Heart Failure, Female Sex, and Atrial Fibrillation Are the Main Drivers of Human Atrial Cardiomyopathy: Results From the CATCH ME Consortium.

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<0.001), while women had more endomysial fibrosis (LA: +0.99±0.56 µm, P=0.003). Patients with heart failure showed more endomysial fibrosis (LA: +1.85±0.48 µm, P<0.001) and extracellular matrix content (LA: +3.07±1.29%, P=0.016), and a higher capillary density (LA: +0.13±0.06, P=0.007) and size (LA: +0.46±0.22 µm, P=0.044). Fuzzy k-means clustering of histological features identified 2 subtypes of atCM: 1 characterized by enhanced endomysial fibrosis (LA: +3.17 µm, P<0.001; RA: +2.86 µm, P<0.001), extracellular matrix content (LA: +3.53%, P<0.001; RA: +6.40%, P<0.001) and fibroblast density (LA: +4.38%, P<0.001), and 1 characterized by cardiomyocyte hypertrophy (LA: +1.16 µm, P=0.008; RA: +2.58 µm, P<0.001). Patients with fibrotic atCM were more frequently female (LA: odds ratio [OR], 1.33, P=0.002; RA: OR, 1.54, P=0.004), with persistent AF (LA: OR, 1.22, P=0.036) or heart failure (LA: OR, 1.62, P<0.001). Hypertrophic features were more common in men (LA: OR=1.33, P=0.002; RA: OR, 1.54, P=0.004). CONCLUSIONS: Fibrotic atCM is associated with female sex, persistent AF, and heart failure, while hypertrophic features are more common in men.

Long-Term Training Increases Atrial Fibrillation Sustainability in Standardbred Racehorses.

Atrial fibrillation (AF) is more prevalent in athletes, and currently, the mechanisms are not fully understood. Atrial fibrillation inducibility and stability was investigated in trained and untrained Standardbred racehorses. The horses underwent echocardiography for evaluation of atrial size. High-density mapping during AF was performed, and the presence of structural remodeling, as well as the expression of inflammatory and pro-inflammatory markers in the atria, was studied. Atrial fibrillation sustained significantly longer after tachypacing in the trained horses, whereas no difference in AF inducibility was found. The untrained horses displayed a significant difference in the AF complexity when comparing right and left atria, whereas such difference was not observed in the trained animals. No evidence of increased structural remodeling or inflammation could be identified. Left atrial dimensions were not significantly increased. The increased AF sustainability in trained horses was not related to fibrosis or inflammation as seen in other animal exercise models.

High-density and high coverage composite mapping of repetitive atrial activation patterns.

BACKGROUND: Repetitive atrial activation patterns (RAAPs) during atrial fibrillation (AF) may be associated with localized mechanisms that maintain AF. Current electro-anatomical mapping systems are unsuitable for analyzing RAAPs due to the trade-off between spatial coverage and electrode density in clinical catheters. This work proposes a technique to overcome this trade-off by constructing composite maps from spatially overlapping sequential recordings. METHODS: High-density epicardial contact mapping was performed during open-chest surgery in goats (n=16, left and right atria) with 3 or 22 weeks of sustained AF (249-electrode array, electrode distance 2.4 mm). A dataset mimicking sequential recordings was generated by segmenting the grid into four spatially overlapping regions (each region 6.5 cm2, 48±10% overlap) without temporal overlap. RAAPs were detected in each region using recurrence plots of activation times. RAAPs in two different regions were joined in case of RAAP cross-recurrence between overlapping electrodes. We quantified the reconstruction success rate and quality of the composite maps. RESULTS: Of 1021 RAAPs found in the full mapping array (32±13 per recording), 328 spatiotemporally stable RAAPs were analyzed. 247 composite maps were generated (75% success) with a quality of 0.86±0.21 (Pearson correlation). Success was significantly affected by the RAAP area. Quality was weakly correlated with the number of repetitions of RAAPs (r=0.13, p<0.05) and not affected by the atrial side (left or right) or AF duration (3 or 22 weeks of AF). CONCLUSIONS: Constructing composite maps by combining spatially overlapping sequential recordings is feasible. Interpretation of these maps can play a central role in ablation planning.

Extended ECG Improves Classification of Paroxysmal and Persistent Atrial Fibrillation Based on P- and f-Waves.

Background: The 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. Objective: The 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). Methods: In 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. Results: Significant 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]. Conclusion: The 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.

Thrombin generation by calibrated automated thrombography in goat plasma: Optimization of an assay.

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.

Coagulation Factor Xa Induces Proinflammatory Responses in Cardiac Fibroblasts via Activation of Protease-Activated Receptor-1.

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.

Increased fibroblast accumulation in the equine heart following persistent atrial fibrillation.

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 < 0.05 for all) in horses with persistent AF. The percentage of α-SMA expressing fibroblasts remained the same between the groups. CONCLUSION: Persistent AF resulted in fibroblast accumulation in several regions, particularly in the left atrial appendage. The increased number of fibroblasts could be a mediator of altered electrophysiology during AF. Targeting the fibroblast proliferation and differentiation could potentially serve as a novel therapeutic target slowing down the structural remodeling associated with AF.

Effective termination of atrial fibrillation by SK channel inhibition is associated with a sudden organization of fibrillatory conduction.

AIMS: Pharmacological termination of atrial fibrillation (AF) remains a challenge due to limited efficacy and potential ventricular proarrhythmic effects of antiarrhythmic drugs. SK channels are proposed as atrial-specific targets in the treatment of AF. Here, we investigated the effects of the new SK channel inhibitor AP14145. METHODS AND RESULTS: Eight goats were implanted with pericardial electrodes for induction of AF (30 days). In an open-chest study, the atrial conduction velocity (CV) and effective refractory period (ERP) were measured during pacing. High-density mapping of both atrial free-walls was performed during AF and conduction properties were assessed. All measurements were performed at baseline and during AP14145 infusion [10 mg/kg/h (n = 1) or 20 mg/kg/h (n = 6)]. At an infusion rate of 20 mg/kg/h, AF terminated in five of six goats. AP14145 profoundly increased ERP and reduced CV during pacing. AP14145 increased spatiotemporal instability of conduction at short pacing cycle lengths. Atrial fibrillation cycle length and pathlength (AF cycle length × CV) underwent a strong dose-dependent prolongation. Conduction velocity during AF remained unchanged and conduction patterns remained complex until the last seconds before AF termination, during which a sudden and profound organization of fibrillatory conduction occurred. CONCLUSION: AP14145 provided a successful therapy for termination of persistent AF in goats. During AF, AP14145 caused an ERP and AF cycle length prolongation. AP14145 slowed CV during fast pacing but did not lead to a further decrease during AF. Termination of AF was preceded by an abrupt organization of AF with a decline in the number of fibrillation waves.

The relation between the atrial blood supply and the complexity of acute atrial fibrillation.

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.

Incidence, prevalence, and trajectories of repetitive conduction patterns in human atrial fibrillation.

AIMS: Repetitive conduction patterns in atrial fibrillation (AF) may reflect anatomical structures harbouring preferential conduction paths and indicate the presence of stationary sources for AF. Recently, we demonstrated a novel technique to detect repetitive patterns in high-density contact mapping of AF. As a first step towards repetitive pattern mapping to guide AF ablation, we determined the incidence, prevalence, and trajectories of repetitive conduction patterns in epicardial contact mapping of paroxysmal and persistent AF patients. METHODS AND RESULTS: A 256-channel mapping array was used to record epicardial left and right AF electrograms in persistent AF (persAF, n = 9) and paroxysmal AF (pAF, n = 11) patients. Intervals containing repetitive conduction patterns were detected using recurrence plots. Activation movies, preferential conduction direction, and average activation sequence were used to characterize and classify conduction patterns. Repetitive patterns were identified in 33/40 recordings. Repetitive patterns were more prevalent in pAF compared with persAF [pAF: median 59%, inter-quartile range (41-72) vs. persAF: 39% (0-51), P < 0.01], larger [pAF: = 1.54 (1.15-1.96) vs. persAF: 1.16 (0.74-1.56) cm2, P < 0.001), and more stable [normalized preferentiality (0-1) pAF: 0.38 (0.25-0.50) vs. persAF: 0.23 (0-0.33), P < 0.01]. Most repetitive patterns were peripheral waves (87%), often with conduction block (69%), while breakthroughs (9%) and re-entries (2%) occurred less frequently. CONCLUSION: High-density epicardial contact mapping in AF patients reveals frequent repetitive conduction patterns. In persistent AF patients, repetitive patterns were less frequent, smaller, and more variable than in paroxysmal AF patients. Future research should elucidate whether these patterns can help in finding AF ablation targets.

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

AIMS: Complex 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 RESULTS: Two 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. CONCLUSIONS: Destabilization 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.

Inhibition of Small-Conductance Calcium-Activated Potassium Current (I K,Ca) Leads to Differential Atrial Electrophysiological Effects in a Horse Model of Persistent Atrial Fibrillation.

BACKGROUND: Small-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 (I K,Ca) inhibition-might be negatively related to AF duration and the extent of AF-induced remodeling. EXPERIMENTAL APPROACH AND METHODS: To address the hypothesis of the efficacy of I K,Ca inhibition being dependent on AF duration, the anti-arrhythmic properties of the I K,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. RESULTS: I K,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. CONCLUSIONS: Intra-atrial heterogeneity in response to I K,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, I K,Ca inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.

Electrophysiological effects of ranolazine in a goat model of lone atrial fibrillation.

BACKGROUND: There is still an unmet need for pharmacologic treatment of atrial fibrillation (AF) with few effects on ventricular electrophysiology. Ranolazine is an antiarrhythmic drug reported to have strong atrial selectivity. OBJECTIVE: The purpose of this study was to investigate the electrophysiological effects of ranolazine in atria with AF-induced electrical remodeling in a model of lone AF in awake goats. METHODS: Electrode patches were implanted on the atrial epicardium of 8 Dutch milk goats. Experiments were performed at baseline and after 2 and 14 days of electrically maintained AF. Several electrophysiological parameters and AF episode duration were measured during infusion of vehicle and different doses of ranolazine (target plasma levels 4, 8, and 16 µM, respectively). RESULTS: The highest dose of ranolazine significantly prolonged atrial effective refractory period and decreased atrial conduction velocity at baseline and after 2 days of AF. After 2 weeks of AF, ranolazine prolonged the p5 and p50 of AF cycle length distribution in a dose-dependent manner but was not effective in restoring sinus rhythm. No adverse ventricular arrhythmic events (eg, premature ventricular beats or signs of hemodynamic instability) were observed during infusion of ranolazine at any point in the study. CONCLUSION: The lowest investigated dose of ranolazine, which is expected to block both late INa and atrial peak INa, had no effect on the investigated electrophysiological parameters. The highest dose affected both atrial and ventricular electrophysiological parameters at different stages of AF-induced remodeling but was not efficacious in cardioverting AF to sinus rhythm in a goat model of lone AF.

A Novel Tool for the Identification and Characterization of Repetitive Patterns in High-Density Contact Mapping of Atrial Fibrillation.

INTRODUCTION: Electrical 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 METHODS: Recurrence 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). RESULTS: Recurrence 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. CONCLUSION: Recurrence 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.

Acute hyperglycaemia is not associated with the development of atrial fibrillation in healthy pigs.

Development and progression of atrial fibrillation (AF) is driven by comorbidities such as arterial hypertension and diabetes mellitus. In animal models of chronic hyperglycaemia, progression of AF has been proposed to be triggered by oxidative stress, apoptosis and fibrosis. Acute glycosylation of CaMKII has been associated with increased susceptibility to arrhythmias in acute hyperglycaemia. However, the proarrhythmogenic effect of acute hyperglycaemia has not been investigated. Nine healthy, anesthetized pigs (54 ± 6 kg) were instrumented with electrophysiologic catheters and a multielectrode array on the epicardium of the left atrial anterior wall. Left and right atrial effective refractory periods (AERP), inducibility of AF and left atrial epicardial conduction velocities (CV) were measured at baseline (BL), increasing steps of blood glucose (200-500 mg/dL in steps of 100 mg/dL by glucose infusion) and repeated after normalisation of blood glucose levels (recovery). Serum electrolytes were kept constant during measurements by means of sodium and potassium infusion. There were no significant differences in AERP, CV or AF inducibility between BL and recovery. Heart rate remained constant regardless of blood glucose levels (BL: 103 ± 18 bpm, 500 mg/dL: 103 ± 18 bpm, r = 0.02, p = 0.346). Mean left as well as right AERP increased with higher glucose levels. CV increased with glucose levels (1.25 (1.04, 1.67) m/s at BL vs. 1.53 (1.22, 2.15) m/s at 500 mg/dL, r = 0.85, p = 0.034). Rate of AF inducibility in the left atrium remained constant throughout the whole protocol (AF episodes > 10 s: mean inducibility of 80% at BL vs. 69% at 500 mg/dL, p = 0.32, episodes > 30 s: 0% at BL vs. 0% at 500 mg/dL, p = 0.17). Our data imply that acute hyperglycaemia is associated with lower arrhythmogenic substrate and does not promote AF inducibility.

The Acetylcholine-Activated Potassium Current Inhibitor XAF-1407 Terminates Persistent Atrial Fibrillation in Goats.

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 (<10%). No ventricular proarrhythmic events were observed. Conclusion: XAF-1407 showed an antiarrhythmic effect in a goat model of AF. The study indicates that IKACh represents an interesting therapeutic target for treatment of AF. To assess the efficacy of XAF-1407 in later time points of AF-induced remodeling, follow-up studies with longer period of AF maintenance would be necessary.

Rotors Detected by Phase Analysis of Filtered, Epicardial Atrial Fibrillation Electrograms Colocalize With Regions of Conduction Block.

BACKGROUND: Several recent studies suggest rotors detected by phase mapping may act as main drivers of persistent atrial fibrillation. However, the electrophysiological nature of detected rotors remains unclear. We performed a direct, 1:1 comparison between phase and activation time mapping in high-density, epicardial, direct-contact mapping files of human atrial fibrillation. METHODS: Thirty-eight unipolar electrogram files of 10 s duration were recorded in patients with atrial fibrillation (n=20 patients) using a 16×16 electrode array placed on the epicardial surface of the left atrial posterior wall or the right atrial free wall. Phase maps and isochrone wave maps were constructed for all recordings. For each detected phase singularity (PS) with a lifespan of >1 cycle length, the corresponding conduction pattern was investigated in the isochrone wave maps. RESULTS: When using sinusoidal recomposition and Hilbert Transform, 138 PSs were detected. One hundred and four out of 138 PSs were detected within 1 electrode distance (1.5 mm) from a line of conduction block between nonrotating wavefronts detected by activation mapping. Far fewer rotating wavefronts were detected when rotating activity was identified based on wave mapping (18 out of 8219 detected waves). Fourteen out of these 18 cases were detected as PSs in phase mapping. Phase analysis of filtered electrograms produced by simulated wavefronts separated by conduction block also identified PSs on the line of conduction block. CONCLUSIONS: PSs identified by phase analysis of filtered epicardial electrograms colocalize with conduction block lines identified by activation mapping. Detection of PSs using phase analysis has a low specificity for identifying rotating wavefronts during human atrial fibrillation using activation mapping.

Stationary Atrial Fibrillation Properties in the Goat Do Not Entail Stable or Recurrent Conduction Patterns.

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.

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

BACKGROUND: Arterial hypertension (HT) contributes to progression of atrial fibrillation (AF) via unknown mechanisms. OBJECTIVE: 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. METHODS: 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. RESULTS: 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 in vivo experiments associated with increased atrial size. CONCLUSION: In this model of secondary HT, higher AF stability after 2 weeks of RAP is mainly driven by atrial dilatation.

Vernakalant does not alter early repolarization or contractility in normal and electrically remodelled atria.

Aims: Besides the inhibition of the sodium inward current, vernakalant also inhibits the ultra rapid rectifier (IKur) and transient outward current (Ito). Inhibition of these currents increases contractility in canine atrial myocytes and goat atria. We investigated the effect of vernakalant on early repolarization and contractility in normal and electrically remodelled atria. Methods and results: Goats were implanted a pressure catheter, piezoelectric crystals, and electrodes to obtain atrial contractility and effective refractory period (ERP). The active component in pressure distance loops was used to compute the atrial work index (AWI). Experiments were performed in normal and electrically remodelled atria at clinically relevant plasma levels of vernakalant. As a positive control, the Ito/IKur blocker AVE0118 was investigated. Monophasic action potentials were recorded in anaesthetized goats and in explanted hearts to determine changes in action potential morphology. Vernakalant did not affect atrial work loops during sinus rhythm. Likewise vernakalant did not increase atrial fractional shortening or AWI during pacing with fixed heart rate and AV-delay. In contrast, AVE0118 did increase AWI, with a positive force frequency relation. Both in normal and remodelled atria, vernakalant strongly increased ERP but did not prolong early repolarization. Conclusion: In goat atria, vernakalant does not have an atrial positive inotropic effect and does not affect early repolarization. At high rates vernakalant may even have a negative inotropic effect.