Use of autonomic nervous system neurotransmitters inhibition and atrial parasympathetic fibers ablation for the treatment of atrial arrhythmias and to preserve drug effects

Abstract

Atrial arrhythmias, a major contributor to cardiovascular morbidity, are believed to be influenced by autonomic nervous system tone. The main purpose of this invention was to highlight new findings that have emerged in the study of effects of autonomic nervous system tone on atrial arrhythmias, and its interaction with class III antiarrhythmic drug effects. This invention evaluates the significance of sympathetic and parasympathetic activation by determining the effects of autonomic nervous system using a vagal and stellar ganglions stimulation, and by using autonomic nervous system neurotransmitters infusion (norepinephrine, acetylcholine). This invention evaluates the autonomic nervous system effects on the atrial effective refractory period duration and dispersion, atrial conduction velocity, atrial wavelength duration, excitable gap duration during a stable circuit (such atrial flutter circuit around an anatomical obstacle), and on the susceptibility of occurrence (initiation, maintenance and termination) of atrial re-entrant arrhythmias in canine. This invention also evaluates whether autonomic nervous system activation effects via a local neurotransimitters infusion into the right atria can alter those of class III antiarrhythmic drug, sotalol, during a sustained right atrial flutter. This invention represents an emergent need to set-up and develop a new class of anti-cholinergic drug therapy for the treatment of atrial arrhythmias and to combine this new anti-cholinergic class to antiarrhythmic drugs. Furthermore, this invention also highlights the importance of a local application of parasympathetic neurotransmitters / blockers and a catheter ablation of the area of right atrium with the highest density of parasympathetic fibers innervation. This may significantly reduce the occurrence of atrial arrhythmias and may preserve the antiarrhythmic effects of any drugs used for the treatment of atrial re-entrant arrhythmias.

Description

FIELD OF THE INVENTION[0001]Cardiac rhythm disturbances are a major cause of morbidity and even mortality in our ageing population. Most of these rhythms are based on reentry, i.e. the continuous circulation of a wavefront of excitation around a functional or anatomical circuit such atrial fibrillation and flutter. Atrial fibrillation could exist as a stable state, self-sustained and independent of its initiating trigger in the presence of non-uniform distribution (i.e. dispersion) of atrial refractory periods. In addition, maintenance of atrial fibrillation may require a critically short wavelength in order to sustain reentry. However, the cellular and pathophysiological mechanisms in the initiation and maintenance of atrial fibrillation remain poorly understood. It has been reported that inducibility and maintenance of this atrial arrhythmia are associated with an increased dispersion in atrial refractoriness. In addition, alterations in the electrophysiologic properties of the at...

AI Technical Summary

Benefits of technology

[0009]In summary, both neurotransmitters infusions (acetylcholine>>norepinephrine) significantly increased the occurrence of the initiation of atrial flutter and decreased the duration of its maintenance by rapid (less than 2 minutes) conversion to a non sustained atrial fibrillation and then to a sinus rhythm state. Both neurotransmitters significantly increased the safety margin of excitability ahead of the wavefront and decreased the effective refractory. Autonomic and, in particular, vagal effects significantly diminish the action of pure class III antiarrhythmic drug, d-sotalol. However, in the presence of d,l-sotalol, a class III combined with anti-adrenergic effects, only acetylcholine still completely reversed its electrophysiological effects. This suggests that class III antiarrhythmic drugs with class II properties could resist the effects of sympathetic but not that of vagal activation. The effects of autonomic nervous system stimulation also significantly increased the occurrence of atrial fibrillation initiation and persistence. The effects of vagus activation significantly exceed those of sympathetic on the occurrence of atrial fibrillation, on the atrial effective refractory period duration and dispersion, on the conduction velocity and on the wavelength. In a particular interest, when the stellar ganglions denervation facilitates the occurrence of the initiation of a non sustained atrial fibrillation following the premature stimulation (S1S2) (data described the relation between initiation vs. duration of atrial fibrillation are not presented in this invention), the vagal denervation significantly reduced its initiation and maintenance. Furthermore, in the presence of class III drug therapy, the vagal stimulation significantly and markedly reversed the antiarrhythmic therapeutic effects of d,l-sotalol. These results demonstrate an absolute and emergent need to consider the effects of the presence and of the activation of parasympathetic nervous system tone during the pharmacological treatment of atrial arrhythmias. In addition, this invention targets the areas with the greatest density of parasympathetic innervation for ablation, such as the areas located near the sinoatrial nodal fat pad and septal, for the treatment of atrial arrhythmias during a catheter ablation manner.

Problems solved by technology

Both neurotransmitters significantly increased the safety margin of excitability ahead of the wavefront and decreased the effective refractory.