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Arrhythmogenic Substrate of the Pulmonary Veins Assessed by High-Resolution Optical Mapping
Abstract
It has recently been recognized that atrial fibrillation can originate from focal sources in the pulmonary veins (PVs). However, the mechanisms of focal atrial fibrillation have not been well characterized. We assessed the electrophysiological characteristics of the PVs using high-resolution optical mapping.
Coronary-perfused, isolated whole-atrial preparations from 33 normal dogs were studied. Programmed electrical stimulation was performed, and a 4-cm2 area of the PV underwent optical mapping of transmembrane voltage to obtain 256 simultaneous action potentials. Marked conduction slowing was seen at the proximal PV, compared with the rest of the vein, on both the epicardial (31.3+/-4.47 versus 90.2+/-20.7 cm/s, P=0.001) and endocardial (45.8+/-6.90 versus 67.6+/-10.4 cm/s, P=0.012) aspects. Pronounced repolarization heterogeneity was also noted, with action potential duration at 80% repolarization being longest at the PV endocardium. Nonsustained reentrant beats were induced with single extrastimuli, and the complete reentrant loop was visualized (cycle length, 155+/-30.3 ms); reentrant activity could be sustained with isoproterenol. Sustained focal discharge (cycle length, 330 to 1100 ms) was seen from the endocardial surface in the presence of isoproterenol; each focus was localized near the venous ostium.
The normal PV seems to have the necessary substrate to support reentry as well as focal activity. Although reentry occurred more distally in the vein, focal activity seemed to occur more proximally.
... On the other hand, several studies have reported that the presence of effective refractory period (ERP) heterogeneity and anisotropic conduction properties within the PVs and at the PV-left atrium (LA) junction may be crucial to promote re-entry formation and thus might play an important role as a substrate for the maintenance of AF [6][7][8]. Jaïs et al. showed that the ERP of the PV ostia were shorter than that of the LA, possibly explaining not only the presence of ectopic foci in PVs, but also sustained fibrillatory activity in the PVs [9]. Lin et al. have also said that the highest dominant frequency was observed inside or around the ostium of the arrhythmogenic PV, resulting in the frequency gradient between the arrhythmogenic vein and atrium [10]. ...
... Regarding the spatial dispersion in refractory periods, several studies have reported that the ERP of the PV or PV ostium was significantly shorter than that of the LA [7,9,10,15,20,21]. On the other hand, conduction abnormalities such as conduction delay and conduction heterogeneity have been seen in the PV in other studies [7,8]. The complex arrangement of myocardial fibers at the PV ostium is a possible reason for conduction abnormalities in the area of PV ostium [6,21,22], forming the functional block or slow conduction, resulting in unstable reentrant circuits such as pivoting activation, wave breakup, and wave fusion in the area of the PV and/or PV ostium. ...
... Although the frequency of activation sequences was different between the LA and PV groups, AF was terminated by only PV isolation in all patients in this study. The PV have played an important role not only as a source of ectopic foci [1][2][3] but also the driver for sustained fibrillatory activities [7][8][9][10]. Furthermore, the frequency of pivoting activation, wave breakup, and wave fusion were decreased by the lesion of PV isolation in this study. ...
Background:
It has been shown that most paroxysmal atrial fibrillation (AF) can be terminated by pulmonary vein (PV) isolation alone, suggesting that rapid discharges from PV drive AF. To define the driving mechanism of AF, we compared the activation sequence in the body of left atrium (LA) to that within PV.
Methods:
Endocardial noncontact mapping of LA body (LA group; n = 16) and selective endocardial mapping of left superior PV (LSPV) (PV group; n = 13) were performed in 29 paroxysmal AF patients. The frequency of pivoting activation, wave breakup, and wave fusion observed in LA were compared to those in LSPV to define the driving mechanism of AF. Circumferential ablation lesion around left PV was performed after right PV isolation to examine the effect of linear lesion around PV on AF termination both in LA and PV groups.
Results:
The frequency of pivoting activation, wave breakup, and wave fusion in PV group were significantly higher than those in LA group (36.5 ± 17.7 vs 5.0 ± 2.2 times/seconds, p < 0.001, 10.1 ± 4.3 vs 5.0 ± 2.2 times/seconds, p = 0.004, 18.1 ± 5.7 vs 11.0 ± 5.2, p = 0.002). Especially in the PV group, the frequency of pivoting activation was significantly higher than that of wave breakup and wave fusion (36.5 ± 17.7 vs 10.1 ± 4.3 times/seconds, p < 0.001, 36.5 ± 17.7 vs 18.1 ± 5.7 times/seconds, p < 0.001). These disorganized activations in LSPV were eliminated by the circumferential ablation lesion around left PV (pivoting activation; 36.5 ± 17.7 vs 9.3 ± 2.3 times/seconds, p < 0.001, wave breakup; 10.1±1.3 times/seconds, p = 0.003, wave fusion; 18.1 ± 5.7 vs 5.7 ± 1.8, p < 0.001), resulted in AF termination in all patients in both LA and PV groups.
Conclusions:
Activation sequence within PV was more disorganized than that in LA body. Frequent episodes of pivoting activation rather than wave breakup and fusion observed within PV acted as the driving sources of paroxysmal AF.
... Experimental studies have demonstrated that a high frequency ectopic activity contributes to the generation of fibrillatory conduction (19,22,27,28). A single focal trigger may result in a rapid reentrant circuit or rotor maintained in the PVs, since a tight-coupled extra-stimulus within PVs or in its proximities can result in unidirectional conduction block and reentry (27,29). ...
... Experimental studies have demonstrated that a high frequency ectopic activity contributes to the generation of fibrillatory conduction (19,22,27,28). A single focal trigger may result in a rapid reentrant circuit or rotor maintained in the PVs, since a tight-coupled extra-stimulus within PVs or in its proximities can result in unidirectional conduction block and reentry (27,29). Other functional regions, such as the left atrial free wall, superior vena cava, inferior vena cava, crista terminalis, coronary sinus and interatrial septum, have also been found to play critical roles in the initiation of AF. ...
... Other functional regions, such as the left atrial free wall, superior vena cava, inferior vena cava, crista terminalis, coronary sinus and interatrial septum, have also been found to play critical roles in the initiation of AF. Besides in many patients it is possible that multiple ectopic foci co-exist (12,13,27,28,30,31), and their interactions may generate complex atrial conduction patterns facilitating the development and maintenance of AF. ...
Atrial fibrillation (AF) is the most common tachyarrhythmia. It has been demonstrated that extra-stimuli could act as triggers for AF. In many patients it is possible that multiple ectopic foci co-exist, and their interactions may generate complex conduction patterns. Our goal is to investigate the influence of the focus frequency, conduction velocity, and anisotropy on fibrillatory pattern generation during the interaction of multiple ectopic activities under electrical remodeling conditions. Our results support the broadly accepted theory that ectopic activity acting in remodeled tissue is an initiator of reentrant mechanisms. These reentrant circuits can generate fibrillatory activity when interacting with other rapid ectopic foci and under the following conditions: high ectopic focus frequency, slow conduction velocity, and anisotropic tissue. Analyses of electrogram polymorphism allow determination of which zones of tissue permit one to know in which zone of tissue unstable activity exists. Our results give useful insights into the electrophysiological parameters that determine the initiation and maintenance of fibrillatory conduction by two ectopic foci interaction in a simulated two-dimensional sheet of human atrial cells, under chronic AF conditions.
... To cover the clinically observed range of PV CVs, longitudinal and transverse tissue conductivities were divided by 1, 2, 3 or 5, resulting in CVs, measured along the PV axis, in the range: 0.28-0.67m/s [3,[21][22][23][24]. To model heterogeneous conduction slowing, conductivities were varied as a function of distance from the LA/PV junction, ranging from baseline at the Pulmonary vein electrophysiology, fibrosis and arrhythmia junction to a maximum rescaling (minimum conductivity) at the distal boundary. ...
... PV repolarisation is heterogeneous in the PVs [23], and exhibits distinct properties in AF patients, with Rostock et al. reporting a greater decrease in PV ERP than LA ERP in patients with AF, termed AF begets AF in the PVs [21]. Jais et al. found that PV ERP is greater than LA ERP in AF patients, but this gradient is reversed in AF patients [3]. ...
... Multiple studies have measured conduction slowing in the PVs [3,5,[21][22][23][24]. We modelled changes in tissue conductivity either homogeneously, or as a function of distance along the PV. ...
Success rates for catheter ablation of persistent atrial fibrillation patients are currently low; however, there is a subset of patients for whom electrical isolation of the pulmonary veins alone is a successful treatment strategy. It is difficult to identify these patients because there are a multitude of factors affecting arrhythmia susceptibility and maintenance, and the individual contributions of these factors are difficult to determine clinically. We hypothesised that the combination of pulmonary vein (PV) electrophysiology and atrial body fibrosis determine driver location and effectiveness of pulmonary vein isolation (PVI). We used bilayer biatrial computer models based on patient geometries to investigate the effects of PV properties and atrial fibrosis on arrhythmia inducibility, maintenance mechanisms, and the outcome of PVI. Short PV action potential duration (APD) increased arrhythmia susceptibility, while longer PV APD was found to be protective. Arrhythmia inducibility increased with slower conduction velocity (CV) at the LA/PV junction, but not for cases with homogeneous CV changes or slower CV at the distal PV. Phase singularity (PS) density in the PV region for cases with PV fibrosis was increased. Arrhythmia dynamics depend on both PV properties and fibrosis distribution, varying from meandering rotors to PV reentry (in cases with baseline or long APD), to stable rotors at regions of high fibrosis density. Measurement of fibrosis and PV properties may indicate patient specific susceptibility to AF initiation and maintenance. PV PS density before PVI was higher for cases in which AF terminated or converted to a macroreentry; thus, high PV PS density may indicate likelihood of PVI success.
... Previous studies of AF investigated the difference of electrophysiological properties between the distal PV and the PV-LA junction. 4,8 In addition, a number of studies discussed the "longitudinal" PV-LA conduction delay; 3,4,7-9 however, no previous study quantitatively discussed the "axial" circumferential intra-PV conduction delay. ...
... It remains an unsolved argument whether the mechanism of the AF onset is due to reentries or a focal activation with decremental conduction. 8,14,15 It is difficult to confirm a reentry by entrainment study in this field due to the short duration of stable activation pattern. On the other hand, the demonstration of first few beats with identical activation pattern at the onset of AF has been considered as an implication for a reentrant mechanism. ...
Background and objective:
Ectopic beats originating from the pulmonary vein (PV) trigger atrial fibrillation (AF). The purpose of this study was to clarify the electrophysiological determinant of AF initiation from the PVs.
Methods:
Pacing studies were performed with a single extra stimulus mimicking an ectopic beat in the left superior pulmonary veins (LSPVs) in 62 patients undergoing AF ablation. Inducibility of AF, effective refractory period (ERP) and conduction properties within the PVs were analyzed.
Results:
A single extra stimulus in LSPV induced AF in 20 patients (32% of all patients) at the mean coupling interval (CI) of 172 ms. A CI-dependent anisotropic conduction at the AF onset was visualized in a 3D-mapping. Onset of AF was site-specific with reproducibility in each individual. Mean ERP in LSPV in the AF inducible group was shorter than that in the AF non-inducible group (182 ± 55 ms vs 254 ± 51 ms, P<0.0001). LSPV ERP dispersion was greater in the AF inducible group than in the AF non-inducible group (45 ± 28 ms vs 27 ± 19 ms, P<0.01). Circumferential intra-PV conduction time (IPVCT) exhibited decremental properties in response to shortening of CI, and the prolongation of IPVCT in the AF inducible site was greater than that in the AF non-inducible site (P<0.05) in each individual.
Conclusions:
Location and coupling interval of an ectopic excitation ultimately determine the initiation of AF from the PVs. ERP dispersion and circumferential conduction delay may lead to anisotropic conduction and reentry within the PVs that initiate AF. This article is protected by copyright. All rights reserved.
... Previous studies of AF investigated the difference of electrophysiological properties between the distal PV and the PV-LA junction. 4,8 In addition, a number of studies discussed the 'longitudinal' PV-LA conduction delay, 3,4,7-9 however, no previous study quantitatively discussed the 'axial' circumferential intra-PV conduction delay. ...
... It remains an unsolved argument whether the mechanism of the AF onset is due to reentries or a focal activation with decremental conduction. 8,14,15 It is difficult to confirm a reentry by entrainment study in this field due to the short duration of stable activation pattern. On the other hand, the demonstration of first few beats with identical activation pattern at the onset of AF has been considered as an implication for a reentrant mechanism. ...
Background and Objective: Ectopic beats originating from the pulmonary vein (PV) trigger atrial fibrillation (AF). The purpose of this study was to clarify the electrophysiological determinant of AF initiation from the PVs. Methods: Pacing studies were performed with a single extra stimulus mimicking an ectopic beat in the left superior pulmonary veins (LSPVs) in 62 patients undergoing AF ablation. Inducibility of AF, effective refractory period (ERP) and conduction properties within the PVs were analyzed. Results: A single extra stimulus in LSPV induced AF in 20 patients (32% of all patients) at the mean coupling interval (CI) of 172 ms. A CI-dependent anisotropic conduction at the AF onset was visualized in a 3D-mapping. Onset of AF was site-specific with reproducibility in each individual. Mean ERP in LSPV in the AF inducible group was shorter than that in the AF non-inducible group (182 ± 55 ms vs 254 ± 51 ms, P<0.0001). LSPV ERP dispersion was greater in the AF inducible group than in the AF non-inducible group (45 ± 28 ms vs 27 ± 19 ms, P<0.01). Circumferential intra-PV conduction time (IPVCT) exhibited decremental properties in response to shortening of CI, and the prolongation of IPVCT in the AF inducible site was greater than that in the AF non-inducible site (P<0.05) in each individual. Conclusions: Location and coupling interval of an ectopic excitation ultimately determine the initiation of AF from the PVs. ERP dispersion and circumferential conduction delay may lead to anisotropic conduction and reentry within the PVs that initiate AF.
... This has led to the development of ablation therapy which aims to electrically isolate the pulmonary veins from the left atrium and thereby prevent triggers from reaching the myocardium (Haissaguerre et al., 1998). Although triggers can arise from other areas of the atria such as the left atrial appendage (Santangeli et al., 2016), the key role of the pulmonary vein sleeves is supported by mechanistic studies demonstrating features that predispose these tissues to abnormal firing (Arora et al., 2003). ...
... In addition to the electrophysiological and calcium handling differences, the anatomy of the veins also promotes re-entry due to the combination of abrupt changes in fiber orientation and reduced electrical connectivity between muscle bundles creating areas of heterogeneous conduction velocity and localized block (Hocini et al., 2002;Arora et al., 2003). Calcium may also play a role in the propagation of triggered impulses from the pulmonary veins to the atria via small conductance calciumactivated potassium channels. ...
Atrial fibrillation (AF) is commonly associated with heart failure. A bidirectional relationship exists between the two—AF exacerbates heart failure causing a significant increase in heart failure symptoms, admissions to hospital and cardiovascular death, while pathological remodeling of the atria as a result of heart failure increases the risk of AF. A comprehensive understanding of the pathophysiology of AF is essential if we are to break this vicious circle. In this review, the latest evidence will be presented showing a fundamental role for calcium in both the induction and maintenance of AF. After outlining atrial electrophysiology and calcium handling, the role of calcium-dependent afterdepolarizations and atrial repolarization alternans in triggering AF will be considered. The atrial response to rapid stimulation will be discussed, including the short-term protection from calcium overload in the form of calcium signaling silencing and the eventual progression to diastolic calcium leak causing afterdepolarizations and the development of an electrical substrate that perpetuates AF. The role of calcium in the bidirectional relationship between heart failure and AF will then be covered. The effects of heart failure on atrial calcium handling that promote AF will be reviewed, including effects on both atrial myocytes and the pulmonary veins, before the aspects of AF which exacerbate heart failure are discussed. Finally, the limitations of human and animal studies will be explored allowing contextualization of what are sometimes discordant results.
... Wide antral isolation has been proved to be more effective than ostial pulmonary vein isolation [20]. The rationale for a better outcome by ablating a larger area at the junction of pulmonary veins with the left atrium, is the removal of electrophysiological heterogeneity that is capable of promoting micro-reentry that might maintain AF [21][22][23][24][25]. ...
Pulsed Field Ablation (PFA) is the latest and most intriguing technology for catheter ablation of atrial fibrillation, due to its capability to generate irreversible and cardiomyocytes-selective electroporation of cell membranes by delivering microsecond-lasting high-voltage electrical fields, leading to high expectations. The first trials to assess the clinical success of PFA, reported an arrhythmia-free survival at 1-year of 78.5%, while other trials showed less enthusiastic results: 66.2% in paroxysmal and 55.1% in persistent AF. Nevertheless, real world data are encouraging. The isolation of pulmonary veins with PFA is easily achieved with 100% acute success. Systematic invasive remapping showed a high prevalence of durable pulmonary vein isolation at 75 and 90 days (range 84–96%), which were significatively lower in redo procedures (64.3%). The advent of PFA is prompting a reconsideration of the role of the autonomic nervous system in AF ablation, as PFA-related sparing of the ganglionated plexi could lead to the still undetermined effect on late arrhythmias’ recurrences. Moreover, a new concept of a blanking period could be formulated with PFA, according to its different mechanism of myocardial injury, with less inflammation and less chronic fibrosis. Finally, in this review, we also compare PFA with thermal energy.
... Isoproterenol is a synthetic amine with β 1 -agonist and β 2 -agonist activity, the latter of which results in vasodilation and is responsible for the potential hypotension side effect, often necessitating the use of an α1 receptor agonist, such as phenylephrine, to augment blood pressure. Isoproterenol decreases sinus cycle length, shortens the refractory period, releases calcium from the sarcoplasmic reticulum, and promotes early after-depolarizations, automaticity, and triggered activity [11][12][13][14]. Interestingly, AF induced by isoproterenol has been shown to persist beyond the point of complete washout, which suggests that once AF is triggered, self-perpetuating mechanisms, such as pulmonary vein tachycardias, were activated [15]. ...
Background
High-dose isoproterenol infusion is a useful provocative maneuver to elicit triggers of atrial fibrillation (AF) during ablation. We evaluated whether the use of isoproterenol infusion to elicit triggers of AF after ablation is associated with differential outcomes.
Methods
We performed a retrospective study of all patients who underwent de novo radiofrequency catheter ablation of AF enrolled in the University of California, San Diego AF Ablation Registry. The primary outcome was freedom from atrial arrhythmias on or off antiarrhythmic drugs (AAD).
Results
Of 314 patients undergoing AF ablation, 235 (74.8%) received isoproterenol while 79 (25.2%) did not. Among those who received isoproterenol, 11 (4.7%) had additional triggers identified. There were no statistically significant differences in procedure time (p = 0.432), antiarrhythmic drug use (p = 0.289), procedural complications (p = 0.279), recurrences of atrial arrhythmias on or off AAD [adjusted hazard ratio (AHR) 0.92 (95% CI 0.58–1.46); p = 0.714], all-cause hospitalizations [AHR 1.00 (95% CI 0.60–1.67); p = 0.986], or all-cause mortality [AHR 0.14 (95% CI 0.01–3.52); p = 0.229] between groups.
Conclusions
In this registry analysis, use of isoproterenol is safe but was not associated with a reduction in recurrence of atrial arrhythmias.
... Another tissue characteristic that has been shown to affect electrophysiologic characteristics in atrial and ventricular tissue is myofibril orientation, with nonuniform myofiber orientation (ie, greater anisotropy of fiber orientation) thought to be related to slow and inhomogeneous conduction. 5,23,24 We therefore assessed the uniformity of fiber orientation in all 6 regions of the atria and evaluated the relationship between myofiber anisotropy index (AI) and all EGM measures. Figure 5A demonstrates varying degrees of fiber orientation in terms of AI in representative LAFW and LAA tissue sections. ...
Traditional anatomically guided ablation and attempts to perform electrogram-guided atrial fibrillation (AF) ablation (CFAE, DF, and FIRM) have not been shown to be sufficient treatment for persistent AF. Using biatrial high-density electrophysiologic mapping in a canine rapid atrial pacing model of AF, we systematically investigated the relationship of electrogram morphology recurrence (EMR) (Rec% and CLR) with established AF electrogram parameters and tissue characteristics. Rec% correlates with stability of rotational activity and with the spatial distribution of parasympathetic nerve fibers. These results have indicated that EMR may therefore be a viable therapeutic target in persistent AF.
... The size of the LA, as a predictor of AF recurrence post-ablation, is associated with the degree of atrial structural remodeling and fibrosis (17), and the fibrosis of the atrium and complex fractional atrial electrograms have an important influence on the perpetuation and long-term outcomes of PersAF patients and CPVI might not be sufficient for AF patients with LVA of the LA > 10%. Besides, the CS is one of the targeting regions where complex fractionated atrial electrograms are frequently recorded (18,19). For example, in a previous study with a canine AF model, atrial fibrosis was considered a vulnerable substrate for AF development (20). ...
Background
The musculature of the coronary sinus (CS), especially its distal connection with the post wall of the left atrial (LA), has been associated with the genesis and maintenance of atrial flutter (AFL) and atrial fibrillation (AF). However, the relative contributions of the distal coronary sinus (CSD)-LA connection to PersAF with various degrees of atrial fibrosis remain unknown.
Objective
This study aimed to explore the different roles of blocking the CSD-LA connection in the induction of acute AF and middle-term follow-up of recurrence among PersAF patients with various degrees of LA fibrosis.
Methods and results
A retrospective cohort of 71 patients with drug-refractory and symptomatic PersAF underwent ablation for the first time were studied. The population was divided into two groups according to disconnection of the CSD-LA or not. All patients enrolled accepted the unified ablation procedure (circumferential pulmonary vein isolation, non-pulmonary vein trigger ablation and ablation of the CSD-LA connection). Group A ( n = 47) successfully blocked the CSD-LA electrical connection and Group B ( n = 24) failed. Twenty-five patients could be induced into sustained AF in the Group A compared to 20 in the Group B (53.2 vs. 83.3%, p = 0.013). After a mean follow-up of 185 ± 8 days, 24 (33.8%) patients experienced atrial arrhythmia recurrences. The Group A had significantly fewer recurrences (25.5%) compared to Group B (50%). Meanwhile, in Group A, the ROC curve analysis suggested that in the case of blocking CSD-LA, low voltage area (LVA) of LA can act as a predictive factor for acute AF induction (AUC = 0.943, Cut-off = 0.190, P < 0.001) with sensitivity and specificity of 92.3 and 90.5%, and middle-term recurrence (AUC = 0.889, Cut-off = 0.196, P < 0.001) with sensitivity and specificity of 100 and 65.7%.
Conclusion
Disconnection of CSD-LA could reduce the inducible rate of acute AF and the recurrences of atrial arrhythmia during middle-term follow-up. The PersAF patients with CSD-LA muscular connection blocked, experienced a higher acute AF inducible rate with larger proportion of LVA of LA (≥19%) and a higher recurrent rate of atrial arrhythmias with a larger proportion of LA fibrosis (≥19.6%).
... physiological, mechanical, and anatomical features of the atrium. Rapid triggering has been proven to initiate propagating reentrant waves in atrial substrate via altering ion channel function [19]. Remodeling also leads to changes in calcium ion handling, which promote triggered activity and re-entry [20]. ...
Atrial fibrillation (AF) is the most common type of symptomatic arrhythmias, which was induced by multiple causes and dyslipidemia is a well-known causal factor for the atherosclerotic cardiovascular disease (ASCVD). Interestingly, emerging data has suggested that lipid disorder may be also associated with AF. Several previous studies have shown a link of the prevalence of AF with decreased concentration of low-density lipoproteins (LDL)-cholesterol, total cholesterol (TC), high-density lipoproteins (HDL)-cholesterol, and elevated lipoprotein(a) [Lp(a)]. In this manuscript, we try to summarize the current evidence regarding the relation of dyslipidemia to the incident AF, present the potential lipid-related mechanisms of AF development, which is involved in cell membrane properties, LDL-receptors reduction, reverse cholesterol transport, adiposity-induced inflammation, apoptosis, and autophagy. Such information may boost our understandings concerning the lipid disorder and AF, which may help future exploration in the link of dyslipidemia and AF.
... In our study, CV estimates from the PVA were even higher compared with the RA and BB in all used techniques. Arora et al. 17 High-density conduction velocity estimation computed using the DVV technique and the LA recordings. However, even larger CV estimates were computed using the FiD and PSF techniques at these areas. ...
Aims
Accurate determination of intra-atrial conduction velocity (CV) is essential to identify arrhythmogenic areas. The most optimal, commonly used, estimation methodology to measure conduction heterogeneity, including finite differences (FiD), polynomial surface fitting (PSF), and a novel technique using discrete velocity vectors (DVV), has not been determined. We aim (i) to identify the most suitable methodology to unravel local areas of conduction heterogeneities using high-density CV estimation techniques, (ii) to quantify intra-atrial differences in CV, and (iii) to localize areas of CV slowing associated with paroxysmal atrial fibrillation (PAF).
Methods and results
Intra-operative epicardial mapping (>5000 sites, interelectrode distances 2 mm) of the right and left atrium and Bachmann’s bundle (BB) was performed during sinus rhythm (SR) in 412 patients with or without PAF. The median atrial CV estimated using the DVV, PSF, and FiD techniques was 90.0 (62.4–116.8), 92.0 (70.6–123.2), and 89.4 (62.5–126.5) cm/s, respectively. The largest difference in CV estimates was found between PSF and DVV which was caused by smaller CV magnitudes detected only by the DVV technique. Using DVV, a lower CV at BB was found in PAF patients compared with those without atrial fibrillation (AF) [79.1 (72.2–91.2) vs. 88.3 (79.3–97.2) cm/s; P < 0.001].
Conclusions
Areas of local conduction heterogeneities were most accurately identified using the DVV technique, whereas PSF and FiD techniques smoothen wavefront propagation thereby masking local areas of conduction slowing. Comparing patients with and without AF, slower wavefront propagation during SR was found at BB in PAF patients, indicating structural remodelling.
... ПД клеток ЛВ короче, что вызвано выраженным калиевым током задержанного выпрямления, как быстро активируемым I Kr , так и медленно активируемым I Ks компонентами. В опытах на нормальном сердце собаки [17] была спровоцирована триггерная активность проксимально от устья вены при введении изопротеренола и после физической нагрузки. Однако связь триггерной активности с пейсмекерными потенциалами или постдеполяризацией не была установлена. ...
The aim of this review was to study the role of the autonomic nervous system in the pathogenesis of atrial fibrillation (AF), as well as to establish the relationship of autonomic regulation with other mechanisms underlying the AF At present, the molecular and cellular mechanisms underlying the AF have not been precisely established. There is interest in evidence showing that both sympathetic outflow and an increased vagal tone can initiate and support AF. As modern studies have shown, autonomic cardiac regulation can be an important factor in the pathogenesis of AF.
... In addition to triggered activity, it has been suggested that heterogeneity in action potential duration within the PVs, together with changes in fiber orientation at the PV ostium, represent a substrate for reentry (Arora et al., 2003;Po et al., 2005). In this regard, heterogeneous responses to NA, if replicated in the intact PVs, could potentially contribute to the maintenance of reentry during sympathetic stimulation. ...
The electrophysiological properties of pulmonary vein (PV)-cardiomyocytes, and their responses to the sympathetic neurotransmitter, noradrenaline (NA), are thought to differ from those of the left atrium (LA) and contribute to atrial ectopy. The aim of this study was to examine rat PV cardiomyocyte electrophysiology and responses to NA in comparison with LA cells. LA and PV cardiomyocytes were isolated from adult male Wistar rat hearts, and membrane potentials and ion currents recorded at 36°C using whole-cell patch-clamp techniques. PV and LA cardiomyocytes did not differ in size. In control, there were no differences between the two cell-types in zero-current potential or action potential duration (APD) at 1 Hz, although the incidence of early afterdepolarizations (EADs) was greater in PV than LA cardiomyocytes. The L-type Ca2+ current (ICaL ) was ~×1.5 smaller (p = .0029, Student's t test) and the steady-state K+ current (IKss ) was ~×1.4 larger (p = .0028, Student's t test) in PV than in LA cardiomyocytes. PV cardiomyocyte inward-rectifier current (IK1 ) was slightly smaller than LA cardiomyocyte IK1 . In LA cardiomyocytes, NA significantly prolonged APD30 . In PV cells, APD30 responses to 1 μM NA were heterogeneous: while the mean percentage change in APD30 was not different from 0 (16.5 ± 9.7%, n cells/N animals = 12/10, p = .1177, one-sample t test), three cells showed shortening (-18.8 ± 6.0%) whereas nine showed prolongation (28.3 ± 10.1%, p = .008, Student's t test). NA had no effect on IK1 in either cell-type but inhibited PV IKss by 41.9 ± 4.1% (n/N = 23/11 p < .0001), similar to LA cells. NA increased ICaL in most PV cardiomyocytes (median × 2.2-increase, p < .0001, n/N = 32/14, Wilcoxon-signed-rank test), although in 7/32 PV cells ICaL was decreased following NA. PV cardiomyocytes differ from LA cells and respond heterogeneously to NA.
... Deux mécanismes seraient à l'origine de l'autorythmicité du noeud sinusal : l'existence dans la VP de zones où la vitesse de conduction est réduite Kumagai et al. 2004). Ces phénomènes sont connus pour favoriser les réentrées (Arora et al. 2003). Cette anisotropie de conduction électrique pourrait être expliquée par l'orientation complexe des fibres myocardiques dans les VP (Nathan et Eliakim 1966). ...
La fibrillation atriale (FA) est le trouble du rythme le plus fréquemment rencontré en clinique. Elle est responsable d’une importante morbi-mortalité et d’une forte majoration durisque d’accident vasculaire cérébral. La FA est réfractaire aux traitements pharmacologiques anti-arythmiques, elle constitue donc un problème de santé publique. À son stade initial, la FA est principalement déclenchée par des foyers d’activité électriques anormaux situés dans le manchon de cardiomyocytes (CM) des veines pulmonaires (VP). Le mécanisme à l’origine de leur génération très mal connu. Les ions calcium (Ca 2+ ) étant fréquemment impliqués dans la génération de signaux électriques arythmogènes, nous avons émis l’hypothèse qu’ils pouvaient être impliqués dans les arythmies générées dans la VP.Les caractéristiques structurelles et fonctionnelles du cycle du Ca 2+ n’étant pas connues dans les CM de VP, nous avons donc exploré et comparé ce cycle à celui des CM d’oreillette gauche (OG) et de ventricule gauche (VG) chez le rat.L’étude de l’architecture de la membrane plasmique – point d’entrée du Ca 2+ dans le CM – a nécessité le développement d’un algorithme d’analyse spécifique pour les CM de VP (TTorg). Contrairement aux CM d’OG et de VG, la longueur du réseau de tubules transverses (TT) est variable dans les CM de VP et son niveau d’organisation est très hétérogène d’un CM à l’autre. Cette organisation hétérogène des TT d’un CM à l’autre implique une grande variabilité de distribution spatiale des canaux calciques (Ca v 1.2) par rapport aux récepteurs de la ryanodine (RyR2) et ainsi une grande hétérogénéité de forme et d’amplitude des transitoires calciques. Ces différents types de CM ne sont pas dispersés aléatoirement au sein de la veine, mais regroupés en « îlots » de CM présentant le même type d’organisation.Dans les CM de VP, la cinétique de recapture du Ca 2+ cytoplasmique dans le réticulum sarcoplasmique par la SERCA est identique à celle des CM d’OG, mais plus rapide que celle des CM de VG. En revanche, dans les CM de VP, la cinétique globale de diminution de la concentration calcique du cytoplasme par les mécanismes sarcolemmaux et les mitochondries est plus rapide que dans les CM d’OG, mais plus lente que dans les CM de VG.Dans les CM de VP, la stimulation des récepteurs β 1 -adrénergiques induit une augmentation de l’amplitude du transitoire calcique identique à celle des CM d’OG mais plus faible que celle des CM de VG. La stimulation des récepteurs α 1 -adrénergique induit une diminution de l’amplitude des transitoires calcique qui est plus importante dans les CM de VP que dans ceux d’OG.L’étude de l’amplitude de contraction des CM isolés a nécessité le développement d’un algorithme d’analyse spécifique pour les CM de VP (SarcOptiM). Cette amplitude est très hétérogène dans les CM de VP, à l’image de l’amplitude de leurs transitoires calciques. Contrairement aux anneaux isolés d’OG, la force de contraction des anneaux de VP n’est augmentée ni par l’augmentation de la concentration du Ca 2+ extracellulaire ni par le Bay K 8644, un ouvreur des canaux calciques de type L. Ces différences de réponses ne sont pas dues à une différence de sensibilité des myofilaments pour le Ca 2+ . Les CM de VP ne semblent donc pas présenter de réserve contractile dans les conditions d’étirement permettant d’obtenir une réponse contractile maximale.L’étude des libérations calciques spontanées dans le cytoplasme des CM a montré une plus grande fréquence des sparks et des waves dans les CM de VP que dans les CM d’OG.En conclusion, la forte hétérogénéité des CM de VP ainsi que la plus grande fréquence des libérations calciques spontanées dans leur cytoplasme pourraient expliquer le fort potentiel arythmogène des VP.
... 19 Arora et al menunjukkan bahwa konduksi pada bagian proksimal dari PV anjing memiliki konduksi yang jauh lebih rendah daripada bagian atrium kiri lainnya. 20 Bukti dari dugaan ini diberikan oleh Verheule et al yang menunjukkan bahwa, walaupun miosit dari PV mirip dengan LA, gap junction pada kerah miokardial terutama mengekspresikan Cx43 dan bahwa level dari Cx40 lebih rendah secara bermakna daripada LA. 21 Sel-sel mirip nodus teridentifikasi dalam kerah miokardial PV dan intercalated disc dari sel-sel ini terdiri atas spesialisasi gap junction kecil-kecil yang serupa dengan nodus SA. ...
Initiation of atrial fibrillation (AF) occurred when there is a combination of triggering factors (mainly originated from thoracic veins) and arrhytmogenic substrate, such as : reduction of effective refractory period (ERP), increase in refractory spatial dispersion, or abnormal atrial impulse conduction. Atrial fibrillation has an ability to maintain its own progression, so called ‘AF begets AF’. Prologed AF episodes will lead to structural and electrical remodeling, making the patient prone to the recurrent and sustained AF. Structural remodeling, detected in the late phase, involve changes in mitochodrial size, disorder of sarcoplasmic reticulum in subcellular level, and myocardial cell hypertrophy, fiber disarray and elevated collagen deposition in the tissue level. Meanwhile, electrical remodeling of AF will cause delayed effective refractory period, promoting reentry mechanisms. Changes in gap junction regulation and distribution has been noted as part of this remodeling process. Mutation of connexin40 gene, a component protein of gap junction, also has a role in some cases of lone AF.
... 16,17 CV can also be estimated in experimental settings using optical mapping systems. 18,19 In the clinical setting, CV can be estimated based on planar wavefront propagation by applying a fit model based on the neighboring electrodes' spatial locations and local activation times. The fitting can be performed either based on a predefined arrangement of measurement points depending on catheter design 20,21 or more generalizable techniques such as polynomial surface fitting 22,23 or triangulation. ...
Background:
Conduction velocity (CV) is an important property that contributes to the arrhythmogenicity of the tissue substrate. The aim of this study was to investigate the association between local CV versus late gadolinium enhancement (LGE) and myocardial wall thickness in a swine model of healed left ventricular infarction.
Methods:
Six swine with healed myocardial infarction underwent cardiovascular magnetic resonance imaging and electroanatomic mapping. Two healthy controls (one treated with amiodarone and one unmedicated) underwent electroanatomic mapping with identical protocols to establish the baseline CV. CV was estimated using a triangulation technique. LGE+ regions were defined as signal intensity >2 SD than the mean of remote regions, wall thinning+ as those with wall thickness <2 SD than the mean of remote regions. LGE heterogeneity was defined as SD of LGE in the local neighborhood of 5 mm and wall thickness gradient as SD within 5 mm. Cardiovascular magnetic resonance and electroanatomic mapping data were registered, and hierarchical modeling was performed to estimate the mean difference of CV (LGE+/-, wall thinning+/-), or the change of the mean of CV per unit change (LGE heterogeneity, wall thickness gradient).
Results:
Significantly slower CV was observed in LGE+ (0.33±0.25 versus 0.54±0.36 m/s; P<0.001) and wall thinning+ regions (0.38±0.28 versus 0.55±0.37 m/s; P<0.001). Areas with greater LGE heterogeneity ( P<0.001) and wall thickness gradient ( P<0.001) exhibited slower CV.
Conclusions:
Slower CV is observed in the presence of LGE, myocardial wall thinning, high LGE heterogeneity, and a high wall thickness gradient. Cardiovascular magnetic resonance may offer a valuable imaging surrogate for estimating CV, which may support noninvasive identification of the arrhythmogenic substrate.
... The possible reason for the smaller extent of increased currents of these 2 mutants is that the clinical phenotype of the patients harboring these mutations is not that of significant bradycardia but of AF. It has also been reported that heterogeneity in repolarization may promote AF. 42,43 Thus, we hypothesize that the KCNJ3 p.N496H and KCNJ5 p.D262G mutants may produce atrial repolarization heterogeneity to cause AF development in affected patients. With regard to the other 3 mutations (KCNJ3 p.F85L, KCNJ5 p.V303I, and KCNJ5 p.G387R), we could not demonstrate functional significance or pathophysiological relevance to AF with the data from our present analyses. ...
Background:
Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life.
Methods:
We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model.
Results:
We identified one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel ( IKACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p.N83H mutation caused a gain of IKACh channel function by increasing the basal current, even in the absence of m2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective IKACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish.
Conclusions:
The IKACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant IKACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective IKACh channel blocker. Thus, the IKACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the IKACh channel.
... In this study we analyze ten patients before AF procedure. We registered bipolar electrograms from PVs electrical activity because their abnormal electrical activation can be responsible for the generation of AF in many patients [15]. Considering that during AF, atria is a complex system which consist of many parts or subsystems that interact in a complex way, our goal is to estimate whether there exists differences in correlation along each PV in patients that have recurrences in the arrhythmia and those patients that maintenance sinus rhythm. ...
... Interestingly, there is clinical evidence of a LA-RA gradient in the DF in paroxysmal AF (Lazar et al., 2004), which may be underlain by APD differences between the RA and LA in pathological conditions which promote AF (Voigt et al., 2010). Furthermore, regional differences in APD between PV/LA regions have been identified previously as high frequency excitation or microreentrant sources underlying AF (Mandapati et al., 2000;Arora et al., 2003;Kumagai et al., 2004)-this suggests that localized increases in the spatial dispersion of repolarisation could be a mechanism by which atrial arrhythmogenesis is promoted in SQT1, as suggested in the previous experimental study (Nof et al., 2010). FIGURE 7 | Arrhythmia termination in 3D anatomical human atria by representative concentrations of disopyramide, propafenone, and quinidine under SQT1 mutation conditions. ...
Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-à-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs–disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human atrial action potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.
... Importantly, the PLA has been shown to harbor substrate for not only triggered activity, but also reentry (38), with most rapidly firing PV foci thought to be reentrant in nature. Furthermore, since HF leads to both electrical and structural remodeling in the atrium, reentry may be a key electrophysiological mechanism involved in the maintenance of the AF disease in HF. ...
The precise mechanisms by which oxidative stress (OS) causes atrial fibrillation (AF) are not known. Since AF frequently originates in the posterior left atrium (PLA), we hypothesized that OS, via calmodulin-dependent protein kinase II (CaMKII) signaling, creates a fertile substrate in the PLA for triggered activity and reentry. In a canine heart failure (HF) model, OS generation and oxidized-CaMKII-induced (Ox-CaMKII-induced) RyR2 and Nav1.5 signaling were increased preferentially in the PLA (compared with left atrial appendage). Triggered Ca2+ waves (TCWs) in HF PLA myocytes were particularly sensitive to acute ROS inhibition. Computational modeling confirmed a direct relationship between OS/CaMKII signaling and TCW generation. CaMKII phosphorylated Nav1.5 (CaMKII-p-Nav1.5 [S571]) was located preferentially at the intercalated disc (ID), being nearly absent at the lateral membrane. Furthermore, a decrease in ankyrin-G (AnkG) in HF led to patchy dropout of CaMKII-p-Nav1.5 at the ID, causing its distribution to become spatially heterogeneous; this corresponded to preferential slowing and inhomogeneity of conduction noted in the HF PLA. Computational modeling illustrated how conduction slowing (e.g., due to increase in CaMKII-p-Nav1.5) interacts with fibrosis to cause reentry in the PLA. We conclude that OS via CaMKII leads to substrate for triggered activity and reentry in HF PLA by mechanisms independent of but complementary to fibrosis.
... Previous studies on the arrhythmogenicity of the PVA mainly focused on the PVs as a source of ectopic triggers with the potential to initiate AF. 26,27 The PVs have also been reported as structures that may have a critical role in AF maintenance by abnormal automaticity, triggered activity, or localized reentry. 28,29 In a recent study by Lee et al 27 the right superior PV-LA junction was mapped epicardially in 18 patients undergoing cardiac surgery. At the junction of the PV with the LA, functional lines of CD and CB were observed in the majority of patients and were mainly orientated across the short axis of the vein. ...
Background:
Extensiveness of conduction delay and block at the pulmonary vein area (PVA) was quantified in a previous study. We hypothesized that the combination of lines of conduction block with multiple concomitantly entering sinus rhythm wavefronts at the PVA may result in increased arrhythmogenicity and susceptibility to atrial fibrillation (AF).
Methods:
Intraoperative high-density epicardial mapping of PVA (N≈450 sites, interelectrode distances: 2 mm) was performed during sinus rhythm in 327 patients (241 male [74%], 67±10 [21-84] years) with and without preoperative AF. For each patient, activation patterns at the PVA were quantified, including the location of entry sites of wavefronts, direction of propagation, and their relative activation times. The association between activation patterns and the presence of AF was examined.
Results:
Excitation of the PVA occurred via multiple consecutive wavefronts in the vast majority of patient (N=216, 81%). In total, 561 wavefronts were observed, which mostly propagated through the septal or paraseptal regions towards the PVA (N=461, 82%). A substantial dissociation of consecutive wavefronts was observed with Δactivation times of 10.6±8.8 (0-46) ms. No difference was observed in Δactivation times of consecutive wavefronts during sinus rhythm between patients without and with AF. An excitation-based risk factor model, including conduction delay ≥6 mm, conduction block ≥6 mm, and conduction delay and block ≥16 mm, wavefronts via the posteroinferior to posterosuperior regions and multiple opposing wavefronts, demonstrated a 5-fold risk of AF when multiple risk factors were present.
Conclusions:
In contrast to previous findings, quantification of activation patterns at the PVA on high-resolution scale demonstrated complex patterns with often multiple entry sites and high interindividual variability. Altered patterns of activation, consisting of multiple opposing wavefronts combined with long lines of conduction slowing, were associated with the presence of AF.
... The focal ectopic activity is an important source of reentrant propagation (Haïssaguerre et al., 1998;Arora et al., 2003). There is experimental evidence suggesting that the mechanisms determining the tissue vulnerability to reentry are related with structural and electrical remodeling interactions (Narayan et al., 2017). ...
The mechanisms of atrial fibrillation (AF) are a challenging research topic. The rotor hypothesis states that the AF is sustained by a reentrant wave that propagates around an unexcited core. Cardiac tissue heterogeneities, both structural and cellular, play an important role during fibrillatory dynamics, so that the ionic characteristics of the currents, their spatial distribution and their structural heterogeneity determine the meandering of the rotor. Several studies about rotor dynamics implement the standard diffusion equation. However, this mathematical scheme carries some limitations. It assumes the myocardium as a continuous medium, ignoring, therefore, its discrete and heterogeneous aspects. A computational model integrating both, electrical and structural properties could complement experimental and clinical results. A new mathematical model of the action potential propagation, based on complex fractional order derivatives is presented. The complex derivative order appears of considering the myocardium as discrete-scale invariant fractal. The main aim is to study the role of a myocardial, with fractal characteristics, on atrial fibrillatory dynamics. For this purpose, the degree of structural heterogeneity is described through derivatives of complex order γ = α + jβ. A set of variations for γ is tested. The real part α takes values ranging from 1.1 to 2 and the imaginary part β from 0 to 0.28. Under this scheme, the standard diffusion is recovered when α = 2 and β = 0. The effect of γ on the action potential propagation over an atrial strand is investigated. Rotors are generated in a 2D model of atrial tissue under electrical remodeling due to chronic AF. The results show that the degree of structural heterogeneity, given by γ, modulates the electrophysiological properties and the dynamics of rotor-type reentrant mechanisms. The spatial stability of the rotor and the area of its unexcited core are modulated. As the real part decreases and the imaginary part increases, simulating a higher structural heterogeneity, the vulnerable window to reentrant is increased, as the total meandering of the rotor tip. This in silico study suggests that structural heterogeneity, described by means of complex order derivatives, modulates the stability of rotors and that a wide range of rotor dynamics can be generated.
... PVs also have shorter APD associated with larger delayed rectifier K + currents (I Kr and I Ks ). To date only one study in the normal dog heart has described what has been interpreted as triggered activity, arising just proximal to the venous ostium in the presence of isoproterenol, with an increased rate after rapid pacing (Arora et al., 2003). However, a role for triggered activity is uncertain because no pacemaker potentials or afterdepolarizations were demonstrated. ...
Atrial fibrillation is a highly prevalent cardiac arrhythmia and the most important cause of embolic stroke. Although genetic studies have identified an increasing assembly of AF-related genes, the impact of these genetic discoveries is yet to be realized. In addition, despite more than a century of research and speculation, the molecular and cellular mechanisms underlying AF have not been established, and therapy for AF, particularly persistent AF, remains suboptimal. Current antiarrhythmic drugs are associated with a significant rate of adverse events, particularly proarrhythmia, which may explain why many highly symptomatic AF patients are not receiving any rhythm control therapy. This review focuses on recent advances in AF research, including its epidemiology, genetics, and pathophysiological mechanisms. We then discuss the status of antiarrhythmic drug therapy for AF today, reviewing molecular mechanisms, and the possible clinical use of some of the new atrial-selective antifibrillatory agents, as well as drugs that target atrial remodeling, inflammation and fibrosis, which are being tested as upstream therapies to prevent AF perpetuation. Altogether, the objective is to highlight the magnitude and endemic dimension of AF, which requires a significant effort to develop new and effective antiarrhythmic drugs, but also improve AF prevention and treatment of risk factors that are associated with AF complications.
... Such microstructural features cannot be visualized by current LGE-MRI and, accordingly, could not be incorporated in our models. Electrophysiological heterogeneities near the PVs, which are not represented in our models, can also promote reentry (Arora et al., 2003), which may explain why these two regions accounted for 61% of ECGI+/Sim− regions. ...
Electrocardiographic mapping (ECGI) detects reentrant drivers (RDs) that perpetuate arrhythmia in persistent AF (PsAF). Patient-specific computational models derived from late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) identify all latent sites in the fibrotic substrate that could potentially sustain RDs, not just those manifested during mapped AF. The objective of this study was to compare RDs from simulations and ECGI (RDsim/RDECGI) and analyze implications for ablation. We considered 12 PsAF patients who underwent RDECGI ablation. For the same cohort, we simulated AF and identified RDsim sites in patient-specific models with geometry and fibrosis distribution from pre-ablation LGE-MRI. RDsim- and RDECGI-harboring regions were compared, and the extent of agreement between macroscopic locations of RDs identified by simulations and ECGI was assessed. Effects of ablating RDECGI/RDsim were analyzed. RDsim were predicted in 28 atrial regions (median [inter-quartile range (IQR)] = 3.0 [1.0; 3.0] per model). ECGI detected 42 RDECGI-harboring regions (4.0 [2.0; 5.0] per patient). The number of regions with RDsim and RDECGI per individual was not significantly correlated (R = 0.46, P = ns). The overall rate of regional agreement was fair (modified Cohen's κ0 statistic = 0.11), as expected, based on the different mechanistic underpinning of RDsim- and RDECGI. nineteen regions were found to harbor both RDsim and RDECGI, suggesting that a subset of clinically observed RDs was fibrosis-mediated. The most frequent source of differences (23/32 regions) between the two modalities was the presence of RDECGI perpetuated by mechanisms other than the fibrotic substrate. In 6/12 patients, there was at least one region where a latent RD was observed in simulations but was not manifested during clinical mapping. Ablation of fibrosis-mediated RDECGI (i.e., targets in regions that also harbored RDsim) trended toward a higher rate of positive response compared to ablation of other RDECGI targets (57 vs. 41%, P = ns). Our analysis suggests that RDs in human PsAF are at least partially fibrosis-mediated. Substrate-based ablation combining simulations with ECGI could improve outcomes.
Background: Sole pulmonary vein (PV) isolation by ablation therapy prevents atrial fibrillation (AF) in patients with short episodes of AF and without comorbidities. Since incomplete PV isolation can be curative, we tested the hypothesis that the PV in the absence of remodeling and comorbidities contains structural and functional properties that are proarrhythmic for AF initiation by reentry.
Methods: We performed percutaneous transvenous in vivo endocardial electrophysiological studies and quantitative histological analysis of PV from healthy sheep.
Results: The proximal PV contained more myocytes than the distal PV and a higher percentage of collagen and fat tissue relative to myocytes than the left atrium. Local fractionated electrograms occurred in both the distal and proximal PVs, but a large local activation (>0.75 mV) was more often present in the proximal PV than in the distal PV (86 vs. 50% of electrograms, respectively, p = 0.017). Atrial arrhythmias (run of premature atrial complexes) occurred more often following the premature stimulation in the proximal PV than in the distal PV (p = 0.004). The diastolic stimulation threshold was higher in the proximal PV than in the distal PV (0.7 [0.3] vs. 0.4 [0.2] mA, (median [interquartile range]), p = 0.004). The refractory period was shorter in the proximal PV than in the distal PV (170 [50] vs. 248 [52] ms, p < 0.001). A linear relation existed between the gradient in refractoriness (distal-proximal) and atrial arrhythmia inducibility in the proximal PV.
Conclusion: The structural and functional properties of the native atrial-PV junction differ from those of the distal PV. Atrial arrhythmias in the absence of arrhythmia-induced remodeling are caused by reentry in the atrial-PV junction. Ablative treatment of early paroxysmal AF, rather than complete isolation of focal arrhythmia, may be limited to inhibition of reentry.
Atrial fibrillation (AF) is the most common non-physiological arrhythmia in dogs and humans. Its high prevalence in both species and the impact it has on survival time and quality of life of affected patients, makes it a very relevant topic of medical research. Significant developments in understanding the mechanisms underlying this arrhythmia in humans has occurred over the last decades and some of this knowledge is being applied to veterinary medicine, despite the many differences between species. This article reviews the current understanding of the pathophysiology of AF. The epidemiology and classification of AF in dogs will also be discussed.
Significance
Electrophysiological mapping of chronic atrial fibrillation (AF) at high throughput and high resolution is critical for understanding its underlying mechanism and guiding definitive treatment such as cardiac ablation, but current electrophysiological tools are limited by either low spatial resolution or electromechanical uncoupling of the beating heart. We herein introduce a microfabricated high-density, fully elastic electrode (termed elastrode) array for complex electrophysiological signal recording in vivo. We demonstrated the capability to identify clinically relevant electrophysiological heterogeneity in the pathologic state of pacing-induced chronic AF that was captured and correlated with state-of-the-art clinical techniques, which show the potential to apply this elastrode array toward elucidating the mechanism of AF at a cellular level and developing targeted AF therapy.
Atrial fibrillation (AF) is defined by complex electrical and structural remodeling within the atria, which promote triggered activity and reentry. The precise understanding of reentry has evolved over the last decades, with several paradigms of reentry having been proposed.
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Atrial fibrillation (AF) is the most frequent sustained arrhythmia and a major cause of morbidity and mortality. Increasing physical activity has convincingly shown to reduce the risk of AF. However, repetitive bouts of prolonged and vigorous endurance exercise have recently emerged as a risk factor for AF in middle-aged male athletes. Thus, a growing body of literature supports a U-shaped relation between lifetime-accumulated high-intensity endurance training and AF in men. The pathophysiology underlying this relation poses a puzzling question with multiple hypothesized mechanisms, which probably in combination create the necessary substrate and trigger for AF onset. Presumably adaptive atrial changes secondary to long-standing endurance training as part of the “athlete’s heart” add special considerations as they build up a grey zone of diagnostic uncertainty with atrial changes seen in individuals with AF. Evolving functional diagnostic modalities may re-shape this diagnostic grey zone and facilitate diagnostic workup. Initiating management of AF requires documentation of an AF episode, which can be challenging in athletes as it usually occurs intermittent. New wearable devices hold promise to facilitate early documentation and follow-up, but their reliability still has to be established, especially during exercise. When counseling competitive athletes and highly active people regarding treatment options of AF, special considerations should be taken into account to reduce risk associated with AF but also sustain the numerous health benefits of regular exercise and the lifestyle of being a competitive endurance athlete.
Rapid firing from pulmonary veins (PVs) frequently initiates atrial fibrillation, which is a common comorbidity associated with hypertension, heart failure, and valvular disease, i.e., conditions that pathologically increase cardiomyocyte stretch. Autonomic tone plays a crucial role in PV arrhythmogenesis, while its interplay with myocardium stretch remains uncertain. Two-microelectrode technique was used to characterize electrophysiological response of Wistar rat PV to adrenaline at baseline and under mild (150 mg of applied weight that corresponds to a pulmonary venous pressure of 1 mmHg) and moderate (10 g, ∼26 mmHg) stretch. Low concentrations of adrenaline (25–100 nmol/L) depolarized the resting membrane potential selectively within distal PV (by 26 ± 2 mV at baseline, by 18 ± 1 mV at 150 mg, P < 0.001, and by 5.9 ± 1.1 mV at 10 g, P < 0.01) suppressing action potential amplitude and resulting in intra-PV conduction dissociation and rare episodes of spontaneous activity (arrhythmia index of 0.4 ± 0.2, NS vs. no activity at baseline). In contrast, 1–10 μmol/L of adrenaline recovered intra-PV propagation. While mild stretch did not affect PV electrophysiology at baseline, moderate stretch depolarized the resting potential within distal PV (-56 ± 2 mV vs. -82 ± 1 mV at baseline, P < 0.01), facilitated the triggering of rapid PV firing by adrenaline (arrhythmia index: 4.4 ± 0.2 vs. 1.3 ± 0.4 in unstretched, P < 0.001, and 1.7 ± 0.8 in mildly stretched preparations, P < 0.005, at 10 μmol/L adrenaline) and induced frequent episodes of potentially arrhythmogenic atrial “echo” extra beats. Our findings demonstrate complex interactions between the sympathetic tone and mechanical stretch in the development of arrhythmogenic activity within PVs that may impact an increased atrial fibrillation vulnerability in patients with elevated blood pressure.
Cardiac myocytes are specialized cells responsible for both mechanical contraction and conduction of electrical impulses. Some myocytes demonstrate automaticity, defined by the capability of cardiac cells to undergo spontaneous diastolic depolarization and to initiate an electrical impulse in the absence of external electrical stimulation [1]. Spontaneously originated action potentials (AP) are propagated through cardiac myocytes, which are excitable, referring to their ability to respond to a stimulus with a regenerative AP [2]. Propagation of the cardiac impulse is enabled by gap junctions. Gap junctions are membrane structures composed of multiple intercellular ion channels that facilitate chemical and electrical communication between cells. Cardiac AP are regionally distinct due to each myocyte type expressing different numbers and types of ion channels [3].
Background
Atrial fibrillation often occurs in the setting of hypertension and associated atrial dilation with pathologically increased cardiomyocyte stretch. In the setting of atrial dilation, mechanoelectric feedback has been linked to the development of ectopic beats that trigger paroxysmal atrial fibrillation mainly originating from pulmonary veins ( PVs ). However, the precise mechanisms remain poorly understood.
Methods and Results
We identify mechanosensitive, swelling‐activated chloride ion channels ( I C l,swell ) as a crucial component of the caveolar mechanosensitive complex in rat and human cardiomyocytes. In vitro optical mapping of rat PV , single rat PV , and human cardiomyocyte patch clamp studies showed that stretch‐induced activation of I Cl,swell leads to membrane depolarization and decreased action potential amplitude, which trigger conduction discontinuities and both ectopic and reentrant activities within the PV . Reverse transcription quantitative polymerase chain reaction, immunofluorescence, and coimmunoprecipitation studies showed that I Cl,swell likely consists of at least 2 components produced by mechanosensitive ClC‐3 (chloride channel‐3) and SWELL 1 (also known as LRRC8A [leucine rich repeat containing protein 8A]) chloride channels, which form a macromolecular complex with caveolar scaffolding protein Cav3 (caveolin 3). Downregulation of Cav3 protein expression and disruption of caveolae structures during chronic hypertension in spontaneously hypertensive rats facilitates activation of I Cl,swell and increases PV sensitivity to stretch 10‐ to 50‐fold, promoting the development of atrial fibrillation.
Conclusions
Our findings identify caveolae‐mediated activation of mechanosensitive I Cl,swell as a critical cause of PV ectopic beats that can initiate atrial arrhythmias including atrial fibrillation. This mechanism is exacerbated in the setting of chronically elevated blood pressures.
The mechanisms of AF induction and maintenance, including those involved in paroxysmal atrial fibrillation, are not completely known; this limits our ablation strategies and prevents us from understanding what we are actually doing when performing pulmonary vein isolation. In this report, we focus on the commonly used ablation strategies for atrial fibrillation and question the importance of complete pulmonary vein isolation in achieving lasting success in the ablation of atrial fibrillation. We also discuss in detail the absence of durable pulmonary vein isolation in patients without arrhythmic recurrences after atrial fibrillation ablation and the possibility to cure paroxysmal atrial fibrillation without concomitant pulmonary vein isolation, provocatively questioning the dogma of pulmonary vein isolation as the cornerstone of atrial fibrillation ablation. Finally, a prospective personalized approach in the individual patient is advocated.
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Characterized by lack of evidence of structural heart disease or any secondary causes of atrial fibrillation (AF), “lone AF” is used to represent a unique subtype of AF among young individuals aged less than 60 years. Although the longstanding definition has been proposed for years, the diagnostic criteria for “lone AF” remain ambiguous. As more contributing factors causing AF are recognized gradually, the validity of the term “lone AF” is in question. Despite advances in the past few decades, the mechanism of AF remains poorly understood, particularly in the absence of other structural changes. It is generally accepted that three essential electrophysiological elements (trigger, substrate, and modulators)contribute to the initiation and maintenance of lone AF. In addition, the role of microRNAs and genomic variations in the pathogenesis of lone AF has been also gaining attention. Some changes in relevant biomarker levels have also been proven to correlate with lone AF. Accumulating insights into the pathogenesis of lone AF strongly suggest coexistent disorders in patients with lone AF. Consequently, the growing evidence of these numerous and diverse pathogenic mechanisms and factors related to lone AF inevitably raises the question of whether the term “lone AF” is a meaningful category. The classification of lone AF as a separate identity has not lead to any unique clinical management. In this review, we update knowledge of definition, mechanisms, genetics, biomarkers, and clinical management of “lone AF.” With this comprehensive review, we suggest that the term “lone AF” should be abandoned for its futility.
This book focuses on how to induce clinical arrhythmias in the electrophysiology (EP) laboratory, a procedure that is indispensable for analyzing the underlying mechanisms, and identifying the most effective treatment of the arrhythmia. In the main part of the book, the authors share their own experiences with 13 different medications that can be injected or infused for arrhythmia induction – ranging from isoprenaline and atropine to ephedrine – all of which can be easily found in any cardiology department.
Each chapter begins with a description of the drug’s chemical structure and mechanism of actions, then illustrates the infusion preparation, dosage and side effects and lastly analyzes its electrophysiological properties and highlights the most important clinical studies on it. For each drug the authors list – in dedicated tables – administration protocols from their own hospital.
This book is of interest to postgraduate students, cardiology residents, cardiologists and pediatric cardiologists with special interest in arrhythmias, as well as to trainees, technicians and nurses involved in the EP lab.
Adenosine is a nucleoside that is normally found inside the human body. It has a negative chronotropic and dromotropic effect. It slows the sinus node rate and also the conduction through the AV node. Adenosine’s mechanism of action is mainly on the sinus node and atrioventricular node. It stimulates the potassium current Ikr, Ado and Ach , inducing cellular hyperpolarization and blocking the conduction through the AV node with subsequent interruption of PSVT that is node-dependent. Adenosine can induce reentry using an accessory pathway. By slowing the anterograde conduction through the AV node, it allows retrograde activation of the atrium through the accessory pathway. Human studies have also demonstrated that adenosine administration reveals dormant PV conduction. The ADVICE trial demonstrated that 53% of the patients that received adenosine had dormant conduction.
Heterogeneities of repolarization (R) across the myocardium have been invoked to explain most reentrant arrhythmias. The measurement of refractory periods (RPs) has been widely used to assess R, but conventional electrode and extrastimulus mapping techniques have not provided reliable maps of RPs.
Guinea pig hearts were stained with a voltage-sensitive dye to measure fluorescence (F) action potentials (APs) from 124 sites with a photodiode array. AP duration (APD) was defined as the time between depolarization (dF/dt)max and R time points (ie, the time when AP returns to baseline or some percent thereof). However, R time points are difficult to determine because AP downstrokes are often encumbered by drifting baselines and motion artifacts, which make this definition ambiguous. In optical and microelectrode recordings, the second derivative of AP downstrokes is shown to contain an easily detected, unique local maximum. The correlation between the position of this maximum (d2F/dt2)max and R has been tested during altered AP characteristics induced by changes in cycle length, ischemia, and hypoxia. Under these various modifications of the AP, the time points of (d2F/dt2)max fell at 97.0 +/- 2.1% of recovery to baseline. Extrastimulus techniques applied to (1) isolated myocytes, (2) intact hearts, and (3) mathematical simulations indicated that (d2V/dt2)max coincided with the effective RPs of APs. The coincidence of RPs and (d2V/dt2)max was valid within 5 milliseconds, for resting potentials of -75 to -90 mV and extrastimuli three times threshold voltage.
Thus, optical APs and (d2F/dt2)max can be used to map activation, R, and RPs with AP recordings from a single heartbeat.
Mechanisms and electropharmacological characteristics in adult patients with atrial tachycardia (AT) are not well described. We proposed that a combination of electropharmacological characteristics, recording of monophasic action potential, and effects of radiofrequency ablation could further determine the mechanisms and achieve a new classification in adults with various types of AT because they were important in regard to the correlation between mechanisms and pathophysiology, clinical syndrome, and responses to specific pharmacological or nonpharmacological therapies.
Thirty-six patients (11 female, 25 male; mean age, 57 +/- 13 years) with AT were referred for electropharmacological studies and radiofrequency ablation. Resetting response pattern, entrainment phenomenon, recording of monophasic action potential, serial drug test, response to Valsalva maneuver, endocardial mapping technique, and radiofrequency ablation were performed. Seven patients had automatic AT provocable with isoproterenol; neither initiation nor termination was related to programmed electrical stimulation. The other 29 patients had AT initiated or terminated by electrical stimulation and mechanisms related to triggered activity or reentry; nine of them needed isoproterenol to facilitate initiation of AT, associated with delayed afterdepolarization in monophasic action potential. All responded to adenosine (15 to 60 micrograms/kg) and Valsalva maneuver. Dipyridamole terminated AT and decreased the slope of afterdepolarization. Afterdepolarization was not found in the patients with automatic or reentrant AT. In 40 of 41 (98%), AT was ablated successfully, with late recurrence in 2 of 40 (5%) (follow-up, 18 +/- 4 months).
This study demonstrates the diverse mechanisms and electropharmacological characteristics of AT in adults. Furthermore, radiofrequency ablation of various types of AT could achieve high success and low recurrence rates.
The effects of subthreshold stimulation (STS) delivered during right atrial pacing and ventricular tachycardia (VT) were investigated in Langendorff-perfused guinea pig hearts. The hearts were stained with a voltage-sensitive dye (RH 421) to map the propagation of optical action potentials. Sustained VT was reliably induced by 5-second trains (cycle length [CL], 25 to 50 milliseconds; duration, 0.5 to 10 milliseconds; and voltage, 2x threshold voltage) of impulses (n = 12 hearts) or a single premature beat (n = 6). The location of extrastimuli was not critical to the induction of VT, but the diameter of the heart had to be > or = 14.5 mm. During VT, heart rate increased from 200 to 600 beats per minute; action potential durations decreased from 112 to 175 milliseconds to 60 to 105 milliseconds, with no diastolic interval. Activation on the epicardium spread anisotropically, but VT decreased the "apparent" maximum conduction velocity (theta max) by 68% and altered the orientation of the major axis from beat to beat. Activation patterns and theta max measured during VT were similar to patterns recorded during direct pacing of the ventricle and indicated that Purkinje fibers no longer propelled ventricular excitation. STS (CL, 25 to 50 milliseconds; duration, 0.5 to 25 milliseconds; and voltage, 0.5x to 0.8x threshold; trains of 2.0 to 2.5 seconds) interrupted VT when applied to Purkinje fibers lining the endocardium (n = 6) but failed to interrupt VT when applied to the epicardium (n = 8). In atrial pacing, STS delivered to the endocardium increased theta max from 2.44 +/- 0.32 (mean +/- SEM) to 3.63 +/- 0.21 m/s in a local region surrounding the first activation sites (n = 4). Alternatively, VT could be terminated by reducing theta max (approximately 55%) with procainamide (10 mumol/L) (n = 6). STS terminates VT by synchronizing ventricular excitation most likely by increasing local conduction and/or improving the coupling between Purkinje and ventricular cells.
Atrial fibrillation (AF) can be initiated by ectopic beats originating from the atrial or great venous tissues. This study investigated the anatomic characteristics and electrophysiological properties of pulmonary veins (PVs), as well as the possible mechanisms and response to drugs of ectopic foci, and assessed the effects of radiofrequency (RF) ablation on AF initiated by ectopic beats originating from PVs.
Seventy-nine patients with frequent episodes of paroxysmal AF and 10 control patients were included. Distal PVs showed the shortest effective refractory periods (ERPs), and right superior PVs showed a higher incidence of intra-PV conduction block than left superior PVs. Superior and left PVs had longer myocardial sleeves than inferior and right PVs, respectively. These electrophysiological characteristics were similar between AF and control patients. Propranolol, verapamil, and procainamide suppressed ectopic beats that originated from the PVs. Of 116 ectopic foci that initiated AF, 103 (88.8%) originated from PVs. A mean of 7+/-3 RF applications completely eliminated 110 ectopic foci (94.8%). During the 6+/-2-month follow-up period, 68 patients (86. 1%) were free of AF without any antiarrhythmic drugs. Follow-up transesophageal echocardiogram showed 42.4% of ablated PVs had focal stenosis. One patient had mild exertional dyspnea after ablation, but it resolved 3 months later; 1 patient had onset of mild exertional dyspnea 5 months after ablation.
Electrophysiological characteristics of PVs are different from those in the atria. Ectopic beats from PVs can initiate AF, and beta-adrenergic receptor blocker, calcium channel blockers, and sodium channel blockers can suppress these ectopic beats. Careful mapping and elimination of these ectopic foci can cure paroxysmal AF.
Atrial fibrillation (AF) has traditionally been described as aperiodic or random. Yet, ongoing sources of high-frequency periodic activity have recently been suggested to underlie AF in the sheep heart. Our objective was to use a combination of optical and bipolar electrode recordings to identify sites of periodic activity during AF and elucidate their mechanism.
AF was induced by rapid pacing in the presence of 0.1 to 0.5 micromol/L acetylcholine in 7 Langendorff-perfused sheep hearts. We used simultaneous optical mapping of the right and left atria (RA and LA) and frequency sampling of optical and bipolar electrode recordings (including a roving electrode) to identify sites having the highest dominant frequency (DF). Rotors were identified from optical recordings, and their rotation period, core area, and perimeter were measured. In all, 35 AF episodes were analyzed. Mean LA and RA DFs were 14.7+/-3.8 and 10.3+/-2.1 Hz, respectively. Spatiotemporal periodicity was seen in the LA during all episodes. In 5 of 7 experiments, a single site having periodic activity at the highest DF was localized. The highest DF was most often (80%) localized to the posterior LA, near or at the pulmonary vein ostium. Rotors (n=14) were localized on the LA. The mean core perimeter and area were 10.4+/-2.8 mm and 3.8+/-2.8 mm(2), respectively.
Frequency sampling allows rapid identification of discrete sites of high-frequency periodic activity during AF. Stable microreentrant sources are the most likely underlying mechanism of AF in this model.
We assessed the mode of reinitiation of atrial fibrillation (AF) after cardioversion and the efficacy of ablating these foci of reinitiation in patients with chronic AF.
Fifteen patients, 7 with structural heart disease, underwent mapping and catheter ablation of drug-resistant AF documented to be persistent for 5 +/- 4 months. In all patients, cardioversion was followed by documentation of P on T atrial ectopy and early recurrence, which allowed mapping of the reinitiating trigger or the source of ectopy. Radiofrequency (RF) ablation was performed at pulmonary vein (PV) ostia using a target temperature of 50 degrees C and a power limit of 30 to 40 W, with the endpoint being interruption of all local muscle conduction. A total of 32 arrhythmogenic PVs and 2 atrial foci (left septum and left appendage) were identified: 1, 2, and 3 or 4 PVs in 5, 3, and 6 patients. RF applications at the ostial perimeter resulted in progressively increasing delay, followed by abolition of PV potentials in 8, but potentials persisted in 6. A single ablation session was performed in 7 patients and 8 underwent two or three sessions because of recurrence of AF; ablation was directed at the same source due to recovery of local PV potential or at a different PV. No PV stenosis was noted either acutely or at repeated follow-up angiograms. Nine patients (60%) were in stable sinus rhythm without antiarrhythmic drugs at follow-up of 11 +/- 8 months. Anticoagulants were interrupted in 7 patients.
PVs are the dominant triggers reinitiating chronic AF in this patient population. Elimination of PV potentials by ostial RF applications results in stable sinus rhythm in 60%. A larger group and longer follow-up are needed to investigate further the role of trigger ablation in curative therapy for chronic AF.
The reentrant pathways underlying different types of atrioventricular (AV) nodal reentrant tachycardia have not yet been elucidated. This study was performed to optically map Koch's triangle and surrounding atrial tissue in an isolated canine AV nodal preparation. Multiple preferential AV nodal input pathways were observed in all preparations (n=22) with continuous (73%, n=16) and discontinuous (27%, n=6) AV nodal function curves (AVNFCs). AV nodal echo beats (EBs) were induced in 54% (12/22) of preparations. The reentrant circuit of the slow/fast EB (36%, n=8) started as a block in fast pathway (FP) and a delay in slow pathway (SP) conduction to the compact AV node, then exited from the AV node to the FP, and rapidly returned to the SP through the atrial tissue located at the base of Koch's triangle. The reentrant circuit of the fast/slow EB (9%, n=2) was in an opposite direction. In the slow/slow EB (9%, n=2), anterograde conduction was over the intermediate pathway (IP) and retrograde conduction was over the SP. Unidirectional conduction block occurred at the junction between the AV node and its input pathways. Conduction over the IP smoothed the transition from the FP to the SP, resulting in a continuous AVNFC. A "jump" in AH interval resulted from shifting of anterograde conduction from the FP to the SP (n=4) or abrupt conduction delay within the AV node through the FP (n=2). These findings indicate that (1) multiple AV nodal anterograde pathways exist in all normal hearts; (2) atrial tissue is involved in reentrant circuits; (3) unidirectional block occurs at the interface between the AV node and its input pathways; and (4) the IP can mask the existence of FP and SP, producing continuous AVNFCs.
Pulmonary veins (PVs) are important sources of paroxysmal atrial fibrillation. Long-term rapid atrial pacing (RAP) changes atrial electrophysiology and facilitates the maintenance of atrial fibrillation. It is not clear whether RAP alters the arrhythmogenic activity of PVs. The purpose of this study was to isolate single PV cardiomyocytes from control and RAP dogs and evaluate their electrophysiological characteristics.
The action potential and ionic currents were investigated in PV cardiomyocytes from control and long-term (6 to 8 weeks) RAP (780 bpm) dogs by use of the whole-cell clamp technique. Dissociation of PVs yielded rod-shaped single cardiomyocytes without (n=91, 60%) or with (n=60, 40%) pacemaker activity. Compared with the control group, the RAP dog PV cardiomyocytes had faster beating rates (0.86+/-0.28 versus 0.45+/-0.07 Hz, P<0.05) and shorter action potential duration. The RAP dog PV cardiomyocytes with pacemaker activity have a higher incidence of delayed (59% versus 7%, P<0.001) or early (24% versus 0%, P<0.005) after depolarization. The RAP dog PV cardiomyocytes with pacemaker activity had smaller slow inward and transient outward but larger transient inward (0.017+/-0.004 versus 0.009+/-0.002 pA/pF, P<0.05) and pacemaker (0.111+/-0.019 versus 0.028+/-0.008 pA/pF, P<0.001) currents. The RAP dog PV cardiomyocytes without pacemaker activity had only smaller slow inward and transient outward and larger pacemaker currents.
PVs contain multiple cardiomyocytes with distinct electrophysiological characteristics. RAP changes the electrophysiological characteristics and arrhythmogenic activity of PVs.
Paroxysmal atrial fibrillation in patients is often initiated by foci in the pulmonary veins. The mechanism of these initiating arrhythmias is unknown. The aim of this study was to determine electrophysiological characteristics of canine pulmonary veins that may predispose to initiating arrhythmias.
Extracellular recordings were obtained from the luminal side of 9 pulmonary veins in 6 Langendorff-perfused dog hearts after the veins were incised from the severed end to the ostium. Pulmonary veins were paced at the distal end, the ostium, and an intermediate site. During basic and premature stimulation, extracellular electrical activity was recorded with a grid electrode that harbored 247 electrode terminals. In 4 hearts, intracellular electrograms were recorded with microelectrodes. Myocyte arrangement immediately beneath the venous walls was determined by histological analysis in 3 hearts. Extracellular mapping revealed slow and complex conduction in all pulmonary veins. Activation delay after premature stimulation could be as long as 96 ms over a distance of 3 mm. Action potential duration was shorter at the distal end of the veins than at the orifice. No evidence for automaticity or triggered activity was found. Histological investigation revealed complex arrangements of myocardial fibers that often showed abrupt changes in fiber direction and short fibers arranged in mixed direction.
Zones of activation delay were observed in canine pulmonary veins and correlated with abrupt changes in fascicle orientation. This architecture of muscular sleeves in the pulmonary veins may facilitate reentry and arrhythmias associated with ectopic activity.
Rapid electrical activity in pulmonary veins (PVs) has been proposed as a mechanism for focal atrial fibrillation. The way in which the myocardial sleeve inside PVs can form a substrate for focal activity is not well understood. Therefore, we have studied tissue structure and connexin distribution at the veno-atrial transition in the dog.
In adult mongrel dogs, the anatomy of the PV area was studied. Tissue structure in individual veins was assessed in formalin fixed sections using Masson's Trichrome staining. Gap junction protein distribution was examined using antibodies against connexin40 (Cx40) and connexin43 (Cx43). The ultrastructure of myocytes in myocardial sleeves was studied using electron microscopy.
Individual PVs in the dog had a gross morphology similar to that observed in the human, with myocardial sleeves extending into the veins for 4-20 mm. In all veins examined, myocytes in myocardial sleeves had a normal atrial morphology and anti-desmin staining pattern. Cx43 was expressed throughout the sleeve at levels comparable to normal atrial myocardium. By contrast, Cx40 expression was lower in myocardial sleeves than in the rest of the left atrium. Myocytes in the sleeve, which were ultrastructurally similar to normal atrial myocytes, were predominantly organized in a circumferential pattern.
PVs in the dog and various canine models of heart disease will be a suitable model for (patho)physiology of the veno-atrial transition. Myocytes in myocardial sleeves are similar to normal atrial myocytes. The circumferential orientation of these myocytes may provide a substrate for rapid circular reentry.
Effects of rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytes from pulmonary veins
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Chen YJ, Chen SA, Chen YC, et al. Effects of rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytes from pulmonary veins. Circulation 2001;104:2849–2854. [PubMed: 11733406]