Abstract
The cardiac autonomic nervous system (ANS) plays an integral role in normal cardiac physiology as well as in disease states that cause cardiac arrhythmias. The cardiac ANS, comprised of a ...complex neural hierarchy in a nested series of interacting feedback loops, regulates atrial electrophysiology and is itself susceptible to remodelling by atrial rhythm. In light of the challenges of treating atrial fibrillation (AF) with conventional pharmacologic and myoablative techniques, increasingly interest has begun to focus on targeting the cardiac neuraxis for AF. Strong evidence from animal models and clinical patients demonstrates that parasympathetic and sympathetic activity within this neuraxis may trigger AF, and the ANS may either induce atrial remodelling or undergo remodelling itself to serve as a substrate for AF. Multiple nexus points within the cardiac neuraxis are therapeutic targets, and neuroablative and neuromodulatory therapies for AF include ganglionated plexus ablation, epicardial botulinum toxin injection, vagal nerve (tragus) stimulation, renal denervation, stellate ganglion block/resection, baroreceptor activation therapy, and spinal cord stimulation. Pre-clinical and clinical studies on these modalities have had promising results and are reviewed here.
Myocardial ischemia disrupts the cardio-spinal neural network that controls the cardiac sympathetic preganglionic neurons, leading to sympathoexcitation and ventricular tachyarrhythmias (VTs). Spinal ...cord stimulation (SCS) is capable of suppressing the sympathoexcitation caused by myocardial ischemia. However, how SCS modulates the spinal neural network is not fully known.
In this pre-clinical study, we investigated the impact of SCS on the spinal neural network in mitigating myocardial ischemia-induced sympathoexcitation and arrhythmogenicity. Ten Yorkshire pigs with left circumflex coronary artery (LCX) occlusion-induced chronic myocardial infarction (MI) were anesthetized and underwent laminectomy and a sternotomy at 4-5 weeks post-MI. The activation recovery interval (ARI) and dispersion of repolarization (DOR) were analyzed to evaluate the extent of sympathoexcitation and arrhythmogenicity during the left anterior descending coronary artery (LAD) ischemia. Extracellular
and
spinal dorsal horn (DH) and intermediolateral column (IML) neural recordings were performed using a multichannel microelectrode array inserted at the T2-T3 segment of the spinal cord. SCS was performed for 30 min at 1 kHz, 0.03 ms, 90% motor threshold. LAD ischemia was induced pre- and 1 min post-SCS to investigate how SCS modulates spinal neural network processing of myocardial ischemia. DH and IML neural interactions, including neuronal synchrony as well as cardiac sympathoexcitation and arrhythmogenicity markers were evaluated during myocardial ischemia pre- vs. post-SCS.
ARI shortening in the ischemic region and global DOR augmentation due to LAD ischemia was mitigated by SCS. Neural firing response of ischemia-sensitive neurons during LAD ischemia and reperfusion was blunted by SCS. Further, SCS showed a similar effect in suppressing the firing response of IML and DH neurons during LAD ischemia. SCS exhibited a similar suppressive impact on the mechanical, nociceptive and multimodal ischemia sensitive neurons. The LAD ischemia and reperfusion-induced augmentation in neuronal synchrony between DH-DH and DH-IML pairs of neurons were mitigated by the SCS.
These results suggest that SCS is decreasing the sympathoexcitation and arrhythmogenicity by suppressing the interactions between the spinal DH and IML neurons and activity of IML preganglionic sympathetic neurons.
Key points
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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.
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The majority of its local circuit neurons receive indirect central (sympathetic and parasympathetic) inputs, lesser proportions transducing the cardiac milieu.
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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.
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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.
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Modulation of such stochastic IC local circuit neuronal recruitment may represent a novel target for the treatment of select cardiac disease, including atrial arrhythmias.
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. It was 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.
Imbalances in the opposing actions of sympathetic and parasympathetic nerves controlling the heart enhance risk for arrhythmia and sudden cardiac death after myocardial infarction (MI). Plasticity in ...peripheral neuron function may underlie the observed changes in cardiomotor nerve activity. We studied vagal control of the heart in pigs after chronic infarction of the left ventricle. Stimulation of the cervical vagus nerve produced greater bradycardic responses 8-weeks after MI. Recordings of epicardial electrocardiograms demonstrate increased severity and duration of atrioventricular (AV) block in MI-pigs during 20 Hz vagal stimulation. Intracellular voltage recordings from isolated neurons of the inferior vena cava-inferior left atrium (IVC-ILA) ganglionated plexus, a cluster of epicardial neurons receiving innervation from the vagus known to regulate the AV node, were used to assess plasticity of membrane and synaptic physiology of intrinsic cardiac neurons (ICNs) after MI. Changes to both passive and active membrane properties were observed, including more negative resting membrane potentials and greater input resistances in MI-pig ICNs, concomitant with a depression of neuronal excitability. Immunoreactivity to pituitary adenylate cyclase-activating polypeptide (PACAP), a cardiotropic peptide known to modulate cardiac neuron excitability, was localized to perineuronal varicosities surrounding pig IVC-ILA neurons. Exogenous application of PACAP increased excitability of control but not MI-ICNs. Stimulation (20 Hz) of interganglionic nerves in the
ex vivo
whole-mount preparations elicited slow excitatory postsynaptic potentials (sEPSPs) which persisted in hexamethonium (500 μM), but were blocked by atropine (1 μM), indicating muscarinic receptor-mediated inhibition of M-current. Extracellular application of 1 mM BaCl
2
to inhibit M-current increased neuronal excitability. The muscarine-sensitive sEPSPs were observed more frequently and were of larger amplitude in IVC-ILA neurons from MI animals. In conclusion, we suggest the increased probability of muscarinic sEPSPs play a role in the potentiation of the vagus nerve mediated-slowing of AV nodal conduction following chronic MI. We identify both a novel role of a muscarinic sensitive current in the regulation of synaptic strength at ICNs projecting to the AV node, and demonstrate changes to both intrinsic plasticity and synaptic plasticity of IVC-ILA neurons which may contribute to greater risk for heart block and sudden cardiac death after MI.
Neuromodulation of peripheral nerves has been clinically used for a wide range of indications. Wireless and batteryless stimulators offer important capabilities such as no need for reoperation, and ...extended life compared to their wired counterparts. However, there are challenging trade-offs between the device size and its operating range, which can limit their use. This study aimed to examine the functionality of newly designed wirelessly powered and controlled implants in vagus nerve stimulation for pigs. The implant used near field inductive coupling at 13.56 MHz industrial, scientific, and medical band to harvest power from an external coil. The circular implant had a diameter of 13 mm and weighed 483 mg with cuff electrodes. The efficiency of the inductive link and robustness to distance and misalignment were optimized. As a result, the specific absorption rate was orders of magnitude lower than the safety limit, and the stimulation can be performed using only 0.1 W of external power. For the first time, wireless and batteryless VNS with more than 5 cm operation range was demonstrated in pigs. A total of 84 vagus nerve stimulations (10 s each) have been performed in three adult pigs. In a quantitative comparison of the effectiveness of VNS devices, the efficiency of systems on reducing heart rate was similar in both conventional (75%) and wireless (78.5%) systems. The pulse width and frequency of the stimulation were swept on both systems, and the response for physiological markers was drawn. The results were easily reproducible, and methods used in this study can serve as a basis for future wirelessly powered implants.
Mapping the structure/function organization of the cardiac nervous system is foundational for implementation of targeted neuromodulation-based therapeutics for the treatment of cardiac disease.
The ...purpose of this study was to define the spatial organization of intrathoracic parasympathetic and sympathetic efferent projections to the heart.
Yucatan mini-pigs (N = 11) were anesthetized and the thoracic cavity exposed. Electrical stimulation of the cervical vagi and stellate ganglia was performed individually, and hemodynamic responses were assessed in the intact state and after progressive debranching of each thoracic vagosympathetic trunk (VST). Subsequently, residual cardiac efferent projections arising from paravertebral chain ganglia (T1-T4) were evaluated by stimulation before and after individual ganglionic debranching.
Stimulation of the cervical vagi decreased heart rate and contractility while prolonging the activation-recovery interval (ARI). Stimulation of the stellate ganglia increased heart rate and contractility and decreased ARI. The majority of parasympathetic and sympathetic cardiac-evoked responses were mitigated after debranching of the right VST rostral to heart, whereas the left VST demonstrated a distribution with greater dispersion and caudal intrathoracic shift compared to the right. After complete thoracic VST debranching, stimulation of the T4 paravertebral chain ganglia demonstrated residual cardiac sympathetic efferent innervation to the heart in ∼50% of animals. That response was mitigated by transecting medial ganglionic branches.
The nexus point for optimum neuromodulation engagement of parasympathetic efferent projections to the heart is the cervical vagus and the T1-T2 paravertebral chain ganglia for sympathetic control. Removal of principal sympathetic efferent projections to heart requires targeting the T1-T4 regions of the paravertebral chain.
The cardiac nervous system continuously controls cardiac function whether or not pathology is present. While myocardial infarction typically has a major and catastrophic impact, population studies ...have shown that longer-term risk for recurrent myocardial infarction and the related potential for sudden cardiac death depends mainly upon standard atherosclerotic variables and autonomic nervous system maladaptations. Investigative neurocardiology has demonstrated that autonomic control of cardiac function includes local circuit neurons for networked control within the peripheral nervous system. The structural and adaptive characteristics of such networked interactions define the dynamics and a new normal for cardiac control that results in the aftermath of recurrent myocardial infarction and/or unstable angina that may or may not precipitate autonomic derangement. These features are explored here via a mathematical model of cardiac regulation. A main observation is that the control environment during pathology is an extrapolation to a setting outside prior experience. Although global bounds guarantee stability, the resulting closed-loop dynamics exhibited while the network adapts during pathology are aptly described as 'free-floating' in order to emphasize their dependence upon details of the network structure. The totality of the results provide a mechanistic reasoning that validates the clinical practice of reducing sympathetic efferent neuronal tone while aggressively targeting autonomic derangement in the treatment of ischemic heart disease.
Key points
Intrinsic cardiac (IC) neurons undergo differential morphological and phenotypic remodelling that reflects the site of myocardial infarction (MI).
Afferent neural signals from the ...infarcted region to IC neurons are attenuated, while those from border and remote regions are preserved post‐MI, giving rise to a ‘neural sensory border zone’.
Convergent IC local circuit (processing) neurons have enhanced transduction capacity following MI.
Functional network connectivity within the intrinsic cardiac nervous system is reduced post‐MI.
MI reduces the response and alters the characteristics of IC neurons to ventricular pacing.
Autonomic dysregulation following myocardial infarction (MI) is an important pathogenic event. The intrinsic cardiac nervous system (ICNS) is a neural network located on the heart that is critically involved in autonomic regulation. The aims of this study were to characterize structural and functional remodelling of the ICNS post‐MI in a porcine model (control (n = 16) vs. healed anteroapical MI (n = 16)). In vivo microelectrode recordings of basal activity, as well as responses to afferent and efferent stimuli, were recorded from intrinsic cardiac neurons. From control 118 neurons and from MI animals 102 neurons were functionally classified as afferent, efferent, or convergent (receiving both afferent and efferent inputs). In control and MI, convergent neurons represented the largest subpopulation (47% and 48%, respectively) and had enhanced transduction capacity following MI. Efferent inputs to neurons were maintained post‐MI. Afferent inputs were attenuated from the infarcted region (19% in control vs. 7% in MI; P = 0.03), creating a ‘neural sensory border zone’, or heterogeneity in afferent information. MI reduced transduction of changes in preload (54% in control vs. 41% in MI; P = 0.05). The overall functional network connectivity, or the ability of neurons to respond to independent pairs of stimuli, within the ICNS was reduced following MI. The neuronal response was differentially decreased to ventricular vs. atrial pacing post‐MI (63% in control vs. 44% in MI to ventricular pacing; P < 0.01). MI induced morphological and phenotypic changes within the ICNS. The alteration of afferent neural signals, and remodelling of convergent neurons, represents a ‘neural signature’ of ischaemic heart disease.
Key points
Intrinsic cardiac (IC) neurons undergo differential morphological and phenotypic remodelling that reflects the site of myocardial infarction (MI).
Afferent neural signals from the infarcted region to IC neurons are attenuated, while those from border and remote regions are preserved post‐MI, giving rise to a ‘neural sensory border zone’.
Convergent IC local circuit (processing) neurons have enhanced transduction capacity following MI.
Functional network connectivity within the intrinsic cardiac nervous system is reduced post‐MI.
MI reduces the response and alters the characteristics of IC neurons to ventricular pacing.
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