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Heart failure (HF) is associated with significant morbidity and mortality. The disease is characterised by autonomic imbalance with increased sympathetic activity and withdrawal of parasympathetic activity. Despite the use of medical therapies that target, in part, the neurohormonal axis, rates of HF progression, morbidity and mortality remain high. Emerging therapies centred on neuromodulation of autonomic control of the heart provide an alternative device-based approach to restoring sympathovagal balance. Preclinical studies have proven favourable, while clinical trials have had mixed results. This article highlights the importance of understanding structural/functional organisation of the cardiac nervous system as mechanistic-based neuromodulation therapies evolve.

Richer LP, Vinet A, Kus T, Cardinal R, Ardell JL, Armour JA. α-Adrenoceptor blockade modifies neurally induced atrial arrhythmias. Am J Physiol Regul Integr Comp Physiol 295: RI 175-Ri 180, 2008. First published August 20, 2008; doi: 10.11 52/ajpregu.00840.2007.-Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by α-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; I ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (α[sub1]-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (α[sub2]-adrenergic blocker: 1 mg/kg, n 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined α-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by α[sub1,2]-adrenergic blockade. Naftopidil or yohimbine alone eliminated atnal arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal α-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that α-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system. [ABSTRACT FROM AUTHOR]