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

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

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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