In silico study of multicellular automaticity of heterogeneous cardiac cell monolayers: Effects of automaticity strength and structural linear anisotropy.

The biological pacemaker approach is an alternative to cardiac electronic pacemakers. Its main objective is to create pacemaking activity from added or modified distribution of spontaneous cells in the myocardium. This paper aims to assess how automaticity strength of pacemaker cells (i.e. their ability to maintain robust spontaneous activity with fast rate and to drive neighboring quiescent cells) and structural linear anisotropy, combined with density and spatial distribution of pacemaker cells, may affect the macroscopic behavior of the biological pacemaker. A stochastic algorithm was used to randomly distribute pacemaker cells, with various densities and spatial distributions, in a semi-continuous mathematical model. Simulations of the model showed that stronger automaticity allows onset of spontaneous activity for lower densities and more homogeneous spatial distributions, displayed more central foci, less variability in cycle lengths and synchronization of electrical activation for similar spatial patterns, but more variability in those same variables for dissimilar spatial patterns. Compared to their isotropic counterparts, in silico anisotropic monolayers had less central foci and displayed more variability in cycle lengths and synchronization of electrical activation for both similar and dissimilar spatial patterns. The present study established a link between microscopic structure and macroscopic behavior of the biological pacemaker, and may provide crucial information for optimized biological pacemaker therapies.

Rate-Dependent Role of IKur in Human Atrial Repolarization and Atrial Fibrillation Maintenance.

The atrial-specific ultrarapid delayed rectifier K+ current (IKur) inactivates slowly but completely at depolarized voltages. The consequences for IKur rate-dependence have not been analyzed in detail and currently available mathematical action-potential (AP) models do not take into account experimentally observed IKur inactivation dynamics. Here, we developed an updated formulation of IKur inactivation that accurately reproduces time-, voltage-, and frequency-dependent inactivation. We then modified the human atrial cardiomyocyte Courtemanche AP model to incorporate realistic IKur inactivation properties. Despite markedly different inactivation dynamics, there was no difference in AP parameters across a wide range of stimulation frequencies between the original and updated models. Using the updated model, we showed that, under physiological stimulation conditions, IKur does not inactivate significantly even at high atrial rates because the transmembrane potential spends little time at voltages associated with inactivation. Thus, channel dynamics are determined principally by activation kinetics. IKur magnitude decreases at higher rates because of AP changes that reduce IKur activation. Nevertheless, the relative contribution of IKur to AP repolarization increases at higher frequencies because of reduced activation of the rapid delayed-rectifier current IKr. Consequently, IKur block produces dose-dependent termination of simulated atrial fibrillation (AF) in the absence of AF-induced electrical remodeling. The inclusion of AF-related ionic remodeling stabilizes simulated AF and greatly reduces the predicted antiarrhythmic efficacy of IKur block. Our results explain a range of experimental observations, including recently reported positive rate-dependent IKur-blocking effects on human atrial APs, and provide insights relevant to the potential value of IKur as an antiarrhythmic target for the treatment of AF.

Noise-induced effects on multicellular biopacemaker spontaneous activity: Differences between weak and strong pacemaker cells.

Self-organization of spontaneous activity of a network of active elements is important to the general theory of reaction-diffusion systems as well as for pacemaking activity to initiate beating of the heart. Monolayer cultures of neonatal rat ventricular myocytes, consisting of resting and pacemaker cells, exhibit spontaneous activation of their electrical activity. Similarly, one proposed approach to the development of biopacemakers as an alternative to electronic pacemakers for cardiac therapy is based on heterogeneous cardiac cells with resting and spontaneously beating phenotypes. However, the combined effect of pacemaker characteristics, density, and spatial distribution of the pacemaker cells on spontaneous activity is unknown. Using a simple stochastic pattern formation algorithm, we previously showed a clear nonlinear dependency of spontaneous activity (occurrence and amplitude of spontaneous period) on the spatial patterns of pacemaker cells. In this study, we show that this behavior is dependent on the pacemaker cell characteristics, with weaker pacemaker cells requiring higher density and larger clusters to sustain multicellular activity. These multicellular structures also demonstrated an increased sensitivity to voltage noise that favored spontaneous activity at lower density while increasing temporal variation in the period of activity. This information will help researchers overcome the current limitations of biopacemakers.

Potassium Channel Blockade Enhances Atrial Fibrillation-Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade.

BACKGROUND: The development of effective and safe antiarrhythmic drugs for atrial fibrillation (AF) rhythm control is an unmet clinical need. Multichannel blockers are believed to have advantages over single-channel blockers for AF, but their development has been completely empirical to date. We tested the hypothesis that adding K(+)-channel blockade improves the atrium-selective electrophysiological profile and anti-AF effects of optimized Na(+)-channel blockers. METHODS AND RESULTS: Realistic cardiomyocyte-, tissue-, and state-dependent Na(+)-channel block mathematical models, optical mapping, and action potential recording were used to study the effect of Na(+)-current (INa) blockade with or without concomitant inhibition of the rapid or ultrarapid delayed-rectifier K(+) currents (IKr and IKur, respectively). In the mathematical model, maximal AF selectivity was obtained with an inactivated-state Na(+)-channel blocker. Combining optimized Na(+)-channel blocker with IKr block increased rate-dependent and atrium-selective peak INa reduction, increased AF selectivity, and more effectively terminated AF compared with optimized Na(+)-channel blocker alone. Combining optimized Na(+)-channel blocker with IKur block had similar effects but without IKr block-induced ventricular action potential prolongation. Consistent with the mathematical model, in coronary-perfused canine hearts, the addition of dofetilide (selective IKr blocker) to pilsicainide (selective INa blocker) produced enhanced atrium-selective effects on maximal phase 0 upstroke and conduction velocity. Furthermore, pilsicainide plus dofetilide had higher AF termination efficacy than pilsicainide alone. Pilsicainide alone had no statistically significant effect on AF inducibility, whereas pilsicainide plus dofetilide rendered AF noninducible. CONCLUSIONS: K(+)-channel block potentiates the AF-selective anti-AF effects obtainable with optimized Na(+)-channel blockade. Combining optimized Na(+)-channel block with blockade of atrial K(+) currents is a potentially valuable AF-selective antiarrhythmic drug strategy.

Fibroblast electrical remodeling in heart failure and potential effects on atrial fibrillation.

Fibroblasts are activated in heart failure (HF) and produce fibrosis, which plays a role in maintaining atrial fibrillation (AF). The effect of HF on fibroblast ion currents and its potential role in AF are unknown. Here, we used a patch-clamp technique to investigate the effects of HF on atrial fibroblast ion currents, and mathematical computation to assess the potential impact of this remodeling on atrial electrophysiology and arrhythmogenesis. Atrial fibroblasts were isolated from control and tachypacing-induced HF dogs. Tetraethylammonium-sensitive voltage-gated fibroblast current (IKv,fb) was significantly downregulated (by ?44%), whereas the Ba(2+)-sensitive inward rectifier current (IKir,fb) was upregulated by 79%, in HF animals versus controls. The fibroblast resting membrane potential was hyperpolarized (?53 ± 2 mV vs. ?42 ± 2 mV in controls) and the capacitance was increased (29.7 ± 2.2 pF vs. 17.8 ± 1.4 pF in controls) in HF. These experimental findings were implemented in a mathematical model that included cardiomyocyte-fibroblast electrical coupling. IKir,fb upregulation had a profibrillatory effect through shortening of the action potential duration and hyperpolarization of the cardiomyocyte resting membrane potential. IKv,fb downregulation had the opposite electrophysiological effects and was antifibrillatory. Simulated pharmacological blockade of IKv,fb successfully terminated reentry under otherwise profibrillatory conditions. We conclude that HF induces fibroblast ion-current remodeling with IKv,fb downregulation and IKir,fb upregulation, and that, assuming cardiomyocyte-fibroblast electrical coupling, this remodeling has a potentially important effect on atrial electrophysiology and arrhythmogenesis, with the overall response depending on the balance of pro- and antifibrillatory contributions. These findings suggest that fibroblast K(+)-current remodeling is a novel component of AF-related remodeling that might contribute to arrhythmia dynamics.

Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs.

The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical modelling techniques were used. Selective IKr block (50-100 nmol l(-1) dofetilide) lengthened AP duration at 90% of repolarization (APD90) >3-fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective IK1 block (10 µmol l(-1) BaCl2) and IKs block (1 µmol l(-1) HMR-1556) increased APD90 more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that IK1 and IKs densities were 3- and 4.5-fold larger in dogs than humans, respectively. IKr density and kinetics were similar in human versus dog. ICa and Ito were respectively ~30% larger and ~29% smaller in human, and Na(+)-Ca(2+) exchange current was comparable. Cardiac mRNA levels for the main IK1 ion channel subunit Kir2.1 and the IKs accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (IKr and IKs α-subunits) were not significantly different, in human versus dog. Immunostaining suggested lower Kir2.1 and minK, and higher KvLQT1 protein expression in human versus canine cardiomyocytes. IK1 and IKs inhibition increased the APD-prolonging effect of IKr block more in dog (by 56% and 49%, respectively) than human (34 and 16%), indicating that both currents contribute to increased repolarization reserve in the dog. A mathematical model incorporating observed human-canine ion current differences confirmed the role of IK1 and IKs in repolarization reserve differences. Thus, humans show greater repolarization-delaying effects of IKr block than dogs, because of lower repolarization reserve contributions from IK1 and IKs, emphasizing species-specific determinants of repolarization and the limitations of animal models for human disease.

In silico optimization of atrial fibrillation-selective sodium channel blocker pharmacodynamics.

Atrial fibrillation (AF) is the most common type of clinical arrhythmia. Currently available anti-AF drugs are limited by only moderate efficacy and an unfavorable safety profile. Thus, there is a recognized need for improved antiarrhythmic agents with actions that are selective for the fibrillating atrium. State-dependent Na(+)-channel blockade potentially allows for the development of drugs with maximal actions on fibrillating atrial tissue and minimal actions on ventricular tissue at resting heart rates. In this study, we applied a mathematical model of state-dependent Na(+)-channel blocking (class I antiarrhythmic drug) action, along with mathematical models of canine atrial and ventricular cardiomyocyte action potentials, AF, and ventricular proarrhythmia, to determine the relationship between their pharmacodynamic properties and atrial-selectivity, AF-selectivity (atrial Na(+)-channel block at AF rates versus ventricular block at resting rates), AF-termination effectiveness, and ventricular proarrhythmic properties. We found that drugs that target inactivated channels are AF-selective, whereas drugs that target activated channels are not. The most AF-selective drugs were associated with minimal ventricular proarrhythmic potential and terminated AF in 33% of simulations; slightly fewer AF-selective agents achieved termination rates of 100% with low ventricular proarrhythmic potential. Our results define properties associated with AF-selective actions of class-I antiarrhythmic drugs and support the idea that it may be possible to develop class I antiarrhythmic agents with optimized pharmacodynamic properties for AF treatment.

Mechanisms of atrial tachyarrhythmias associated with coronary artery occlusion in a chronic canine model.

BACKGROUND: Coronary artery disease predisposes to atrial fibrillation (AF), but the effects of chronic atrial ischemia/infarction on AF-related substrates are unknown. METHODS AND RESULTS: Regional right atrial myocardial infarction (MI) was created in 40 dogs by ligating an artery that supplies the right atrial free wall and not the ventricles; 35 sham dogs with the same artery isolated but not ligated were controls. Dogs were observed 8 days after MI and subjected to open-chest study, in vitro optical mapping, and/or cell isolation for patch-clamp and Ca(2+) imaging on day 8. Holter ECGs showed more spontaneous atrial ectopy in MI dogs (eg, 662±281 on day 7 versus 34±25 ectopic complexes per day at baseline; 52±21 versus 1±1 atrial tachycardia episodes per day). Triggered activity was increased in MI border zone cells, which had faster decay of caffeine-evoked Ca(2+) transients and enhanced (by ≈73%) Na(+)-Ca(2+) exchange current. Spontaneous Ca(2+) sparks (confocal microscopy) occurred under ß-adrenergic stimulation in more MI dog cells (66±9%) than in control cells (29±4%; P<0.01). Burst pacing induced long-lasting AF in MI dogs (1146±259 versus 30±14 seconds in shams). Increased border zone conduction heterogeneity was confirmed by both bipolar electrode mapping in vivo and optical mapping. Optical mapping demonstrated stable border zone reentry in all 9 MI preparations but in none of 6 shams. Border zone tissue showed increased fibrous tissue content. CONCLUSIONS: Chronic atrial ischemia/infarction creates substrates for both spontaneous ectopy (Ca(2+)-release events, increased Na(+)-Ca(2+) exchange current) and sustained reentry (conduction abnormalities that anchor reentry). Thus, chronic atrial infarction in dogs promotes both AF triggers and the substrate for AF maintenance. These results provide novel insights into potential AF mechanisms in patients with coronary artery disease.

Novel Analysis Method for Beating Cells Videomicroscopy Data: Functional Characterization of Culture Samples.

Cell culture of cardiac tissue analog is becoming increasingly interesting for regenerative medicine (cell therapy and tissue engineering) and is widely used for high throughput cardiotoxicity. As a cost-effective approach to rapidly discard new compounds with high toxicity risks, cardiotoxicity evaluation is firstly done in vitro requiring cells/tissue with physiological/pathological characteristics (close to in vivo properties). Studying multicellular electrophysiological and contractile properties is needed to assess drug effects. Techniques favoring process automation which could help in simplifying screening drug candidates are thus of central importance. A lot of effort has been made to ameliorate in vitro models including several in vitro platforms for engineering neonatal rat cardiac tissues. However, most of the initial evaluation is done by studying the rate of activity. In this study, we present new approaches that use the videomicroscopy video of monolayer activity to study contractile properties of beating cells in culture. Two new variables are proposed which are linked to the contraction dynamics and are dependent on the rhythm of activity. Methods for evaluation of regional synchronicity within the image field of view are also presented that can rapidly determine regions with abnormal activity or heterogeneity in contraction dynamics.

Mechanisms by which adenosine restores conduction in dormant canine pulmonary veins.

BACKGROUND: Adenosine acutely reconnects pulmonary veins (PVs) after radiofrequency application, revealing "dormant conduction" and identifying PVs at risk of reconnection, but the underlying mechanisms are unknown. METHODS AND RESULTS: Canine PV and left-atrial (LA) action potentials were recorded with standard microelectrodes and ionic currents with whole-cell patch clamp before and after adenosine perfusion. PVs were isolated with radiofrequency current application in coronary-perfused LA-PV preparations. Adenosine abbreviated action potential duration similarly in PV and LA but significantly hyperpolarized resting potential (by 3.9+/-0.5%; P<0.05) and increased dV/dt(max) (by 34+/-10%) only in PV. Increased dV/dt(max) was not due to direct effects on I(Na), which was reduced similarly by adenosine in LA and PV but correlated with resting-potential hyperpolarization (r=0.80). Adenosine induced larger inward rectifier K(+)current (I(KAdo)) in PV (eg, -2.28+/-0.04 pA/pF; -100 mV) versus LA (-1.28+/-0.16 pA/pF). Radiofrequency ablation isolated PVs by depolarizing resting potential to voltages positive to -60 mV. Adenosine restored conduction in 5 dormant PVs, which had significantly more negative resting potentials (-57+/-6 mV) versus nondormant (-46+/-5 mV, n=6; P<0.001) before adenosine. Adenosine hyperpolarized both, but more negative resting-potential values after adenosine in dormant PVs (-66+/-6 mV versus -56+/-6 mV in nondormant; P<0.001) were sufficient to restore excitability. Adenosine effects on resting potential and conduction reversed on washout. Spontaneous recovery of conduction occurring in dormant PVs after 30 to 60 minutes was predicted by the adenosine response. CONCLUSIONS: Adenosine selectively hyperpolarizes canine PVs by increasing I(KAdo). PVs with dormant conduction show less radiofrequency-induced depolarization than nondormant veins, allowing adenosine-induced hyperpolarization to restore excitability by removing voltage-dependent I(Na) inactivation and explaining the restoration of conduction in dormant PVs.

Changes in connexin expression and the atrial fibrillation substrate in congestive heart failure.

RATIONALE: Although connexin changes are important for the ventricular arrhythmic substrate in congestive heart failure (CHF), connexin alterations during CHF-related atrial arrhythmogenic remodeling have received limited attention. OBJECTIVE: To analyze connexin changes and their potential contribution to the atrial fibrillation (AF) substrate during the development and reversal of CHF. METHODS AND RESULTS: Three groups of dogs were studied: CHF induced by 2-week ventricular tachypacing (240 bpm, n=15); CHF dogs allowed a 4-week nonpaced recovery interval after 2-week tachypacing (n=16); and nonpaced sham controls (n=19). Left ventricular (LV) end-diastolic pressure and atrial refractory periods increased with CHF and normalized on CHF recovery. CHF caused abnormalities in atrial conduction indexes and increased the duration of burst pacing-induced AF (DAF, from 22+/-7 seconds in control to 1100+/-171 seconds, P<0.001). CHF did not significantly alter overall atrial connexin (Cx)40 and Cx43 mRNA and protein expression levels, but produced Cx43 dephosphorylation, increased Cx40/Cx43 protein expression ratio and caused Cx43 redistribution toward transverse cell-boundaries. All of the connexin-alterations reversed on CHF recovery, but CHF-induced conduction abnormalities and increased DAF (884+/-220 seconds, P<0.001 versus control) remained. The atrial fibrous tissue content increased from 3.6+/-0.7% in control to 14.7+/-1.5% and 13.3+/-2.3% in CHF and CHF recovery, respectively (both P<0.01 versus control), with transversely running zones of fibrosis physically separating longitudinally directed muscle bundles. In an ionically based action potential/tissue model, fibrosis was able to account for conduction abnormalities associated with CHF and recovery. CONCLUSIONS: CHF causes atrial connexin changes, but these are not essential for CHF-related conduction disturbances and AF promotion, which are rather related primarily to fibrotic interruption of muscle bundle continuity.

Ion channel subunit expression changes in cardiac Purkinje fibers: a potential role in conduction abnormalities associated with congestive heart failure.

Purkinje fibers (PFs) play key roles in cardiac conduction and arrhythmogenesis. Congestive heart failure (CHF) causes well-characterized atrial and ventricular ion channel subunit expression changes, but effects on PF ion channel subunits are unknown. This study assessed changes in PF ion channel subunit expression (real-time PCR, immunoblot, immunohistochemistry), action potential properties, and conduction in dogs with ventricular tachypacing-induced CHF. CHF downregulated mRNA expression of subunits involved in action potential propagation (Nav1.5, by 56%; connexin [Cx]40, 66%; Cx43, 56%) and repolarization (Kv4.3, 43%, Kv3.4, 46%). No significant changes occurred in KChIP2, KvLQT1, ERG, or Kir3.1/3.4 mRNA. At the protein level, downregulation was seen for Nav1.5 (by 38%), Kv4.3 (42%), Kv3.4 (57%), Kir2.1 (26%), Cx40 (53%), and Cx43 (30%). Cx43 dephosphorylation was indicated by decreased larger molecular mass bands (pan-Cx43 antibody) and a 57% decrease in Ser368-phosphorylated Cx43 (phospho-specific antibody). Immunohistochemistry revealed reduced Cx40, Cx43, and phospho-Cx43 expression at intercalated disks. Action potential changes were consistent with observed decreases in ion channel subunits: CHF decreased phase 1 slope (by 56%), overshoot (by 32%), and phase 0 dV/dt(max) (by 35%). Impulse propagation was slowed in PF false tendons: conduction velocity decreased significantly from 2.2+/-0.1 m/s (control) to 1.5+/-0.1 m/s (CHF). His-Purkinje conduction also slowed in vivo, with HV interval increasing from 35.5+/-1.2 (control) to 49.3+/-3.4 ms (CHF). These results indicate important effects of CHF on PF ion channel subunit expression. Alterations in subunits governing conduction properties may be particularly important, because CHF-induced impairments in Purkinje tissue conduction, which this study is the first to describe, could contribute significantly to dyssynchronous ventricular activation, a major determinant of prognosis in CHF-patients.

Impact of tissue geometry on simulated cholinergic atrial fibrillation: a modeling study.

Atrial fibrillation (AF), arising in the cardiac atria, is a common cardiac rhythm disorder that is incompletely understood. Numerous characteristics of the atrial tissue are thought to play a role in the maintenance of AF. Most traditional theoretical models of AF have considered the atrium to be a flat two-dimensional sheet. Here, we analyzed the relationship between atrial geometry, substrate size, and AF persistence, in a mathematical model involving heterogeneity. Spatially periodic properties were created by variations in times required for reactivation due to periodic acetylcholine concentration [ACh] distribution. The differences in AF maintenance between the sheet and the cylinder geometry are found for intermediate gradients of inexcitable time (intermediate [ACh]). The maximum difference in AF maintenance between geometry decreases with increasing tissue size, down to zero for a substrate of dimensions 20 × 10 cm. Generators have the tendency to be anchored to the regions of longer inexcitable period (low [ACh]). The differences in AF maintenance between geometries correlate with situations of moderate anchoring for which rotor-core drifts between low-[ACh] regions occur, favoring generator disappearance. The drift of generators increases their probability of disappearance at the tissue borders, resulting in a decreased maintenance rate in the sheet due to the higher number of no-flux boundaries. These interactions between biological variables and the role of geometry must be considered when selecting an appropriate model for AF in intact hearts.

Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardia-bradycardia syndrome.

BACKGROUND: Sinoatrial node (SAN) dysfunction is frequently associated with atrial tachyarrhythmias (ATs). Abnormalities in SAN pacemaker function after termination of ATs can cause syncope and require pacemaker implantation, but underlying mechanisms remain poorly understood. This study examined the hypothesis that ATs impair SAN function by altering ion channel expression. METHODS AND RESULTS: SAN tissues were obtained from 28 control dogs and 31 dogs with 7-day atrial tachypacing (400 bpm). Ionic currents were measured from single SAN cells with whole-cell patch-clamp techniques. Atrial tachypacing increased SAN recovery time in vivo by approximately 70% (P<0.01), a change which reflects impaired SAN function. In dogs that underwent atrial tachypacing, SAN mRNA expression (real-time reverse-transcription polymerase chain reaction) was reduced for hyperpolarization-activated cyclic nucleotide-gated subunits (HCN2 and HCN4) by >50% (P<0.01) and for the beta-subunit minK by approximately 42% (P<0.05). SAN transcript expression for the rapid delayed-rectifier (I(Kr)) alpha-subunit ERG, the slow delayed-rectifier (I(Ks)) alpha-subunit KvLQT1, the beta-subunit MiRP1, the L-type (I(CaL)) and T-type (I(CaT)) Ca2+-current subunits Cav1.2 and Cav3.1, and the gap-junction subunit connexin 43 (were unaffected by atrial tachypacing. Atrial tachypacing reduced densities of the HCN-related funny current (I(f)) and I(Ks) by approximately 48% (P<0.001) and approximately 34% (P<0.01), respectively, with no change in voltage dependence or kinetics. I(Kr), I(CaL), and I(CaT) were unaffected. SAN cells lacked Ba2+-sensitive inward-rectifier currents, irrespective of AT. SAN action potential simulations that incorporated AT-induced alterations in I(f) accounted for slowing of periodicity, with no additional contribution from changes in I(Ks). CONCLUSIONS: AT downregulates SAN HCN2/4 and minK subunit expression, along with the corresponding currents I(f) and I(Ks). Tachycardia-induced remodeling of SAN ion channel expression, particularly for the "pacemaker" subunit I(f), may contribute to the clinically significant association between SAN dysfunction and supraventricular tachyarrhythmias.

[Multiscale modeling of cardiac electrical activity]. / Approche multi-échelle appliquée à la modélisation de l'activité électrique du coeur.

Models of cardiac electrical activity cover a wide range of spatial scales, from the genesis of the ionic currents in individual cardiomyocytes to the generation of electrocardiograms on the torso. The level of detail that is appropriate and practicable depends on the problem investigated and the scope of the computations that are required. We briefly present three examples of modelling: the dynamics of the entrainment of a single cell, the impact of fibrosis on electrical propagation in a piece of tissue and the generation of ECG in human. In each case, the methods, results and limitations are discussed.

Pulmonary vein region ablation in experimental vagal atrial fibrillation: role of pulmonary veins versus autonomic ganglia.

BACKGROUND: Pulmonary vein (PV) -encircling radiofrequency ablation frequently is effective in vagal atrial fibrillation (AF), and there is evidence that PVs may be particularly prone to cholinergically induced arrhythmia mechanisms. However, PV ablation procedures also can affect intracardiac autonomic ganglia. The present study examined the relative role of PVs versus peri-PV autonomic ganglia in an experimental vagal AF model. METHODS AND RESULTS: Cholinergic AF was studied under carbachol infusion in coronary perfused canine left atrial PV preparations in vitro and with cervical vagal stimulation in vivo. Carbachol caused dose-dependent AF promotion in vitro, which was not affected by excision of all PVs. Sustained AF could be induced easily in all dogs during vagal nerve stimulation in vivo both before and after isolation of all PVs with encircling lesions created by a bipolar radiofrequency ablation clamp device. PV elimination had no effect on atrial effective refractory period or its responses to cholinergic stimulation. Autonomic ganglia were identified by bradycardic and/or tachycardic responses to high-frequency subthreshold local stimulation. Ablation of the autonomic ganglia overlying all PV ostia suppressed the effective refractory period-abbreviating and AF-promoting effects of cervical vagal stimulation, whereas ablation of only left- or right-sided PV ostial ganglia failed to suppress AF. Dominant-frequency analysis suggested that the success of ablation in suppressing vagal AF depended on the elimination of high-frequency driver regions. CONCLUSIONS: Intact PVs are not needed for maintenance of experimental cholinergic AF. Ablation of the autonomic ganglia at the base of the PVs suppresses vagal responses and may contribute to the effectiveness of PV-directed ablation procedures in vagal AF.

Multistability of reentrant rhythms in an ionic model of a two-dimensional annulus of cardiac tissue.

The dynamics of reentry in a model of a two-dimensional annulus of homogeneous cardiac tissue, with a Beeler-Reuter type formulation of the membrane ionic currents, is examined. The bifurcation structure of the sustained propagated solutions is described as a function of Rin and Rout, the inner and outer radii of the annulus. The transition from periodic to quasiperiodic reentry occurs at a critical Rin, which first diminishes and then saturates as Rout is increased. The reduction of the critical Rin is a consequence of the increase of the wave-front curvature. There is a range of Rin below the critical radius in which two distinct quasiperiodic solutions coexist. Each of these solutions disappears at its own specific value of Rin, and their annihilation is preceded by a new type of bifurcation leading to a regime of propagation with transient successive detachments of the wave front from the inner border of the annulus.

Wave block formation in homogeneous excitable media following premature excitations: dependence on restitution relations.

Spiral wave formation and disorganized activity in excitable media require the existence of broken waves and are related to partial wave block. The determinants of wave block in excitable systems are incompletely understood, especially for cardiac excitable tissue. Previous work in one-dimensional cardiac models has suggested that wave break of a premature excitation (PE) requires critical timing and that the conditions for broken waves are improbable. We analyzed the mechanism of unidirectional wave block that occurs when two consecutive PEs interact with a normal plane wave in a generic one-dimensional spatial excitable medium. A nondimensional coupled-map model built from mesoscopic characteristics of the substrate (the velocity and action potential duration restitution functions) shows that block can occur over a large interval of timing between the two PEs and leads to wave break in two-dimensional media. This mechanism may be an important determinant of spiral wave formation by the response to premature excitations.