Time course and mechanisms of endo-epicardial electrical dissociation during atrial fibrillation in the goat

Aims This study aims to determine the degree and mechanisms of endo-epicardial dissociation of electrical activity during atrial fibrillation (AF) and endo-epicardial differences in atrial electrophysiology at different stages of atrial remodelling. Methods and results Simultaneous high-density endo-epicardial mapping of AF was performed on left atrial free walls of goats with acute AF, after 3 weeks, and after 6 months of AF (all n = 7). Endo-epicardial activation time differences and differences in the direction of conduction vectors were calculated, endocardial and epicardial effective refractory periods (ERP) were determined, and fractionation of electrograms was quantified. Histograms of endo-epicardial activation time differences and differences in the direction of conduction vectors revealed two distinct populations, i.e. dissociated and non-dissociated activity. Dyssynchronous activity (dissociated in time) increased from 17 ± 7% during acute AF to 39 ± 17% after 3 weeks, and 68 ± 13% after 6 months of AF. Dissociation was more pronounced in thicker parts of the atrial wall (thick: 49.3 ± 21.4%, thin: 42.2 ± 19.0%, P < 0.05). At baseline, endocardial ERPs were longer when compared with epicardial ERPs (ΔERP, 21.8 ± 18 ms; P < 0.001). This difference was absent after 6 months of AF. The percentage of fractionated electrograms during rapid pacing increased from 9.4 ± 1.9% (baseline) to 18.6 ± 0.6% (6 months). Conclusion During AF, pronounced dissociation of electrical activity occurs between the epicardial layer and the endocardial bundle network. The increase in dissociation is due to owing to progressive uncoupling between the epicardial layer and the endocardial bundles and correlates with increasing stability and complexity of the AF substrat

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

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

Atrial granules as acidic calcium stores in cardiomyocytes

Acidic calcium stores significantly influence basal calcium transient amplitude and β-adrenergic responses in cardiomyocytes. Atrial myocytes contain atrial granules (AGs), small acidic organelles that store and secrete atrial natriuretic peptide (ANP) and are absent in healthy ventricular myocytes. AGs are known to be acidic and calcium-rich, but their number and location relative to other signalling sites remain unexplored. Labelling of acidic organelles in adult guinea pig cardiomyocytes showed the presence of acidic puncta throughout the cytosol. Atrial myocytes exhibited an increased concentration of acidic organelles at the nuclear poles. Live cell fluorescent studies using 4-phenyl-3-butenoic acid (PBA) to inhibit peptidylglycine α-amidating monooxygenase, a crucial component of AGs membranes, effectively eliminated staining at the nuclear poles and most acidic puncta in atrial cells, but not in ventricular cells. Our immunofluorescent labelling also emphasizes the differences in acidic punctae between atrial and ventricular myocytes by showing minimal co-localization between AG-specific ANP and lysosomal-associated membrane protein. Electron microscopy studies on goat atrial fibrillation (AF) and sham control tissue allowed visualization of AGs. Quantitative analysis revealed that AGs were positioned significantly further away from the nearest sarcoplasmic reticulum and were closer to mitochondria in AF compared to sinus rhythm control tissue. We raise the question whether the positioning of AGs is strategic for communication with other calcium-containing organelles

Anatomically-induced Fibrillation in a 3D model of the Human Atria

International audienceAtrial fibrillation (AF) requires both a trigger and a sub-strate that can maintain a complex reentrant activity. In patients and in experimental models this substrate is provided by both electrical and structural remodeling. Since these processes overlap in time it is impossible to assess their individual contributions to AF maintenance experimentally. Therefore we studied the effect of electrical re-modeling alone on AF initiation in a realistic numerical model of the human atria. We attempted to initiate AF by rapid pacing in 10 different locations, both with and without electrical remodeling. The protocols were repeated twice, with small variations in calcium conductivity, so that in total 30 simulations with and 30 simulations without remodeling were performed. In models with electrical remodeling, functional conduction block at structural in-homogeneities induced AF in 27 % of the simulations. In models without electrical remodeling, AF could not be induced. We conclude that in the complex anatomy of the atria electrical remodeling alone increases the probability of AF substantially. This finding supports a mechanism whereby electrical remodeling, which occurs relatively fast, accelerates the slower but irreversible structural remodeling process

Clinical and electrophysiological predictors of device-detected new-onset atrial fibrillation during 3 years after cardiac surgery

Postoperative atrial fibrillation (POAF) after cardiac surgery is an independent predictor of stroke and mortality late after discharge. We aimed to determine the burden and predictors of early (up to 5th postoperative day) and late (after 5th postoperative day) new-onset atrial fibrillation (AF) using implantable loop recorders (ILRs) in patients undergoing open chest cardiac surgery Seventy-nine patients without a history of AF undergoing cardiac surgery underwent peri-operative high-resolution mapping of electrically induced AF and were followed 36 months after surgery using an ILR (Reveal XTTM). Clinical and electrophysiological predictors of late POAF were assessed. POAF occurred in 46 patients (58%), with early POAF detected in 27 (34%) and late POAF in 37 patients (47%). Late POAF episodes were short-lasting (mostly between 2 min and 6 h) and showed a circadian rhythm pattern with a peak of episode initiation during daytime. In POAF patients, electrically induced AF showed more complex propagation patterns than in patients without POAF. Early POAF, right atrial (RA) volume, prolonged PR time, and advanced age were independent predictors of late POAF

Fibrosis explains atrial fibrillation recurrences after pulmonary vein isolations. A simulation study

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

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

Left Atrial Appendage Electrical Isolation Reduces Atrial Fibrillation Recurrences: a simulation study

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Circulating BMP10 Levels Associate With Late Postoperative Atrial Fibrillation and Left Atrial Endomysial Fibrosis

Background: Serum bone morphogenetic protein 10 (BMP10) blood levels are a marker for history of atrial fibrillation (AF) and for major adverse cardiovascular events in patients with AF, including stroke, AF recurrences after catheter ablations, and mortality. The predictive value of BMP10 in patients undergoing cardiac surgery and association with morphologic properties of atrial tissues are unknown. Objectives: This study sought to study the correlation between BMP10 levels and preoperative clinical traits, occurrence of early and late postoperative atrial fibrillation (POAF), and atrial fibrosis in patients undergoing cardiac surgery. Methods: Patients with and without preoperative AF history undergoing first cardiac surgery were included (RACE V, n = 147). Preoperative blood biomarkers were analyzed, left (n = 114) and right (n = 125) atrial appendage biopsy specimens were histologically investigated after WGA staining, and postoperative rhythm was monitored continuously with implantable loop recorders (n = 133, 2.5 years). Results: Adjusted multinomial logistic regression indicated that BMP10 accurately reflected a history of persistent AF (OR: 1.24, 95% CI: 1.10-1.40, P = 0.001), similar to NT-pro-BNP. BMP10 levels were associated with increased late POAF90 occurrence after adjustment for age, sex, AF history, and early POAF occurrence (HR: 1.07 [per 0.1 ng/mL increase], 95% CI: 1.00-1.14, P = 0.041). Left atrial endomysial fibrosis (standardized β = 0.22, P = 0.041) but not overall fibrosis (standardized Β = 0.12, P = 0.261) correlated with circulating BMP10 after adjustment for age, sex, AF history, reduced LVF, and valvular surgery indication. Conclusions: Increased BMP10 levels were associated with persistent AF history, increased late POAF incidence, and LAA endomysial fibrosis in a diverse sample of patients undergoing cardiac surgery.</p