The neuro-cardiac axis in arrhythmogenesis: Role and impact of autonomic modulation

The autonomic nervous system consisting of two limbs, the sympathetic and parasympathetic nervous system, plays a key role in the modulation of various cardiac arrhythmias. Neurotransmitters, including catecholamines and acetylcholine, as well as other co-transmitters mediate supraventricular and ventricular arrhythmogenesis through distinctive electrophysiologic mechanisms. The intricate autonomic interplay depicts that most arrhythmias arise from sympathetic overactivity and parasympathetic attenuation, with the sympathetic nervous system mitigating the effects of antiarrhythmic drugs. While this remains true for adrenergic-driven arrhythmias such as atrial fibrillation, post-infarct ventricular tachycardia, and some long QT syndromes 1 and 2, parasympathetic nervous overactivity may act as a trigger for vagotonic arrhythmias including Brugada syndrome, long QT syndrome 3, and idiopathic ventricular fibrillation. Knowledge of the neuro-cardiac hierarchies and awareness of different methods for assessment of autonomic tone, combined with promising results from animal studies, has established a clear rationale for clinical trials of various autonomic neuromodulatory interventions, which have had varying success for defined arrhythmias. Whereas cardiac sympathetic denervation imparts clear therapeutic benefits in patients with long QT syndrome 1 and polymorphic catecholaminergic ventricular tachycardia, the impact of vagus nerve stimulation in heart failure patients is less defined. Sustainable and relatable therapeutic outcomes from future clinical trials of neuromodulatory interventions dictate conscientious patient selection, optimized study protocols, and the use of reproducible biomarkers. Novel tools such as optogenetics present an exciting direction in the future for noninvasive neuromodulatory interventions.