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IntroductionThe mechanisms leading to the conversion of atrial fibrillation (AF) to sinus rhythm are poorly understood. This study describes the dynamic behavior of electrophysiological parameters and conduction patterns leading to spontaneous and pharmacological AF termination.MethodsFive independent groups of goats were investigated: (1) spontaneous termination of AF, and drug-induced terminations of AF by various potassium channel inhibitors: (2) AP14145, (3) PA-6, (4) XAF-1407, and (5) vernakalant. Bi-atrial contact mapping was performed during an open chest surgery and intervals with continuous and discrete atrial activity were determined. AF cycle length (AFCL), conduction velocity and path length were calculated for each interval, and the final conduction pattern preceding AF termination was evaluated.ResultsAF termination was preceded by a sudden episode of discrete activity both in the presence and absence of an antiarrhythmic drug. This episode was accompanied by substantial increases in AFCL and conduction velocity, resulting in prolongation of path length. In 77% ± 4% of all terminations the conduction pattern preceding AF termination involved medial to lateral conduction along Bachmann’s bundle into both atria, followed by anterior to posterior conduction. This finding suggests conduction block in the interatrial septum and/or pulmonary vein area as final step of AF termination.ConclusionAF termination is preceded by an increased organization of fibrillatory conduction. The termination itself is a sudden process with a critical role for the interplay between spatiotemporal organization and anatomical structure.

Summary: Endolysosomes (EL) are known for their role in regulating both intracellular trafficking and proteostasis. EL facilitate the elimination of damaged membranes, protein aggregates, membranous organelles and play an important role in calcium signaling. The specific role of EL in cardiac atrial fibrillation (AF) is not well understood. We isolated atrial EL organelles from AF goat biopsies and conducted a comprehensive integrated omics analysis to study the EL-specific proteins and pathways. We also performed electron tomography, protein and enzyme assays on these biopsies. Our results revealed the upregulation of the AMPK pathway and the expression of EL-specific proteins that were not found in whole tissue lysates, including GAA, DYNLRB1, CLTB, SIRT3, CCT2, and muscle-specific HSPB2. We also observed structural anomalies, such as autophagic-vacuole formation, irregularly shaped mitochondria, and glycogen deposition. Our results provide molecular information suggesting EL play a role in AF disease process over extended time frames.

Introduction: Repetitive focal and rotational activation patterns are currently used as additional ablation targets for atrial fibrillation (AF). However, there is no evidence that all these detected targets are actual sources of AF. In this paper, we present an approach that detects and ranks AF activation patterns not only based on the degree of pattern repetitiveness but also on the extent to which they are able to entrain their vicinity. This new technique might enable selecting the site with the highest probability of being a source for AF. Methods: We retrospectively analyzed high-density bi-atrial sequential mapping in ablation-naive persistent AF patients (n = 13, PentaRay catheter, 30s recordings). Repetitive focal and rotational activation patterns were detected based on local activation time annotation of unipolar electrograms. The spatial stability was determined as local repetitive pattern duration. The entrainment capability was defined as the average time a directionally coherent repetitive activation pattern was observed in adjacent recordings. Results: A total of 459 recordings were analyzed (35 ± 5 per patient). We detected 131 repetitive focal (10 ± 4 per patient) and 56 rotational activation patterns (4 ± 3 per patient) in total. Focal patterns were more repetitive than rotational patterns (median [IQR] 0.7 [0.4–1.3] seconds vs. 0.5 [0.4–0.6] seconds, p

Background Atrial cardiomyopathy (atCM) is an emerging prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are hallmarks of atCM. The contribution of etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been quantified. This study aimed to evaluate the association between histological features of atCM and the clinical phenotype. Methods and Results We examined left atrial (LA, n=95) and right atrial (RA, n=76) appendages from a European cohort of patients undergoing cardiac surgery. Quantification of histological atCM features was performed following wheat germ agglutinin/CD31/vimentin staining. The contributions of AF, heart failure, sex, and age to histological characteristics were determined with multiple linear regression models. Persistent AF was associated with increased endomysial fibrosis (LA: +1.13±0.47 μm, P=0.038; RA: +0.94±0.38 μm, P=0.041), whereas total extracellular matrix content was not. Men had larger cardiomyocytes (LA: +1.92±0.72 μm, P

Background: Atrial Epicardial Adipose Tissue (EAT) is presumably involved in the pathogenesis of atrial fibrillation (AF). The transient nature of postoperative AF (POAF) suggests that surgery-induced triggers provoke an unmasking of a pre-existent AF substrate. The aim is to investigate the association between the volume of EAT and the occurrence of POAF. We hypothesise that the likelihood of developing POAF is higher in patients with high compared to low left atrial (LA) EAT volumes. Methods: Quantification of LA EAT based on the Hounsfield Units using custom made software was performed on pre-operative coronary computed tomography angiography scans of patients who underwent cardiac surgery between 2009 and 2019. Patients with mitral valve disease were excluded. Results: A total of 83 patients were included in this study (CABG = 34, aortic valve = 33, aorta ascendens n = 7, combination n = 9), of which 43 patients developed POAF. The EAT percentage in the LA wall nor indexed EAT volumes differed between patients with POAF and with sinus rhythm (all P > 0.05). In multivariable analysis, age and LA volume index (LAVI) were the only independent predictors for early POAF (OR: 1.076 and 1.056, respectively). Conclusions: As expected, advanced age and LAVI were independent predictors of POAF. However, the amount of local EAT was not associated with the occurrence of AF after cardiac surgery. This suggests that the role of EAT in POAF is rather limited, or that the association of EAT in the early phase of POAF is obscured by the dominance of surgical-induced triggers.

BackgroundThe standard 12-lead ECG has been shown to be of value in characterizing atrial conduction properties. The added value of extended ECG recordings (longer recordings from more sites) has not been systematically explored yet.ObjectiveThe aim of this study is to employ an extended ECG to identify characteristics of atrial electrical activity related to paroxysmal vs. persistent atrial fibrillation (AF).MethodsIn 247 participants scheduled for AF ablation, an extended ECG was recorded (12 standard plus 3 additional leads, 5 min recording, no filtering). For patients presenting in sinus rhythm (SR), the signal-averaged P-wave and the spatiotemporal P-wave variability was analyzed. For patients presenting in AF, f-wave properties in the QRST (the amplitude complex of the ventricular electrical activity: Q-, R-, S-, and T-wave)-canceled ECG were determined.ResultsSignificant differences between paroxysmal (N = 152) and persistent patients with AF (N = 95) were found in several P-wave and f-wave parameters, including parameters that can only be calculated from an extended ECG. Furthermore, a moderate, but significant correlation was found between echocardiographic parameters and P-wave and f-wave parameters. There was a moderate correlation of left atrial (LA) diameter with P-wave energy duration (r = 0.317, p < 0.001) and f-wave amplitude in lead A3 (r = −0.389, p = 0.002). The AF-type classification performance significantly improved when parameters calculated from the extended ECG were taken into account [area under the curve (AUC) = 0.58, interquartile range (IQR) 0.50–0.64 for standard ECG parameters only vs. AUC = 0.76, IQR 0.70–0.80 for extended ECG parameters, p < 0.001].ConclusionThe P- and f-wave analysis of extended ECG configurations identified specific ECG features allowing improved classification of paroxysmal vs. persistent AF. The extended ECG significantly improved AF-type classification in our analyzed data as compared to a standard 10-s 12-lead ECG. Whether this can result in a better clinical AF type classification warrants further prospective study.

Abstract The goat model of atrial fibrillation (AF) allows investigation of the effect of AF on coagulation. However, assays for goat plasma are not available from commercial sources. Calibrated automated thrombography (CAT) provides a global view of the coagulation profile by assessing in vitro thrombin generation (TG). We describe the customization of the CAT assay in goat platelet‐poor plasma (PPP) and in factor Xa (FXa)‐inhibitor‐anticoagulated PPP. TG was initiated in the presence of phospholipids and either (a) PPP reagent, reagent low, or reagent high; (b) goat brain protein extraction (GBP); or (c) Russell's viper venom‐factor X activator (RVV‐X). Contact activation was assessed by adding corn trypsin inhibitor. Different concentrations of prothrombin complex concentrate (PCC) were used to determine the sensitivity of both the GBP and RVV‐X method. To obtain FXa‐inhibitor anticoagulated plasma, rivaroxaban was added to plasma. TG settings with human reagents were not suitable for goat plasma. TG triggered with GBP increased peak height and ETP values. Similarly, the RVV‐X method produced comparable TG curves and was more sensitive to PCC titration. Finally, both methods were able to detect the decrease in clotting potential induced by FXa inhibition. This is the first study that reports the customization of the CAT assay for goats. The GBP and RVV‐X methods were comparable in triggering TG in goat plasma. The RVV‐X method seemed to better discriminate changes in TG curves due to increases in clotting potential as well as to FXa inhibition by rivaroxaban in goat plasma.

Background: Fibroblasts maintain the extracellular matrix homeostasis and may couple to cardiomyocytes through gap junctions and thereby increase the susceptibility to slow conduction and cardiac arrhythmias, such as atrial fibrillation (AF). In this study, we used an equine model of persistent AF to characterize structural changes and the role of fibroblasts in the development of an arrhythmogenic substrate for AF. Material and methods: Eleven horses were subjected to atrial tachypacing until self-sustained AF developed and were kept in AF for six weeks. Horses in sinus rhythm (SR) served as control. In terminal open-chest experiments conduction velocity (CV) was measured. Tissue was harvested and stained from selected sites. Automated image analysis was performed to assess fibrosis, fibroblasts, capillaries and various cardiomyocyte characteristics. Results: Horses in SR showed a rate-dependent slowing of CV, while in horses with persistent AF this rate-dependency was completely abolished (CV•basic cycle length relation p = 0.0295). Overall and interstitial amounts of fibrosis were unchanged, but an increased fibroblast count was found in left atrial appendage, Bachmann's bundle, intraatrial septum and pulmonary veins (p

Heart disease, as well as systemic metabolic alterations, can leave a ‘fingerprint’ of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy and fatty infiltration, can increase vulnerability to atrial fibrillation (AF), the most relevant manifestation of atrial cardiomyopathy in clinical practice. Atrial cardiomyopathy accompanying AF is associated with thromboembolic events, such as stroke. The interaction between AF and stroke appears to be far more complicated than initially believed. AF and stroke share many risk factors whose underlying pathological processes can reinforce the development and progression of both cardiovascular conditions. In this review, we summarize the main mechanisms by which atrial cardiomyopathy, preceding AF, supports thrombogenic events within the atrial cavity and myocardial interstitial space. Moreover, we report the pleiotropic effects of activated coagulation factors on atrial remodeling, which may aggravate atrial cardiomyopathy. Finally, we address the complex association between AF and stroke, which can be explained by a multidirectional causal relation between atrial cardiomyopathy and hypercoagulability.

Background: Patients with a history of myocardial infarction and coronary artery disease (CAD) have a higher risk of developing AF. Conversely, patients with atrial fibrillation (AF) have a higher risk of developing myocardial infarction, suggesting a link in underlying pathophysiology. The aim of this study was to assess whether coronary angiographic parameters are associated with a substrate for AF in patients without a history of AF. Methods: During cardiac surgery in 62 patients (coronary artery bypass grafting (CABG;n = 47), aortic valve replacement (AVR;n = 9) or CABG + AVR (n = 6)) without a history of clinical AF (age 65.4 ± 8.5 years, 26.2% female), AF was induced by burst pacing. The preoperative coronary angiogram (CAG) was assessed for the severity of CAD, and the adequacy of atrial coronary blood supply as quantified by a novel scoring system including the location and severity of right coronary artery disease in relation to the right atrial branches. Epicardial mapping of the right atrium (256 unipolar electrodes) was used to assess the complexity of induced AF. Results: There was no association between the adequacy of right atrial coronary blood supply on preoperative CAG and AF complexity parameters. Multivariable analysis revealed that only increasing age (B0.232 (0.030;0.433),p = 0.03) and the presence of 3VD (B3.602 (0.187;7.018),p = 0.04) were independently associated with an increased maximal activation time difference. Conclusions: The adequacy of epicardial right atrial blood supply is not associated with increased complexity of induced atrial fibrillation in patients without a history of clinical AF, while age and the extent of ventricular coronary artery disease are.

BackgroundSmall-conductance Ca2+-activated K+ (KCa2) channels have been proposed as a possible atrial-selective target to pharmacologically terminate atrial fibrillation (AF) and to maintain sinus rhythm. However, it has been hypothesized that the importance of the KCa2 current—and thereby the efficacy of small-conductance Ca2+-activated K+ current (IK,Ca) inhibition—might be negatively related to AF duration and the extent of AF-induced remodeling.Experimental Approach and MethodsTo address the hypothesis of the efficacy of IK,Ca inhibition being dependent on AF duration, the anti-arrhythmic properties of the IK,Ca inhibitor NS8593 (5 mg/kg) and its influence on atrial conduction were studied using epicardial high-density contact mapping in horses with persistent AF. Eleven Standardbred mares with tachypacing-induced persistent AF (42 ± 5 days of AF) were studied in an open-chest experiment. Unipolar AF electrograms were recorded and isochronal high-density maps analyzed to allow for the reconstruction of wave patterns and changes in electrophysiological parameters, such as atrial conduction velocity and AF cycle length. Atrial anti-arrhythmic properties and adverse effects of NS8593 on ventricular electrophysiology were evaluated by continuous surface ECG monitoring.ResultsIK,Ca inhibition by NS8593 administered intravenously had divergent effects on right and left AF complexity and propagation properties in this equine model of persistent AF. Despite global prolongation of AF cycle length, a slowing of conduction in the right atrium led to increased anisotropy and electrical dissociation, thus increasing AF complexity. In contrast, there was no significant change in AF complexity in the LA, and cardioversion of AF was not achieved.ConclusionsIntra-atrial heterogeneity in response to IK,Ca inhibition by NS8593 was observed. The investigated dose of NS8593 increased the AF cycle length but was not sufficient to induce cardioversion. In terms of propagation properties during AF, IK,Ca inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.

Aims: The acetylcholine-activated inward rectifier potassium current (IKACh) has been proposed as an atrial-selective target for the treatment of atrial fibrillation (AF). Using a novel selective IKACh inhibitor XAF-1407, the study investigates the effect of IKACh inhibition in goats with pacing-induced, short-term AF.Methods: Ten goats (57 ± 5 kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during intravenous infusion of XAF-1407 (0.3, 3.0 mg/kg) in conscious animals before and after 2 days of electrically induced AF. Following a further 2 weeks of sustained AF, cardioversion was attempted with either XAF-1407 (0.3 followed by 3 mg/kg) or with vernakalant (3.7 followed by 4.5 mg/kg), an antiarrhythmic drug that inhibits the fast sodium current and several potassium currents. During a final open chest experiment, 249 unipolar electrograms were recorded on each atrium to construct activation patterns and AF cardioversion was attempted with XAF-1407.Results: XAF-1407 prolonged atrial effective refractory period by 36 ms (45%) and 71 ms (87%) (0.3 and 3.0 mg/kg, respectively; pacing cycle length 400 ms, 2 days of AF-induced remodeling) and showed higher cardioversion efficacy than vernakalant (8/9 vs. 5/9). XAF-1407 caused a minor decrease in the number of waves per AF cycle in the last seconds prior to cardioversion. Administration of XAF-1407 was associated with a modest increase in QTc (

IntroductionElectrical contact mapping provides a detailed view of conduction patterns in the atria during atrial fibrillation (AF). Identification of repetitive wave front propagation mechanisms potentially initiating or sustaining AF might provide more insights into temporal and spatial distribution of candidate AF mechanism and identify targets for catheter ablation. We developed a novel tool based on recurrence plots to automatically identify and characterize repetitive conduction patterns in high-density contact mapping of AF.Materials and MethodsRecurrence plots were constructed by first transforming atrial electrograms recorded by a multi-electrode array to activation-phase signals and then quantifying the degree of similarity between snapshots of the activation-phase in the electrode array. An AF cycle length dependent distance threshold was applied to discriminate between repetitive and non-repetitive snapshots. Intervals containing repetitive conduction patterns were detected in a recurrence plot as regions with a high recurrence rate. Intervals that contained similar repetitive patterns were then grouped into clusters. To demonstrate the ability to detect and quantify the incidence, duration and size of repetitive patterns, the tool was applied to left and right atrial recordings in a goat model of different duration of persistent AF [3 weeks AF (3 wkAF, n = 8) and 22 weeks AF (22 wkAF, n = 8)], using a 249-electrode mapping array (2.4 mm inter-electrode distance).ResultsRecurrence plots identified frequent recurrences of activation patterns in all recordings and indicated a strong correlation between recurrence plot threshold and AF cycle length. Prolonged AF duration was associated with shorter repetitive pattern duration [mean maximum duration 3 wkAF: 74 cycles, 95% confidence interval (54–94) vs. 22 wkAF: 41 cycles (21–62), p = 0.03], and smaller recurrent regions within repetitive patterns [3 wkAF 1.7 cm2 (1.0–2.3) vs. 22 wkAF 0.5 cm2 (0.0–1.2), p = 0.02]. Both breakthrough patterns and re-entry were identified as repetitive conduction patterns.ConclusionRecurrence plots provide a novel way to delineate high-density contact mapping of AF. Dominant repetitive conduction patterns were identified in a goat model of sustained AF. Application of the developed methodology using the new generation of multi-electrode catheters could identify additional targets for catheter ablation of AF.

BackgroundAtrial fibrillation (AF) is accompanied by progressive epicardial fibrosis, dissociation of electrical activity between the epicardial layer and the endocardial bundle network, and transmural conduction (breakthroughs). However, causal relationships between these phenomena have not been demonstrated yet. Our goal was to test the hypothesis that epicardial fibrosis suffices to increase endo–epicardial dissociation (EED) and breakthroughs (BT) during AF.MethodsWe simulated the effect of fibrosis in the epicardial layer on EED and BT in a detailed, high-resolution, three-dimensional model of the human atria with realistic electrophysiology. The model results were compared with simultaneous endo–epicardial mapping in human atria. The model geometry, specifically built for this study, was based on MR images and histo-anatomical studies. Clinical data were obtained in four patients with longstanding persistent AF (persAF) and three patients without a history of AF.ResultsThe AF cycle length (AFCL), conduction velocity (CV), and EED were comparable in the mapping studies and the simulations. EED increased from 24.1 ± 3.4 to 56.58 ± 6.2% (p < 0.05), and number of BTs per cycle from 0.89 ± 0.55 to 6.74 ± 2.11% (p < 0.05), in different degrees of fibrosis in the epicardial layer. In both mapping data and simulations, EED correlated with prevalence of BTs. Fibrosis also increased the number of fibrillation waves per cycle in the model.ConclusionA realistic 3D computer model of AF in which epicardial fibrosis was increased, in the absence of other pathological changes, showed increases in EED and epicardial BT comparable to those in longstanding persAF. Thus, epicardial fibrosis can explain both phenomena.

Background: The current paradigm is that fibrosis promotes electrophysiological disorders and drives atrial fibrillation (AF). In this current study, we investigated the relation between the degree of fibrosis in human atrial tissue samples of controls and patients in various stages of AF and the degree of electrophysiological abnormalities. Methods: The degree of fibrosis was measured in the atrial tissue and serum of patients in various stages of AF and the controls. Hereto, picrosirius and H&E staining were performed to quantify degree of total, endo-perimysial fibrosis, and cardiomyocyte diameter. Western blot quantified fibrosis markers: neural cell adhesion molecule, tissue inhibitor of metalloproteinase, lysyl oxidase, and α-smooth muscle actin. In serum, the ratio carboxyl-terminal telopeptide of collagen/matrix-metalloproteinase1 was determined. High-resolution epicardial mapping evaluated low-voltage areas and conduction abnormalities. Results: No significant differences were observed in the degree of fibrosis between the groups. Finally, no significant correlation—absolute nor spatial—was observed between all electrophysiological parameters and histological fibrosis markers. Conclusions: No differences in the degree of fibrosis were observed in patients from various stages of AF compared to the controls. Moreover, electrophysiological abnormalities did not correlate with any of the fibrosis markers. The findings indicate that fibrosis is not the hallmark of structural remodeling in AF.

For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an increased amount of fibrous tissue. However, fibrosis is not a singular entity. Various forms can be distinguished, that differ in distribution: replacement fibrosis, endomysial and perimysial fibrosis, and perivascular, endocardial, and epicardial fibrosis. These different forms typically result from diverging pathophysiological mechanisms and can have different consequences for conduction. The impact of fibrosis on propagation depends on exactly how the patterns of electrical connections between myocytes are altered. We will therefore first consider the normal patterns of electrical connections and their regional diversity as determinants of propagation. Subsequently, we will summarize current knowledge on how different forms of fibrosis lead to a loss of electrical connectivity in order to explain their effects on propagation and mechanisms of arrhythmogenesis, including ectopy, reentry, and alternans. Finally, we will discuss a histological quantification of fibrosis. Because of the different forms of fibrosis and their diverging effects on electrical propagation, the total amount of fibrosis is a poor indicator for the effect on conduction. Ideally, an assessment of cardiac fibrosis should exclude fibrous tissue that does not affect conduction and differentiate between the various types that do; in this article, we highlight practical solutions for histological analysis that meet these requirements.

Coagulation factor (F) Xa induces proinflammatory responses through activation of protease-activated receptors (PARs). However, the effect of FXa on cardiac fibroblasts (CFs) and the contribution of PARs in FXa-induced cellular signalling in CF has not been fully characterised. To answer these questions, human and rat CFs were incubated with FXa (or TRAP-14, PAR-1 agonist). Gene expression of pro-fibrotic and proinflammatory markers was determined by qRT-PCR after 4 and 24 h. Gene silencing of F2R (PAR-1) and F2RL1 (PAR-2) was achieved using siRNA. MCP-1 protein levels were measured by ELISA of FXa-conditioned media at 24 h. Cell proliferation was assessed after 24 h of incubation with FXa ± SCH79797 (PAR-1 antagonist). In rat CFs, FXa induced upregulation of Ccl2 (MCP-1; >30-fold at 4 h in atrial and ventricular CF) and Il6 (IL-6; ±7-fold at 4 h in ventricular CF). Increased MCP-1 protein levels were detected in FXa-conditioned media at 24 h. In human CF, FXa upregulated the gene expression of CCL2 (>3-fold) and IL6 (>4-fold) at 4 h. Silencing of F2R (PAR-1 gene), but not F2RL1 (PAR-2 gene), downregulated this effect. Selective activation of PAR-1 by TRAP-14 increased CCL2 and IL6 gene expression; this was prevented by F2R (PAR-1 gene) knockdown. Moreover, SCH79797 decreased FXa-induced proliferation after 24 h. In conclusion, our study shows that FXa induces overexpression of proinflammatory genes in human CFs via PAR-1, which was found to be the most abundant PARs isoform in this cell type.

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.

Introduction: Electro-anatomical mapping of the atria is used to identify the substrate of atrial fibrillation (AF). Targeting this substrate by ablation in addition to pulmonary vein ablation did not consistently improve outcome in clinical trials. Generally, the assessment of the substrate is based on short recordings (≤10 s, often even shorter). Thus, targeting the AF substrate assumes spatiotemporal stationarity but little is known about the variability of electrophysiological properties of AF over time.Methods: Atrial fibrillation (AF) was maintained for 3–4 weeks after pericardial electrode implantation in 12 goats. Within a single AF episode 10 consecutive minutes were mapped on the left atrial free wall using a 249-electrode array (2.25 mm inter-electrode spacing). AF cycle length, fractionation index (FI), lateral dissociation, conduction velocity, breakthroughs, and preferentiality of conduction (Pref) were assessed per electrode and AF property maps were constructed. The Pearson correlation coefficient (PCC) between the 10 AF-property maps was calculated to quantify the degree spatiotemporal stationarity of AF properties. Furthermore, the number of waves and presence of re-entrant circuits were analyzed in the first 60-s file. Comparing conduction patterns over time identified recurrent patterns of AF with the use of recurrence plots.Results: The averages of AF property maps were highly stable throughout the ten 60-s-recordings. Spatiotemporal stationarity was high for all 6 property maps, PCC ranged from 0.66 ± 0.11 for Pref to 0.98 ± 0.01 for FI. High stationarity was lost when AF was interrupted for about 1 h. However, the time delay between the recorded files within one episode did not affect PCC. Yet, multiple waves (7.7 ± 2.3) were present simultaneously within the recording area and during 9.2 ± 11% of the analyzed period a re-entrant circuit was observed. Recurrent patterns occurred rarely and were observed in only 3 out of 12 goats.Conclusions: During non-self-terminating AF in the goat, AF properties were stationary. Since this could not be attributed to stable recurrent conduction patterns during AF, it is suggested that AF properties are determined by anatomical and structural properties of the atria even when the conduction patterns are very variable.