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Neurocardiology: Structure‐Based Function

Jeffrey L. Ardell, John Andrew Armour

10.1002/cphy.c150046

Source: Volume 6, Issue 4, October 2016

Published online: September 2016

Full Article on Wiley Online Library



ABSTRACT

Cardiac control is mediated via a series of reflex control networks involving somata in the (i) intrinsic cardiac ganglia (heart), (ii) intrathoracic extracardiac ganglia (stellate, middle cervical), (iii) superior cervical ganglia, (iv) spinal cord, (v) brainstem, and (vi) higher centers. Each of these processing centers contains afferent, efferent, and local circuit neurons, which interact locally and in an interdependent fashion with the other levels to coordinate regional cardiac electrical and mechanical indices on a beat‐to‐beat basis. This control system is optimized to respond to normal physiological stressors (standing, exercise, and temperature); however, it can be catastrophically disrupted by pathological events such as myocardial ischemia. In fact, it is now recognized that autonomic dysregulation is central to the evolution of heart failure and arrhythmias. Autonomic regulation therapy is an emerging modality in the management of acute and chronic cardiac pathologies. Neuromodulation‐based approaches that target select nexus points of this hierarchy for cardiac control offer unique opportunities to positively affect therapeutic outcomes via improved efficacy of cardiovascular reflex control. As such, understanding the anatomical and physiological basis for such control is necessary to implement effectively novel neuromodulation therapies. © 2016 American Physiological Society. Compr Physiol 6:1635‐1653, 2016.

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Figure 1. Figure 1. Network interactions occurring within and between peripheral ganglia and the central nervous system for control of the heart. The intrinsic cardiac nervous system (ICNS) possesses sympathetic (Sympath) and parasympathetic (Parasym) efferent postganglionic neurons, LCNs and afferent neurons. Extracardiac intrathoracic ganglia contain afferent neurons, LCN's and sympathetic efferent postganglionic neurons. Neurons in intrinsic cardiac and extracardiac networks form nested feedback loops that act in concert with CNS feedback loops (spinal cord, brainstem, hypothalamus, and forebrain) to coordinate cardiac function on a beat‐to‐beat basis. Primary nexus points for neuromodulation of the neural hierarchy are indicated: these include carotid sinus nerve (CSN) stimulation; spinal cord stimulation (SCS); vagus nerve stimulation (VNS); axonal modulation therapy (AMT); surgical ablation of the carotid body chemoreceptors (CBx); surgical decentralization (decent) of the stellate ganglia from the central nervous system; and an example of selective pharmacological interruption of cardiac afferent inputs with resiniferatoxin (RTX). Adapted, with permission, from (62).
Figure 2. Figure 2. Neural recordings from intrinsic cardiac ganglia. Left panel: An afferent neuron in the right atrial ganglionated plexus that was activated by a discrete mechanical stimulus applied to the LV epicardium. In this animal, all connections to and from the ICNS to higher centers were interrupted chronically. Middle panel: Intrinsic cardiac parasympathetic efferent postganglionic neurons in an atrial ganglion respond with fix latency to low‐frequency stimuli delivered to a cervical vagus. Right panel: Intrinsic cardiac neurons responded after a fixed latency to low‐frequency stimuli delivered to a subclavia ansae—thereby being classified as sympathetic efferent postganglionic neurons. The latter was no longer activated following hexamethonium. Adapted from (10,33,34) with permission.
Figure 3. Figure 3. Functional classification of intrinsic cardiac neurons. Left panel: Neural responses evoked from intrinsic cardiac neurons in response to: (i) discrete cardiac mechanoreceptor stimuli (right or left ventricular touch: RV; LV); (ii) global activation of cardiac mechanoreceptors via transient occlusion of the (iii) inferior vena cava (IVC) or (iv) descending aorta; (v) activation of cardiac nociceptors via transient MI (LAD CAO): or (vi) low‐level cervical vagal (right or left, RCV; LCV), or (vii) stellate ganglion (right or left, RSS; LSS) stimulation. Significance for each intervention was based on a Skellam distribution and was subdivided based on induced increases (green) or decreases (red) in evoked activity. IC LCN populations can be functionally subdivided into: (1) afferent LCNs, which transduce cardiac sensory information; (2) efferent LCNs or (3) convergent LCNs, which transduce both afferent and efferent inputs (pie chart, upper right). Bottom right panel illustrates the different functional characteristics of cardiac‐related neuronal activity including that related to isovolumetric contraction (neuron 2), the left ventricular ejection phase (neuron 1), or neurons with activity unrelated to the cardiac cycle (neuron 3). Adapted from (46) with permission.
Figure 4. Figure 4. Neurochemical diversity in human intrinsic cardiac ganglia. Top panels: Intrinsic cardiac neurons that demonstrate the cholinergic phenotype and receive cholinergic input. (A‐C) Confocal images of a ganglion that was double labeled to show high affinity choline transporter (CHT) (A) and choline acetyltransferase (ChAT) (B). Staining for CHT (A, red) was prominent in varicose nerve fibers around intrinsic cardiac neurons and faint or absent in the neuronal cell bodies. ChAT immunoreactivity (B, green) was associated with neuronal somata with less intensity in surrounding nerve processes. (C) Colocalization of CHT and ChAT was evident from the yellow color of some cell bodies and nerve processes in an overlay image (CHT+ChAT). Scale bar = 100 μm in A‐C. Bottom panels: Most intrinsic cardiac neurons stained for vesicular monoamine transporter type 2 (VMAT2), but only a subpopulation of these neurons were also tyrosine hydroxylase (TH)‐positive (D‐F). Confocal images of a section that was double labeled to show TH and VMAT2. (D) A few neurons and nerve fibers show TH immunoreactivity. (E) Prominent staining for VMAT2 occurred in most somata and many nerves fibers. VMAT2‐positive nerve varicosities are evident around several neurons. (F) OVL of TH and VMAT2 images shows that much of the TH is colocalized (yellow) with VMAT2. Adapted from (128) with permission.
Figure 5. Figure 5. Neuronal recordings obtained from canine middle cervical ganglia. Efferent neurons respond with fixed latency to stimuli delivered to preganglionic axons (left panel). LCNs were only activated by trains of stimuli delivered to axons in nerves connected to their ganglia and then with variable latency (middle panel). Middle cervical ganglia afferent neurons can be activated when discrete mechanical stimuli are applied to the heart, even when disconnected from the central nervous system right panel. Adapted from (18,20,36) with permission.
Figure 6. Figure 6. Temporal changes in cardiac innervation with disease progression: NE, norepinephrine; LIF, leukemia inhibitory factor; NGF, nerve growth factor. Taken from (98) with permission.
Figure 7. Figure 7. Photomicrographs of intrinsic cardiac ganglia obtained from the posterior right atrial ganglionated plexus from two patients with ischemic heart disease. (A) Neurons in this ganglion have a normal appearance, with many lipofuscin granules and a pale, eccentrically located nucleus. (B) In this ganglion, many neurons are enlarged and filled with dark (black arrow) or lucent (white arrow) inclusions. One neuron (arrowhead) that appears to be degenerating has very darkly stained cytoplase and is misshapen. Scale bars: A,B = 100 μm. Taken from (135) with permission.
Figure 8. Figure 8. Chronic MI functionally remodels the ICNS. Panel A: From an in vitro whole mount preparation, fiber bundles synapsing with the intrinsic cardiac neurons were stimulated via an extracellular electrode. Panel A: Recordings from preparations at 4, 7, and 14 days recovery from MI. Panel B shows summary data from multiple cells, including shams. The output frequency with fiber tract stimulation was significantly greater in neurons from 7‐day recovery preparations as compared with neurons from shams, 4 and 14 days recovery. Panel C: Adrenergic (norepinephrine: NE) modulation of IC neuronal excitability following MI. Excitability assessed by short‐term (500 μs) direct current intracellular injections into soma. The maximal responses (at 0.6 nA) shows a significant increase in evoked action potentials with NE application in control (NE), shams, and post‐MI preparations. Panel D: Muscarinic modulation of IC neuronal excitability following MI. The maximal response (at 0.6 nA) shows significant increase in action potential generation versus baseline with bethanechol application under all conditions. The maximal responses with bethanechol application in sham preparations and at 7 days post‐MI were significantly less than all other bethanechol application states. Adapted from (118) with permission.
Figure 9. Figure 9. Chronic myocardial infarction (MI) induces bilateral changes in stellate ganglia. Panel A: Somata neuropeptide Y (NPY) immunoreactivity increased following MI in left and right stellate ganglia (LSG and RSG). Specimens obtained from control animals versus left circumflex (LCX) artery or right coronary artery (RCA) occlusions that created left and right‐sided myocardial infarctions (Scale bar = 50 μm). Panel B: Quantification of NPY immunoreactivity in left and right stellate ganglia of control subjects compared to LCX and RCA infarcts. Panel C: Representative images of thionin‐stained sections of right and left stellate ganglia from control animals, compared to animals with LCX or RCA induced chronic myocardial infarctions (Scale bar 50 μm). Panel D: Quantification of mean neuronal size in left and right stellate ganglia of control subjects compared to LCX and RCA infarcts are presented. Adapted from (5) with permission.
Figure 10. Figure 10. Bursts of electrical stimuli delivered to intracardiac mediastinal nerves (MSNS, panels A and B) reproducibly evoke transient periods of atrial fibrillation (1 s latency, duration of AF ∼30 s). This methodology provides a reproducible stressor to evaluate cardiac network stability in the applications of various modes of autonomic regulation therapy (ART). Panel B: Preemptive ART with T1‐T3 SCS blunted the MSNS‐induced augmentation in IC neural activity, with a resultant decrease in the arrhythmogenic potential (panel C). Blockade of ganglionic nicotinic receptors with hexamethonium exerted similar suppression of neuronal activity concomitant with decreased atrial arhythmia formation in response to MSNS. Adapted from (108) with permission.
Figure 11. Figure 11. SCS alters peripheral autonomic reflex responses to acute ventricular ischemia, thereby exerting overall cardioprotective effects. Panel A. Coronary artery occlusion (CAO) increased middle cervical ganglia (MCG) neural activity, indicative of cardiac afferent neuron‐mediated sympathoexcitation. Right columns: While SCS by itself did not change overall MCG activity, it blunted the neuronal response previously evoked by transient CAO. Adapted from (12) with permission. Panel B: Preemptive SCS delivered either to the high cervical or upper thoracic dorsal columns reduce infarct size in response to transient MI. Adapted from (230,231) with permission.


Figure 1. Network interactions occurring within and between peripheral ganglia and the central nervous system for control of the heart. The intrinsic cardiac nervous system (ICNS) possesses sympathetic (Sympath) and parasympathetic (Parasym) efferent postganglionic neurons, LCNs and afferent neurons. Extracardiac intrathoracic ganglia contain afferent neurons, LCN's and sympathetic efferent postganglionic neurons. Neurons in intrinsic cardiac and extracardiac networks form nested feedback loops that act in concert with CNS feedback loops (spinal cord, brainstem, hypothalamus, and forebrain) to coordinate cardiac function on a beat‐to‐beat basis. Primary nexus points for neuromodulation of the neural hierarchy are indicated: these include carotid sinus nerve (CSN) stimulation; spinal cord stimulation (SCS); vagus nerve stimulation (VNS); axonal modulation therapy (AMT); surgical ablation of the carotid body chemoreceptors (CBx); surgical decentralization (decent) of the stellate ganglia from the central nervous system; and an example of selective pharmacological interruption of cardiac afferent inputs with resiniferatoxin (RTX). Adapted, with permission, from (62).


Figure 2. Neural recordings from intrinsic cardiac ganglia. Left panel: An afferent neuron in the right atrial ganglionated plexus that was activated by a discrete mechanical stimulus applied to the LV epicardium. In this animal, all connections to and from the ICNS to higher centers were interrupted chronically. Middle panel: Intrinsic cardiac parasympathetic efferent postganglionic neurons in an atrial ganglion respond with fix latency to low‐frequency stimuli delivered to a cervical vagus. Right panel: Intrinsic cardiac neurons responded after a fixed latency to low‐frequency stimuli delivered to a subclavia ansae—thereby being classified as sympathetic efferent postganglionic neurons. The latter was no longer activated following hexamethonium. Adapted from (10,33,34) with permission.


Figure 3. Functional classification of intrinsic cardiac neurons. Left panel: Neural responses evoked from intrinsic cardiac neurons in response to: (i) discrete cardiac mechanoreceptor stimuli (right or left ventricular touch: RV; LV); (ii) global activation of cardiac mechanoreceptors via transient occlusion of the (iii) inferior vena cava (IVC) or (iv) descending aorta; (v) activation of cardiac nociceptors via transient MI (LAD CAO): or (vi) low‐level cervical vagal (right or left, RCV; LCV), or (vii) stellate ganglion (right or left, RSS; LSS) stimulation. Significance for each intervention was based on a Skellam distribution and was subdivided based on induced increases (green) or decreases (red) in evoked activity. IC LCN populations can be functionally subdivided into: (1) afferent LCNs, which transduce cardiac sensory information; (2) efferent LCNs or (3) convergent LCNs, which transduce both afferent and efferent inputs (pie chart, upper right). Bottom right panel illustrates the different functional characteristics of cardiac‐related neuronal activity including that related to isovolumetric contraction (neuron 2), the left ventricular ejection phase (neuron 1), or neurons with activity unrelated to the cardiac cycle (neuron 3). Adapted from (46) with permission.


Figure 4. Neurochemical diversity in human intrinsic cardiac ganglia. Top panels: Intrinsic cardiac neurons that demonstrate the cholinergic phenotype and receive cholinergic input. (A‐C) Confocal images of a ganglion that was double labeled to show high affinity choline transporter (CHT) (A) and choline acetyltransferase (ChAT) (B). Staining for CHT (A, red) was prominent in varicose nerve fibers around intrinsic cardiac neurons and faint or absent in the neuronal cell bodies. ChAT immunoreactivity (B, green) was associated with neuronal somata with less intensity in surrounding nerve processes. (C) Colocalization of CHT and ChAT was evident from the yellow color of some cell bodies and nerve processes in an overlay image (CHT+ChAT). Scale bar = 100 μm in A‐C. Bottom panels: Most intrinsic cardiac neurons stained for vesicular monoamine transporter type 2 (VMAT2), but only a subpopulation of these neurons were also tyrosine hydroxylase (TH)‐positive (D‐F). Confocal images of a section that was double labeled to show TH and VMAT2. (D) A few neurons and nerve fibers show TH immunoreactivity. (E) Prominent staining for VMAT2 occurred in most somata and many nerves fibers. VMAT2‐positive nerve varicosities are evident around several neurons. (F) OVL of TH and VMAT2 images shows that much of the TH is colocalized (yellow) with VMAT2. Adapted from (128) with permission.


Figure 5. Neuronal recordings obtained from canine middle cervical ganglia. Efferent neurons respond with fixed latency to stimuli delivered to preganglionic axons (left panel). LCNs were only activated by trains of stimuli delivered to axons in nerves connected to their ganglia and then with variable latency (middle panel). Middle cervical ganglia afferent neurons can be activated when discrete mechanical stimuli are applied to the heart, even when disconnected from the central nervous system right panel. Adapted from (18,20,36) with permission.


Figure 6. Temporal changes in cardiac innervation with disease progression: NE, norepinephrine; LIF, leukemia inhibitory factor; NGF, nerve growth factor. Taken from (98) with permission.


Figure 7. Photomicrographs of intrinsic cardiac ganglia obtained from the posterior right atrial ganglionated plexus from two patients with ischemic heart disease. (A) Neurons in this ganglion have a normal appearance, with many lipofuscin granules and a pale, eccentrically located nucleus. (B) In this ganglion, many neurons are enlarged and filled with dark (black arrow) or lucent (white arrow) inclusions. One neuron (arrowhead) that appears to be degenerating has very darkly stained cytoplase and is misshapen. Scale bars: A,B = 100 μm. Taken from (135) with permission.


Figure 8. Chronic MI functionally remodels the ICNS. Panel A: From an in vitro whole mount preparation, fiber bundles synapsing with the intrinsic cardiac neurons were stimulated via an extracellular electrode. Panel A: Recordings from preparations at 4, 7, and 14 days recovery from MI. Panel B shows summary data from multiple cells, including shams. The output frequency with fiber tract stimulation was significantly greater in neurons from 7‐day recovery preparations as compared with neurons from shams, 4 and 14 days recovery. Panel C: Adrenergic (norepinephrine: NE) modulation of IC neuronal excitability following MI. Excitability assessed by short‐term (500 μs) direct current intracellular injections into soma. The maximal responses (at 0.6 nA) shows a significant increase in evoked action potentials with NE application in control (NE), shams, and post‐MI preparations. Panel D: Muscarinic modulation of IC neuronal excitability following MI. The maximal response (at 0.6 nA) shows significant increase in action potential generation versus baseline with bethanechol application under all conditions. The maximal responses with bethanechol application in sham preparations and at 7 days post‐MI were significantly less than all other bethanechol application states. Adapted from (118) with permission.


Figure 9. Chronic myocardial infarction (MI) induces bilateral changes in stellate ganglia. Panel A: Somata neuropeptide Y (NPY) immunoreactivity increased following MI in left and right stellate ganglia (LSG and RSG). Specimens obtained from control animals versus left circumflex (LCX) artery or right coronary artery (RCA) occlusions that created left and right‐sided myocardial infarctions (Scale bar = 50 μm). Panel B: Quantification of NPY immunoreactivity in left and right stellate ganglia of control subjects compared to LCX and RCA infarcts. Panel C: Representative images of thionin‐stained sections of right and left stellate ganglia from control animals, compared to animals with LCX or RCA induced chronic myocardial infarctions (Scale bar 50 μm). Panel D: Quantification of mean neuronal size in left and right stellate ganglia of control subjects compared to LCX and RCA infarcts are presented. Adapted from (5) with permission.


Figure 10. Bursts of electrical stimuli delivered to intracardiac mediastinal nerves (MSNS, panels A and B) reproducibly evoke transient periods of atrial fibrillation (1 s latency, duration of AF ∼30 s). This methodology provides a reproducible stressor to evaluate cardiac network stability in the applications of various modes of autonomic regulation therapy (ART). Panel B: Preemptive ART with T1‐T3 SCS blunted the MSNS‐induced augmentation in IC neural activity, with a resultant decrease in the arrhythmogenic potential (panel C). Blockade of ganglionic nicotinic receptors with hexamethonium exerted similar suppression of neuronal activity concomitant with decreased atrial arhythmia formation in response to MSNS. Adapted from (108) with permission.


Figure 11. SCS alters peripheral autonomic reflex responses to acute ventricular ischemia, thereby exerting overall cardioprotective effects. Panel A. Coronary artery occlusion (CAO) increased middle cervical ganglia (MCG) neural activity, indicative of cardiac afferent neuron‐mediated sympathoexcitation. Right columns: While SCS by itself did not change overall MCG activity, it blunted the neuronal response previously evoked by transient CAO. Adapted from (12) with permission. Panel B: Preemptive SCS delivered either to the high cervical or upper thoracic dorsal columns reduce infarct size in response to transient MI. Adapted from (230,231) with permission.
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Article Title: Neurocardiology: Structure‐Based Function
 

How to Cite

Jeffrey L. Ardell, John Andrew Armour. Neurocardiology: Structure‐Based Function. Compr Physiol 2016, 6: 1635-1653. doi: 10.1002/cphy.c150046