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.
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).
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 substrate.
Atrial 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.
We 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.
The 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% (
< 0.05), and number of BTs per cycle from 0.89 ± 0.55 to 6.74 ± 2.11% (
< 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.
A 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.
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.
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,
= 8) and 22 weeks AF (22 wkAF,
= 8), using a 249-electrode mapping array (2.4 mm inter-electrode distance).
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),
= 0.03, and smaller recurrent regions within repetitive patterns 3 wkAF 1.7 cm
(1.0-2.3) vs. 22 wkAF 0.5 cm
(0.0-1.2),
= 0.02. Both breakthrough patterns and re-entry were identified as repetitive conduction patterns.
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.
ECG-based representation of atrial fibrillation (AF) progression is currently limited. We propose a novel framework for a more sensitive noninvasive characterization of the AF substrate during ...persistent AF. An atrial activity (AA) recurrence signal is computed from body surface potential map (BSPM) recordings, and a set of characteristic indices is derived from it which captures the short- and long-term recurrent behaviour in the AA patterns. A novel measure of short- and long-term spatial variability of AA propagation is introduced, to provide an interpretation of the above indices, and to test the hypothesis that the variability in the oscillatory content of AA is due mainly to a spatially uncoordinated propagation of the AF waveforms. A simple model of atrial signal dynamics is proposed to confirm this hypothesis, and to investigate a possible influence of the AF substrate on the short-term recurrent behaviour of AA propagation. Results confirm the hypothesis, with the model also revealing the above influence. Once the characteristic indices are normalized to remove this influence, they show to be significantly associated with AF recurrence 4 to 6 weeks after electrical cardioversion. Therefore, the proposed framework improves noninvasive AF substrate characterization in patients with a very similar substrate.
Graphical Abstract
Schematic representation of the proposed framework for the noninvasive characterization of short-term atrial signal dynamics during persistent AF. The proposed framework shows that the faster the AA is propagating, the more stable its propagation paths are in the short-term (larger values of Speed in the bottom right plot should be interpreted as lower speed of propagation of the corresponding AA propagation patters).
Early detection of atrial fibrillation (AF) enables initiation of anticoagulation and early rhythm control therapy to reduce stroke, cardiovascular death, and heart failure. In a cross-sectional, ...observational study, we aimed to identify a combination of circulating biomolecules reflecting different biological processes to detect prevalent AF in patients with cardiovascular conditions presenting to hospital. Twelve biomarkers identified by reviewing literature and patents were quantified on a high-precision, high-throughput platform in 1485 consecutive patients with cardiovascular conditions (median age 69 years Q1, Q3 60, 78; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. Logistic regression with backward elimination and a neural network approach considering 7 key clinical characteristics and 12 biomarker concentrations were applied to a randomly sampled discovery cohort (n = 933) and validated in the remaining patients (n = 552). In addition to age, sex, and body mass index (BMI), BMP10, ANGPT2, and FGF23 identified patients with prevalent AF (AUC 0.743 95% CI 0.712, 0.775). These circulating biomolecules represent distinct pathways associated with atrial cardiomyopathy and AF. Neural networks identified the same variables as the regression-based approach. The validation using regression yielded an AUC of 0.719 (95% CI 0.677, 0.762), corroborated using deep neural networks (AUC 0.784 95% CI 0.745, 0.822). Age, sex, BMI and three circulating biomolecules (BMP10, ANGPT2, FGF23) are associated with prevalent AF in unselected patients presenting to hospital. Findings should be externally validated. Results suggest that age and different disease processes approximated by these three biomolecules contribute to AF in patients. Our findings have the potential to improve screening programs for AF after external validation.
Introduction The 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. Methods Five 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. Results AF 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. Conclusion AF 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.
This proof-of-concept study aimed to investigate atrial and ventricular lesion formation by a 20-mm linear laser ablation catheter, regarding lesion depth and tissue damage.
In total, 6 female swines ...underwent standard femoral vein access to introduce a novel 20-mm linear laser ablation catheter in the right atrium to perform endocardial cavotricuspid isthmus (CTI) ablations. The navigation took place under fluoroscopy with additional visualization by intracardiac echocardiograph.
a sternotomy, epicardial ablations were performed on the surface of the left ventricle (LV), right ventricle (RV), and right atrial appendage (RAA). Procedural safety was assessed by registration of intraprocedural adverse events and by macroscopic examination of the excised hearts for the presence of charring or tissue disruption at the lesion site.
Altogether 39 lesions were created, including 8 endocardial CTI (mean lesion length 20.6 ± 1.65 mm), 26 epicardial ventricle (mean lesion length LV: 25.3 ± 1.35 mm, RV: 24.9 ± 2.40 mm), and 5 epicardial appendage ablations (mean lesion length RAA: 26.0 ± 3.16 mm). Transmurality was achieved in all CTI and atrial appendage ablations, in 62% of the RV ablations and in none of the LV ablations. No perforation or steam pop occurred, and no animal died during the procedure.
In this porcine study, the 20-mm linear laser ablation catheter has shown excellent results for endocardial cavotricuspid isthmus ablation, and it resulted in acceptable lesion depth during atrial and ventricular epicardial ablation. The absence of tissue charring, steam pops, or microbubbles under the experimental conditions suggests a high degree of procedural safety.
In persistent atrial fibrillation (AF), localized extra-pulmonary vein sources may contribute to arrhythmia recurrences after pulmonary vein isolation. This in-silico study proposes a high-density ...sequential mapping strategy to localize such sources.
Catheter repositioning was guided by repetitive conduction patterns, moving against the prevailing conduction direction (upstream) toward the sources. Sources were found either by locally identifying conduction patterns or by encircling the region harboring them. We simulated source tracking in an in-silico atrial model, comparing random vs. upstream-guided catheter repositioning (with and without encircling). To assess performance in increasing AF complexities, we simulated AF in 3 groups: atria with reentry-anchoring scars, without fibrosis, and with severe endomysial fibrosis.
Compared to random mapping, the upstream-guided approach successfully located sources more often (anchored reentries: 70.6% vs. 10.6%; no fibrosis: 87.9% vs. 22.1%; with fibrosis: 95.0% vs. 60.9% of tracking procedures, all p<0.001), using fewer steps (median IQR: 11 7;23 vs. 26 13;35; 10 6;19 vs. 19 10;27; 11 7;19 vs. 16 8;30, respectively, all p<0.05). Adding source encircling increased source detection (98.1 %, 100 %, and 99.5 %, all p<0.01 vs. local detection only), reducing required steps (9 6;12, 8 6;12, and 9 6;13, all p<0.05). In some cases (11.9 %, 17.1 %, and 10.5 % of procedures), the algorithm encircled regions >15 mm from the source.
Moving mapping catheters upstream improves source detection efficiency, even in the presence of severe fibrosis. Encircling sources may help find regions of interest in fewer steps.
•Extra-pulmonary vein sources may lead to atrial fibrillation recurrences.•We propose a mapping strategy to find sources from repetitive activation patterns.•Guiding catheters upstream of the conduction direction leads efficiently to sources.•Encircling sources may improve their detection, but slightly reduces accuracy.•The mapping approach was robust to high fibrosis-related AF complexity.
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.
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,
=0.038; RA: +0.94±0.38 μm,
=0.041), whereas total extracellular matrix content was not. Men had larger cardiomyocytes (LA: +1.92±0.72 μm,
<0.001), while women had more endomysial fibrosis (LA: +0.99±0.56 μm,
=0.003). Patients with heart failure showed more endomysial fibrosis (LA: +1.85±0.48 μm,
<0.001) and extracellular matrix content (LA: +3.07±1.29%,
=0.016), and a higher capillary density (LA: +0.13±0.06,
=0.007) and size (LA: +0.46±0.22 μm,
=0.044). Fuzzy k-means clustering of histological features identified 2 subtypes of atCM: 1 characterized by enhanced endomysial fibrosis (LA: +3.17 μm,
<0.001; RA: +2.86 μm,
<0.001), extracellular matrix content (LA: +3.53%,
<0.001; RA: +6.40%,
<0.001) and fibroblast density (LA: +4.38%,
<0.001), and 1 characterized by cardiomyocyte hypertrophy (LA: +1.16 μm,
=0.008; RA: +2.58 μm,
<0.001). Patients with fibrotic atCM were more frequently female (LA: odds ratio OR, 1.33,
=0.002; RA: OR, 1.54,
=0.004), with persistent AF (LA: OR, 1.22,
=0.036) or heart failure (LA: OR, 1.62,
<0.001). Hypertrophic features were more common in men (LA: OR=1.33,
=0.002; RA: OR, 1.54,
=0.004).
Fibrotic atCM is associated with female sex, persistent AF, and heart failure, while hypertrophic features are more common in men.
The pathophysiological relevance of complex fractionated atrial electrograms (CFAE) in atrial fibrillation (AF) remains poorly understood.
The aim of this study was to comprehensively investigate how ...bipolar CFAE correlates with unipolar electrogram fractionation and the underlying electrophysiological substrate of AF.
Ten-second unipolar AF electrograms were recorded using a high-density electrode from the left atrium of 20 patients with AF (10 with persistent AF and 10 with paroxysmal AF) undergoing cardiac surgery. Semiautomated bipolar CFAE algorithms: complex fractionated electrogram-mean, interval confidence interval, continuous electrical activity, average complex interval, and shortest complex interval were evaluated against AF substrate complexity measures following fibrillation wave reconstruction derived from local unipolar activation time. The effect of interelectrode spacing and electrode orientation on bipolar CFAE was also examined.
All 5 semiautomated bipolar CFAE algorithms showed poor correlation with each other and AF substrate complexity measures (conduction velocity, number of waves or breakthroughs per AF cycle, and electrical dissociation). Bipolar CFAE also correlated poorly with fractionation index derived from unipolar electrograms. Increased interelectrode spacing resulted in an increase in bipolar CFAE detected except for the interval confidence interval algorithm. CFAE appears unaffected by bipolar electrode orientation (vertical vs horizontal). By contrast, unipolar fractionation index correlated well with AF substrate complexity measures and can be regarded as a marker for conduction block.
The lack of pathophysiological relevance of bipolar CFAE analysis may in part contribute to the divergent and limited success rates of catheter ablation strategies targeting CFAE.
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