Bart Maesen

Post-operative atrial fibrillation: a maze of mechanisms

Post-operative atrial fibrillation (POAF) is one of the most frequent complications of cardiac surgery and an important predictor of patient morbidity as well as of prolonged hospitalization. It significantly increases costs for hospitalization. Insights into the pathophysiological factors causing POAF have been provided by both experimental and clinical investigations and show that POAF is ‘multi-factorial’. Facilitating factors in the mechanism of the arrhythmia can be classified as acute factors caused by the surgical intervention and chronic factors related to structural heart disease and ageing of the heart. Furthermore, some proarrhythmic mechanisms specifically occur in the setting of POAF. For example, inflammation and beta-adrenergic activation have been shown to play a prominent role in POAF, while these mechanisms are less important in non-surgical AF. More recently, it has been shown that atrial fibrosis and the presence of an electrophysiological substrate capable of maintaining AF also promote the arrhythmia, indicating that POAF has some proarrhythmic mechanisms in common with other forms of AF. The clinical setting of POAF offers numerous opportunities to study its mechanisms. During cardiac surgery, biopsies can be taken and detailed electrophysiological measurements can be performed. Furthermore, the specific time course of POAF, with the delayed onset and the transient character of the arrhythmia, also provides important insight into its mechanisms. This review discusses the mechanistic interaction between predisposing factors and the electrophysiological mechanisms resulting in POAF and their therapeutic implications.

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 substrate.

Transmural conduction is the predominant mechanism of breakthrough during atrial fibrillation: evidence from simultaneous endo-epicardial high-density activation mapping.

Background—Endo-epicardial dissociation (EED) of electric activations resulting in transmural conduction of fibrillation waves (breakthroughs) has been postulated to contribute to the complexity of the substrate of atrial fibrillation (AF). The aim of this study was to elucidate the correlation between EED and incidence of breakthrough and to test the plausibility of transmural conduction versus ectopic focal discharges as sources of breakthrough. Methods and Results—We analyzed high-resolution simultaneous endo-epicardial in vivo mapping data recorded in left atrial free walls of goats with acute AF, 3 weeks and 6 months of AF (all n=7). Waves were analyzed for number, size, and width and categorized according to their origin outside (peripheral wave) or within the mapping area (breakthrough). Breakthrough incidence was lowest (2.1±1.0%) in acute AF, higher (11.4±6.1%) after 3 weeks (P<0.01 versus acute AF) and highest (14.2±3.8%) after 6 months AF (P<0.001 versus acute AF) and similar in the epicardium and endocardium. Most of the breakthroughs (86%; n=564) could be explained by transmural conduction, whereas only 13% (n=85) could be explained by ectopic focal discharges. Transmural microreentry did not play a role as source of breakthrough. Conclusions—This is the first study to present simultaneous endo-epicardial in vivo mapping data at sites of breakthrough events. Breakthrough incidence and degree of EED increased with increasing AF substrate complexity. In goat left atrial free walls, most of the breakthroughs can be explained by transmural conduction, whereas ectopic focal discharges play a limited role as source of breakthrough.Background— Endo-epicardial dissociation (EED) of electric activations resulting in transmural conduction of fibrillation waves (breakthroughs) has been postulated to contribute to the complexity of the substrate of atrial fibrillation (AF). The aim of this study was to elucidate the correlation between EED and incidence of breakthrough and to test the plausibility of transmural conduction versus ectopic focal discharges as sources of breakthrough. Methods and Results— We analyzed high-resolution simultaneous endo-epicardial in vivo mapping data recorded in left atrial free walls of goats with acute AF, 3 weeks and 6 months of AF (all n=7). Waves were analyzed for number, size, and width and categorized according to their origin outside (peripheral wave) or within the mapping area (breakthrough). Breakthrough incidence was lowest (2.1±1.0%) in acute AF, higher (11.4±6.1%) after 3 weeks ( P <0.01 versus acute AF) and highest (14.2±3.8%) after 6 months AF ( P <0.001 versus acute AF) and similar in the epicardium and endocardium. Most of the breakthroughs (86%; n=564) could be explained by transmural conduction, whereas only 13% (n=85) could be explained by ectopic focal discharges. Transmural microreentry did not play a role as source of breakthrough. Conclusions— This is the first study to present simultaneous endo-epicardial in vivo mapping data at sites of breakthrough events. Breakthrough incidence and degree of EED increased with increasing AF substrate complexity. In goat left atrial free walls, most of the breakthroughs can be explained by transmural conduction, whereas ectopic focal discharges play a limited role as source of breakthrough.

Reconstruction of instantaneous phase of unipolar atrial contact electrogram using a concept of sinusoidal recomposition and Hilbert transform

The Hilbert transform has been used to characterize wave propagation and detect phase singularities during cardiac fibrillation. Two mapping modalities have been used: optical mapping (used to map atria and ventricles) and contact electrode mapping (used only to map ventricles). Due to specific morphology of atrial electrograms, phase reconstruction of contact electrograms in the atria is challenging and has not been investigated in detail. Here, we explore the properties of Hilbert transform applied to unipolar epicardial electrograms and devise a method for robust phase reconstruction using the Hilbert transform. We applied the Hilbert transform to idealized unipolar signals obtained from analytical approach and to electrograms recorded in humans. We investigated effects of deflection morphology on instantaneous phase. Application of the Hilbert transform to unipolar electrograms demonstrated sensitivity of reconstructed phase to the type of deflection morphology (uni- or biphasic), the ratio of R and S waves and presence of the noise. In order to perform a robust phase reconstruction, we propose a signal transformation based on the recomposition of the electrogram from sinusoidal wavelets with amplitudes proportional to the negative slope of the electrogram. Application of the sinusoidal recomposition transformation prior to application of the Hilbert transform alleviates the effect of confounding features on reconstructed phase.

Stability of Complex Fractionated Atrial Electrograms: A Systematic Review

Stability of CFAE. Introduction: The efficacy of complex fractionated atrial electrograms (CFAE) ablation as additional substrate modification in atrial fibrillation (AF) patients has been shown to be highly variable. Recently, the validity of sequential CFAE mapping has been challenged by concerns regarding temporal stability of CFAE. Existing studies on CFAE stability are small with very different CFAE definitions. Here, we undertook a systematic literature review to address these controversial findings.

Indices of bipolar complex fractionated atrial electrograms correlate poorly with each other and atrial fibrillation substrate complexity

BACKGROUND The pathophysiological relevance of complex fractionated atrial electrograms (CFAE) in atrial fibrillation (AF) remains poorly understood. OBJECTIVE The aim of this study was to comprehensively investigate how bipolar CFAE correlates with unipolar electrogram fractionation and the underlying electrophysiological substrate of AF. METHODS 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. RESULTS 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. CONCLUSION 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.

Rearrangement of Atrial Bundle Architecture and Consequent Changes in Anisotropy of Conduction Constitute the 3-Dimensional Substrate for Atrial Fibrillation

Background— Anisotropy of conduction facilitates re-entry and is, therefore, a key determinant of the stability of atrial fibrillation (AF). Little is known about the effect of AF on atrial bundle architecture and consequent changes in anisotropy of conduction and maintenance of AF. Methods and Results— Direct contact mapping was performed in left atria of goats with acute AF (n=6) or persistent AF (n=5). The degree and direction of anisotropic conduction were analyzed. Mapped tissue regions were imaged by high-resolution MRI for identification of endocardial and epicardial bundle directions. Correlation between endocardial and epicardial bundle directions and between bundle directions and anisotropic conduction was quantified. In persistent AF, epicardial bundles were oriented more perpendicularly to endocardial bundles than in acute AF (% angles <20° between epicardial and endocardial bundle directions were 7.63% and 21.25%, respectively; P<0.01). In acute AF, the direction of epicardially mapped anisotropic conduction correlated with endocardial but not with epicardial bundles. In persistent AF, the direction of anisotropic conduction correlated better with epicardial than with endocardial bundles (% angles <20° between direction of anisotropic conduction and bundle direction were 28.77% and 18.45%, respectively; P<0.01). Conclusions— During AF, atrial bundle rearrangement manifests itself in more perpendicular orientation of epicardial to endocardial bundles. Propagation of fibrillation waves is dominated by endocardial bundles in acute AF and by epicardial bundles in persistent AF. Together with the loss of endo-epicardial electrical connections, rearrangement of atrial bundles underlies endo-epicardial dissociation of electrical activity and the development of a 3-dimensional AF substrate.

The need for standardization of time- and frequency-domain analysis of body surface electrocardiograms for assessment of the atrial fibrillation substrate

This editorial refers to ‘Measures of spatiotemporal organization differentiate persistent from long-standing atrial fibrillation’ by L. Uldry et al ., on page 1125 Despite some progress in the earlier decades, the current therapy of atrial fibrillation (AF) is still far from being satisfactory. Antiarrhythmic drugs can restore sinus rhythm only during the first few days after onset of the arrhythmia, are unable to effectively prevent recurrence of AF, and their use carries substantial risk of pro-arrhythmia. Catheter or surgical ablation therapy is effective in patients with paroxysmal AF, but its efficacy to cure persistent AF is still under debate. Moreover, AF ablation is afflicted with a number of potentially serious side effects. Preclinical as well as clinical investigations demonstrate that rhythm control therapy is more successful in individuals with low degree of structural remodelling in the atria. Structural heart diseases and AF itself cause cellular hypertrophy, interstitial fibrosis, inflammatory changes, and amyloidosis, which, in turn, lead to progressive electrical uncoupling between muscle bundles and conduction disturbances. Recent direct contact mapping studies in patients with AF have provided evidence that these alterations result in an increased incidence of conduction block and a higher number and smaller size of separate fibrillation waves.1 This enhancement in the complexity of the substrate for AF is regarded as the key mechanism underlying increasing stability of the arrhythmia in structurally remodelled atria.2 Thus, non-invasive tools for the assessment of AF complexity might be of value for better identification of patients in whom sinus rhythm can be restored and successfully maintained. Quantification of the AF substrate by advanced analysis of surface ECGs appears to be a logical step towards non-invasive quantification of the individual degree of electropathological alterations in the atria. The study by Uldry et al 3 . published in this issue of the Journal …

Automated quantification of atrial fibrillation complexity by probabilistic electrogram analysis and fibrillation wave reconstruction

The analysis of high-density activation maps of atrial fibrillation (AF) provides fundamental insights into the fibrillation wave propagation patterns and thus the mechanisms of AF. Current annotation of local activations in unipolar atrial electrograms and the construction of fibrillation waves require labor-intensive manual editing. To enhance the possibilities for spatiotemporal analysis of AF, we developed a rapid and fully automated procedure to accurately identify local, intrinsic atrial deflections and construct fibrillation waves based on these deflections. In this study, the automated procedure was validated using manually annotated electrograms and wave maps. We show that the novel procedure accurately detects intrinsic deflections (sensitivity=87%, positive predictive value=89%) and that reconstructed wave maps correlate well with manually edited wave maps in terms of number of waves (r=0.96), intra-wave conduction velocity (r=0.97), AF cycle length (r=0.97), and wave size (r=0.96) (p<;60;0.01 in all cases). The automated procedure is therefore an adequate substitute for manual annotation.

A prospective randomized controlled trial on the incidence and predictors of late-phase postoperative atrial fibrillation up to 30 days and the preventive value of biatrial pacing

BACKGROUND Postoperative atrial fibrillation (POAF) is considered to be a transient arrhythmia in the first week after cardiac surgery. OBJECTIVE To determine the 30-day incidence and predictors of POAF and the value of postoperative overdrive biatrial pacing in the prevention of POAF. METHODS Patients (n = 148) without a history of atrial fibrillation undergoing aortic valve replacement or coronary artery bypass graft (CABG) were randomized into a pacing group (n = 75) and a control group. Patients were treated with standardized sotalol postoperatively. Rhythm was continuously monitored for 30 days by a transtelephonic event recorder. RESULTS POAF occurred in 73 (49.3%) patients, of whom 60 (40.5%) patients showed POAF during postoperative days (PODs) 0-5 and 37 (25%) patients during PODs 6-30. Prolonged aortic cross-clamp time was an important univariate predictor of 30-day and of late POAF (PODs 6-30; P = .017 and P = .03, respectively). Best-fit model analysis using 15 predetermined risk factors for POAF showed different positive interactive effects for early POAF (ie, baseline C-reactive protein levels with a history of myocardial infarction or low body mass index) and late POAF (ie, high body mass index, diabetes mellitus, baseline C-reactive protein, early POAF, creatinine levels, type of operation, smoking, and male gender). Biatrial pacing reduced the late POAF incidence in patients with aortic cross-clamp time >50 minutes (P = .006). CONCLUSION POAF is not limited to the first week after cardiac surgery but also occurs frequently in the postoperative month. It is desirable to regularly follow patients with POAF for atrial fibrillation recurrences after discharge.