Network interactions within the canine intrinsic cardiac nervous system: implications for reflex control of regional cardiac function

Abstract

Key points• Control of regional cardiac function, as mediated by the intrinsic cardiac (IC) nervous system, is dependent upon its cardiac afferent neuronal inputs, changes in its central neuronal drive and interactions mediated within via local circuit neurons.• The majority of its local circuit neurons receive indirect central (sympathetic and parasympathetic) inputs, lesser proportions transducing the cardiac milieu.• Fifty per cent of IC neurons exhibit cardiac cycle-related periodicity that is primarily related to direct cardiac mechano-sensory afferent inputs and, secondarily, to indirect central autonomic efferent inputs.• In response to mediastinal nerve stimulation, most IC neurons became excessively activated in the induction of atrial arrhythmias such that their stochastic interactivity precedes and persists throughout neuronally induced atrial fibrillation.• Modulation of such stochastic IC local circuit neuronal recruitment may represent a novel target for the treatment of select cardiac disease, including atrial arrhythmias.Abstract The aims of the study were to determine how aggregates of intrinsic cardiac (IC) neurons transduce the cardiovascular milieu versus responding to changes in central neuronal drive and to determine IC network interactions subsequent to induced neural imbalances in the genesis of atrial fibrillation (AF). Activity from multiple IC neurons in the right atrial ganglionated plexus was recorded in eight anaesthetized canines using a 16-channel linear microelectrode array. Induced changes in IC neuronal activity were evaluated in response to: (1) focal cardiac mechanical distortion; (2) electrical activation of cervical vagi or stellate ganglia; (3) occlusion of the inferior vena cava or thoracic aorta; (4) transient ventricular ischaemia, and (5) neurally induced AF. Low level activity (ranging from 0 to 2.7 Hz) generated by 92 neurons was identified in basal states, activities that displayed functional interconnectivity. The majority (56%) of IC neurons so identified received indirect central inputs (vagus alone: 25%; stellate ganglion alone: 27%; both: 48%). Fifty per cent transduced the cardiac milieu responding to multimodal stressors applied to the great vessels or heart. Fifty per cent of IC neurons exhibited cardiac cycle periodicity, with activity occurring primarily in late diastole into isovolumetric contraction. Cardiac-related activity in IC neurons was primarily related to direct cardiac mechano-sensory inputs and indirect autonomic efferent inputs. In response to mediastinal nerve stimulation, most IC neurons became excessively activated; such network behaviour preceded and persisted throughout AF. concluded that stochastic interactions occur among IC local circuit neuronal populations in the control of regional cardiac function. Modulation of IC local circuit neuronal recruitment may represent a novel approach for the treatment of cardiac disease, including atrial arrhythmias.

Parasympathetic dysfunction and antiarrhythmic effect of vagal nerve stimulation following myocardial infarction

“…A parasympathetic neuron (classified by its response to right or left VNS) that also responded to an afferent stimulus, including epicardial mechanosensory stimuli and/or changes in preload and afterload, was further classified as a convergent parasympathetic neuron. Convergent neurons are thought to be responsible for the majority of local cardiac neural processing (14,15). A neuron that did not respond to afferent stimuli was classified as an efferent neuron.…”

“…In vivo recordings from these neurons were obtained using a multielectrode array. An increase (Figure 2) or decrease ( Figure 3) in firing frequency of a recorded neuron in response to right or left VNS was used to classify it as a parasympathetic efferent neuron (14). Basal activity of neurons that increased their firing frequency in response to left VNS was reduced in infarcted compared with normal animals (0.14 ± 0.04 Hz vs. 0.29 ± 0.07 Hz, respectively, P < 0.05; Figure 2C).…”

“…The vago-sympathetic trunk, the primary highway of the parasympathetic nervous system, carries preganglionic cardiomotor fibers from the brainstem that synapse on postganglionic neurons within the intrinsic cardiac ganglia on the surface of the heart. The cardiac ganglia are an important processing center for the heart, responding to beat-by-beat changes in mechanoelectrical function (14,20,21). Parasympathetic neurons within these ganglia send postganglionic projections to atrial and ventricular myocardium, which release ACh.…”

“…Arterial blood gas levels were measured hourly. After completion of surgical exposure, anesthetics were switched from isoflurane to α-chloralose (Sigma-Aldrich; 50 mg/kg initial bolus, then 20-35 mg/kg/hr) (14,28,48) for in vivo neuronal recordings, followed by stabilization period of 1 hour. Animals were euthanized by an overdose of i.v.…”

“…Neuronal waveforms (filter 300 Hz to 3 KHz) were recorded continuously via a data acquisition system (Cambridge Electronic Design). Data analysis and signal processing was performed offline using the software Spike2 (Cambridge Electronic Design) (14).…”