Relevance of Conduction Disorders in Bachmann's Bundle During Sinus Rhythm in Humans.

BACKGROUND: Bachmann's bundle (BB) is considered to be the main route of interatrial conduction and to play a role in development of atrial fibrillation (AF). The goals of this study are to characterize the presence of conduction disorders in BB during sinus rhythm and to study their relation with AF. METHODS AND RESULTS: High-resolution epicardial mapping (192 unipolar electrodes, interelectrode distance: 2 mm) of sinus rhythm was performed in 185 patients during coronary artery bypass surgery of whom 13 had a history of paroxysmal AF. Continuous rhythm monitoring was used to detect postoperative AF during the first 5 postoperative days. In 67% of the patients, BB was activated from right to left; in the remaining patients from right and middle (21%), right, central, and left (8%), or central (4%) site. Mean effective conduction velocity was 89 cm/s. Conduction block was present in most patients (75%; median 1.1%, range 0-12.8) and was higher in patients with paroxysmal AF compared with patients without a history of AF (3.2% versus 0.9%; P=0.03). A high amount of conduction block (>4%) was associated with de novo postoperative AF (P=0.02). Longitudinal lines of conduction block >10 mm were also associated with postoperative AF (P=0.04). CONCLUSIONS: BB may be activated through multiple directions, but the predominant route of conduction is from right to left. Conduction velocity across BB is around 90 cm/s. Conduction is blocked in both longitudinal and transverse direction in the majority of patients. Conduction disorders, particularly long lines of longitudinal conduction block, are more pronounced in patients with AF episodes.

QUest for the Arrhythmogenic Substrate of Atrial fibRillation in Patients Undergoing Cardiac Surgery (QUASAR Study): Rationale and Design.

The heterogeneous presentation and progression of atrial fibrillation (AF) implicate the existence of different pathophysiological processes. Individualized diagnosis and therapy of the arrhythmogenic substrate underlying AF may be required to improve treatment outcomes. Therefore, this single-center study aims to identify the arrhythmogenic areas underlying AF by intra-operative, high-resolution, multi-site epicardial mapping in 600 patients with different heart diseases. Participants are divided into 12 groups according to the underlying heart diseases and presence of prior AF episodes. Mapping is performed with a 192-electrode array for 5-10 s during sinus rhythm and (induced) AF of the entire atrial surface. Local activation times are converted into activation and wave maps from which various electrophysiological parameters are derived. Postoperative cardiac rhythm registrations and a 5-year follow-up will show the incidence of postoperative and persistent AF. This project provides the first step in the development of a tool for individual AF diagnosis and treatment.

Dynamics of Endo- and Epicardial Focal Fibrillation Waves at the Right Atrium in a Patient With Advanced Atrial Remodelling.

Focal waves appear frequently at the epicardium during persistent atrial fibrillation (AF), however, the origin of these waves is under debate. We performed simultaneous endo-epicardial mapping of the right atrial wall during longstanding persistent AF in a patient undergoing cardiac surgery. During 10 seconds 53 and 59 focal waves appeared at random at respectively the endocardium and epicardium. Repetitive focal activity did not last longer than 3 cycles. Transmural asynchrony and conduction might be the origin of focal waves. Asynchronous propagation of fibrillation waves in 3 dimensions would stabilize the arrhythmia and could explain the limited success of persistent AF ablation.

Dynamics of Focal Fibrillation Waves during Persistent Atrial Fibrillation.

The incidence and appearance of focal fibrillation waves on the right and left atrial epicardial surface were visualized during 10 seconds of persistent atrial fibrillation in a 71-year-old woman with valvular heart disease. The frequent, nonrepetitive, widespread, and capricious distribution of focal waves suggests that transmural conduction of fibrillation waves is most likely the mechanism underlying focal fibrillation waves.

HALT & REVERSE: Hsf1 activators lower cardiomyocyt damage; towards a novel approach to REVERSE atrial fibrillation.

BACKGROUND: Atrial fibrillation is a progressive arrhythmia, the exact mechanism underlying the progressive nature of recurrent AF episodes is still unknown. Recently, it was found that key players of the protein quality control system of the cardiomyocyte, i.e. Heat Shock Proteins, protect against atrial fibrillation progression by attenuating atrial electrical and structural remodeling (electropathology). HALT & REVERSE aims to investigate the correlation between electropathology, as defined by endo- or epicardial mapping, Heat Shock Protein levels and development or recurrence of atrial fibrillation following pulmonary vein isolation, or electrical cardioversion or cardiothoracic surgery. STUDY DESIGN: This study is a prospective observational study. Three separate study groups are defined: (1) cardiothoracic surgery, (2) pulmonary vein isolation and (3) electrical cardioversion. An intra-operative high-resolution epicardial (group 1) or endocardial (group 2) mapping procedure of the atria is performed to study atrial electropathology. Blood samples for Heat Shock Protein determination are obtained at baseline and during the follow-up period at 3 months (group 2), 6 months (groups 1 and 2) and 1 year (group 1 and 2). Tissue samples of the right and left atrial appendages in patients in group 1 are analysed for Heat Shock Protein levels and for tissue characteristics. Early post procedural atrial fibrillation is detected by continuous rhythm monitoring, whereas late post procedural atrial fibrillation is documented by either electrocardiogram or 24-h Holter registration. CONCLUSION: HALT & REVERSE aims to identify the correlation between Heat Shock Protein levels and degree of electropathology. The study outcome will contribute to novel diagnostic tools for the early recognition of clinical atrial fibrillation. TRIAL REGISTRATIONS: Rotterdam Medical Ethical Committee MEC-2014-393, Dutch Trial Registration NTR4658.

A novel intra-operative, high-resolution atrial mapping approach.

PURPOSE: A new technique is demonstrated for extensive high-resolution intra-operative atrial mapping that will facilitate the localization of atrial fibrillation (AF) sources and identification of the substrate perpetuating AF. METHODS: Prior to the start of extra-corporal circulation, a 8 × 24-electrode array (2-mm inter-electrode distance) is placed subsequently on all the right and left epicardial atrial sites, including Bachmann's bundle, for recording of unipolar electrograms during sinus rhythm and (induced) AF. AF is induced by high-frequency pacing at the right atrial free wall. A pacemaker wire stitched to the right atrium serves as a reference signal. The indifferent pole is connected to a steal wire fixed to subcutaneous tissue. Electrograms are recorded by a computerized mapping system and, after amplification (gain 1000), filtering (bandwidth 0.5-400 Hz), sampling (1 kHz) and analogue to digital conversion (16 bits), automatically stored on hard disk. During the mapping procedure, real-time visualization secures electrogram quality. Analysis will be performed offline. RESULTS: This technique was performed in 168 patients of 18 years and older, with coronary and/or structural heart disease, with or without AF, electively scheduled for cardiac surgery and a ventricular ejection fraction above 40 %. The mean duration of the entire mapping procedure including preparation time was 9 ± 2 min. Complications related to the mapping procedure during or after cardiac surgery were not observed. CONCLUSIONS: We introduce the first epicardial atrial mapping approach with a high resolution of ≥1728 recording sites which can be performed in a procedure time of only 9±2 mins. This mapping technique can potentially identify areas responsible for initiation and persistence of AF and hopefully can individualize both diagnosis and therapy of AF.

Electrophysiological effects of acute atrial stretch on persistent atrial fibrillation in patients undergoing open heart surgery.

BACKGROUND: The electrophysiologic effects of acute atrial dilatation and dedilatation in humans with chronic atrial fibrillation remains to be elucidated. OBJECTIVE: To study the electrophysiological effects of acute atrial dedilatation and subsequent dilatation in patients with long-standing persistent atrial fibrillation (AF) with structural heart disease undergoing elective cardiac surgery. METHODS: Nine patients were studied. Mean age was 71 ± 10 years, and left ventricular ejection was 46% ± 6%. Patients had at least moderate mitral valve regurgitation and dilated atria. After sternotomy and during extracorporal circulation, mapping was performed on the beating heart with 2 multielectrode arrays (60 electrodes each, interelectrode distance 1.5 mm) positioned on the lateral wall of the right atrium (RA) and left atrium (LA). Atrial pressure and size were altered by modifying extracorporal circulation. AF electrograms were recorded at baseline after dedilation and after dilatation of the atria afterward. RESULTS: At baseline, the median AF cycle length (mAFCL) was 184 ± 27 ms in the RA and 180 ± 17 ms in the LA. After dedilatation, the mAFCL shortened significantly to 168 ± 13 ms in the RA and to 168 ± 20 ms in the LA. Dilatation lengthened mAFCL significantly to 189 ± 17 ms in the RA and to 185 ± 23 ms in the LA. Conduction block (CB) at baseline was 14.3% ± 3.6% in the RA and 17.3% ± 5.5% in the LA. CB decreased significantly with dedilatation to 7.4% ± 2.9% in the RA and to 7.9% ± 6.3% in the LA. CB increased significantly with dilatation afterward to 15.0% ± 8.3% in the RA and to 18.5% ± 16.0% in the LA. CONCLUSIONS: Acute dedilatation of the atria in patients with long-standing persistent AF causes a decrease in the mAFCL in both atria. Subsequent dilatation increased the mAFCL. The amount of CB decreased with dedilatation and increased with dilatation afterward in both atria.

Electropathological substrate of longstanding persistent atrial fibrillation in patients with structural heart disease: epicardial breakthrough.

BACKGROUND: During persistent atrial fibrillation (AF), waves with a focal spread of activation are frequently observed. The origin of these waves and their relevance for the persistence of AF are unknown. METHODS AND RESULTS: In 24 patients with longstanding persistent AF and structural heart disease, high-density mapping of the right and left atria was performed during cardiac surgery. In a reference group of 25 patients, AF was induced by rapid pacing. For data analysis, a mapping algorithm was developed that separated the fibrillatory process into its individual wavelets and identified waves with a focal origin. During persistent AF, the incidence of focal fibrillation waves in the right atrium was almost 4-fold higher than during acute AF (median, 0.46 versus 0.12 per cycle per 1 cm² (25th to 75th percentile, 0.40 to 0.77 and 0.01 to 0.27; P<0.0001). They were widely distributed over both atria and were recorded at 46 ± 18 of all electrodes. A large majority (90.5) occurred as single events. Repetitive focal activity (>3) happened in only 0.8. The coupling interval was not more than 11 ms shorter than the average AF cycle length (P=0.04), and they were not preceded by a long interval. Unipolar electrograms at the site of origin showed small but clear R waves. These data favor epicardial breakthrough rather than a cellular focal mechanism as the underlying mechanism. Often, conduction from a site of epicardial breakthrough was blocked in 1 or more directions. This generated separate multiple wave fronts propagating in different directions over the epicardium. CONCLUSIONS: Focal fibrillation waves are due to epicardial breakthrough of waves propagating in deeper layers of the atrial wall. In patients with longstanding AF, the frequency of epicardial breakthroughs was 4 times higher than during acute AF. Because they provide a constant source of independent fibrillation waves originating over the entire epicardial surface, they offer an adequate explanation for the high persistence of AF in patients with structural heart disease.

Electropathological substrate of long-standing persistent atrial fibrillation in patients with structural heart disease: longitudinal dissociation.

BACKGROUND: The electropathological substrate of persistent atrial fibrillation (AF) in humans is largely unknown. The aim of this study was to compare the spatiotemporal characteristics of the fibrillatory process in patients with normal sinus rhythm and long-standing persistent AF. METHODS AND RESULTS: During cardiac surgery, epicardial mapping (244 electrodes) of the right atrium (RA), the left lateral wall (LA), and the posterior left atrium (PV) was performed in 24 patients with long-standing persistent AF. Twenty-five patients with normal sinus rhythm, in whom AF was induced by rapid pacing, served as a reference group. A mapping algorithm was developed that separated the complex fibrillation process into its individual elements (wave mapping). Parameters used to characterize the substrate of AF were (1) the total length of interwave conduction block, (2) the number of fibrillation waves, and (3) the ratio of block to collision of fibrillation waves (dissociation index). In 4403 maps of persistent AF, no evidence for the presence of stable foci or rotors was found. Instead, many narrow wavelets propagated simultaneously through the atrial wall. The lateral boundaries of these waves were formed by lines of interwave conduction block, predominantly oriented parallel to the atrial musculature. Lines of block were not fixed but continuously changed on a beat-to-beat basis. In patients with persistent AF, the total length of block in the RA was more than 6-fold higher than during acute AF (median, 21.1 versus 3.4 mm/cm(2); P<0.0001). The highest degree of interwave conduction block was found in the PV area (33.0 mm/cm(2)). The number of fibrillation waves during persistent AF was 4.5/cm(2) compared with 2.3 during acute AF, and the dissociation index was 7.3 versus 1.5 (P<0.0001). The interindividual variation of these parameters among patients was high. CONCLUSIONS: Electric dissociation of neighboring atrial muscle bundles is a key element in the development of the substrate of human AF. The degree of the pathological changes can be measured on an individual basis by electrophysiological parameters in the spatial domain.

Analysis of fractionated atrial fibrillation electrograms by wavelet decomposition.

This study introduces the use of wavelet decomposition of unipolar fibrillation electrograms for the automatic detection of local activation times during complex atrial fibrillation (AF). The purpose of this study was to evaluate this technique in patients with structural heart disease and longstanding persistent AF. In 46 patients undergoing cardiac surgery, unipolar fibrillation electrograms were recorded from the right atrium, using a mapping array of 244 electrodes. In 25 patients with normal sinus rhythm, AF was induced by rapid pacing, whereas 21 patients were in persistent AF. In patients with longstanding AF, the atrial electrograms showed a high degree of fractionation. In each patient, 12 s of AF were analyzed by wavelet transformation (15 scales). The finest scales (1-7) were used to reconstruct a "local" fibrillation electrogram, whereas with the coarse scales (9-15), a far-field signal was generated. With these local and far-field electrograms, the "primary" fibrillation potentials, due to wave propagation underneath the electrode, could be distinguished from double potentials and multiple components generated by remote wavefronts. Wavelet transformation resulted in AF histograms with a closely gaussian distribution and the automatically generated activation maps showed a good resemblance with fibrillation maps obtained by laborious manual editing. A special chaining algorithm was developed to detect multiple components in fractionated electrograms. The degree of fractionation showed a positive correlation with the complexity of fibrillation, thus providing an objective quantification of the degree of electrical dissociation of the atria. Wavelet transformation can be a useful technique to detect the primary potentials and quantify the degree of fractionation of fibrillation electrograms. This could enable real-time mapping of complex cases of human AF and classification of the underlying electropathological substrate.

Automatic mapping of human atrial fibrillation by template matching.

BACKGROUND: The high spatiotemporal variation in morphology of fibrillation electrograms makes mapping of atrial fibrillation (AF) a difficult and burdensome task. OBJECTIVES: The purpose of this study was to evaluate the results of automatic detection of fibrillation electrograms by a template matching technique. METHODS: During cardiac surgery in 25 patients without a history of AF, paroxysms of AF were induced by rapid atrial pacing. A mapping array of 244 unipolar electrodes (3.6-cm diameter, 2.25-mm interelectrode distance) was positioned on the free wall of the right atrium. All fibrillation electrograms were correlated with a mathematically constructed library of 128 potentials of different duration, RS ratio, and short double components. The moments of maximal correlation, coinciding with the negative deflection in the fibrillation potentials, were used to create fibrillation maps. RESULTS: In each patient, a segment of 18.6 +/- 3.8 seconds of AF was analyzed, resulting in 80 to 130 maps per patient. The output of the automatic algorithm was compared with careful manual analysis by an experienced investigator. Of the total database of 398,796 fibrillation potentials, 93.6% +/- 4.2% resulted in a good correlation with one of the templates in the library (correlation coefficient >= 0.7). At a correlation threshold of 0.6, on average template matching yielded slightly more false-positive than false-negative detections (sensitivity 96.6% +/- 2.5%, positive predictive value 94.3% +/- 5.4%). The majority of false-positive detections were due to electrotonic potentials recorded along the lateral boundaries of the fibrillation waves. This led to a slight overlap of fibrillation waves but not to false detection of nonexisting wavefronts. Undersensing was mainly due to the presence of long double and fractionated potentials (2.6%) that were not represented in the template library. Fractionated parts in the electrograms were identified by failure of template matching and can be analyzed separately. CONCLUSION: Template matching is a useful technique for characterizing unipolar fibrillation electrograms and for visualizing the complex activation patterns during AF. It allows automatic evaluation of the electropathologic substrate of AF on an individual basis.

Evaluation of epicardial microwave ablation lesions: histology versus electrophysiology.

BACKGROUND: Pulmonary vein isolation is a hallmark in current surgical ablation for atrial fibrillation. However, validation of isolation remains cumbersome. We evaluated electrophysiologic and not histologic means to test isolation. METHODS: In 16 mongrel dogs, robot-assisted epicardial beating-heart microwave ablation (FLEX 10) was performed around the pulmonary veins. Electrophysiologic isolation was tested by pacing at 4 times threshold values inside and outside the pulmonary veins (exit and entrance block). The histology of lesions was studied for transmurality and continuity of the lesion lines. In 5 dogs, lesions were studied at various time intervals. RESULTS: Histologic evaluation of the lesions showed incomplete (48% +/- 20%) circumferential myocardial damage in all dogs with acute lesions. Electrophysiologic evaluation showed completion of the box (entrance and exit block) in 8 dogs and in another 5 dogs after repeated ablation (p < 0.01 compared with histologic evaluation). Electrophysiologic evaluation of the dogs with chronic lesions showed completed lesions in 4 of 5 dogs directly after ablation. At follow-up (1 to 3 weeks), the isolations remained electrophysiologically complete. Histologic evaluation of the lesions 1 to 3 weeks after ablation showed complete (100%) circumferential lesions in all 4 dogs (p < 0.001 compared with the histology of dogs with acute lesions). CONCLUSIONS: Directly after treatment, ablation lesions are best evaluated electrophysiologically, because complete (transmural and circumferential) lesions are not shown by histologic evaluation in the acute stage. After 1 to 3 weeks, the histology is in accordance with the electrophysiology. To obtain a complete isolation, online electrophysiologic evaluation during pulmonary vein microwave ablation is necessary to optimize the results.

S-wave predominance of epicardial electrograms during atrial fibrillation in humans: indirect evidence for a role of the thin subepicardial layer.

OBJECTIVES: The purpose of this study was to characterize the morphology of fibrillation electrograms in patients in order to provide insight into the underlying electropathologic substrate of atrial fibrillation (AF). BACKGROUND: Electrograms recorded during AF show a high degree of spatiotemporal variation. METHODS: AF was induced by rapid atrial pacing in 25 patients undergoing cardiac surgery. A unipolar mapping array of 244 electrodes was positioned on the free wall of the right atrium to record multiple epicardial fibrillation electrograms. Local anisotropy in conduction and epicardial wavefront curvature during AF were determined by fitting the best quadratic surface on the activation times of rectangular areas of 3 x 3 electrodes. RESULTS: During AF, unipolar epicardial electrograms revealed a clear predominance of S waves. The average RS difference during type I and II AF was -0.15 +/- 0.08 and -0.22 +/- 0.08. During type III AF, the predominance of S waves was less prominent (-0.07 +/- 0.05; P < .005). In all types of AF, the degree of anisotropy in conduction was remarkably low (anisotropy ratio: 1.24 +/- 0.09), and no clear directional effect on the relative amplitude of R and S waves was found. There was a weak relationship between local curvature of wavefronts and RS difference (r = 0.23; P < .01). Computer simulations showed that the negative RS difference could result from transmural activation in an epicardial to endocardial direction. CONCLUSIONS: The clear predominance of S waves in epicardial fibrillation electrograms is not due to anisotropy and can only be partly explained by a high curvature of fibrillation waves. Predominant epicardial to endocardial activation seems to be important in producing rS electrograms on the epicardium. This finding provides indirect evidence that the thin epicardial layer of atrial myocardium plays an important role in propagation of fibrillation waves.

The L-type Ca2+-channel subunits alpha1C and beta2 are not downregulated in atrial myocardium of patients with chronic atrial fibrillation.

OBJECTIVE: Electrical remodeling as well as atrial contractile dysfunction after the conversion of atrial fibrillation (AF) to sinus rhythm (SR) are mainly caused by a reduction of the inward L-type Ca(2+) current (I(CaL)). We investigated whether the expression of L-type Ca2+-channel subunits was reduced in atrial myocardium of AF patients. METHODS: Right atrial appendages were obtained from patients undergoing coronary artery bypass graft surgery (CAD, n = 35) or mitral valve surgery (MVD, n = 37). Seventeen of the CAD patients and 18 of the MVD patients were in chronic (>3 months) AF, whereas the others were in SR. The protein expression of the L-type Ca2+-channel subunits alpha1C and beta2 was quantified by western blot analysis. Furthermore, we measured the density of dihydropyridine (DHP)-binding sites of the L-type Ca2+ channel using 3H-PN220-100 as radioligand. RESULTS: Surprisingly, the alpha1C and the beta2-subunit expression was not altered in atrial myocardium of AF patients. Also, the DHP-binding site density was unchanged. CONCLUSION: The protein expression of the L-type Ca2+-channel subunits alpha1C or beta2 is not reduced in atrial myocardium of AF patients. Therefore, the reduced I(CaL) might be due to downregulation of other accessory subunits (alpha2delta), expression of aberrant subunits, changes in channel trafficking or alterations in channel function.