Stability Of Atrial Fibrillation Research Articles

Bioenergetics and mitochondrial deregulation underlie self-sustained persistency of atrial fibrillation in an ovine model

Abstract Background Atrial fibrillation (AF) often transitions from paroxysmal to more sustained forms in a 4-15/100 person-year range(1). It is well-recognized from both clinical and animal studies that some individuals undergo this transition much more readily than others, but the underlying mechanisms remain unclear. Purpose To identify potential differences in atrial bioenergetics between animals developing stable AF (AF-S) versus those resistant to this transition (AF-R) in a sheep AF-model. Methods AF was induced through repeated bursts of atrial tachystimulation (2). Stability of AF was monitored with telemetry. In-vivo electrophysiological remodeling was assessed via contact mapping. Metabolic and bioenergetic remodeling were evaluated using frozen left atrial appendage (LAA) tissues and isolated LAA mitochondria. Results AF-S sheep developed stable (>24-hour self-sustained) AF after 13 (range 5-22) days on average, whereas AF-R sheep failed to develop stable AF despite 120-day tachystimulation. Contact mapping and histological analysis revealed similar electro-anatomical remodeling in AF-S and AF-R groups, with the only significant difference observed in the decrease of activation time and conduction velocity in the AF-S atria. Both AF-S and AF-R animals displayed a notable increase in mitochondrial mass. Proteomic analysis showed significant differences in metabolism-related proteins and pathways between AF-S and AF-R, in particular concerning the anaplerotic supplementation of the tricarboxylic acid cycle at the level of α-ketoglutarate. Furthermore, compared to AF-R, AF-S LAA exhibited a 45% increase in succinate content, and a 23% decrease in ATP and Creatine Phosphate (PCr) content, suggesting a pathological metabolic alteration linked to a bioenergetic default. AF-S mitochondria presented abnormal succinate-oxidation, associated with a significant 20% decrease in ATP-synthesis rate, 22% increase in ROS-production, mitochondrial-membrane hyperpolarization, and decreased Complex I/II specific activity ratio. AF-S mitochondria alterations were prevented by complex I inhibitor S1QEL1.1, hinting to a participation of mitochondrial ROS into the mechanism of AF stabilization. In vivo acute intravenous perfusion of succinate in rats made them more susceptible to more frequent (OR 35 CI=[1.63-449.80]) and longer AF episodes upon treansesophageal stimulation; this vulnerability to AF was prevented by intraperitoneal pretreatment with SQEL1.1. Conclusions Resistance to AF-stabilization is associated with specific bioenergetic remodeling. These findings provide new mechanistic insights into AF-resistance and might open avenues for novel therapeutic strategies for AF-management.

Development of a Care Pathway for Atrial Fibrillation Patients in the Emergency Department.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and its prevalence is continuously increasing in the United States, leading to a progressive rise in the number of disease-related emergency department (ED) visits and hospitalizations. Although optimal long-term outpatient management for AF is well defined, the guidelines for optimal ED management of acute AF episodes is less clear. Studies have demonstrated that discharging patients with AF from the ED after acute stabilization is both safe and cost effective; however, the majority of these patients in the United States and in our institution are admitted to the hospital. To improve care of these patients, we established a multidisciplinary collaboration to develop an evidence-based systematic approach for the treatment and management of AF in the ED, that led to the creation of the University of California-Cardioversion, Anticoagulation, Rate Control, Expedited Follow-up/Education Atrial Fibrillation Pathway. Our pathway focuses on the acute stabilization of AF, adherence to best practices for anticoagulation, and reduction in unnecessary admissions through discharge from the ED with expedited outpatient follow-up whenever safe. A novel aspect of our pathway is that it is primarily driven by the ED physicians, while other published protocols primarily involve consulting cardiologists to guide management in the ED. Our protocol is very pertinent considering the current trend toward increased AF prevalence in the United States, coupled with a need for widespread implementation of strategies aimed at improving management of these patients while safely reducing hospital admissions and the economic burden of AF.

Utility of Simultaneous Biatrial Atrial Anti-Tachycardia Pacing for the Termination of Atrial Fibrillation during Catheter Ablation of Atrial Fibrillation.

Background: Atrial anti-tachycardia pacing (A-ATP) of the right atrium (RA) has been shown to decrease the burden of atrial fibrillation (AF) in patients with dual-chamber pacemakers. The aim of this study is to identify the novel predictors of effective A-ATP for terminating AF in patients with AF undergoing catheter ablation. Methods: This study included 41 consecutive patients undergoing a first ablation procedure for paroxysmal (PAF: n = 21) or persistent (PEF: n = 20) AF. We prospectively evaluated predictors of AF termination after A-ATP. The coefficient of variation (CoV = SD/mean × 100) of the dominant frequencies (DFs) was calculated to evaluate the variability in atrial activation. Results: AF was terminated by A-ATP in 29% of PAF and 5% of PEF patients. In these patients, simultaneous high-rate pacing from the RA and the coronary sinus (CS) terminated AF in 71% of patients, in whom the mean AF cycle length (CL) before A-ATP was longer (214 ± 23 vs. 177 ± 35 ms, p = 0.02) and became slower after A-ATP (234 ± 37 vs. 176 ± 32 ms, p < 0.01), compared to unsuccessful patients. The CoV of the DFs before A-ATP were lower in both RA (6.2 ± 2.0 vs. 15.3 ± 7.9, p = 0.02) and CS (11.0 ± 7.9 vs. 24.3 ± 9.3, p < 0.01) in successful patients. Conclusions: Simultaneous biatrial A-ATP from the RA and CS could terminate AF in patients with PAF. The predictors for successful termination include longer AF CL and higher AF stability.

Aldosterone enhances stability of atrial fibrillation in the rat model of chronic volume overload

Aldosterone enhances stability of atrial fibrillation in the rat model of chronic volume overload

Bi-atrial high-density mapping reveals inhibition of wavefront turning and reduction of complex propagation patterns as main antiarrhythmic mechanisms of vernakalant.

AimsComplex propagation patterns are observed in patients and models with stable atrial fibrillation (AF). The degree of this complexity is associated with AF stability. Experimental work suggests reduced wavefront turning as an important mechanism for widening of the excitable gap. The aim of this study was to investigate how sodium channel inhibition by vernakalant affects turning behaviour and propagation patterns during AF.Methods and resultsTwo groups of 8 goats were instrumented with electrodes on the left atrium, and AF was maintained by burst pacing for 3 or 22 weeks. Measurements were performed at baseline and two dosages of vernakalant. Unipolar electrograms were mapped (249 electrodes/array) on the left and right atrium in an open-chest experiment. Local activation times and conduction vectors, flow lines, the number of fibrillation waves, and local re-entries were determined. At baseline, fibrillation patterns contained numerous individual fibrillation waves conducting in random directions. Vernakalant induced conduction slowing and cycle length prolongation and terminated AF in 13/15 goats. Local re-entries were strongly reduced. Local conduction vectors showed increased preferential directions and less beat-to-beat variability. Breakthroughs and waves were significantly reduced in number. Flow line curvature reduced and waves conducted more homogenously in one direction. Overall, complex propagation patterns were strongly reduced. No substantial differences in drug effects between right and left atria or between goats with different AF durations were observed.ConclusionsDestabilization of AF by vernakalant is associated with a lowering of fibrillation frequency and inhibition of complex propagation patterns, wave turning, local re-entries, and breakthroughs.

The effect of complex intramural microstructure caused by structural remodeling on the stability of atrial fibrillation: Insights from a three-dimensional multi-layer modeling study.

BackgroundRecent researches have suggested that the complex three-dimensional structures caused by structural remodeling play a key role in atrial fibrillation (AF) substrates. Here we aimed to investigate this hypothesis using a multi-layer model representing intramural microstructural features.MethodsThe proposed multi-layer model was composed of the endocardium, connection wall, and epicardium. In the connection wall, intramural fibrosis was simulated using fibrotic patches randomly scattered in the myocardial tissue of fibrotic layers, while endo-epicardial dissociation was simulated using myocardial patches randomly scattered in the fibrotic tissue of isolation layers. Multiple simulation groups were generated to quantitatively analyze the effects of endo-epicardial dissociation and intramural fibrosis on AF stability, including a stochastic group, interrelated groups, fibrosis-degree-controlled groups, and dissociation-degree-controlled groups.Results1. Stable intramural re-entries were observed to move along complete re-entrant circuits inside the transmural wall in four of 65 simulations in the stochastic group. 2. About 21 of 23 stable simulations in the stochastic group were distributed in the areas with high endo-epicardial dissociation and intramural fibrosis. 3. The difference between fibrosis-degree-controlled groups and dissociation-degree-controlled groups suggested that some distributions of connection areas may affect AF episodes despite low intramural fibrosis and endo-epicardial dissociation. 4. The overview of tracking phase singularities revealed that endo-epicardial dissociation played a visible role in AF substrates.ConclusionThe complex intramural microstructure is positively correlated with critical components of AF maintenance mechanisms. The occurrence of intramural re-entry further indicates the complexity of AF wave-dynamics.

Effect of Na+-channel blockade on the three-dimensional substrate of atrial fibrillation in a model of endo-epicardial dissociation and transmural conduction.

Atrial fibrillation (AF) is a progressive arrhythmia characterized by structural alterations that increase its stability. Both clinical and experimental studies showed a concomitant loss of antiarrhythmic drug efficacy in later stages of AF. The mechanisms underlying this loss of efficacy are not well understood. We hypothesized that structural remodelling may explain this reduced efficacy by making the substrate more three-dimensional. To investigate this, we simulated the effect of sodium (Na+)-channel block on AF in a model of progressive transmural uncoupling. In a computer model consisting of two cross-connected atrial layers, with realistic atrial membrane behaviour, structural remodelling was simulated by reducing the number of connections between the layers. 100% of endo-epicardial connectivity represented a healthy atrium. At various degrees of structural remodelling, we assessed the effect of 60% sodium channel block on AF stability, endo-epicardial electrical activity dissociation (EED), and fibrillatory conduction pattern complexity quantified by number of waves, phase singularities (PSs), and transmural conduction ('breakthrough', BT). Sodium channel block terminated AF in non-remodelled but not in remodelled atria. The temporal excitable gap (EG) and AF cycle length increased at all degrees of remodelling when compared with control. Despite an increase of EED and EG, sodium channel block decreased the incidence of BT because of transmural conduction block. Sodium channel block decreased the number of waves and PSs in normal atrium but not in structurally remodelled atrium. This simple atrial model explains the loss of efficacy of sodium channel blockers in terminating AF in the presence of severe structural remodelling as has been observed experimentally and clinically. Atrial fibrillation termination in atria with moderate structural remodelling in the presence of sodium channel block is caused by reduction of AF complexity. With more severe structural remodelling, sodium channel block fails to promote synchronization of the two layers of the model.

Loss of Side-to-Side Connections Affects the Relative Contributions of the Sodium and Calcium Current to Transverse Propagation Between Strands of Atrial Myocytes.

Background: Atrial fibrillation (AF) leads to a loss of transverse connections between myocyte strands that is associated with an increased complexity and stability of AF. We have explored the interaction between longitudinal and transverse coupling, and the relative contribution of the sodium (INa) and calcium (ICa) current to propagation, both in healthy tissue and under diseased conditions using computer simulations.Methods: Two parallel strands of atrial myocytes were modeled (Courtemanche et al. ionic model). As a control condition, every single cell was connected both transversely and longitudinally. To simulate a loss of transverse connectivity, this number was reduced to 1 in 4, 8, 12, or 16 transversely. To study the interaction with longitudinal coupling, anisotropy ratios of 3, 9, 16, and 25:1 were used. All simulations were repeated for varying degrees of INa and ICa block and the transverse activation delay (TAD) between the paced and non-paced strands was calculated for all cases.Results: The TAD was highly sensitive to the transverse connectivity, increasing from 1 ms at 1 in 1, to 25 ms at 1 in 4, and 100 ms at 1 in 12 connectivity. The TAD also increased when longitudinal coupling was increased. Both decreasing transverse connectivity and increasing longitudinal coupling enhanced the synchronicity of activation of the non-paced strand and increased the propensity for transverse conduction block. Even after long TADs, the action potential upstroke in the non-paced strand was still mainly dependent on the INa. Nevertheless, ICa in the paced strand was essential to provide depolarizing current to the non-paced strand. Loss of transverse connections increased the sensitivity to both INa and ICa block. However, when longitudinal coupling was relatively high, transverse propagation was more sensitive to ICa block than to INa block.Conclusions: Although transverse propagation depends on both INa and ICa, their relative contribution, and sensitivity to channel blockade, depends on the distribution of transverse connections and the axial conductivity. This simple two-strand model helps to explain the nature of atrial discontinuous conduction during structural remodeling and provides an opportunity for more effective drug development.

Arterial hypertension drives arrhythmia progression via specific structural remodeling in a porcine model of atrial fibrillation

Arterial hypertension (HT) contributes to progression of atrial fibrillation (AF) via unknown mechanisms. We aimed to characterize electrical and structural changes accounting for increased AF stability in a large animal model of rapid atrial pacing (RAP)-induced AF combined with desoxycorticosterone acetate (DOCA)-induced HT. Eighteen pigs were instrumented with right atrial endocardial pacemaker leads and custom-made pacemakers to induce AF by continuous RAP (600 beats/min). DOCA pellets were subcutaneously implanted in a subgroup of 9 animals (AF+HT group); the other 9 animals served as controls (AF group). Final experiments included electrophysiology studies, endocardial electroanatomic mapping, and high-density mapping with epicardial multielectrode arrays. In addition, 3-dimensional computational modeling was performed. DOCA implantation led to secondary HT (median [interquartile range] aortic pressure 109.9 [100-137] mm Hg in AF+HT vs 82.2 [79-96] mm Hg in AF; P < .05), increased AF stability (55.6% vs 12.5% of animals with AF episodes lasting >1 hour; P < .05), concentric left ventricular hypertrophy, atrial dilatation (119 ± 31 cm2 in AF+HT vs 78 ± 23 cm2 in AF; P<.05), and fibrosis. Collagen accumulation in the AF+HT group was mainly found in non-intermyocyte areas (1.62 ± 0.38 cm3 in AF+HT vs 0.96 ± 0.3 cm3 in AF; P < .05). Left and right atrial effective refractory periods, action potential durations, endo- and epicardial conduction velocities, and measures of AF complexity were comparable between the 2 groups. A 3-dimensional computational model confirmed an increase in AF stability observed in the invivo experiments associated with increased atrial size. In this model of secondary HT, higher AF stability after 2 weeks of RAP is mainly driven by atrial dilatation.

Nerve Growth Factor Mediates the Vious Cycle between Hyperactivity of Ganglionated Plexus and Atrial Fibrillation

Ganglionated Plexus (GP) is a complex neural network composed by intrinsic cardiac autonomic nervous system (ANS) and is mainly located in fat pads around the antrum of the pulmonary veins (PVs). Recent studies demonstrated hyperactivity of GPs and atrial fibrillation (AF) formed a vicious cycle, to be specific, hyperactivity of the cardiac GPs facilitated the initiation and maintenance of AF and the activity of cardiac GPs increased as AF continued. In addition, research has confirmed that the Nav1.8 channel is highly expressed in GPs and is closely related to activity of GPs and the inducibility of AF. Nerve growth factor (NGF) is an important neurotrophic factor and the expression of NGF in GPs is up-regulated during AF over time, which could trigger the release of SP in the heart via TRPV1 signaling pathways. Besides, SP could rapidly increase the activity of the Nav1.8 channel, demonstrating the increment of Sensory nerve action potentials. Therefore, we hypothesized that up-regulated NGF during AF could increase the activity of GPs through TRPV1-SP-Nav1.8 channel pathways and contributes to stability of AF. If this hypothesis is proved to be correct, future studies based on this link may help to find new therapeutic targets for the treatment of AF.

How disruption of endo-epicardial electrical connections enhances endo-epicardial conduction during atrial fibrillation.

Loss of side-to-side electrical connections between atrial muscle bundles is thought to underlie conduction disturbances predisposing to atrial fibrillation (AF). Putatively, disruption of electrical connections occurs not only within the epicardial layer but also between the epicardial layer and the endocardial bundle network, thus impeding transmural conductions (‘breakthroughs’). However, both clinical and experimental studies have shown an enhancement of breakthroughs during later stages of AF. We tested the hypothesis that endo-epicardial uncoupling enhances endo-epicardial electrical dyssynchrony, breakthrough rate (BTR), and AF stability. In a novel dual-layer computer model of the human atria, 100% connectivity between the two layers served as healthy control. Atrial structural remodelling was simulated by reducing the number of connections between the layers from 96 to 6 randomly chosen locations. With progressive elimination of connections, AF stability increased. Reduction in the number of connections from 96 to 24 resulted in an increase in endo-epicardial dyssynchrony from 6.6 ± 1.9 to 24.6 ± 1.3%, with a concomitant increase in BTR. A further reduction to 12 and 6 resulted in more pronounced endo-epicardial dyssynchrony of 34.4 ± 1.15 and 40.2 ± 0.52% but with BTR reduction. This biphasic relationship between endo-epicardial coupling and BTR was found independently from whether AF was maintained by re-entry or by ectopic focal discharges. Loss of endo-epicardial coupling increases AF stability. There is a biphasic relation between endo-epicardial coupling and BTR. While at high degrees of endo-epicardial connectivity, the BTR is limited by the endo-epicardial synchronicity, at low degrees of connectivity, it is limited by the number of endo-epicardial connections.

A porcine model of early atrial fibrillation using a custom-built, radio transmission-controlled pacemaker

Mechanisms underlying atrial remodeling toward atrial fibrillation (AF) are incompletely understood. We induced AF in 16 pigs by 6weeks of rapid atrial pacing (RAP, 600bpm) using a custom-built, telemetrically controlled pacemaker. AF evolution was monitored three times per week telemetrically in unstressed, conscious animals. We established a dose–response relationship between RAP duration and occurrence of sustained AF >60minutes. Left atrial (LA) dilatation was present already at 2weeks of RAP. There was no evidence of left ventricular heart failure after 6weeks of RAP. As a proof-of-principle, arterial hypertension was induced in 5/16 animals by implanting desoxycorticosterone acetate (DOCA, an aldosterone-analog) subcutaneously to accelerate atrial remodeling. RAP+DOCA resulted in increased AF stability with earlier onset of sustained AF and accelerated anatomical atrial remodeling with more pronounced LA dilatation. This novel porcine model can serve to characterize effects of maladaptive stimuli or protective interventions specifically during early AF.

A computer model of endo-epicardial electrical dissociation and transmural conduction during atrial fibrillation

Structural alterations during atrial fibrillation (AF) not only lead to electrical dissociation within the epicardial layer, but also between the epicardial layer and the endocardial bundle network. The aim of the study was to investigate the role of transmural conduction in the stability of AF episodes using a dual-layer computer model. A proof-of-principle dual-layer model was developed in which connections between the layers can be introduced or removed at any time during the simulation. Using an S1-S2 protocol, a spiral wave was initiated in one of the layers, which degenerated into a complex AF pattern after connection with the other layer at six randomly chosen sites. After 6 s, connections were either retained (dual-layer simulations) or removed (single-layer simulations). Dual-layer simulations were more complex, as indicated by the higher number of waves and phase singularities. Tracking waves through both layers revealed that the number of waves in dual-layer simulations was significantly higher than in the single-layer simulations, reflecting more opportunities for reentry and a concomitant increase in AF stability. In the dual-layer model, only 12% of the AF episodes died out within 6 s, while 59% died out in the single-layer model. Atrial fibrillation patterns are more complex and AF episodes are more stable in a dual-layer model. This study indicates an important role for endo-epicardial conduction for the stabilization of AF.

Rotors and breakthroughs as three-dimensional perpetuators of atrial fibrillation

This editorial refers to ‘Heterogeneous atrial wall thickness and stretch promote scroll waves anchoring during atrial fibrillation’ by M. Yamazaki et al. , pp. 48–57, this issue. In previous years, disruption of electrical coupling between cardiac myocytes and muscle bundles, resulting in narrower—and thus more—fibrillation waves, was identified as the main mechanism underlying enhanced stability of atrial fibrillation (AF) in structurally remodelled atria.1 In addition, the rate of epicardial breakthrough was found to be enhanced in patients with persistent AF, which was hypothesized to be caused by more electrical dissociation between the epicardial layer and the endocardial bundle network.2 While endo-epicardial dissociation of electrical activity and breakthrough during AF were already described many years ago,3–5 this phenomenon was only recently demonstrated to be enhanced after several weeks to months of AF or rapid atrial pacing.6,7 Endo-epicardial dissociation of electrical activity is regarded the conditio sine qua non for the occurrence of transmural conduction and epicardial breakthrough. Such a ‘three-dimensional substrate’ for AF is believed to significantly contribute to the stabilization of AF over time. The study of Yamazaki et al. 8 adds several new aspects to the emerging concept of the three-dimensional substrate for AF. By the use of simultaneous endo-epicardial optical mapping, the authors were able to match two-dimensional high-resolution mapping data with each other and the underlying anatomical structures. This sophisticated …

Fibrillatory Conduction in the Atrial Free Walls of Goats in Persistent and Permanent Atrial Fibrillation

Over a time course of months, the stability of atrial fibrillation (AF) gradually increases and the efficacy of pharmacological cardioversion declines both in humans and in animal models. Changes in fibrillatory conduction over this period largely are unexplored. Goats were instrumented with an atrial endocardial pacemaker lead and a burst pacemaker. AF was maintained for 3 weeks (short-term AF [ST], n = 10) or 6 months (long-term AF [LT], n = 7). AF could be cardioverted pharmacologically at the early time point (persistent AF), but not at the later time point (permanent AF). At follow-up, a high-resolution mapping electrode was used to record epicardial conduction patterns in the free walls of the right atrium (RA) and left atrium (LA). A new method for mapping of fibrillation waves was used to describe AF conduction patterns. Wavefronts propagated uniformly during slow pacing in both groups, although conduction velocity was significantly lower in the LT group (LA, 93 ± 14 versus 72 ± 10 cm/s; RA, 94 ± 8 versus 78 ± 8 cm/s). Median AF cycle length (AFCL) was not significantly different between the groups. However, the LT group showed highly complex activation patterns during AF, with an increased number of simultaneously propagating waves (LT group RA, 8.4 ± 3.0 waves/AFCL; LA, 12.8 ± 2.4 waves/AFCL; versus ST group RA, 4.3 ± 2.2 waves/AFCL; LA, 4.5 ± 2.5 waves/AFCL). Fibrillation waves in the LT group showed pronounced dissociation with large activation time differences. The incidence of waves newly appearing within the recording area also was increased in both atria. These alterations in conduction were accompanied by myocyte hypertrophy and increased endomysial fibrosis. Long-term AF in goats leads to dissociated conduction in the atrial free walls that may contribute to increased AF stability.

Effects of angiotensin receptor blockade on atrial electrical remodelling and the ‘second factor’ in a goat burst-paced model of atrial fibrillation

Atrial fibrillation (AF) is self-perpetuating, via mechanisms of acute electrical remodelling and 'second factors' acting over a longer time course. Renin-angiotensin system (RAS) blockade may inhibit AF self-perpetuation. We evaluated the effects of RAS blockade with candesartan in a burst-paced goat model of lone AF in which both mechanisms are known to operate. Bioactivity of oral candesartan was demonstrated in 10 goats by inhibition of the pressor effect of angiotensin II. The effects of candesartan on electrical remodelling were assessed in 12 placebo and 12 candesartan-treated goats in a 28-day burst pacing protocol. To assess the effects of candesartan on second factors (structural remodelling), 16 goats underwent further 28-day periods of burst pacing (two periods in 16 goats, three periods in eight goats) each separated by periods of sinus rhythm sufficient for electrical remodelling to reverse. There was a progressive rise in angiotensin levels in both groups. Candesartan (0.5 mg/kg/day) achieved a 76% blunting of the pressor effect of angiotensin II and had no effect on electrical remodelling; the half time for fall of atrial effective refractory period (AERP) was 22.3 ± 4.9 h (placebo) and 22.0 ± 3.2 h (candesartan) (p = ns). Candesartan had no effect on AF stability, which progressively increased over successive 28-day periods (ANOVA p < 0.05). Candesartan had no effect on atrial electrical remodelling or the operation of 'second factors' in a goat model of lone AF. These findings suggest that any benefits of RAS blockade in patients with AF are unlikely to be due to direct effects on atrial remodelling.

Abstract 3491: Endo-Epicardial Dissociation of Electrical Activity Increases During the Development of the Substrate for Atrial Fibrillation in the Goat

Background: The high incidence of transmural conduction of fibrillation waves (breakthroughs) in a complex substrate for atrial fibrillation (AF) implies the presence of electrical dissociation between the subepicardial layer (Epi) and the endocardial bundle network (Endo). The presence of this Endo/Epi dissociation (EED) in remodeled atria and its role in the progressive stabilization of AF over time has not been studied yet. Methods: We developed a mapping tool for synchronous Endo/Epi mapping (spatial resolution 1.6mm) with 90 exactly opposing electrode pairs (open chest experiment). We included 3 groups of goats: C = Control (acute AF induced by 50Hz burst pacing, n=7), 3wk = 3weeks AF (n=7) and 6mo = 6months AF (n=7). Dissociated activity was postulated when either activation times differed by more than 12ms vertically or 8ms horizontally (indicating a local conduction velocity &lt; 20cm/s) or local direction of propagation between Endo and Epi differed by more than 90 degrees. To monitor AF stability, repetitive in-vivo cardioversion experiments with class 1C drugs were performed in 6 of the 6mo goats at 2,6,10 and 14wk AF. Results: Applying the time criterion, EED increased from 15±4% (C) to 22±11% (3wk) and 35±13% (6mo, p=0.002 vs. C). Also the differences in the direction of propagation significantly contributed to EED. Using the combined criterion, EED increased from 38±5% (C) to 46±10% (3wk) and 53±11% (6mo, p=0.007 vs. C). Dissociation within the epicardial and the endocardial layer (time criterion) increased to a comparable extent (19±8% vs. 27±14% vs. 37± 7%, p&lt;0.001 C vs. 6mo). Mean Endo/Epi activation time differences were close to 0ms in all three groups (−1.0±15ms vs. −0.8±16ms vs. −0.3±20ms), ruling out preferential conduction from Endo to Epi or vice versa. Success rate of cardioversion experiments decreased from 83% (2w) to 33% (6wk) to 16% (10wk) to 0% (14wk) indicating increasing stability of AF over time. Conclusion: During AF, pronounced EED occurs. EED (like dissociation within Endo and Epi) increases over time, contributing to the progressive stabilization of AF. Enhanced EED might explain the high incidence of transmural conduction (breakthroughs) in a complex substrate for AF.

Rate-dependence of atrial tachycardia effects on atrial refractoriness and atrial fibrillation maintenance

Although atrial-tachycardia remodelling is a significant atrial fibrillation (AF) promoting factor, little information is available about how atrial-tachycardia rate determines remodelling effects. This study assessed the effects of atrial tachypacing (ATP) over a range of clinically relevant rates on atrial electrophysiology and AF. Chronically instrumented dogs underwent sequential 7 day ATP at 400, 300, 200, and 160 bpm in random order with 2 day recovery intervals between periods of ATP. ATP at 400, 300, and 200 bpm significantly decreased atrial effective refractory period (ERP) by 41 +/- 2, 37 +/- 3, and 7 +/- 1 ms, respectively, with no significant effects at 160 bpm. Mean duration of induced AF was increased by 400 and 300 bpm ATP (404 +/- 284 and 410 +/- 283 s on day 4, respectively, vs. 12 +/- 4 s at baseline, P < 0.01), but not by 200 or 160 bpm ATP. ATP effects developed slowly with 200 bpm pacing, so we studied 5 week ATP at 200 and 160 bpm in additional dogs. ERP shortened gradually over 3 weeks at 200 bpm (131 +/- 5 ms baseline vs. 112 +/- 4 and 105 +/- 4 ms at 2 and 3 weeks, respectively), but no decrease occurred thereafter (5-week value: 104 +/- 3 ms) and AF duration was not significantly affected. No change in ERP or AF duration occurred at 160 bpm. Because of the limited effects of 200 bpm ATP on AF duration despite significant effects on ERP, we tested 200 bpm ATP effects in the presence of AF substrates. When 200 bpm ATP was induced in the presence of a fibrotic AF substrate induced by 2 weeks of ventricular tachypacing followed by 1 week recovery, no change in AF duration or atrial vulnerability occurred. However, when 200 bpm ATP was followed by 400 bpm ATP, the onset of remodelling and AF duration increases was accelerated. There is a non-linear relationship between atrial rate and the extent of atrial electrical remodelling. Remodelling at rates equivalent to paroxysmal supraventricular tachycardias in man is insufficient to promote AF alone or in the presence of an atrial fibrotic substrate, but can accelerate the remodelling and stabilization of AF when followed by faster atrial tachyarrhythmias.

P4-17: Conduction in the atrial free walls after short and long term atrial fibrillation in the goat

We have studied activation patterns during pacing and atrial fibrillation (AF) in goats after short term (2.5 weeks) and long term (6 months) AF. After 2.5 weeks of AF, electrical remodeling is complete. After 6 months of AF, structural remodeling has also become pronounced. At this time point, chemical cardioversion was no longer possible (permanent AF). We have evaluated whether the increased stability of AF is related to changes in conduction properties of the atrial free walls (AFWs).

Development of a Substrate of Atrial Fibrillation During Chronic Atrioventricular Block in the Goat

Atrial dilatation is an important risk factor for atrial fibrillation (AF). In the present study, we monitored the electrophysiological changes during progressive atrial dilatation in chronically instrumented goats. In 8 goats, 2 screw-in leads with piezoelectric crystals were implanted transvenously in the right atrium. After 2 weeks, atrial diameter and effective refractory period were measured. AF paroxysms were induced by burst pacing to determine the baseline AF cycle length and stability of AF. After His-bundle ablation, the above measurements were repeated once a week. After 4 weeks of complete AV block, the free wall of the right atrium was mapped and the atrium was fixed in formalin for histological analysis. After His-bundle ablation, the ventricular rate decreased from 113.8+/-4.8 to 44.6+/-2.5 bpm. Right atrial diameter increased gradually by 13.5+/-3.9% during 4 weeks of AV block (P<0.01). The duration of induced AF paroxysms increased from 4.6 seconds to 6.4 minutes (P<0.05). Atrial effective refractory period and AF cycle length remained constant. Spontaneous paroxysms of AF were not observed. Atrial mapping during rapid pacing revealed that slow conduction (<30 cm/s) was present in 3.7+/-1.0% of the mapped area (control, 0.9+/-0.5%, P<0.05). Histological analysis showed hypertrophy without atrial fibrosis. Connexin40 and connexin43 expression was unchanged. Chronic AV block in the goat leads to progressive atrial dilatation, prolongation of induced AF paroxysms, and local conduction delays. The increase in AF stability was not a result of a shortening of atrial refractoriness or atrial fibrosis.