HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (19) Citing Articles via Google Scholar Google Scholar Articles by Armour, J. A. Search for Related Content PubMed PubMed Citation Articles by Armour, J. A.

INVITED REVIEW

Cardiac neuronal hierarchy in health and disease

Department of Pharmacology, Faculty of Medicine, University of Montréal, Montréal, Québec, H3C 3J7 Canada

	ABSTRACT

TOP ABSTRACT GENERAL PRINCIPLES OF... TRANSDUCTION OF THE... LOCAL CIRCUIT NEURONS IN... MOTOR CONTROL OF CARDIAC... INTERACTIVE HIERARCHICAL CONTROL NEURONAL MEMORY REMODELING OF THE CARDIAC... GRANTS REFERENCES

 
The cardiac neuronal hierarchy can be represented as a redundant control system made up of spatially distributed cell stations comprising afferent, efferent, and interconnecting neurons. Its peripheral and central neurons are in constant communication with one another such that, for the most part, it behaves as a stochastic control system. Neurons distributed throughout this hierarchy interconnect via specific linkages such that each neuronal cell station is involved in temporally dependent cardio-cardiac reflexes that control overlapping, spatially organized cardiac regions. Its function depends primarily, but not exclusively, on inputs arising from afferent neurons transducing the cardiovascular milieu to directly or indirectly (via interconnecting neurons) modify cardiac motor neurons coordinating regional cardiac behavior. As the function of the whole is greater than that of its individual parts, stable cardiac control occurs most of the time in the absence of direct cause and effect. During altered cardiac status, its redundancy normally represents a stabilizing feature. However, in the presence of regional myocardial ischemia, components within the intrinsic cardiac nervous system undergo pathological change. That, along with any consequent remodeling of the cardiac neuronal hierarchy, alters its spatially and temporally organized reflexes such that populations of neurons, acting in isolation, may destabilize efferent neuronal control of regional cardiac electrical and/or mechanical events.

adrenergic efferent neurons; afferent neurons; autonomic nervous system; cardiac arrhythmias; cardiac force; cardiac rate; cholinergic efferent neurons; heart failure; intrinsic cardiac ganglia; local circuit neurons; memory; middle cervical ganglion; parasympathetic; sympathetic; stellate ganglion; stochastic behavior

Emerging evidence indicates that synergistic interactions occur among neurons located from the level of the cerebral cortex (105, 107) to that of the intrinsic cardiac nervous system (4, 5, 12, 72, 117) in the beat-to-beat coordination of cardiac motor neuronal output in response to vascular impedance and body metabolic demands. The various reflexes involved depend on specific linkages in the medulla, spinal cord, and intrathoracic ganglia initiated by transduction of the cardiovascular milieu (2, 9, 10, 16, 17, 31, 52, 74, 92, 97). If any component within this hierarchy becomes deranged, imbalance in cardiac motor control may arise (127, 151). Given that the regulatory role of central neurons in maintaining cardiovascular status has been the subject of excellent reviews (2, 52, 96), the intrathoracic nervous system is emphasized herein.

	GENERAL PRINCIPLES OF NEUROCARDIOLOGY

TOP ABSTRACT GENERAL PRINCIPLES OF... TRANSDUCTION OF THE... LOCAL CIRCUIT NEURONS IN... MOTOR CONTROL OF CARDIAC... INTERACTIVE HIERARCHICAL CONTROL NEURONAL MEMORY REMODELING OF THE CARDIAC... GRANTS REFERENCES

 
As has been pointed out by Lipski et al. (94), this hierarchy is not represented by collections of neurons acting as simple pattern generators or a dependent serial control system (59, 91) such as is found in crustacean cardiac control (124). When some of its neurons generate activity that relates to the cardiac cycle, they do so because they receive direct or indirect (multisynaptic) inputs from afferent neurons that transduce regional cardiac or vascular mechanical events differentially throughout each cardiac cycle. An important anatomical feature of its intrathoracic component is that its widely distributed neurons form linkages at specific nexus points. The relevance of specific linkages interconnecting spatially distributed populations of neurons lies in the fact that they represent anatomically distinct loci where afferent and efferent neuronal elements functionally interact and, as such, are potential targets for selective therapy (see below).

	TRANSDUCTION OF THE CARDIOVASCULAR MILIEU

TOP ABSTRACT GENERAL PRINCIPLES OF... TRANSDUCTION OF THE... LOCAL CIRCUIT NEURONS IN... MOTOR CONTROL OF CARDIAC... INTERACTIVE HIERARCHICAL CONTROL NEURONAL MEMORY REMODELING OF THE CARDIAC... GRANTS REFERENCES

 
Overview

The milieu of diverse cardiac regions, the coronary vasculature, as well as major intrathoracic and cervical vessels, is continuously transduced by mechano- and/or chemosensing afferent neurons (2, 3, 7, 9, 29, 44, 45, 53, 92, 97, 110, 131, 140). This information is fed to second-order neurons located in spatially distributed cell stations throughout the cardiac neuronal hierarchy (Fig. 1). It is proposed that the function of efferent neurons coordinating regional cardiodynamics is predicated to a considerable extent on how the cardiovascular milieu is transduced throughout this hierarchy (8). Because the function of the whole network is greater than its individual parts, stable cardiac control generally occurs in the absence of obvious direct cause and effect (Table 1).

View larger version (32K): [in this window] [in a new window]   Fig. 1. Hypothetical model of the cardiac neuronal hierarchy, with emphasis being placed on its peripheral neuronal components. Cardiac sensory information is transduced by afferent neuronal somata in intrathoracic intrinsic and extrinsic cardiac ganglia via intrathoracic local circuit neurons to cardiac motor neurons. Cardiac sensory information is also transduced centrally to generate longer-loop medullary and spinal cord reflexes. Bottom right box indicates that circulating catecholamines exert direct effects on the intrinsic cardiac nervous system to affect cardiac motor output to the heart. CNS, central nervous system.

Experimental evidence indicates that limited populations of cardiac afferent neurons transduce purely mechanosensory or chemosensory signals. Mechanosensory afferent neurons are defined as those that demonstrate the capacity to transduce mechanical deformation in the region of their sensory neurites. Chemosensory afferent neurons transduce alterations in the chemical milieu surrounding their sensory neurites. Most cardiac afferents transduce multimodal stimuli in as much as they can simultaneously sense local mechanical and chemical alterations (17, 74, 97, 140). Anatomical and functional data indicate that cardiovascular afferent neuronal somata are distributed throughout the nodose ganglia (69, 139), as well as caudal cervical and cranial thoracic dorsal root ganglia bilaterally (69, 144). They are also present in intrathoracic ganglia (10, 31, 72), including those intrinsic to the heart (6, 28, 41). Their sensory neurites lie concentrated at the origins of the superior and inferior vena cava and in the sinoatrial (SA) node, the dorsal atria, the outflow tracts of both ventricles (epicardial, midwall, and endocardial locations) and the inner arch of the aorta (7, 44, 45, 92, 110, 140).

Cardiac Mechanosensory Transduction

A relatively limited population of cardiac afferent neurons solely transduces the phasic mechanical changes that their sensory neurites undergo during each cardiac cycle (7, 39, 92, 110). In physiological states their phasic activity relates to where their associated sensory neurites are located in the heart (9, 24, 39, 44, 45, 53, 92, 97, 110, 131, 140) reflective of local muscle deformation during each normal cardiac cycle (7, 45, 97, 110, 131). An example of their unique transduction capabilities is represented by mechanosensory neurites located in the ventral right ventricular papillary muscle that transduce local muscle fascicle deformation in a nearly linear fashion (7, 9). Because of the fact that this papillary muscle stretches when increasing loads are placed on its cordae tendinea, this muscle segment undergoes a reduction in length change when right ventricular chamber systolic pressure increases (23) to initiate a reduction in their activity (9). When right ventricular systolic pressure falls as less blood enters that chamber from the right atrium, the right ventricular papillary muscle readily overcomes the consequent lesser tension placed on its corda tendinea to generate greater length change (23); in that state their activity increases (9).

Right and left ventricular outflow tract mechanosensory neurons transduce local deformation in a positive, exponential fashion, their behavior peaking during maximum chamber pressure development (7). Left ventricular mechanosensory neurons display 1) increasing, 2) decreasing, or 3) complex activity patterns in response to increasing left ventricular systolic pressure (74). Thus ventricular mechanosensory neurons do not necessarily transduce ventricular dynamics in an algebraic fashion with respect to peak chamber pressure development. That other ventricular mechanosensory neurons transduce diastole (9, 140) indicates that collectively mechanosensory neurons sense a wide range of ventricular dynamics.

Intrathoracic Vascular Mechanosensory Transduction

Significant populations of afferent neurons in nodose, dorsal root, and especially intrathoracic, extracardiac ganglia have sensory neurites in the adventitia of major intrathoracic vessels, particularly along the inner arch of the thoracic aorta and at the bases of both vena cavae (7, 9, 10). They transduce with considerable precision phasic mechanical changes that the underlying vascular wall undergoes during each cardiac cycle (7). For instance, the activity generated by aortic ones reflects not only systolic pressure, but also the diastolic events (10).

Chemosensory Transduction

Most nodose and many dorsal root ganglion cardiac afferent neurons transduce the cardiac chemical milieu (33). Their activity is aperiodic in nature (0.1–1 Hz), reflective of a relatively slowly varying cardiac chemical milieu (7), thus normally bearing little relationship to regional cardiac mechanics (17, 138). In the presence of hypoxemia, their activity increases (9). Individual cardiac chemosensory neurons are capable of transducing a host of chemicals (74, 76, 78, 97, 138, 139, 142, 143). When their sensory neurites are exposed to multiple chemicals, their activity may reflect the relative concentration of each chemical that they are capable of transducing (138). Thus one afferent neuron can generate activity patterns in different frequency domains of their power spectra when its sensory neurites are exposed to increasing quantities of different chemicals. This suggests that one afferent neuron can simultaneously transduce to second-order neurons unique information regarding multiple chemicals (74). These include chemicals known to be liberated in increasing quantities by the ischemic myocardium (17, 29, 56, 65, 123, 153). That individual cardiac afferent neurons respond to multiple chemicals presumably increases the efficiency of information transduced to second-order neurons by such a limited population.

	LOCAL CIRCUIT NEURONS IN CARDIAC CONTROL

TOP ABSTRACT GENERAL PRINCIPLES OF... TRANSDUCTION OF THE... LOCAL CIRCUIT NEURONS IN... MOTOR CONTROL OF CARDIAC... INTERACTIVE HIERARCHICAL CONTROL NEURONAL MEMORY REMODELING OF THE CARDIAC... GRANTS REFERENCES

 
Hamos et al. (63) applied the term local circuit neurons to neurons in the hippocampus that project to others in divergent regions of that structure. Intrathoracic ganglia also possess local circuit neurons that project to adjacent neurons or neurons in other intrathoracic ganglia, thereby accounting for the varied functional interconnectivity present within the intrathoracic nervous system (16, 116). The multiple linkages within this nervous system render the sum greater than its individual parts such that ultimately its capacity to influence cardiodynamics must be studied in situ. This is relevant when attempting to unravel the role of intrathoracic local circuit neurons in cardiac control (18).

Intrathoracic ganglia contain unipolar (afferent), bipolar, and multipolar neurons that form multiple synaptic contacts (20, 28, 47, 66, 73, 86, 113, 128, 134, 147, 148) to process centripetal and centrifugal information (5, 12, 120). Many ganglia contain large diameter (25–40 µm) neurons organized as rosettes with central axo-dendritic and axo-somatic synapses, as well as dendritic membrane specializations (20, 28, 47, 111, 113, 148). These features may represent the anatomical substrate for two-way information processing within intrathoracic ganglia (8, 10, 12, 31, 72, 117, 137). Although many short-loop intrathoracic cardio-cardiac reflexes apparently involve direct afferent and efferent neuronal interactions (8), most of the cardiac sensory information transduced to cardiac motor neurons within the intrathoracic nervous system occurs via interposed local circuit neurons (18). Such transduction involves a host of neurochemicals so that the removal of one may result in insignificant loss in their overall function (12). That some intrinsic cardiac neurons project axons to not only neurons in the same ganglionated plexus (129) but also those in other ganglionated plexuses (61) presumably accounts for the ability of neurons in one intrathoracic locus to exert control over widely divergent atrial (109) and ventricular (149) regions (Fig. 2).

View larger version (60K): [in this window] [in a new window]   Fig. 2. Atrial and ventricular electrical events affected by neurons within a locus in the right atrial ganglionated plexus (RAGP). When nicotine (100 µM, 0.1 ml) was applied locally to neurons in the caudal portion of the RAGP of an anesthetized open-chest dog, changes were identified in some of the 127 epicardial unipolar electrograms recorded from the atria (top shows changes in the areas subtended by local electrograms reflecting modification of the repolarization phase) and in the 127 electrograms recorded simultaneously from the ventricular epicardium (bottom shows alterations in repolarization intervals from control states). Initial phase (phase 1) was dominated by electrical alterations adjacent to the sinoatrial node, in the interatrial septum and the cranial left atrium, as well as in the left ventricular apical region. During the subsequent tachycardia phase, whereas limited atrial areas were modified, most of the ventricular epicardium underwent electrical change. This representative figure is illustrative of the fact that right atrial neurons influence adjacent atrial tissues as well as distant atrial and ventricular regions. Ventricular surfaces are depicted according to a polar representation in which the outer circumference represents the ventricular base and the apex is at the center. lad, Left anterior descending; pda, posterior descending coronary artery. This research was performed in collaboration with René Cardinal and Michel Vermeulen.

	MOTOR CONTROL OF CARDIAC FUNCTION

TOP ABSTRACT GENERAL PRINCIPLES OF... TRANSDUCTION OF THE... LOCAL CIRCUIT NEURONS IN... MOTOR CONTROL OF CARDIAC... INTERACTIVE HIERARCHICAL CONTROL NEURONAL MEMORY REMODELING OF THE CARDIAC... GRANTS REFERENCES

Neurons in each major ganglionated plexus exert control over electrical (Fig. 2) and mechanical (149) events in all cardiac chambers. This is in accord with the fact that neurons in each intrinsic cardiac ganglionated plexus are in constant communication with one another (116). In that regard, it should be recalled that different cardiac responses are elicited when neuronal elements in each major intrinsic cardiac ganglionated plexus are activated by local application of electrical (34) vs. chemical (149) stimuli. That occurs because local electrical stimuli activate adjacent somata and axons of passage, whereas local application of chemicals recruits somata, not axons, of passage (12). Cholinergic neurons in the right atrial ganglionated plexus, when activated chemically, exert control over the SA node, the AV node, the left atrium, and distant ventricular tissues (109, 149). Cholinergic neurons in the inferior vena cava-inferior ganglionated plexus affect the adjacent AV node (58) as well as the SA node, left atrial tissue, and both ventricles (149); so do ventricular cholinergic neurons (48). Adrenergic neurons in each major ganglionated plexus do likewise (34, 149).

It is known that respiratory mechanics reflexly affect normal intersinus timing (87, 130). One tool used to characterize cardiac autonomic efferent control in the clinical setting is the determination of heart rate variability, an index that when altered is considered to represent an early sign of cardiac dysfunction (87, 98, 108). As cardiac motor control is not represented by a simplistic reciprocal balance of adrenergic/cholinergic motor function (105) and because many neurons responsible for heart rate variability reside outside the pericardial sac (103), it may be difficult to attribute alterations in that index to malfunction of a specific neuronal population (104).

	INTERACTIVE HIERARCHICAL CONTROL

TOP ABSTRACT GENERAL PRINCIPLES OF... TRANSDUCTION OF THE... LOCAL CIRCUIT NEURONS IN... MOTOR CONTROL OF CARDIAC... INTERACTIVE HIERARCHICAL CONTROL NEURONAL MEMORY REMODELING OF THE CARDIAC... GRANTS REFERENCES

 
Sensory data arising from the heart (7, 9) and major vessels (84, 141) initiate central (2, 52, 145) and peripheral (11) reflexes controlling cardiac motor neurons (48, 133). Such control can be resolved into two basic issues: 1) how afferent neurons transduce the cardiovascular milieu directly or indirectly to cardiac motor neurons and 2) the type and time scale (latency of reflexes) of information transduced to such neurons. As some intrathoracic neurons are sensitive to excitatory or inhibitory amino acids (75), these reflexes involve excitatory and inhibitory synapses (12). Their varied latencies depend on the distance of afferent somata from the target organ (distance of the control center from the heart) and the number of synapses they use. Direct transduction of cardiac mechanical events to cardiac motor neurons may represent an unstable control state (82). The relatively slow transduction of the cardiac chemical milieu via local circuit neurons to cardiac motor neurons over many cardiac cycles imparts longer-term, stable control.

Mechanosensory-Based Cardio-Cardiac Reflexes

The short-term scaling properties of fast-responding cardiac mechanosensory neurons generate short-latency reflexes that exert rapid control over select populations of cardiac motor neurons. Their relatively short distance to first synapse permits differential activation of cardiac motor neurons during specific phases of the cardiac cycle (8) to exert beat-to-beat coordination of heart rate and regional contractility (22). These short-loop mechanosensory-based reflexes are under central neuronal control (12).

Mechanosensory-Based Vascular-Cardiac Reflexes

Arterial-cardiac reflexes are initiated by mechanosensory neurites in the carotid arteries and intrathoracic aorta. Mechanosensory neurites associated with individual afferent neurons are concentrated in the adventitia of the carotid bulbs as well as the inner arch of the thoracic aorta (9). They transduce deformation of the arterial wall in which they are located with considerable fidelity (2, 7) via their nodose ganglion somata to neurons in the nucleus of solitary tract, initiating short-latency medulla-based activation of cardiac parasympathetic efferent preganglionic neurons (2). They presumably account for the fact that many cardiac vagal efferent neurons display phase-related activity reflecting arterial events (8, 85), thereby influencing parasympathetic efferent neuronal control of the SA node differentially throughout each cardiac cycle (90) to initiate short-term heart rate variability (87). Some intrathoracic sympathetic efferent neurons also display phase-related activity reflective of reflexes initiated by carotid artery, aortic, or cardiac mechanosensory neurons (10, 16). Vena cava mechanosensory afferent neurons also modulate cardiac efferent neurons via intrathoracic reflexes (16).

Chemosensory-Based Cardio-Cardiac Reflexes

Populations of afferent neurons transduce the cardiac and arterial blood chemical milieu to intrathoracic and higher center neurons, doing so over longer timescales reflective of a normally slowly changing local chemical milieu (81). The effects of exposing the sensory neuritis of individual cardiac chemosensory neurons to increased amounts of a chemical can reset their activity for a considerable period of time after removal of that chemical stimulus (138), presumably indicative of memory (81). Because of their relative numbers, chemosensory-based reflexes can influence large numbers of cardiac motor neurons over multiple cardiac cycles (12). For these reasons it appears that intrathoracic sympathetic efferent postganglionic neurons display either phase-related or stochastic behavior predicated primarily on whether they transduce mechanosensory- vs. chemosensory-based inputs, respectively.

	NEURONAL MEMORY

TOP ABSTRACT GENERAL PRINCIPLES OF... TRANSDUCTION OF THE... LOCAL CIRCUIT NEURONS IN... MOTOR CONTROL OF CARDIAC... INTERACTIVE HIERARCHICAL CONTROL NEURONAL MEMORY REMODELING OF THE CARDIAC... GRANTS REFERENCES

 
In the context of this review, memory can be defined as a faculty displayed by populations of interactive neurons in various animal species such that past events affect their current status (60). It has been hypothesized that the interposition of a class of neurons that collectively display memory assures stable control over cardiac motor neuronal function in the presence of altered cardiac status (82). Precise coordination of heart rate and regional dynamics apparently depends to a considerable extent on mechanosensory transduction that requires little memory, being essentially short-latency reflex based (8). As mentioned above, cardiac chemosensory neurons display working memory reflective in part of a changing local cardiac chemical milieu (81) such that, once the stimulus is removed, behavioral modification frequently persists (138). Such thresholded adaptation reflective of events in the immediate past may assure "smoothing" of information transduced to second-order neurons throughout the neuroaxis (81). The cardiac milieu transduced during one cardiac cycle can be stored among populations of intrathoracic local circuit neurons via their interactive linkages to exert control over cardiac motor neurons during subsequent cardiac cycles (10). That short-term retention of information occurs among intrathoracic neurons chronically disconnected from central ones (10) indicates that this capacity can reside solely within the intrathoracic neuronal hierarchy.

	REMODELING OF THE CARDIAC NEURONAL HIERARCHY IN CARDIAC DISEASE

TOP ABSTRACT GENERAL PRINCIPLES OF... TRANSDUCTION OF THE... LOCAL CIRCUIT NEURONS IN... MOTOR CONTROL OF CARDIAC... INTERACTIVE HIERARCHICAL CONTROL NEURONAL MEMORY REMODELING OF THE CARDIAC... GRANTS REFERENCES

 
It is now recognized that remodeling of the cardiac neuronal hierarchy may either initiate or exacerbate cardiac disease. Selected intrinsic cardiac neuronal components remodel during the evolution of heart failure (36, 136) or after long-term removal of their central neuronal inputs (104, 132). This is in agreement with the fact that arterial baroreceptor transduction resets during the evolution of hypertension (3) or heart failure (152). The overbuilt cardiac nervous system apparently can withstand some linkage malfunction such as occurs when the arterial blood supply to some of its neurons becomes compromised. This may be because the filtering capacity of its relatively large intrathoracic local circuit neuronal population acts to stabilize cardiac efferent neuronal function in the presence of excessive sensory inputs arising from an ischemic myocardium (19, 54). In contrast to irreversible cardiomyocyte (122) or intrinsic cardiac neuronal (70) damage secondary to any reduction in their arterial blood supply, remodeling of this nervous system occurs in the absence of cellular damage and, as such, represents state change that can be subsequently retrieved.

Regional Myocardial Ischemia

When myocardial ischemia is transduced to second-order neurons throughout the cardiac neuronal hierarchy (33, 97, 101, 121), some neurons can become sufficiently activated to influence suprabulbar neurons (e.g., the limbic system, hypothalamus, insular cortex, etc.) and initiate symptoms (135).

Central neuron-derived myocardial ischemia reflexes. Cardiac parasympathetic and sympathetic efferent preganglionic neurons become activated when sufficient populations of centrally projecting cardiac afferent neurons transduce myocardial ischemia to central neurons (101). Myocardial ischeia initiates cardiac depressor or augmentor reflexes, depending on how alterations in the local cardiac milieu are transduced throughout the neuroaxis (106).

Ischemia in either the anterior or posterior wall of the left ventricle is transduced by both dorsal root and nodose ganglion afferent neurons (17, 74, 76, 138). Bradycardia occurs when sufficient populations of nodose ganglion cardiac afferent neurons transducing such an event activate parasympathetic motor neurons (2, 80). Ischemia-induced excitation of dorsal root ganglion afferent neurons reflexly activates sympathetic efferent neurons innervating the heart and systemic vasculature (8, 97) to initiate arterial hypertension (133). Regional myocardial ischemia can also influence ascending spinal cord pathways to affect medullary cardiomotor neurons (2), yet another cardio-cardiac reflex. Given the multiplicity of these reflexes, it is difficult to sustain the thesis that select heart rate changes can be ascribed to reflexes initiated from a specific left ventricular region. Rather, anatomical (69) and functional (17, 74, 138) data indicate that central reflexes initiated by regional ventricular ischemia induce regionally specific or global (cardiac and systemic vasculature) effects depending on how that event is transduced throughout the entire cardiac neuroaxis (21, 106). How these reflexes act to stabilize or destabilize cardiac control in the presence of altered baroreceptor sensitivity (152) remains unknown.

Ischemia-induced intrathoracic reflexes. Compromised regional coronary arterial blood flow can affect intrinsic cardiac neuronal function and initiate intrathoracic reflexes.

Direct ischemia effects. Somata of intrinsic cardiac neurons perfused by a coronary artery that is involved in an obstructive process may undergo pathological change over time (70) such that their function becomes compromised (15). Regional ventricular ischemia can also induce regional nerve terminal sprouting (40) or pathology (38), the latter resulting in loss of local sensory (102) and motor (64, 100) neurite function. On the other hand, the viability of nerves coursing over a transmural ventricular infarction remains unimpaired by that state as major intrinsic cardiac nerves are accompanied by their own rich blood supply arising from extracardiac sources (79).

Indirect ischemia effects. Chemicals such as purinergic agents (123), peptides (65), and hydroxyl radicals (78, 142, 143) liberated in increasing quantities from the ischemic myocardium modify local cardiac sensory neurite function (17, 29, 78, 97, 140). Many cardiac afferent neurons are further affected on restoration of the arterial blood supply to their sensory neurites during early reperfusion (19, 25, 54). Presumably that is when the greatest concentration of locally accumulated metabolites becomes available to affect their sensory neurites. The various ischemia-induced reflexes so initiated modulate not only cardiodynamics (15), but also regional coronary arterial blood flow (83, 141).

Symptomatology. Regional ventricular ischemia excites many cardiac afferent neurons maximally (17, 33, 74, 78, 121, 140). Current information indicates that symptoms associated with myocardial ischemia depend to a considerable extent on the capacity of afferent neuron P₁-purinoceptors to transduce such an event (135). That their capacity to transduce myocardial ischemia becomes blunted in the presence of adenosine receptor blockade (76, 139) lends support to that contention. Peptides liberated from the ischemic myocardium reportedly play a supportive role in the genesis of such symptoms (57).

Cardiac failure. Central (51, 152) and peripheral (26, 136) processing of cardiovascular sensory inputs undergo remodeling during the evolution of heart failure (126). Arterial baroreflexes become blunted (152). Heart failure is associated with increased circulating levels of catecholamines due to global enhancement of sympathetic efferent neuronal tone (43). It has been reported that chronic activation of adrenergic efferent neurons attending heart failure downregulates cardiac myocyte -adrenoceptor function such that their responsiveness to adrenergic agonist becomes obtunded (32). Thus far heart failure therapy involving adrenergic receptor blockade has been considered in terms of cardiomyocyte -adrenoceptor modulation (32) and afterload reduction (49).

It is now evident that -adrenergic or angiotensin receptor blockade also target select populations of intrathoracic cardiac neurons (12, 50, 136). Despite a reduction of ventricular norepinephrine content in canine models of heart failure, adrenergic efferent neurons when activated liberate sufficient amounts of catecholamines into the myocardial interstitium (136) to enhance ventricular contractility (36). That is due, in part, to retention of cardiomyocyte cell surface -adrenoceptor function in such a state (89). Not only do cardiomyocytes possess -adrenoceptors (32), so do intrathoracic neurons (12). The latter are also sensitive to angiotensin II (71). That -adrenoceptor or angiotensin II receptor blockade affects neurons within the intrathoracic nervous system indicates that these therapies share a common target (12, 71). For instance, angiotensin II receptor blockade reduces sympathetic efferent neuronal inputs to the SA node and ventricles (71), accounting in part for the concomitant fall in heart rate and blood pressure attending such therapy. These therapies minimize remodeling that the cardiac neuronal hierarchy undergoes during the evolution of heart failure as well (136).

Cardiac Arrhythmias: Rate vs. Rhythm Control

Neurons from the level of the insular cortex (107) to the intrinsic cardiac nervous system (77) can be involved in the genesis of cardiac arrhythmias (35, 37, 62, 77, 125, 127, 151). Select populations of extracardiac sympathetic and parasympathetic efferent neurons, when maximally activated, initiate atrial (95, 118, 125) or ventricular (35) arrhythmias. In accord with that, ventricular fibrillation can occur when sufficient populations of intrinsic cardiac neurons are activated by, for instance, locally applied neurochemicals such as adrenoceptor agonists, angiotensin II, or endothelin I (13, 14). From a therapeutic standpoint, it may be relevant that the enhancement of intrinsic cardiac neuronal activity secondary to their transduction of an ischemic myocardium can be overcome by increasing their spinal cord neuronal inputs (93). Thus the harmful consequences that activating large populations of intrinsic cardiac neurons consequent to their transducing regional ventricular ischemia may be amenable to therapy.

Rate control. Activating select populations of intrinsic cardiac cholinergic efferent neurons that innervate either the SA or AV node can suppress heart rate or AV nodal transmission, respectively. Although it has been reported that neurons in the right atrial ganglionated plexus project solely to the adjacent SA node, whereas those in the inferior vena cava-inferior atrial ganglionated plexus project solely to the adjacent AV node (42, 58, 68, 150), cholinergic efferent neurons that control SA nodal or AV nodal function are located throughout the intrinsic cardiac nervous system (149). Thus AV nodal conduction delay can be induced to stabilize ventricular rate in the presence of atrial tachydysrhythmias by activating not only neurons in right atrial ganglionated plexuses (1, 150), but those in others as well. Focal electrical stimuli delivered to loci within an intrinsic cardiac ganglionated plexus activate adjacent somata as well as afferent and efferent axons of passage (34), whereas locally applied chemicals affect adjacent somata (149). That, along with the fact that local circuit neurons throughout the intrinsic cardiac nervous system are in constant communication (116), presumably accounts for the varied cardiac responses elicited among subjects by such interventions.

Rhythm control. Atrial or ventricular arrhythmias can be elicited when select populations of intrinsic cardiac neurons become activated excessively (77); depending on the population of neurons involved, these can degenerate into fibrillation (13, 14). Thus removal of select neuronal elements responsible for such events may be contemplated for rhythm control (37). By ablating somata rather that axons of passage, long-term results can be contemplated as axons rapidly reinnervate distal cardiac tissues after their sectioning (104). The functional interconnectivity displayed among atrial and ventricular neurons makes it likely that ablating or stimulating a locus within one intrinsic cardiac ganglionated plexus or, for that matter, an entire intrinsic cardiac ganglionated plexus, will lead to variable and even unexpected results among individuals (146). In that regard, it should be recalled that activating select intrathoracic neuronal elements can also elicit atrial or ventricular arrhythmias (14, 35, 62, 77, 125). By targeting somata at major centrifugal and centripetal convergence points, nexus points within this hierarchy (Fig. 3), perhaps more predictable and long-term results will accrue (112).

View larger version (149K): [in this window] [in a new window]   Fig. 3. Photograph of mediastinal nerves at the base of a human heart. Note that the nexus point (N) where multiple mediastinal nerves coalesce contains mediastinal ganglia. Neurons and axons therein project to neurons throughout the intrinsic cardiac nervous system. Tip of the metal probe to the left has been placed under this major nexus; the white band to the right above it underlies major mediastinal nerves connecting to this nexus point. SVC, superior vena cava; RA, right atrial appendage; A, aortic root; Ao, sectioned aorta; RPA, right main pulmonary artery; TS, transverses sinus; MPA, main pulmonary artery; Ad, adventitia of the pericardium; IV, exposed 4th rib. This anatomical research was performed in collaboration with David Hopkins and David Murphy.

The cardiac nervous system is made up of spatially distributed collections of neurons displaying tightly coupled or stochastic behavior that is predicated to a considerable extent on whether they transduce the regional mechanical or chemical milieu. The transduction of alterations in the cardiac chemical milieu throughout the entire cardiac neuronal hierarch occurs for the most part in a stochastic manner (82). Transduction of regional cardiovascular mechanical events occurs with fidelity by fewer afferent neurons in the genesis of phase-related behavior displayed by some cardiac motor neurons. Given the centrifugal and centripetal transduction of information within its periphery, a far richer picture is emerging concerning the capacity of the cardiac neuronal hierarchy to regulate cardiodynamics on a beat-to-beat basis than has been considered heretofore. Targeting points of its redundancy rather than its nexus points may exert minor impact on the overall function of this hierarchy or produce unpredicted results. The relevance of understanding its interactive linkages and how they remodel during the evolution of cardiac disease may be key to successfully targeting its select components to retard disease progression.

	GRANTS

TOP ABSTRACT GENERAL PRINCIPLES OF... TRANSDUCTION OF THE... LOCAL CIRCUIT NEURONS IN... MOTOR CONTROL OF CARDIAC... INTERACTIVE HIERARCHICAL CONTROL NEURONAL MEMORY REMODELING OF THE CARDIAC... GRANTS REFERENCES

 
The author gratefully acknowledges the support of the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. A. Armour, Centre de recherche, Hôpital du Sacré-Cur de Montréal, 5400 boul. Gouin Ouest, Montréal, Québec, H4J 1C5 Canada (E-mail: ja-armour{at}crhsc.umontreal.ca).

	REFERENCES

TOP ABSTRACT GENERAL PRINCIPLES OF... TRANSDUCTION OF THE... LOCAL CIRCUIT NEURONS IN... MOTOR CONTROL OF CARDIAC... INTERACTIVE HIERARCHICAL CONTROL NEURONAL MEMORY REMODELING OF THE CARDIAC... GRANTS REFERENCES

 

1. Ali IM, Butler CK, Armour JA, and Murphy DA. Modification of supraventricular tachyarrhythmias by stimulating atrial neurons. Ann Thorac Surg 50: 251–256, 1990.
2. Andresen MC and Kunze DL. Nucleus tractus solitarius: gateway to neural circulatory control. Annu Rev Physiol 56: 93–116, 1994.
3. Andresen MC and Yang M. Arterial baroreceptor resetting: contributions of chronic and acute processes. Clin Exper Pharmacol Physiol 15, Suppl: 19–30, 1989.
4. Ardell JL. Structure and function of mammalian intrinsic cardiac neurons. In: Neurocardiology, edited by Armour JA and Ardell JL. New York: Oxford University Press, 1994, p. 95–114.
5. Ardell JL. Neurohumoral control of cardiac function. In: Heart Physiology and Pathophysiology, edited by Sperelakis N, Kurachi Y, Terzic A, and Cohen MV. New York: Academic, 2001, p. 45–59.
6. Ardell JL, Butler CK, Smith FM, Hopkins DA, and Armour JA. Activity of in vivo atrial and ventricular neurons in chronically decentralized canine hearts. Am J Physiol Heart Circ Physiol 260: H713–H721, 1991.
7. Armour JA. Physiological behavior of thoracic cardiovascular receptors. Am J Physiol 225: 177–185, 1973.
8. Armour JA. Instant-to-instant reflex cardiac regulation. Cardiology 61: 309–328, 1976.
9. Armour JA. Thoracic and cardiovascular afferent nerves. In: Neural Regulation of the Heart, edited by Randall WC. New York: Oxford University Press, 1977, p. 131–156.
10. Armour JA. Neuronal activity recorded extracellularly in chronically decentralized in situ canine middle cervical ganglia. Can J Physiol Pharmacol 64: 1038–1046, 1986.
11. Armour JA. Cardiac effects of electrically induced intrathoracic autonomic reflexes. Can J Physiol Pharmacol 66: 714–720, 1988.
12. Armour JA. Anatomy and function of the intrathoracic neurons regulating the mammalian heart. In: Reflex Control of the Circulation, edited by Zucker IH and Gilmore JP. Boca Raton, FL: CRC, 1991, p. 1–37.
13. Armour JA. Histamine-sensitive intrinsic cardiac and intrathoracic extracardiac neurons influence cardiodynamics. Am J Physiol Regul Integr Comp Physiol 270: R906–R913, 1996.
14. Armour JA. Comparative effects of endothelin and neurotensin on intrinsic cardiac neurons. Peptides 17: 1047–1052, 1996.
15. Armour JA. Myocardial ischemia and the cardiac nervous system. Cardiovasc Res 41: 41–54, 1999.
16. Armour JA, Collier K, Kimber G, and Ardell JL. Differential selectivity of cardiac neurons in separate intrathoracic ganglia. Am J Physiol Regul Integr Comp Physiol 274: R939–R949, 1998.
17. Armour JA, Huang MH, Pelleg A, and Sylvén C. Responsiveness of in situ canine nodose ganglion cardiac afferent neurons to epicardial mechanoreceptor and/or chemoreceptor stimuli. Cardiovasc Res 28: 1218–1225, 1994.
18. Armour JA and Janes RD. Neuronal activity recorded extracellularly from in situ mediastinal ganglia. Can J Physiol Pharmacol 66: 119–127, 1988.
19. Armour JA, Linderoth B, Arora RC, DeJongste MJL, Ardell JL, Kingma J, Hill M, and Foreman RD. Long-term modulation of the intrinsic cardiac nervous system by spinal cord neurons in normal and ischemic hearts. Auton Neurosci 95: 71–79, 2002.
20. Armour JA, Murphy DA, Yuan BX, MacDonald S, and Hopkins DA. Anatomy of the human intrinsic cardiac nervous system. Anat Rec 294: 289–298, 1997.
21. Armour JA and Pace JB. Cardiovascular effects of thoracic afferent nerve stimulation in conscious dogs. Can J Physiol Pharmacol 60: 1193–1199, 1982.
22. Armour JA, Pace JB, and Randall WC. Interrelationship of architecture and function of the right ventricle. Am J Physiol 218: 174–179, 1970.
23. Armour JA and Randall WC. Observations upon in-situ papillary muscle function. Proc Soc Exp Biol Med 143: 736–745, 1973.
24. Arndt JO, Brambling P, Hindorf K, and Röhnelt R. The afferent discharge pattern of atrial mechano-receptors of the cat during sinusoidal stretch of atrial strip in situ. J Physiol 240: 33–52, 1974.
25. Arora RC and Armour JA. Intrinsic cardiac neuronal adenosine A₁ receptor activation reduces myocardial reperfusion effects on the intrinsic cardiac nervous system. Am J Physiol Regul Integr Comp Physiol 284: R1314–R1321, 2003.
26. Arora RC, Cardinal R, Smith FM, Ardell JL, Dell'Italia LJ, and Armour JA. Intrinsic cardiac nervous system in tachycardia induced heart failure. Am J Physiol Regul Integr Comp Physiol 285: R1212–R1223, 2003.
27. Arora RC, Hirsch G, Hirsch K, and Armour JA. Transmyocardial laser revascularization remodels the intrinsic cardiac nervous system in a chronic setting. Circulation 104: I101–I120, 2001.
28. Arora RC, Waldmann M, Hopkins DA, and Armour JA. Porcine intrinsic cardiac ganglia. Anat Rec 271: 249–258, 2003.
29. Baker D, Coleridge HM, Coleridge JCG, and Nerdum T. Search for cardiac nociceptor: stimulation by bradykinin of sympathetic afferent nerve endings in the heart of cat. J Physiol 306: 519–536, 1980.
30. Blomquist TM, Priola DV, and Romero AM. Source of intrinsic innervation of canine ventricles: a functional study. Am J Physiol Heart Circ Physiol 252: H638–H644, 1987.
31. Bosnjak Z and Kampine JP. Cardiac sympathetic afferent cell bodies are located in the peripheral nervous system of the cat. Circ Res 64: 554–562, 1989.
32. Brodde OE and Zerkowski HR. Neural control of cardiac myocyte function. In: Neurocardiology, edited by Armour JA and Ardell JL. New York: Oxford University Press, 1994, p. 193–218.
33. Brown AM. Excitation of afferent cardiac sympathetic nerve fibers during myocardial ischemia. J Physiol 190: 35–53, 1967.
34. Butler CK, Smith FM, Cardinal R, Murphy DA, Hopkins DA, and Armour JA. Cardiac responses to electrical stimulation of discrete loci in canine atrial or ventricular ganglionated plexi. Am J Physiol Heart Circ Physiol 259: H1365–H1373, 1990.
35. Cardinal R. Autonomic modulation of myocardial electrical properties and cardiac rhythm. In: Neurocardiology, edited by Armour JA and Ardell JL. New York: Oxford University Press, 1994, p. 165–191.
36. Cardinal R, Nadeau R, Novak V, Laurent C, Boudreau G, and Armour JA. Reduced capacity of cardiac efferent sympathetic neurons to release norepinephrine and modify cardiac function in tachycardia-induced canine heart failure. Can J Physiol Pharmacol 74: 1070–1078, 1996.
37. Carlson MD, Smith ML, and Thames MD. Autonomic influences on arrhythmia development. Prog Cardiol 511: 59–63, 1992.
38. Chahine R, Olivia L, Lockwell H, and Nadeau R. Oxygen-free radicals and myocardial nerve fiber endings. Exp Toxicol Pathol 46: 403–408, 1994.
39. Chapman KM and Pankhurst JH. Strain sensitivity and directionality in cat atrial mechanosensitive nerve endings in vitro. J Physiol 259: 405–426, 1976.
40. Chen PS, Chen LS, Cao JM, Sharifi B, Karagueuzian MC, and Fishbein HS. Sympathetic nerve sprouting. Electrical remodeling and the mechanism of sudden cardiac death. Cardiovasc Res 50: 409–416, 2001.
41. Cheng Z, Powley TL, Schwaber JS, and Doyle FJ. Vagal afferent innervation of the atria of the rat heart reconstructed with confocal microscopy. J Comp Neurol 381: 1–17, 1997.
42. Chiou CW and Zypes DP. Selective vagal denervation of the atria eliminates heart rate variability and baroreflex sensitivity while preserving ventricular innervation. Circulation 98: 360–368, 1998.
43. Cohn JN. Abnormalities of peripheral sympathetic nervous system control in congestive heart failure. Circ 82, Suppl I: I59–I67, 1990.
44. Coleridge HM, Coleridge JCG, and Kidd C. Cardiac receptors in the dog, with particular reference to two types of afferent endings in the ventricular wall. J Physiol 174: 323–339, 1964.
45. Coleridge JCG, Hemmingway A, Holmes RL, and Linden RJ. Location of atrial receptors in the dog: a physiological and histological study. J Physiol 136: 174–197, 1957.
46. Darvesh S, Losier AM, MacDonald SE, Martin E, Hopkins DA, and Armour JA. Cholinesterase modulation of canine intrinsic cardiac neurons. J Auton Nerv Syst 71: 75–84, 1998.
47. Darvesh S, Nance DM, Hopkins DA, and Armour JA. Distribution of neuropeptide immunoreactivity in intact and chronically decentralized middle cervical and stellate ganglia of dogs. J Auton Nerv Syst 21: 167–180, 1987.
48. Dickerson LW, Rodak DJ, Flemming TJ, Gatti PJ, Massari VJ, McKenzie JC, and Gillis RA. Parasympathetic neurons in the cranial medial ventricular pat on the dog heart selectively decrease ventricular contractility. J Auton Nerv Syst 70: 129–141, 1998.
49. Esler M, Kaye D, Lambert G, Esler D, and Jennings G. Adrenergic nervous system in heart failure. Am J Cardiol 80: 7L–14L, 1997.
50. Farrell DM, Wei CC, Ardell JL, Armour JA, Hageman GR, Bradley WE, and Dell'Italia LJ. Angiotensin II modulates norepinephrine release into the interstitial fluid of the canine myocardium in vivo. Am J Physiol Heart Circ Physiol 281: H813–H822, 2001.
51. Felder RB, Francis J, Zhang ZH, Wei SG, Weiss RM, and Johnson AK. Heart Failure and the brain: new perspectives. Am J Physiol Regul Integr Comp Physiol 284: R259–R276, 2003.
52. Foreman RD. Mechanisms of cardiac pain. Annu Rev Physiol 61: 143–167, 1999.
53. Foreman RD, Blair RW, Holmes HR, and Armour JA. Correlation of activity generated by sympathetic afferent ventricular mechanosensory neurites with sensory field deformation in the normal and ischemic myocardium. Am J Physiol Regul Integr Comp Physiol 276: R976–R989, 1999.
54. Foreman RD, Linderoth B, Ardell JL, Barron KW, Chandler MJ, Hull SS, TerHorst GJ, DeJongste MJL, and Armour JA. Modulation of intrinsic cardiac neural activity by spinal cord stimulation: implications for its therapeutic use in angina pectoris. Cardiovasc Res 47: 367–375, 2000.
55. Forsgren S, Moravec M, and Moravec J. Catecholamine-synthesizing enzymes and neuropeptides in rat heart epicardial ganglia: an immunological study. Histochem J 22: 667–676, 1990.
56. Fox AC, Reed GE, Meilman H, and Silk BB. Release of nucleosides from canine and human hearts as an index of prior ischemia. Am J Cardiol 43:52–59, 1979.
57. Gaspardone A, Crea F, Tomai F, Lamele M, Crossman DC, Pappagallo M, Versaci F, Chiariello L, and Gioffre PA. Substance P potentiates the algogenic affects of intraarterial infusion of adenosine. J Am Coll Cardiol 24: 477–482, 1994.
58. Gatti PJ, Johnson TA, Phan P, Jordan IK, Coleman W, and Massari VJ. The physiological and anatomical demonstration of functionally selective parasympathetic ganglia located in discrete fat pads on the feline heart. J Auton Nerv Syst 51: 255–259, 1995.
59. Gebber GL, Zhong S, and Paitel Y. Bispectral analysis of complex patterns of sympathetic nerve discharge. Am J Physiol Regul Integr Comp Physiol 271: R1173–R1185, 1996.
60. Glanzman DL. The cellular basis of classical conditioning in Aplesia californics—it's less simple than you think. Trends Neurosci 18: 30–36, 1995.
61. Gray AL, Johnson TA, Ardell JL, and Massari VJ. Parasympathetic control of the heart: II. A novel interganglionic intrinsic cardiac circuit mediates neural control of heart rate. J Appl Physiol 96: 2273–2278, 2004.
62. Hageman GR, Goldberg JM, Armour JA, and Randall WC. Cardiac dysrhythmias induced by autonomic nerve stimulation. Am J Cardiol 2: 823–830, 1973.
63. Hamos JE, Van Horn SC, Raczkowski D, Uhlrich DJ, and Sherman SM. Synaptic connectivity of a local circuit neurone in lateral geniculate nucleus of the cat. Nature 317: 618–621, 1985.
64. Hartikainen J, Kuikka J, Mäntysaari M, Länsimies E, and Pyörälä K. Sympathetic reinnervation after acute myocardial infarction. Am J Cardiol 77: 5–9, 1966.
65. Hashimoto K, Hirose M, Furukawa S, Hayakawa H, and Kimura E. Changes in hemodynamics and bradykinin concentration in coronary sinus blood in experimental coronary artery occlusion. Jpn Heart J 18: 679–689, 1977.
66. Hassall CJS and Burnstock G. Intrinsic neurons and associated cells of the guinea-pig heart in culture. Brain Res 364: 102–113, 1986.
67. Hillarp NA. Peripheral autonomic mechanisms. In: Handbook of Physiology. Neurophysiology. Bethesda, MD: Am Physiol Soc, vol. II, sect. I, p. 979–1006, 1960.
68. Hirose M, Leatmanoratn Z, Laurita KR, and Carlson MD. Partial vagal denervation increases vulnerability to vagal induced atrial fibrillation. J Cardiovasc Electrophysiol 13: 1272–1279, 2002.
69. Hopkins DA and Armour JA. Ganglionic distribution of afferent neurons innervating the canine heart and physiologically identified cardiopulmonary nerves. J Auton Nerv Syst 26: 213–222, 1989.
70. Hopkins DA, MacDonald SE, Murphy DA, and Armour JA. Pathology of intrinsic cardiac neurons associated with ischemic human hearts. Anat Rec 259: 424–436, 2000.
71. Horackova M and Armour JA. ANG II modifies cardiomyocyte function via extracardiac and intrinsic cardiac neurons: in situ and in vivo studies. Am J Physiol Regul Integr Comp Physiol 272: R766–R775, 1997.
72. Horackova M and Armour JA. Role of peripheral autonomic neurons in maintaining adequate cardiac function. Cardiovasc Res 30: 326–335, 1995.
73. Horackova M, Armour JA, and Byczko Z. Multiple neurochemical coding of intrinsic cardiac neurons in whole-mount guinea-pig atria: confocal microscopic study. Cell Tissue Res 297: 409–421, 1999.
74. Huang MH, Negoescu RM, Horackova M, Wolf S, and Armour JA. Polysensory response characteristics of dorsal root ganglion neurones that may serve sensory functions during myocardial ischemia. Cardiovasc Res 32: 503–515, 1996.
75. Huang MH, Smith FM, and Armour JA. Amino acids modify the activity of canine intrinsic cardiac neurons involved in cardiac regulation. Am J Physiol Heart Circ Physiol 264: H1275–H1282, 1993.
76. Huang MH, Sylvén C, Horackova M, and Armour JA. Ventricular sensory neurons in canine dorsal root ganglia: effects of adenosine and substance P. Am J Physiol Regul Integr Comp Physiol 269: R318–R324, 1995.
77. Huang MH, Wolf SG, and Armour JA. Ventricular arrhythmias induced by chemically modified intrinsic cardiac neurons. Cardiovasc Res 28: 636–642, 1994.
78. Huang HS, Pan HL, Stahl GL, and Longhorst JC. Ischemia- and reperfusion-sensitive cardiac sympathetic afferents: influence of H₂O₂ and hydroxyl radicals. Am J Physiol Heart Circ Physiol 269: H888–H901, 1995.
79. Janes RD, Johnstone DE, and Armour JA. Functional integrity of intrinsic cardiac nerves located over an acute transmural myocardial infarction. Can J Physiol Pharmacol 65: 64–69, 1987.
80. Katchenova G, Xu J, Hurt CM, and Pelleg A. Electrophysiological-anatomical correlates of ATP-triggered vagal reflex in the dog. III Role of cardiac afferents. Am J Physiol Heart Circ Physiol 270: H1785–H1790, 1996.
81. Kember GC, Fenton GA, Armour JA, and Kalyaniwalla N. A competition model for aperiodic stochastic resonance in a Fitz-Hugh Nagumo model of cardiac sensory neurons. Physiol Rev 63: 1–6, 2001.
82. Kember GC, Fenton GA, Collier K, and Armour JA. Stochastic resonance in a hysteretic population of cardiac neurons. Physiol Rev 61: 1816–1824, 2000.
83. Kingma JG, Armour JA, and Rouleau JR. Chemical modulation of in situ canine intrinsic cardiac neurones influences myocardial blood flow in the anesthetized dog. Cardiovasc Res 28: 1403–1406, 1994.
84. Klassen GA and Armour JA. Coronary venous pressure and flow. Effects of vagal stimulation, aortic occlusion and vasodilators. Can J Physiol Pharmacol 62: 531–538, 1984.
85. Kollai M and Koizumi K. Reciprocal and non-reciprocal action of the vagal and sympathetic nerves innervating the heart. J Auton Nerv Syst 1: 33–52, 1979.
86. Kuntz A. The Autonomic Nervous System. Philadelphia: Lea & Febiger, 1934.
87. Lanfranchi PA and Somers VK. Arterial baroreflex function and cardiovascular variability: interactions and implications. Am J Physiol Regul Integr Comp Physiol 283: R815–R826, 2002.
88. Lathrop DA and Spooner PM. On the neural connection. J Cardiovasc Electrophysiol 12: 841–844, 2001.
89. Laurent CE, Cardinal R, Rousseau G, Vermeulen M, Bouchard C, Wilkinson M, Armour JA, and Bouvier M. Functional desensitization to isoproterenol without reduction cAMP production in failing cardiomyocytes. Am J Physiol Regul Integr Comp Physiol 280: R355–R364, 2001.
90. Levy MN and Martin PJ. Neural control of the heart. In: Handbook of Physiology. The cardiovascular system: The Heart. Bethesda, MD: Am Physiol Soc, sect. 2, vol. 1, 1979, p. 581–620.
91. Lewis CD, Gebber GL, Larsen PD, and Barman SM. Long-term correlations in the spike trains of medullary sympathetic neurons. J Neurophysiol 85: 1614–1622, 2000.
92. Linden RJ and Kappagoda CT. Atrial Receptors. Cambridge, UK: Cambridge University Press, 1982.
93. Linderoth B and Foreman RD. Physiology of spinal cord stimulation: review and update. Neuromodulation 2: 150–164, 1999.
94. Lipski J, Lin J, Teo MY, and van Wyk M. The network vs. pacemaker theory of the activity of RVL presympathetic neurons—a comparison with another putative pacemaker system. Auton Neurosci Bas Clin 98: 85–89, 2002.
95. Liu L and Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol Heart Circ Physiol 273: H805–H816, 1997.
96. Lowie AD and Spyer KM. Central Regulation of Autonomic Functions. New York: Oxford University Press, 1990.
97. Malliani A. Cardiovascular sympathetic afferent fibers. Rev Physiol Biochem Pharmacol 94: 11–74, 1982.
98. Malliani A. Principles of Cardiovascular Neural Regulation in Health and Disease. Norwell, MA: Kluwer Academic, 2000.
99. McAllen RM and Spyer KM. The location of cardiac vagal preganglionic motorneurons in the medulla of the cat. J Physiol 258: 187–204, 1976.
100. Minardo JD, Tuli MM, Mock BM, Weiner RE, Pride HP, Wellman HN, and Zypes DP. Scintigraphic and electrophysiologial evidence of canine myocardial sympathetic denervation and reinnervation produced by myocardial infarction of phenol application. Circulation 78: 1008–1019, 1988.
101. Minsi AJ and Thames MD. Reflexes from ventricular receptors with vagal afferents. In: Reflex Control of the Circulation, edited by Zucker IH and Gilmore JP. Boca Raton, FL: CRC, 1991, p. 359–406.
102. Minsi AJ, Nashed TB, and Quinn MS. Regional left ventricular deafferentation increases baroreflex sensitivity following myocardial infarction. Cardiovasc Res 58: 136–141, 2003.
103. Murphy DA, O'Blenes S, Hanna BD, and Armour JA. Capacity of intrinsic cardiac neurons to modify the acutely autotransplanted mammalian heart. J Heart Lung Transplant 13: 847–856, 1994.
104. Murphy DA, Thompson GW, Ardell JL, McCraty R, Stevenson R, Sangalang VE, Cardinal R, Wilkinson M, Craig S, Smith FM, Kingma JG, and Armour JA. The heart reinnervates post-transplantation. Ann Thorac Surg 69: 1769–1781, 2000.
105. Nalivaiko E, DePasquale CG, and Blessing WW. Electrocardiographic changes associated with the nasopharyngeal reflex in conscious rabbits: vago-sympathetic co-activation. Auton Neurosci Basic Clin 105: 101–104, 2003.
106. Neely BH and Hageman GH. Differential cardiac sympathetic activity during acute myocardial ischemia. Am J Physiol Heart Circ Physiol 258: H1534–H1541, 1990.
107. Oppenheimer SM and Hopkins DA. Suprabulbar neuronal regulation of the heart. In: Neurocardiology, edited by Armour JA and Ardell JL. New York: Oxford University Press, 1994, p. 309–342.
108. Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, Sandrone G, Malfatto G, Dell'Orto S, Piccaluga E, Turiel M, Baselli G, Cerutti S, and Malliani A. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res 59: 178–193, 1986.
109. Pagé PL, Dandan N, Savard P, Armour JA, and Cardinal R. Regional distribution of atrial electrical changes induced by stimulation of extracardiac and intracardiac neural elements. J Thorac Cardiovasc Surg 109: 377–388, 1995.
110. Paintal AS. A study of right and left atrial receptors. J Physiol 120: 596–610, 1953.
111. Papka RE. Studies of cardiac ganglia in pre- and postnatal rabbits. Cell Tissue Res 175: 17–35, 1976.
112. Pappone C, Santinelli V, Manguso F, Vicedomini G, Gugliotta F, Mazzone P, Tortoriello V, Landoni G, Zangrillo A, Lang C, Tomita T, Mesas C, Mastella E, and Alfieri O. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 109: 327–334, 2004.
113. Pauziene N and Pauza DH. Electron microscopic study of intrinsic cardiac ganglia in the adult human. Ann Anat 185: 135–148, 2003.
114. Plecha DM, Randall WC, Geis GS, and Wurster RD. Localization of vagal preganglionic somata controlling sinoatrial and atrioventricular nodes. Am J Physiol Regul Integr Comp Physiol 255: R703–R708, 1988.
115. Quan KJ, Lee JH, Van Hare GF, Biblo LA, Mackall JA, and Carlson MD. Identification and characterization of atrioventricular parasympathetic innervation in humans. J Cardiovasc Electrophysiol 13: 735–739, 2002.
116. Randall DC, Brown DR, McGuirt AS, Thompson GW, Armour JA, and Jeffrey Ardell L. Interactions within the intrinsic cardiac nervous system contribute to chronotropic regulation. Am J Physiol Regul Integr Comp Physiol 285: R1066–R1075, 2003.
117. Randall WC. Changing perspectives concerning neural control of the heart. In: Neurocardiology, edited Armour JA and Ardell JL. New York: Oxford University Press, 1994, p. 3–17.
118. Randall WC and Armour JA. Regional vagosympathetic control of the heart. Am J Physiol 227: 444–452, 1974.
119. Randall WC, Armour JA, Geis WP, and Lippincott DB. Regional cardiac distribution of sympathetic nerves. Fed Proc 31: 1199–1208, 1972.
120. Randall WC, Wurster RD, Randall DC, and Xi-Moy SX. From cardioaccelerator and inhibitory nerves to a heart brain: an evolution of concepts. In: Nervous Control of the Heart, edited by Shepherd JT and Vatner SF. Amsterdam: Harwood Academic, 1996, p. 173–200.
121. Recordati G, Schwartz PJ, Pagani M, Malliani A, and Brown AM. Activation of cardiac vagal receptors during myocardial ischemia. Experientia 27: 1423–1424, 1971.