the pattern seen in control atrial flutter, was established in the right atrium. We conclude that (1) the transitions among atrial fibrillation, atrial flutter, and sinus rhythm occur between different functional states of the same circus movement substratum primarily located in the lower right atrial free wall, and (2) the anisotropic conduction properties of the right atrium may contribute to these reentrant arrhythmias and may be potentiated by acute pericarditis.     

Adenosine-sensitive perinodal atrial tachycardia. What is the mechanism?

Termination of focal atrial tachycardia with adenosine is considered a defining feature for triggered activity. Recent evidence, however, suggests that the perinodal adenosine-sensitive AT has reentry as the mechanism of tachycardia. In this report, we were able to confirm the mechanism of AT as reentry by observing the response to programmed electrical stimulation and demonstrating the fallacy of traditional teaching that the adenosine responsiveness of AT is a criterion for labeling the mechanism as triggered activity.     

山羊房颤模型中左心房与肺静脉外膜碎裂电位的动态比较

目的:比较在持续性房颤发生、发展过程中,房颤模型山羊左心房与肺静脉外膜碎裂电位(CFAEs)的变 化,以期探讨肺静脉外膜碎裂电位(CFAEs)在持续性房颤中的作用.方法:选取10只雌性山羊,使用左心房快速刺激,发送输出电压为6 V、周长为20 ms的脉冲1 s,间隔2 s后重复发放,以此方法建立持续性房颤模型(房颤持续...     

Theoretical analysis of the magnetocardiographic pattern for reentry wave propagation in a three-dimensional human heart model

We present a computational study of reentry wave propagation using electrophysiological models of human cardiac cells and the associated magnetic field map of a human heart. We examined the details of magnetic field variation and related physiological parameters for reentry waves in two-dimensional (2-D) human atrial tissue and a three-dimensional (3-D) human ventricle model. A 3-D mesh system representing the human ventricle was reconstructed from the surface geometry of a human heart. We used existing human cardiac cell models to simulate action potential (AP) propagation in atrial tissue and 3-D ventricular geometry, and a finite element method and the Galerkin approximation to discretize the 3-D domain spatially. The reentry wave was generated using an S1-S2 protocol. The calculations of the magnetic field pattern assumed a horizontally layered conductor for reentry wave propagation in the 3-D ventricle. We also compared the AP and magnetocardiograph (MCG) magnitudes during reentry wave propagation to those during normal wave propagation. The temporal changes in the reentry wave motion and magnetic field map patterns were also analyzed using two well-known MCG parameters: the current dipole direction and strength. The current vector in a reentry wave forms a rotating spiral. We delineated the magnetic field using the changes in the vector angle during a reentry wave, demonstrating that the MCG pattern can be helpful for theoretical analysis of reentry waves.     

Mechanistic Inquiry into the Role of Tissue Remodeling in Fibrotic Lesions in Human Atrial Fibrillation

Atrial fibrillation (AF), the most common arrhythmia in humans, is initiated when triggered activity from the pulmonary veins propagates into atrial tissue and degrades into reentrant activity. Although experimental and clinical findings show a correlation between atrial fibrosis and AF, the causal relationship between the two remains elusive. This study used an array of 3D computational models with different representations of fibrosis based on a patient-specific atrial geometry with accurate fibrotic distribution to determine the mechanisms by which fibrosis underlies the degradation of a pulmonary vein ectopic beat into AF. Fibrotic lesions in models were represented with combinations of: gap junction remodeling; collagen deposition; and myofibroblast proliferation with electrotonic or paracrine effects on neighboring myocytes. The study found that the occurrence of gap junction remodeling and the subsequent conduction slowing in the fibrotic lesions was a necessary but not sufficient condition for AF development, whereas myofibroblast proliferation and the subsequent electrophysiological effect on neighboring myocytes within the fibrotic lesions was the sufficient condition necessary for reentry formation. Collagen did not alter the arrhythmogenic outcome resulting from the other fibrosis components. Reentrant circuits formed throughout the noncontiguous fibrotic lesions, without anchoring to a specific fibrotic lesion.     

Mechanistic Inquiry into the Role of Tissue Remodeling in Fibrotic Lesions in Human Atrial Fibrillation

Atrial fibrillation (AF), the most common arrhythmia in humans, is initiated when triggered activity from the pulmonary veins propagates into atrial tissue and degrades into reentrant activity. Although experimental and clinical findings show a correlation between atrial fibrosis and AF, the causal relationship between the two remains elusive. This study used an array of 3D computational models with different representations of fibrosis based on a patient-specific atrial geometry with accurate fibrotic distribution to determine the mechanisms by which fibrosis underlies the degradation of a pulmonary vein ectopic beat into AF. Fibrotic lesions in models were represented with combinations of: gap junction remodeling; collagen deposition; and myofibroblast proliferation with electrotonic or paracrine effects on neighboring myocytes. The study found that the occurrence of gap junction remodeling and the subsequent conduction slowing in the fibrotic lesions was a necessary but not sufficient condition for AF development, whereas myofibroblast proliferation and the subsequent electrophysiological effect on neighboring myocytes within the fibrotic lesions was the sufficient condition necessary for reentry formation. Collagen did not alter the arrhythmogenic outcome resulting from the other fibrosis components. Reentrant circuits formed throughout the noncontiguous fibrotic lesions, without anchoring to a specific fibrotic lesion.     

Direction-dependent conduction abnormalities in a canine model of atrial fibrillation due to chronic atrial dilatation

Chronic rapid atrial pacing (RAP) leads to changes that perpetuate atrial fibrillation (AF). Chronic atrial dilatation due to mitral regurgitation (MR) also increases AF inducibility, but it is not clear whether the underlying mechanism is similar. Therefore, we have investigated atrial electrophysiology in a canine MR model (mitral valve avulsion, 1 mo) using high-resolution optical mapping and compared it with control dogs and with the canine RAP model (6-8 wk of atrial pacing at 600 beats/min, atrioventricular block, and ventricular pacing at 100 beats/min). At followup, optical action potentials were recorded using a 16 x 16 photodiode array from 2 x 2-cm left atrial (LA) and right atrial (RA) areas in perfused preparations, with pacing electrodes around the field of view to study direction dependency of conduction. Action potential duration at 80% repolarization (APD(80)) was not different between control and MR but was reduced in RAP atria. Conduction velocities during normal pacing were not different between groups. However, the MR LA showed increased conduction heterogeneity during pacing at short cycle lengths and during premature extrastimuli, which frequently caused pronounced regional conduction slowing. Conduction in the MR LA during extrastimulation also displayed a marked dependence on propagation direction. These phenomena were not observed in the MR RA and in control and RAP atria. Thus both models form distinctly different AF substrates; in RAP dogs, the decrease in APD(80) may stabilize reentry. In MR dogs, regional LA conduction slowing and increased directional dependency, allowing unidirectional conduction block and preferential paths of conduction, may account for increased AF inducibility.     

Increased vulnerability to inducible atrial fibrillation caused by partial cellular uncoupling with heptanol

We hypothesized that partial cellular uncoupling produced by low concentrations of heptanol increases the vulnerability to inducible atrial fibrillation (AF). The epicardial surface of 12 isolated-perfused canine left atria was optically mapped before and after 1-50 microM heptanol infusion. At baseline, no sustained (>30 s) AF could be induced in any of the 12 tissues. However, after 2 microM heptanol infusion, sustained AF was induced in 9 of 12 tissues (P < 0.001). Heptanol >5 microM caused loss of 1:1 capture during rapid pacing, causing no AF to be induced. AF was initiated by conduction block across the fiber leading to reentry, which broke up after one to two rotations into two to four independent wavelets that sustained the AF. Heptanol at 2 microM had no effect on the cellular action potential duration restitution or on the maximal velocity rate over time of the upstroke. The effects of heptanol were reversible. We conclude that partial cellular uncoupling by heptanol without changing atrial active membrane properties promotes wavebreak, reentry, and AF during rapid pacing.     

Overdrive pacing of early ischemic ventricular tachycardia: evidence for both reentry and triggered activity

Entrainment can be a useful method to identify reentry as a mechanism of ventricular tachycardia (VT). In this study, we evaluated the effect of gradually decreasing cycle lengths of overdrive pacing for stable VT induced in a canine model 1-3 h after coronary occlusion. Intact dogs underwent anterior descending coronary artery occlusion after instrumentation of the risk zone with 21 multipolar plunge needles, each recording 6 bipolar electrograms. Overdrive pacing was attempted if the animals had sustained hemodynamically stable VT, looking for evidence of entrainment. Subsequent three-dimensional mapping determined the mechanism of VT. Fifteen of the 21 dogs studied demonstrated entrainment with overdrive pacing by progressive QRS fusion alone (1), the first nonpaced QRS entrained to the paced cycle length only (7), or both (7). Five of these 15 dogs also had postpacing acceleration of the VT at a subsequent faster pacing cycle length. The mechanism of acceleration in four was a change to a VT with a focal origin. The prepacing mechanism in all 15 dogs was subsequently mapped to reentry. Regarding the six VTs, which demonstrated no evidence for entrainment, the site of earliest activity was mapped to a focal origin in all. These data showing entrainment of inducible reentrant VTs and lack of such for focal VTs support that the focal VTs seen in this study are unlikely the result of microreentry but possibly a mechanism as triggered activity.     

Thoracic vein ablation terminates chronic atrial fibrillation in dogs

The thoracic vein hypothesis of chronic atrial fibrillation (AF) posits that rapid, repetitive activations from muscle sleeves within thoracic veins underlie the mechanism of sustained AF. If this is so, thoracic vein ablation should terminate sustained AF and prevent its reinduction. Six female mongrel dogs underwent chronic pulmonary vein (PV) pacing at 20 Hz to induce sustained (>48 h) AF. Bipolar electrodes were used to record from the atria and thoracic veins, including the vein of Marshall, four PVs, and the superior vena cava. Radio frequency (RF) application was applied around the PVs and superior vena cava and along the vein of Marshall until electrical activity was eliminated. Computerized mapping (1,792 electrodes, 1 mm resolution) was also performed. Sustained AF was induced in 30.6 +/- 6.5 days, and ablation was done 17.3 +/- 8.5 days afterward. Before ablation, the PVs had shorter activation cycle lengths than the atria, and rapid, repetitive activations were observed in the PVs. All dogs converted to sinus rhythm during (n = 4 dogs) or within 90 min of completion of RF ablation. Rapid atrial pacing afterward induced only nonsustained (<60 s) AF in all dogs. Average AF cycle lengths after reinduction were significantly (P = 0.01) longer (183 +/- 31.5 ms) than baseline (106 +/- 16.2 ms). There were no activation cycle length gradients after RF application. We conclude that thoracic vein ablation converts canine sustained AF into sinus rhythm and prevents the reinduction of sustained AF. These findings suggest that thoracic veins are important in the maintenance of AF in dogs.     

基于虚拟心脏的早期后除极导致室颤的仿真研究

为了分析早期后除极(early afterdepolarizations,EADs)诱发室颤的机理,本研究基于精细的浦肯野纤维网络与心室解剖数据,构建了一个三维心室电传导模型.基于该模型,模拟了产生早期后除极的电生理变化,探讨了三种心室细胞的早期后除极的易感性,分析了早期后除极易感细胞对折返波的影响,最后定量比较早期后除极诱发室颤的伪心电图的改变情况.实验结果表明:中间层细胞早期后除极易感性最强,中间层细胞早期后除极的产生能够导致折返波破裂,并且在心电图中表现为紊乱的不规则的颤动心律,这与之前在动物实验观察得到的现象一致,因此中间层细胞可能是一个诱发室颤的重要靶点.     

Modern conceptions of the atrial fibrillation development. The role of the myocardial sleeves in the pulmonary veins

Atrial fibrillation (AF) is the most common supraventricular cardiac arrhythmia. In this review several conceptions focused on the mechanisms of the AF initiation are discussed. At present time viewpoint that the ectopical activity in the pulmonary vien myocardial sleeves (PVs) account for AF in prevailing. PVs myocardium has been the subject of many anatomical and physiological investigations. PVs myocardium differs from left atria tissue and has many moprhological properties that make in convenient substrate for AF initiation and maintenance. PVs cardiomyocytes were shown to have great variability of electrophysiological properties (action potential duration, resting potential, upstroke velocity, etc.). Attempt to discuss afterdepolarization, triggered activity and abnormal automaticity as initiators of AF in PVs was made. It was shown that as in experimental condition, as in vivo in PVs can exist er-entry. Possibly, re-entry from PVs could be the one mechanism by which AF is initiated. In review big attention to the innervations of PVs and role of the sympathetic and the parasympathetic nerves in PVs ectopical activity is paid. Combined influence of autonomic nerves may be critical to initiating AF in PVs. Pharmacological intervention as a possible way to suppress or prevent the activity in the PVs that leads to AF is discussed.