Role of the Autonomic Nervous System in Atrial Fibrillation: Pathophysiology and Therapy

Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia (AT) and atrial fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review we focus on the relationship between the autonomic nervous system and the pathophysiology of AF, and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches and biological therapies. While the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future

Atrial fibrillation: pathophysiology, genetic and epigenetic mechanisms

Atrial fibrillation (AF) is the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence dramatically increases with age and could reach up to ∼10% in the elderly. The management of AF is a complex issue that is object of extensive ongoing basic and clinical research, it depends on its genetic and epigenetic causes, and it varies considerably geographically and also according to the ethnicity. Mechanistically, over the last decade, Genome Wide Association Studies have uncovered over 100 genetic loci associated with AF, and have shown that European ancestry is associated with elevated risk of AF. These AF-associated loci revolve around different types of disturbances, including inflammation, electrical abnormalities, and structural remodeling. Moreover, the discovery of epigenetic regulatory mechanisms, involving non-coding RNAs, DNA methylation and histone modification, has allowed unravelling what modifications reshape the processes leading to arrhythmias. Our review provides a current state of the field regarding the identification and functional characterization of AF-related genetic and epigenetic regulatory networks, including ethnic differences. We discuss clear and emerging connections between genetic regulation and pathophysiological mechanisms of AF

Electrophysiology Model for a Human Heart with Ischemic Scar and Realistic Purkinje Network

The role of Purkinje fibres in the onset of arrhythmias is controversial and computer simulations may shed light on possible arrhythmic mechanisms involving the Purkinje fibres. However, few computational modelling studies currently include a detailed Purkinje network as part of the model. We present a coupled Purkinje-myocardium electrophysiology model that includes an explicit model for the ischemic scar plus a detailed Purkinje network, and compare simulated activation times to those obtained by electro-anatomical mapping in vivo during sinus rhythm pacing. The results illustrate the importance of using sufficiently dense Purkinje networks in patient-specific studies to capture correctly the myocardial early activation that may be influenced by surviving Purkinje fibres in the infarct region

Exponential distribution of long heart beat intervals during atrial fibrillation and their relevance for white noise behaviour in power spectrum

The statistical properties of heart beat intervals of 130 long-term surface electrocardiogram recordings during atrial fibrillation (AF) are investigated. We find that the distribution of interbeat intervals exhibits a characteristic exponential tail, which is absent during sinus rhythm, as tested in a corresponding control study with 72 healthy persons. The rate of the exponential decay lies in the range 3-12 Hz and shows diurnal variations. It equals, up to statistical uncertainties, the level of the previously uncovered white noise part in the power spectrum, which is also characteristic for AF. The overall statistical features can be described by decomposing the intervals into two statistically independent times, where the first one is associated with a correlated process with 1/f noise characteristics, while the second one belongs to an uncorrelated process and is responsible for the exponential tail. It is suggested to use the rate of the exponential decay as a further parameter for a better classification of AF and for the medical diagnosis. The relevance of the findings with respect to a general understanding of AF is pointed out

Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K+ currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K+ currents (ITO, IKSUS and IK1) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in ITO density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p < 0.05; without affecting its voltage-, time- or rate dependence. IK1 was reduced by 34% at −120 mV (p < 0.05). Neither IKSUS, nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of ITO- and IK1-decrease could result in a 28% increase in APD90. Chronic β-blockade did not alter mRNA or protein expression of the ITO pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in IK1. A reduction in atrial ITO and IK1 associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits

Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling

[EN] Atrial fibrillation (AF) results in a remodeling of the electrical and structural characteristics of the cardiac tissue which dramatically reduces the efficacy of pharmacological and catheter-based ablation therapies. Recent experimental and clinical results have demonstrated that the complexity of the fibrillatory process significantly differs in paroxysmal versus persistent AF; however, the lack of appropriate research models of remodeled atrial tissue precludes the elucidation of the underlying AF mechanisms and the identification of appropriated therapeutic targets. Here, we summarize the different research models used to date, highlighting the lessons learned from them and pointing to the new doors that should be open for the development of innovative treatments for AF.The authors were supported by grants from the Spanish Ministry of Science and Innovation (PLE2009-0152), the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain: PI13-01882 and PI13-00903) the Red de Investigacion Cardiovacular (RIC) from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain). F Atienza served on the advisory board of Medtronic and has received research funding from St. Jude Medical Spain. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Climent, A.; Guillem Sánchez, MS.; Atienza Fernández, F.; Fernandez-Aviles, F. (2014). Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling. Expert Review of Cardiovascular Therapy. 13(1):1-3. https://doi.org/10.1586/14779072.2015.986465S1313

Unique Cardiac Purkinje Fiber Transient-Outward Current Beta-Subunit Composition: A Potential Molecular Link to Idiopathic Ventricular Fibrillation.

Rationale: A chromosomal-haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation (IVF). The molecular basis of transient-outward current (Ito) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Ito and that its overexpression might specifically alter PF Ito-properties and repolarization. Objective: To assess the potential role of DPP6 in PF-Ito. Methods and Results: Clinical data in 5 IVF-patients suggested arrhythmia-origin in the PF conducting-system. PF and ventricular-muscle (VM) Ito had similar density, but PF Ito differed from VM in having tetraethylammonium-sensitivity and slower recovery. DPP6-overexpression significantly increased, whereas DPP6-kockdown reduced, Ito-density and tetraethylammonium-sensitivity in canine PF, but not VM-cells. The K+-channel interacting beta-subunit KChIP2, essential for normal expression of transient outward current (Ito) in VM, was weakly-expressed in human PFs, whereas DPP6 and frequenin (NCS-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary (CHO)-cells produced very small Ito; Ito-amplitude was greatly enhanced by co-expression with KChIP2 or DPP6. Co expression of DPP6 with Kv4.3 and KChIP2 failed to alter Ito versus Kv4.3/KChIP2 alone, but DPP6 expression with Kv4.3 and NCS-1 (to mimic PF Ito-composition), greatly enhanced Ito versus Kv4.3/NCS-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that Ito-enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously-unknown central role of DPP6 in PF Ito, with DPP6 gain-of-function selectively enhancing PF-current, and suggest that a DPP6-mediated PF early repolarization syndrome might be a novel molecular paradigm for some forms of IVF

An interactive platform to guide catheter ablation in human persistent atrial fibrillation using dominant frequency, organization and phase mapping

Background and Objective: Optimal targets for persistent atrial fibrillation (persAF) ablation are still debated. Atrial regions hosting high dominant frequency (HDF) are believed to participate in the initiation and maintenance of persAF and hence are potential targets for ablation, while rotor ablation has shown promising initial results. Currently, no commercially available system offers the capability to automatically identify both these phenomena. This paper describes an integrated 3D software platform combining the mapping of both frequency spectrum and phase from atrial electrograms (AEGs) to help guide persAF ablation in clinical cardiac electrophysiological studies. Methods: 30 s of 2048 non-contact AEGs (EnSite Array, St. Jude Medical) were collected and analyzed per patient. After QRST removal, the AEGs were divided into 4 s windows with a 50% overlap. Fast Fourier transform was used for DF identification. HDF areas were identified as the maximum DF to 0.25 Hz below that, and their centers of gravity (CGs) were used to track their spatiotemporal movement. Spectral organization measurements were estimated. Hilbert transform was used to calculate instantaneous phase. Results: The system was successfully used to guide catheter ablation for 10 persAF patients. The mean processing time was 10.4 ± 1.5 min, which is adequate comparing to the normal electrophysiological (EP) procedure time (120∼180 min). Conclusions: A customized software platform capable of measuring different forms of spatiotemporal AEG analysis was implemented and used in clinical environment to guide persAF ablation. The modular nature of the platform will help electrophysiological studies in understanding of the underlying AF mechanisms