Vagus Nerve Stimulation and Atrial Fibrillation: Revealing the Paradox.

BACKGROUND AND OBJECTIVE: The cardiac autonomic nervous system (CANS) plays an important role in the pathophysiology of atrial fibrillation (AF). Cardiovascular disease can cause an imbalance within the CANS, which may contribute to the initiation and maintenance of AF. Increased understanding of neuromodulation of the CANS has resulted in novel emerging therapies to treat cardiac arrhythmias by targeting different circuits of the CANS. Regarding AF, neuromodulation therapies targeting the vagus nerve have yielded promising outcomes. However, targeting the vagus nerve can be both pro-arrhythmogenic and anti-arrhythmogenic. Currently, these opposing effects of vagus nerve stimulation (VNS) have not been clearly described. The aim of this review is therefore to discuss both pro-arrhythmogenic and anti-arrhythmogenic effects of VNS and recent advances in clinical practice and to provide future perspectives for VNS to treat AF. MATERIALS AND METHODS: A comprehensive review of current literature on VNS and its pro-arrhythmogenic and anti-arrhythmogenic effects on atrial tissue was performed. Both experimental and clinical studies are reviewed and discussed separately. RESULTS: VNS exhibits both pro-arrhythmogenic and anti-arrhythmogenic effects. The anatomical site and stimulation settings during VNS play a crucial role in determining its effect on cardiac electrophysiology. Since the last decade, there is accumulating evidence from experimental studies and randomized clinical studies that low-level VNS (LLVNS), below the bradycardia threshold, is an effective treatment for AF. CONCLUSION: LLVNS is a promising novel therapeutic modality to treat AF and further research will further elucidate the underlying anti-arrhythmogenic mechanisms, optimal stimulation settings, and site to apply LLVNS.

Atrial electrophysiological characteristics of aging.

INTRODUCTION: Advancing age is a known risk factor for developing atrial fibrillation (AF), yet it is unknown which electrophysiological changes contribute to this increased susceptibility. The goal of this study is to investigate conduction disturbances and unipolar voltages (UV) related to aging. METHODS: We included 216 patients (182 male, age: 36-83 years) without a history of AF undergoing elective coronary artery bypass surgery. Five seconds of sinus rhythm were recorded intraoperatively at the right atrium (RA), Bachmann's bundle (BB), the left atrium and the pulmonary vein area (PVA). Conduction delay (CD), -block (CB), -velocity (CV), length of longest CB lines and UV were assessed in all regions. RESULTS: With aging, increasing conduction disturbances were found, particularly at RA and BB (RA: longest CB line rs = .158, p = .021; BB: CB prevalence rs = .206, p = .003; CV rs = -.239, p < .0005). Prevalence of low UV areas (UV <5th percentile) increased with aging at the BB and PVA (BB: rs = .237, p < .0005 and PVA: rs = .228, p = .001). CONCLUSIONS: Aging is accompanied by an increase in conduction disturbances during sinus rhythm and a higher prevalence of low UV areas, particularly at BB and in the RA. These electrophysiological alterations could in part explain the increasing susceptibility to AF development associated with aging.

Does conduction heterogeneity determine the supervulnerable period after atrial fibrillation?

Atrial fibrillation (AF) resumes within 90 s in 27% of patients after sinus rhythm (SR) restoration. The aim of this study is to compare conduction heterogeneity during the supervulnerable period immediately after electrical cardioversion (ECV) with long-term SR in patients with AF. Epicardial mapping of both atria was performed during SR and premature atrial extrasystoles in patients in the ECV (N = 17, age: 73 ± 7 years) and control group (N = 17, age: 71 ± 6 years). Inter-electrode conduction times were used to identify areas of conduction delay (CD) (conduction times 7-11 ms) and conduction block (CB) (conduction times ≥ 12 ms). For all atrial regions, prevalences and length of longest CB and continuous CDCB lines, magnitude of conduction disorders, conduction velocity, biatrial activation time, and voltages did not differ between the ECV and control group during both SR and premature atrial extrasystoles (p ≥ 0.05). Hence, our data suggest that there may be no difference in biatrial conduction characteristics between the supervulnerable period after ECV and long-term SR in AF patients. The supervulnerable period after AF termination is not determined by conduction heterogeneity during SR and PACs. It is unknown to what extent intra-atrial conduction is impaired during the supervulnerable period immediately after ECV and whether different right and left atrial regions are equally affected. This high-resolution epicardial mapping study (upper left panel) of both atria shows that during SR the prevalences and length of longest CB and cCDCB lines (upper middle panel), magnitude of conduction disorders, CV and TAT (lower left panel), and voltages did not differ between the ECV and control group. Likewise, these parameters were comparable during PACs between the ECV and control group (lower left panel). †Non-normally distributed. cm/s = centimeters per second; mm = millimeter; ms = millisecond; AF = atrial fibrillation; AT = activation time; BB = Bachmann's bundle; cCDCB = continuous lines of conduction delay and block; CB = conduction block; CD = conduction delay; CT = conduction time; CV = conduction velocity; ECV = electrical cardioversion; LA = left atrium; LAT = local activation times; PAC = premature atrial complexes; PVA = pulmonary vein area; RA = right atrium; SR = sinus rhythm; TAT = total activation time.

Degree of Fibrosis in Human Atrial Tissue Is Not the Hallmark Driving AF.

BACKGROUND: The current paradigm is that fibrosis promotes electrophysiological disorders and drives atrial fibrillation (AF). In this current study, we investigated the relation between the degree of fibrosis in human atrial tissue samples of controls and patients in various stages of AF and the degree of electrophysiological abnormalities. METHODS: The degree of fibrosis was measured in the atrial tissue and serum of patients in various stages of AF and the controls. Hereto, picrosirius and H&E staining were performed to quantify degree of total, endo-perimysial fibrosis, and cardiomyocyte diameter. Western blot quantified fibrosis markers: neural cell adhesion molecule, tissue inhibitor of metalloproteinase, lysyl oxidase, and α-smooth muscle actin. In serum, the ratio carboxyl-terminal telopeptide of collagen/matrix-metalloproteinase1 was determined. High-resolution epicardial mapping evaluated low-voltage areas and conduction abnormalities. RESULTS: No significant differences were observed in the degree of fibrosis between the groups. Finally, no significant correlation-absolute nor spatial-was observed between all electrophysiological parameters and histological fibrosis markers. CONCLUSIONS: No differences in the degree of fibrosis were observed in patients from various stages of AF compared to the controls. Moreover, electrophysiological abnormalities did not correlate with any of the fibrosis markers. The findings indicate that fibrosis is not the hallmark of structural remodeling in AF.

Conduction Disorders during Sinus Rhythm in Relation to Atrial Fibrillation Persistence.

Classification of atrial fibrillation (AF) is currently based on clinical characteristics. However, classifying AF using an objective electrophysiological parameter would be more desirable. The aim of this study was to quantify parameters of atrial conduction during sinus rhythm (SR) using an intra-operative high-resolution epicardial mapping approach and to relate these parameters to clinical classifications of AF. Patients were divided according to the standard clinical classification and spontaneous termination of AF episodes. The HATCH score, a score predictive of AF progression, was calculated, and surface ECGs were evaluated for signs of interatrial block. Conduction disorders mainly differed at Bachmann's bundle (BB). Activation time (AT) at BB was longer in persistent AF patients (AT-BB: 75 (53-92) ms vs. 55 (40-76) ms, p = 0.017), patients without spontaneous termination of AF episodes (AT-BB: 53.5 (39.6-75.8) ms vs. 72.0 (49.6-80.8) ms, p = 0.009) and in patients with a P-wave duration ≥ 120 ms (64.3 (52.3-93.0) ms vs. 50.5 (39.6-56.6) ms, p = 0.014). HATCH scores also correlated positively to AT-BB (rho 0.326, p = 0.029). However, discriminatory values of electrophysiological parameters, as calculated using ROC-curves, were limited. These results may reflect shortcomings of clinical classifications and further research is needed to establish an objective substrate-based classification of AF.

AF Inducibility Is Related to Conduction Abnormalities at Bachmann's Bundle.

We investigated whether patterns of activation at Bachmann's bundle are related to AF inducibility. Epicardial mapping of Bachmann's bundle during sinus rhythm was performed prior to cardiac surgery (192 electrodes, interelectrode distances: 2 mm). Compared to non-inducible patients (N = 20), patients with inducible AF (N = 34) had longer lines of conduction block (18(2-164) mm vs. 6(2-28) mm, p = 0.048), prolonged total activation time (55(28-143) ms vs. 46(24-73) ms, p = 0.012), multiple wavefronts entering Bachmann's bundle more frequently (64% vs. 37%, p = 0.046) and more often areas of simultaneous activation (conduction velocity > 1.7 m/s, 45% vs. 16%, p = 0.038). These observations further support a relation between conduction abnormalities at Bachmann's bundle and AF inducibility. The next step is to examine whether Bachmann's bundle activation patterns can also be used to identify patients who will develop AF after cardiac surgery during both short- and long-term follow-up.

Reduction of Conduction Velocity in Patients with Atrial Fibrillation.

It is unknown to what extent atrial fibrillation (AF) episodes affect intra-atrial conduction velocity (CV) and whether regional differences in local CV heterogeneities exist during sinus rhythm. This case-control study aims to compare CV assessed throughout both atria between patients with and without AF. Patients (n = 34) underwent intra-operative epicardial mapping of the right atrium (RA), Bachmann's bundle (BB), left atrium (LA) and pulmonary vein area (PVA). CV vectors were constructed to calculate median CV in addition to total activation times (TAT) and unipolar voltages. Biatrial median CV did not differ between patients with and without AF (90 ± 8 cm/s vs. 92 ± 6 cm/s, p = 0.56); only BB showed a CV reduction in the AF group (79 ± 12 cm/s vs. 88 ± 11 cm/s, p = 0.02). In patients without AF, there was no predilection site for the lowest CV (P5) (RA: 12%; BB: 29%; LA: 29%; PVA: 29%). In patients with AF, lowest CV was most often measured at BB (53%) and ranged between 15 to 22 cm/s (median: 20 cm/s). Lowest CVs were also measured at the LA (18%) and PVA (29%), but not at the RA. AF was associated with a prolonged TAT (p = 0.03) and decreased voltages (P5) at BB (p = 0.02). BB was a predilection site for slowing of conduction in patients with AF. Prolonged TAT and decreased voltages were also found at this site. The next step will be to determine the relevance of a reduced CV at BB in relation to AF development and maintenance.

Conduction Heterogeneity: Impact of Underlying Heart Disease and Atrial Fibrillation.

OBJECTIVES: The goal of this study is to investigate the impact of various underlying heart diseases (UHDs) and prior atrial fibrillation (AF) episodes on conduction heterogeneity. BACKGROUND: It is unknown whether intra-atrial conduction during sinus rhythm differs between various UHD or is influenced by AF episodes. METHODS: Epicardial sinus rhythm mapping of the right atrium, Bachmann's bundle (BB), left atrium and pulmonary vein area was performed in 447 participants (median age: 67 [interquartile range (IQR): 59 to 73] years) with or without AF undergoing cardiac surgery for ischemic heart disease, (ischemic and) valvular heart disease, or congenital heart disease. Conduction times (CTs) were defined as Δ local activation time between 2 adjacent electrodes and used to assess frequency (CTs ≥ 4 ms) and magnitude of conduction disorders (in increments of 10 ms). RESULTS: When comparing the 3 types of UHD, there were no differences in frequencies and magnitude of CTs at all locations (p ≥ 0.017 and p ≥ 0.005, respectively). Prior AF episodes were associated with conduction slowing throughout both atria (14.9% [IQR: 11.8 to 17.0] vs. 12.8% [IQR: 10.9 to 14.6]; p < 0.001). At BB, CTs with magnitudes ≥30 ms were more common in patients with AF (n = 56.2% vs. n = 36.0%; p < 0.004). CONCLUSIONS: UHD has no impact on the frequency and severity of conduction disorders. AF episodes are associated with more conduction disorders throughout both atria and with more severe conduction disorders at BB. The next step will be to determine the relevance of these conduction disorders for AF development and maintenance.