Role of the vagus nerve and intrinsic cardiac ganglia in both remote and local myocardial ischaemic conditioning

BACKGROUND: There is a clear clinical need for interventions that limit the extent of injury associated with myocardial ischaemia-reperfusion injury (IRI). Two such interventions are classical (IPC) and remote (RIC) ischaemic preconditioning. The mechanism of action in both cases involves release of one or more humoral factors. However, the existence of a neural pathway remains equivocal. The aim of this thesis was to investigate the importance of a neural pathway in both classical and remote ischaemic conditioning, with particular focus on the vagus nerve and intrinsic cardiac ganglia. In addition, the efficacy of noninvasive vagus nerve stimulation was investigated as a novel cardioprotective intervention. Finally, we performed a meta-analysis investigating the efficacy of RIC in animal in vivo models of myocardial infarction. Methods and Results This thesis first aimed to investigate the co-dependence between the neural and humoral pathways of RIC. Bilateral cervical vagotomy abolished release of the humoral blood-borne mediator. Moreover, pharmacological antagonism of intrinsic cardiac ganglia abrogated RIC-mediated protection. This thesis was the first to reveal a neural component to the mechanism of IPC. We suggest a sensory feedback loop in response to IPC, involving activation intrinsic cardiac ganglia and post-ganglionic parasympathetic fibres projecting to the ventricles. Finally, transcutaneous vagus nerve stimulation (tVNS) in healthy human volunteers induced release of a blood-borne cardioprotective factor. However, tVNS was not significantly cardioprotective in an in vivo rat model of IRI. Conclusions Release of the humoral blood-borne mediator following RIC is dependent on prior vagus nerve activation. Furthermore, intrinsic cardiac ganglia are recruited as part of the mechanism of both RIC and IPC. Finally, tVNS is suggested to be a novel cardioprotective intervention

Co-dependence of the neural and humoral pathways in the mechanism of remote ischemic conditioning

The cardioprotection afforded by remote ischaemic conditioning (RIC) is mediated via a complex mechanism involving sensory afferent nerves, the vagus nerve, and release of a humoral blood-borne factor. However, it is unknown whether release of the protective factor depends on vagal activation or occurs independently. This study aimed to evaluate the co-dependence of the neural and humoral pathways of RIC, focussing on the vagus nerve and intrinsic cardiac ganglia. In the first study, anesthetised rats received bilateral cervical vagotomy or sham-surgery immediately prior to RIC (4 × 5 min limb ischemia-reperfusion) or sham-RIC. Venous blood plasma was dialysed across a 12-14 kDa membrane and dialysate perfused through a naïve-isolated rat heart prior to 35-min left anterior descending ischemia and 60-min reperfusion. In the second study, anesthetised rats received RIC (4 × 5-min limb ischemia-reperfusion) or control (sham-RIC). Dialysate was prepared and perfused through a naïve-isolated rat heart in the presence of the ganglionic blocker hexamethonium or muscarinic antagonist atropine, prior to ischemia-reperfusion as above. Dialysate collected from RIC-treated rats reduced infarct size in naïve rat hearts from 40.7 ± 6.3 to 23.7 ± 3.1 %, p < 0.05. Following bilateral cervical vagotomy, the protection of RIC dialysate was abrogated (42.2 ± 3.2 %, p < 0.05 vs RIC dialysate). In the second study, the administration of 50-μM hexamethonium (45.8 ± 2.5 %) or 100-nM atropine (36.5 ± 3.4 %) abrogated the dialysate-mediated protection. Release of a protective factor following RIC is dependent on prior activation of the vagus nerve. In addition, this factor appears to induce cardioprotection via recruitment of intrinsic cardiac ganglia