Cardioversion of persistent atrial fibrillation by a combination of atrial specific and non-specific class III drugs in the goat.

OBJECTIVE: In electrically remodeled atria the effect of blockers of the delayed rectifier K+ current I(Kr) on repolarization is reduced, whereas the efficacy of 'early' class III drugs (I(Kur)/I(to)/I(Kach) blockers) is enhanced. We evaluated the electrophysiological and antifibrillatory effects of AVE0118, dofetilide, and ibutilide (alone and in combination) on persistent atrial fibrillation (AF) in the goat. METHODS AND RESULTS: The effects of separate and combined administration of AVE0118, dofetilide, and ibutilide were determined before and after 48 h of AF. AVE0118 alone markedly prolonged the atrial refractory period (400 ms cycle length) (AERP400) before and after 48 h of AF. The prolongation of AERP(400) by dofetilide and ibutilide, respectively, was reduced by AF from 22+/-2 to 7+/-2 ms (p<0.01) and 25+/-5 to 5+/-2 ms (p=0.01). Pre-treatment with AVE0118 restored the prolongation of AERP400 by dofetilide or ibutilide (to 20+/-3 and 30+/-6 ms; p<0.01). This effect was atrial specific since the QT-interval was not changed. The antifibrillatory action was evaluated in 10 goats that were in persistent AF for 57+/-7 days. Dofetilide (20 microg/kg/h) or ibutilide (4 mg/h) alone restored sinus rhythm in only 20% of the animals. AVE0118 (1, 3 and 10 mg/kg/h) [DOSAGE ERROR CORRECTED] terminated AF in 11, 30, and 60%, respectively. Additional infusion of I(Kr) blockers caused an additional number of cardioversions, resulting in a final cardioversion rate of 56, 80, and 100%, respectively. AVE0118 alone prolonged the AF cycle length (AFCL) while the conduction velocity during AF (CV(AF)) remained unchanged (70+/-1 vs. 68+/-2 cm/s; p=0.3). Addition of dofetilide or ibutilide caused a synergistic increase in AFCL and a slight increase in CV(AF) to 74+/-1 cm/s (p<0.001). The length of the reentrant trajectories increased from 7.6+/-0.3 (control) to 11.6+/-0.5 cm after AVE0118 alone (p<0.001) and 14.8+/-0.8 cm after addition of dofetilide or ibutilide (p<0.001). CONCLUSIONS: In electrically remodeled atria, blockade of I(Kur)/I(to)/I(KAch) restored the class III action of I(Kr) blockers. Persistent AF could be effectively cardioverted by infusion of a combination of AVE0118 and dofetilide or ibutilide. This antifibrillatory action was associated with an almost twofold lengthening of the intra-atrial pathways for reentry.

Minimally invasive mapping guided surgical treatment of atrial fibrillation. Utopia or near future?

Isolation of the pulmonary veins has been used as surgical treatment for atrial fibrillation (AF) from the early 90s, as it was incorporated in the Maze procedure. With the evidence that triggers form this area can induce AF, the Maze III procedure has been adapted and modified towards a single lesion around the pulmonary veins for the treatment of paroxysmal and chronic AF in some centers. New ablation techniques with a diversity of energy sources further paved the way for less invasive procedures. Minimal invasive techniques to prevent major surgery may potentially make the treatment available for a patient population that do not have to undergo cardiac surgery for other reasons. Besides these technical developments, high density mapping can be used to identify the AF substrate in the individual patient and optimization of the treatment by local substrate guided ablation. This review aims to summarize the robotic and thoracoscopic techniques to isolate the pulmonary veins. Furthermore, it is discussed why pulmonary veins isolation may be effective in patients with chronic AF, and whether there is a role for mapping guided minimal invasive surgical treatment of AF in the near future.

Widening of the excitable gap during pharmacological cardioversion of atrial fibrillation in the goat: effects of cibenzoline, hydroquinidine, flecainide, and d-sotalol.

BACKGROUND: Previous studies suggest that the antifibrillatory action of class I and III drugs is due to prolongation of the atrial wavelength. The aim of the present study was to directly evaluate the electrophysiological action of antifibrillatory drugs in a goat model of chronic atrial fibrillation (AF). METHODS AND RESULTS: Six goats were instrumented with multiple atrial electrodes, and sustained AF was induced by electrical remodeling. During sustained AF, the effects of intravenous infusion of cibenzoline, hydroquinidine, flecainide, and d-sotalol on AF cycle length (AFCL), refractory period (RP(AF)), conduction velocity (CV(AF)), pathlength (PL(AF)), wavelength (WL(AF)), temporal (AFCL-RP(AF)), and spatial (PL(AF)-WL(AF)) excitable gap were studied. The RP(AF) was measured by determining the earliest moment at which single stimuli could capture the fibrillating atria. CV(AF) was measured during regional entrainment of AF. Contrary to our expectation, cardioversion of AF could not be attributed to prolongation of WL(AF). Hydroquinidine and d-sotalol did not affect WL(AF) significantly, whereas cibenzoline and flecainide even shortened WL(AF) by 18% and 36%, respectively. PL(AF) was increased by hydroquinidine and d-sotalol by 30%, whereas cibenzoline and flecainide did not prolong PL(AF). The only parameter that correlated consistently with cardioversion of AF was a widening of the temporal excitable gap (cibenzoline 176%, hydroquinidine 105%, flecainide 86%, d-sotalol 88%). CONCLUSIONS: Pharmacological cardioversion of AF cannot be explained by prolongation of WL(AF). An alternative explanation for the antifibrillatory effect of class I and III drugs may be a widening of the temporal excitable gap.

Anisotropic reentry in a perfused 2-dimensional layer of rabbit ventricular myocardium.

BACKGROUND: Anisotropy creates nonuniformity in electrical propagation and may contribute to the occurrence of unidirectional conduction block and reentry. We describe the characteristics of reentrant tachycardia in a 2D layer of anisotropic ventricular myocardium. METHODS AND RESULTS: A Langendorff-perfused epicardial sheet (1.0+/-0.4 mm, n=35) was created by freezing the intramural layers of the rabbit left ventricle. Epicardial activation maps were constructed by use of different high-resolution mapping arrays connected to a mapping system. In 5 experiments, monophasic action potentials were recorded. In the intact left ventricle, no arrhythmias except VF could be induced. After freezing, programmed electrical stimulation or rapid pacing led to the induction of sustained VT (cycle length 130+/-11 ms). VT was caused by reentry around a functional line of block oriented parallel to the epicardial fiber direction. Action potential recordings demonstrated that the central line of block was kept refractory by electrotonic currents generated by the depolarization waves propagating at either side of the line of block. At the pivot points of the line of block, the pronounced curvature of the turning wave and abrupt loading changes created an excitable gap of 30 ms in the reentrant pathway. CONCLUSIONS: In uniform anisotropic myocardium, reentry around a functional Z-shaped line of block may occur. The core of the circuit is kept refractory by electrotonic currents. The pronounced wave-front curvature and abrupt loading changes at the pivot points cause local conduction delay and create a small excitable gap.

"Early" class III drugs for the treatment of atrial fibrillation: efficacy and atrial selectivity of AVE0118 in remodeled atria of the goat.

BACKGROUND: Currently available antiarrhythmic drugs are only moderately effective against atrial fibrillation (AF) and may cause ventricular proarrhythmia. AVE0118 is a blocker of atrium-specific early K+ currents (I(Kur)/I(to)). METHODS AND RESULTS: Effects of intravenous AVE0118 and dofetilide on atrial effective refractory period (AERP) and inducibility of AF were measured before and after 48-hours of AF-induced electrical remodeling in the goat. During persistent AF (53+/-19 days), the cardioversion efficacy and effects on atrial wavelength of AVE0118, dofetilide, and ibutilide were evaluated. QT durations were measured during atrial pacing and persistent AF. After 48 hours of AF, the effect of dofetilide on AERP was reduced, and induction of AF was not prevented. In contrast, the class III action of AVE0118 was enhanced, and AF inducibility decreased from 100% to 32% (P<0.001). At 1, 3, and 10 mg x kg(-1) x h(-1), AVE0118 terminated persistent AF in 1 of 8, 3 of 8, and 5 of 8 goats, respectively. Dofetilide and ibutilide terminated AF in 1 of 5 and 2 of 7 goats. AVE0118 0.5, 1.5, and 5 mg/kg prolonged the AERP during AF and increased the fibrillation wavelength from 6.7+/-0.6 to 8.5+/-0.5, 9.7+/-0.5, and 11.2+/-0.9 cm (P<0.01). Whereas dofetilide and ibutilide prolonged QT duration, AVE0118 had no appreciable effect. CONCLUSIONS: AVE0118 markedly prolongs the AERP during AF without affecting QT duration. Cardioversion of AF was due to an approximately 2-fold increase in fibrillation wavelength. Atrium-selective class III drugs like AVE0118 may be a promising new option for safe and effective cardioversion of AF.

Cellular mechanisms of depressed atrial contractility in patients with chronic atrial fibrillation.

BACKGROUND: After cardioversion of atrial fibrillation (AF), the contractile function of the atria is temporarily impaired. Although this has significant clinical implications, the underlying cellular mechanisms are poorly understood. METHODS AND RESULTS: Forty-nine consecutive patients submitted for mitral valve surgery were investigated. Twenty-three were in persistent AF (>/=3 months); the others were in sinus rhythm. Before extracorporal circulation, the right atrial appendage was excised. ss-Adrenoceptors were quantified by radioligand binding, and G proteins were quantified by Western blot analysis. The isometric contractile response to Ca(2+), isoproterenol, Bay K8644, and the postrest potentiation of contractile force were investigated in thin atrial trabeculae, which were also examined histologically. The contractile force of the atrial preparations obtained from AF patients was 75% less than that in preparations from patients in sinus rhythm. Also, the positive inotropic effect of isoproterenol was impaired, and Bay K8644 failed to increase atrial contractile force. In contrast, the response to extracellular Ca(2+) was maintained, and the postrest potentiation was preserved. Beta-adrenoceptor density and G-protein expression were unchanged. Histological examination revealed 14% more myolysis in the atria of AF patients. CONCLUSIONS: After prolonged AF, atrial contractility was reduced by 75%. The impairment of beta-adrenergic modulation of contractile force cannot be explained by downregulation of ss-adrenoceptors or changes in G proteins. Dysfunction of the sarcoplasmic reticulum does not occur after prolonged AF. Failure of Bay K8644 to restore contractility suggests that the L-type Ca(2+) channel is responsible for the contractile dysfunction. The restoration of contractile force by high extracellular Ca(2+) shows that the contractile apparatus itself is nearly completely preserved after prolonged AF.

Digoxin delays recovery from tachycardia-induced electrical remodeling of the atria.

BACKGROUND: Atrial fibrillation (AF) induces electrical remodeling, which is thought to be responsible for the low success rate of antiarrhythmic treatment in AF of longer duration. Electrical remodeling seems to be related to tachycardia-induced intracellular calcium overload. Due to its vagomimetic action, digoxin is widely used to control the ventricular rate during AF, but it also increases intracellular calcium. On the basis of these characteristics, we hypothesized that digoxin would aggravate tachycardia-induced electrical remodeling. METHODS AND RESULTS: We analyzed the atrial effective refractory period (AERP) at cycle lengths of 430, 300, and 200 ms during 24 hours of rapid atrio/ventricular (300/150 bpm) pacing in 7 chronically instrumented conscious goats treated with digoxin or saline. Digoxin decreased the spontaneous heart rate but had no other effects on baseline electrophysiological characteristics. In addition to a moderate increase in the rate of electrical remodeling during rapid pacing, digoxin significantly delayed the recovery from electrical remodeling after cessation of pacing (at 430, 300, and 200 ms: P=0. 001, P=0.0015, and P=0.007, respectively). This was paralleled by an increased inducibility and duration of AF during digoxin. Multivariate analysis revealed that both a short AERP and treatment with digoxin were independent predictors of inducibility (P=0.001 and P=0.03, respectively) and duration (P=0.001 for both) of AF. CONCLUSIONS: Dioxin aggravates tachycardia-induced atrial electrical remodeling and delays recovery from electrical remodeling in the goat, which increases the inducibility and duration of AF.

Early recurrences of atrial fibrillation after electrical cardioversion: a result of fibrillation-induced electrical remodeling of the atria?

OBJECTIVES: We sought to investigate whether, in humans, the timing and incidence of a relapse of atrial fibrillation (AF) during the first month after cardioversion indicates the presence of electrical remodeling and whether this could be influenced by prevention of intracellular calcium overload during AF. BACKGROUND: Animal experiments have shown that AF induces shortening of the atrial refractory period, resulting in an increased vulnerability for reinduction of AF. This electrical remodeling was completely reversible within 1 week after cardioversion of AF and was presumably related to intracellular calcium overload. METHODS: Using transtelephonic monitoring in 61 patients cardioverted for chronic AF, we evaluated the daily incidence of recurrence of AF and determined, by Cox regression analysis, the influence of patient characteristics and medication on relapse of AF. RESULTS: During 1 month of follow-up, 35 patients (57%) had a relapse of AF, with a peak incidence during the first 5 days after cardioversion. Furthermore, in patients with a recurrence of AF, there was a positive correlation between the duration of the shortest coupling interval of the premature atrial beats after cardioversion and the timing of the recurrence of AF (p = 0.0013). Multivariate analysis revealed that the use of intracellular calcium-lowering drugs during AF was the only significant variable related to maintenance of sinus rhythm after cardioversion (p = 0.03). CONCLUSIONS: The daily distribution of recurrences of AF suggests a temporary vulnerable electrophysiologic state of the atria. Use of intracellular calcium-lowering medications during AF appeared to reduce recurrences, possibly due to a reduction of electrical remodeling during AF.

Cardiomyocyte remodelling during myocardial hibernation and atrial fibrillation: prelude to apoptosis.

OBJECTIVE: Similar structural changes in the myocardium can be observed in chronic hibernating myocardium and in myocardium taken from hearts suffering chronic atrial fibrillation. We investigated whether or not these changes are indicative of apoptosis. METHODS: Myocardial biopsies from 28 strictly selected patients with chronic hibernating myocardium and heart samples from 13 goats with pacing-induced chronic atrial fibrillation were used. Special attention was paid to processing the tissues immediately (fixation/freezing) in order to prevent artificial degenerative changes, thereby excluding false positive identification of apoptosis. Infarcted areas or infarcted border zones were excluded from our study. Apoptosis was detected with light and electron microscopy and terminal deoxynucleotidyl transferase nick end-labelling. Immunohistochemistry was used for detecting Bcl-2, P53 and PCNA-proteins associated with apoptosis/DNA damage. RESULTS: The results obtained for chronic hibernating left ventricular myocardium were similar to those for chronic fibrillating atrial myocardium. No apoptotic nuclei, as characterised by extensive chromatin clumping, could be observed in normal or dedifferentiated cardiomyocytes under the electron microscope. The end-labelling assay did not reveal any cardiomyocytes with damaged DNA. Nor could we find any evidence of substantial expression of Bcl-2, P53 or PCNA, a result indicative of the absence of apoptotic threat or DNA damage. CONCLUSION: Cardiomyocyte dedifferentiation, but not extensive degeneration through apoptosis, can be observed in chronic hibernating myocardium and chronic fibrillating atrium. Dedifferentiation may be the best way to survive prolonged exposure to the unfavourable conditions imposed by increased wall stress, a relative lowered oxygen environment, or both.

Atrial high energy phosphate content and mitochondrial enzyme activity during chronic atrial fibrillation.

OBJECTIVE: Prolonged atrial fibrillation (AF) results in (ultra)structural remodelling of atrial cardiomyocytes resembling alterations seen in ischemia-induced ventricular hibernation. The mechanisms underlying these changes are incompletely understood. In the present study we explored the hypothesis that a profound imbalance in energy status during chronic AF acts as a stimulus for structural remodelling. METHODS AND RESULTS: The content of high energy-phosphates and related compounds together with a selected number of mitochondrial enzymes, known to be altered under ischemic conditions, were determined in tissue samples taken from atria of goats in sinus rhythm (SR) and after 1, 2, 4, 8 and 16 weeks of AF maintained by burst pacing. Atrial remodelling was quantified by counting the percentage of cells with >10% myolysis. During AF structural remodelling developed progressively, after 8 weeks about 40% of the atrial myocytes were affected. The concentration of adenine nucleotides and their degradation products did not change significantly during AF. Also the activity of mitochondrial cytochrome c oxidase activity was similar during AF and SR. Mitochondrial NADH-oxidase and proton-translocating ATPase activities were not induced by AF. The tissue content of phosphocreatine decreased during the first week by 60%, but completely recovered between 8 and 16 weeks of AF. CONCLUSIONS: The analysis of adenine nucleotides during AF provided no indication for the development of severe atrial ischemia. This notion is supported by enzyme cytochemical findings. However, AF-induced atrial remodelling was associated with a transient lowering of phosphocreatine content, suggesting an increase in energy demand during the early phase of AF. The subsequent recovery of the phosphocreatine pool indicates restoration of the balance between energy demand and supply in chronically fibrillating atria.

Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat.

OBJECTIVE: It has been postulated that high atrial rate induced changes at the level of the gap junctions ('gap junctional remodeling', i.e. changes in distribution, intercellular orientation and expression of gap junction proteins), could be part of the vicious circle of electrophysiologic and structural changes leading to sustained atrial fibrillation (AF). To obtain experimental evidence in favour of such a postulate the timing of this remodeling process was studied in relation to the development of sustained AF in a goat model. METHODS AND RESULTS: Thin sections from the left (LAA) and right atrial appendage (RAA) from goats in sinus rhythm (SR) or AF, induced through programmed endocardial burst pacing for time periods between 0 and 16 weeks, were immunolabeled with antibodies against connexin(Cx)40 and Cx43 and analysed by immunofluorescence and confocal laser scanning microscopy. During SR the distribution pattern for Cx43 was completely homogeneous (LAA and RAA) and for Cx40 mostly homogeneous (LAA: all five goats, RAA: three out of five goats). The distribution pattern for Cx43 remained stable during AF, while the Cx40 distribution pattern became increasingly heterogeneous, both in the LAA and RAA, with increasing duration of pacing. This increase in heterogeneity in Cx40 distribution correlated (Spearman rank order) with an increase in stability of AF and the occurrence of structural changes (myolysis) in atrial myocytes. The Cx40/Cx43 immunofluorescence signal ratio in both the LAA and RAA appeared to be significantly lower in AF (1-16 weeks) as compared to SR (0 weeks); going from 0 to 16 weeks average ratios decreased 54.5% (n=5; P=0.026) in the LAA and 35.8 (n=5; P=0.034) in the RAA. Western blot analyses revealed similar decreases in the total Cx40/Cx43 protein ratio, on average 50.0% (n=5; P=0.008) and 47.8% (n=5; P=0.02) in the LAA and RAA, respectively. No changes were measured in the levels of Cx40 or Cx43 mRNA, as was assessed through RT-PCR. CONCLUSION: The time course of changes in the distribution and content of Cx40 gap junctions as observed during endocardial burst pacing of the goat atrium suggests that Cx40 gap junctional remodeling might be involved in the pathogenesis of sustained atrial fibrillation.

Electrophysiologic mechanisms of perpetuation of atrial fibrillation.

The presence of an excitable gap during atrial fibrillation (AF), although short and variable, may be of potential importance for the development of alternative techniques for termination of AF by rapid pacing. Also the notion that perpetuation of AF may be partly dependent on macroreentry around the natural atrial orifices, may provide a new therapeutic option for the permanent cure of AF by interrupting the anatomical circular pathways in the atria by radiofrequency ablation. In our opinion the rapidly growing understanding of the electrophysiologic mechanisms of AF certainly warrants some optimism about the possibility of cure of AF in the near future without causing too much discomfort and without carrying on unacceptable risk.

Electrophysiologic mapping to determine the mechanism of experimental ventricular tachycardia initiated by premature impulses. Experimental approach and initial results demonstrating reentrant excitation.

Epicardial activation patterns were determined during repetitive responses and nonsustained and sustained ventricular tachycardias induced by premature impulses in infarcted canine hearts. A multiplexing system enabled recordings to be obtained from up to 192 electrodes simultaneously either from the entire epicardial surface with a sock electrode array or only from the sheet of epicardial muscle that survives over the infarcts, with a plaque electrode array. In hearts with an infarct caused by permanent occlusion of the left anterior descending coronary artery, the earliest epicardial excitation during nonsustained tachycardias occurred on the anterior left ventricle at the border of the infarcted region and in epicardial muscle surviving over the infarcted region. Circuitous conduction patterns leading to reentry occurred in the epicardial muscle over the infarct and probably caused the arrhythmias. During sustained tachycardia in hearts with an infarct caused either by permanent or temporary occlusion of the left anterior descending coronary artery, the earliest epicardial excitation also occurred at the border of the infarcted region, but there was no evidence of reentry in the surviving epicardial muscle.

Structural changes of atrial myocardium during chronic atrial fibrillation.

Of all known arrhythmia's, atrial fibrillation (AF) is the most often met in the clinical setting and it is associated with an increase in mortality risk. Several risk factors for AF have been described and several mechanisms of induction and maintenance have been proposed. Studies in patients with AF have shown that structural changes occur in the atria, but the relationship between the structural remodelling and the chronicity of the arrhythmia are not well understood. The changes mainly concern adaptive (dedifferentiation of cardiomyocytes) and maladaptive (degeneration of cells with replacement fibrosis) features. In order to characterise the time course of the structural remodelling the need for animal models which adequately mimic chronic atrial fibrillation in humans is felt essential. In this review, the structural changes that are observed during prolonged sustained AF in patients and animal models, are described. Furthermore, the time course and potential mechanisms of structural remodelling are discussed and methods for elucidation of the underlying molecular mechanisms are presented.

Effects of verapamil, diltiazem and disopyramide on sinus function: a comparison with bepridil.

Cardiac drugs known to affect sinus function mostly exhibit negative chronotropic activity. However, impulse conduction within the sinus node can also be influenced. Recently we studied the direct effects of bepridil on rabbit sinus function. It appeared that sinoatrial impulse conduction was depressed markedly with drug concentrations that did not affect sinus automaticity. In the present study the direct effects of verapamil, diltiazem and disopyramide on rabbit sinus function and atrial conduction properties were studied. Verapamil (8.8 x 10(-8) M) reduced the sinoatrial impulse conduction velocity by 35% and prolonged sinoatrial refractoriness by 36%. On the other hand, the sinus rate and atrial conduction parameters were hardly affected. Diltiazem (5 x 10(-6) M) exerted similar actions on the sinoatrial impulse conduction velocity and caused a simultaneous reduction in the sinus rate of 48%. Atrial conduction remained unaffected. Disopyramide (5 x 10(-5) M) depressed both the atrial and nodal conduction properties markedly, whereas the sinus rate was reduced moderately, by almost 20%. Thus, verapamil, diltiazem and disopyramide act differently on sinus function and atrial conduction, whereby the predominant effect of verapamil and diltiazem on sinoatrial conduction properties favours the occurrence of a sinus exit block.

Spatial correlation analysis of atrial activation patterns during sustained atrial fibrillation in conscious goats.

In this study we applied both linear and nonlinear spatial correlation measures to characterize epicardial activation patterns of sustained atrial fibrillation in instrumented conscious goats. It was investigated if nonlinearity was involved in the spatial coupling of atrial regions and to what extent fibrillation was organized in the experimental model of sustained atrial fibrillation (AF) in instrumented goats. Data were collected in five goats during experiments to convert AF by continuous infusion of cibenzoline. Spatial organization during AF was quantified with the linear spatial cross correlation function and the nonlinear spatial cross redundancy which was calculated using the Grassberger-Procaccia correlation integral. Two different types of correlation were evaluated to distinguish simultaneous interaction from non-simultaneous interaction, for instance resulting from propagation of fibrillation waves. The nonlinear association length and the linear correlation length were estimated along the principal axes of iso-correlation contours in two-dimensional correlation maps of the nonlinear spatial redundancy and the linear spatial correlation function, respectively. To quantitatively assess the degree of nonlinearity, the association length was also estimated from the linearized spatial redundancy using multivariate surrogate data. The differences between the nonlinear and linearized association lengths indicated that a nonlinear component in the spatial organization of AF predominantly existed in the right atrium. The degree of organization characterized by association length along the short principal axis was higher in the right atrium (15 +/- 7 mm) than in the left atrium (8 +/- 4 mm). The spatial extension of coherent atrial patches was estimated from a surface of association equal to the area spanned by the principal axes of iso-correlation contours from the redundancy, including the effects from non-simultaneous interaction. Interpreting this area as the spatial domain of a fibrillation wavelet, the results suggest that the mapped region was activated on average by two wavelets in the left atrium and by one wavelet in the right atrium. Therefore, the activation pattern of sustained AF in goats was relatively organized, consistent with type II of AF. It is suggested that the surface of association is a measure of the number of independent wavelets present in the atria during sustained AF, and that larger association lengths result from fewer and larger reentrant circuits.

Spatial correlation analysis of the pharmacological conversion of sustained atrial fibrillation in conscious goats by cibenzoline.

The nonlinear spatial redundancy and the linear spatial correlation function were used to investigate to what extent non-linearity was involved in the coupling of atrial regions and how organization in activation patterns of sustained atrial fibrillation (AF) had been modified by administration of the class IC agent cibenzoline in the experimental model of sustained AF in instrumented conscious goats. Electrograms were measured in five goats during sustained AF and when the fibrillation interval had been prolonged to about 25%, 50% and 85% (CIB25, CIB50, CIB85) with respect to control. The nonlinear association length and linear correlation length were estimated along the principal axes of two-dimensional correlation maps estimated from the spatial redundancy and the spatial correlation function, respectively. The estimated short axis association length in the right atrium increased already shortly after the start of infusion (CIB25, +61%), and remained significantly different from control during the experiment, including the effects of non-simultaneous interaction. At CIB85 the association length had almost become twice as long with respect to control (increase from 16 to 29 mm, 89%), while in the left atrium changes were less pronounced (increase from 9 to 12 mm, +32%). The linearized association length which was estimated using multivariate surrogate data increased more gradually and was less sensitive to changes in spatial organization. The results of the spatial correlation analysis suggest that the drug-induced nonlinearity in the spatio-temporal dynamics of sustained AF is related to activation patterns which are characterized by extended uniformly propagating fibrillation wavefronts (AF type I). We conclude that cibenzoline enhanced the spatial organization of sustained AF associated with a transition from type II to type I AF activation patterns. This may destabilize the perpetuation of AF since an increase in association length is equivalent to a reduction of atrial tissue mass available to support reentrant circuits. The results are consistent with the hypothesis that larger association lengths result from fewer and larger reentrant circuits. It is argued that effects of diminished curvature of fibrillation wavefronts are anti-arrhythmic under conditions of suppressed excitability imposed by cibenzoline. Termination of AF may be mediated by a mechanism resembling a bifurcation of the dynamics which sets in when the ends of fractionated wavefronts cannot sufficiently curve anymore to maintain a positive balance of newly generated wavelets needed to sustain AF.

Mapping of atrial fibrillation.

Cardiac mapping has been defined as: "a method by which cardiac signals are recorded from multiple sites of the heart and spatially depicted as a function of time in an integrated manner". It requires determination of the local activation time at each electrode and the creation of activation maps which provide a spatial model of the activation sequence. With respect to atrial fibrillation, mapping is useful to gain insight into the underlying mechanism of atrial fibrillation. In this review, we will discuss the mapping studies of experimental and clinical atrial fibrillation.

Non-linear time series analysis: methods and applications to atrial fibrillation.

We apply methods from non-linear statistical time series analysis to characterize electrograms of atrial fibrillation. These are based on concepts originating from the theory of non-linear dynamical systems and use the empirical reconstruction density in reconstructed phase space. Application of these methods is not restricted to deterministic chaos but is valid in a general time series context. We illustrate this by applying three recently proposed non-linear time series methods to fibrillation electrograms: 1) a test for time reversibility in atrial electrograms during paroxysmal atrial fibrillation in patients; 2) a test to detect differences in the dynamical behaviour during the pharmacological conversion of sustained atrial fibrillation in instrumented conscious goats; 3) a test for general Granger causality to identify couplings and information transport in the atria during fibrillation. We conclude that a characterization of the dynamics via the reconstruction density offers a useful framework for the non-linear analysis of electrograms of atrial fibrillation.

Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): standardised reporting for model reproducibility, interoperability, and data sharing.

Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.