Cardiac neuronal hierarchy in health and disease

J. Andrew Armour
Am J Physiol Regul Integr Comp Physiol 287:R262-R271, 2004. doi:10.1152/ajpregu.00183.2004 You might find this additional info useful... This article cites 126 articles, 67 of which can be accessed free at: http://ajpregu.physiology.org/content/287/2/R262.full.html#ref-list-1 This article has been cited by 11 other HighWire hosted articles, the first 5 are: Atrial Tachyarrhythmias and Repolarization Changes Induced by Discrete Activation of Dorsal Mediastinal Cardiac Nerves in Canines Ren Cardinal, J. Andrew Armour, Caroline Bouchard, Michel Vermeulen, Alain Vinet, Rginald Nadeau and Pierre Pag Circ Arrhythm Electrophysiol, October , 2010; 3 (5): 511-520. [Abstract] [Full Text] [PDF] The Sympathetic Nervous System in Heart Failure: Physiology, Pathophysiology, and Clinical Implications Filippos Triposkiadis, George Karayannis, Grigorios Giamouzis, John Skoularigis, George Louridas and Javed Butler JACC, October 26, 2009; 54 (19): 1747-1762. [Abstract] [Full Text] [PDF] Cardiac autonomic neural remodeling and susceptibility to sudden cardiac death: effect of endurance exercise training George E. Billman Am J Physiol Heart Circ Physiol, October , 2009; 297 (4): H1171-H1193. [Abstract] [Full Text] [PDF] Remodeling of the guinea pig intrinsic cardiac plexus with chronic pressure overload Jean C. Hardwick, Caitlin N. Baran, E. Marie Southerland and Jeffrey L. Ardell Am J Physiol Regul Integr Comp Physiol 2009; 297 (3): R859-R866. [Abstract] [Full Text] [PDF] Dorsal spinal cord stimulation obtunds the capacity of intrathoracic extracardiac neurons to transduce myocardial ischemia Jeffrey L. Ardell, Ren Cardinal, Michel Vermeulen and J. Andrew Armour Am J Physiol Regul Integr Comp Physiol 2009; 297 (2): R470-R477. [Abstract] [Full Text] [PDF] Updated information and services including high resolution figures, can be found at: http://ajpregu.physiology.org/content/287/2/R262.full.html Additional material and information about American Journal of Physiology - Regulatory, Integrative and Comparative Physiology can be found at: http://www.the-aps.org/publications/ajpregu

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American Journal of Physiology - Regulatory, Integrative and Comparative Physiology publishes original investigations that illuminate normal or abnormal regulation and integration of physiological mechanisms at all levels of biological organization, ranging from molecules to humans, including clinical investigations. It is published 12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2004 by the American Physiological Society. ISSN: 0363-6119, ESSN: 1522-1490. Visit our website at http://www.the-aps.org/.

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Am J Physiol Regul Integr Comp Physiol 287: R262R271, 2004; 10.1152/ajpregu.00183.2004.

Cardiac neuronal hierarchy in health and disease

J. Andrew Armour
Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, H3C 3J7 Canada Armour, J. Andrew. Cardiac neuronal hierarchy in health and disease. Am J Physiol Regul Integr Comp Physiol 287: R262R271, 2004; 10.1152/ajpregu. 00183.2004.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 specic linkages such that each neuronal cell station is involved in temporally dependent cardio-cardiac reexes 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 reexes 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

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PREDICATED ON THE CONCEPT that the cardiac nervous system offers as yet largely unrecognized opportunities to develop novel therapeutic strategies to treat debilitating cardiac diseases (12, 37, 88), it may be timely to review how evolving views concerning this nervous system impact such a premise. Since the pioneering work of the Webber brothers (86, 117), the regulatory role that sympathetic and parasympathetic efferent neurons play in modulating cardiodynamics has been appreciated. Select populations of parasympathetic efferent preganglionic neurons in the medulla oblongata project axons via the vagi to intrinsic cardiac parasympathetic efferent postganglionic neurons (99). The other efferent limb of this nervous system is commonly represented by sympathetic efferent preganglionic neurons in the spinal cord that project axons to postganglionic neurons in paravertebral ganglia that, in turn, innervate the substance of the heart (129). One of the basic tenets of cardiac control has been that, whereas one limb of the autonomic efferent nervous system, represented by sympathetic efferent neurons, enhances cardiac indexes (119), the other, represented by parasympathetic efferent neurons, depresses them (30, 90). The sympathovagal balance hypothesis suggests that activation of sympathetic vs. parasympathetic efferent neurons normally is accompanied by inhibition of the other efferent limb (67). A necessary corollary of this hypoth-

esis is that such interdependent modulation relies on central neuronal interactions controlling cardiac adrenergic and cholinergic efferent neurons in a reciprocal fashion, primarily as a result of central arterial baroceptor inputs (98). 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 reexes involved depend on specic 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

Address for reprint requests and other correspondence: J. A. Armour, Centre de recherche, Hopital du Sacre-Cur de Montreal, 5400 boul. Gouin Ouest, Montreal, Quebec, H4J 1C5 Canada (E-mail: ja-armour@crhsc.umontreal.ca). R262

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
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throughout each cardiac cycle. An important anatomical feature of its intrathoracic component is that its widely distributed neurons form linkages at specic nexus points. The relevance of specic 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

Table 1. Summary of major concepts relevant to the hypothesis that the cardiac neuronal hierarchy behaves primarily as a stochastic control system
1. The constitutive parts of this redundant control system can be represented by the following: Basic elements: spatially distributed stations comprising multiple cell lines (neurons). Individual cell stations controlling overlapping, spatially organized cardiac regions. Cell stations distributed throughout this hierarchy interconnect via specic linkages such that each cell station is involved in temporally dependent cardiocardiac reexes. 2. Afferent neurons transduce the CV milieu directly or indirectly (via interconnecting neurons) 3. to cardiac motor neurons that coordinate regional cardiac behavior 4. such that the function of the whole is greater than that of its individual parts. 5. Thus stable cardiac control occurs in the absence of obvious direct cause and effect. 6. Cardiomyocytes require its tonic inputs to sustain adequate cardiac output. 7. During altered cardiac status, its redundancy normally represents a stabilizing feature. 8. It is proposed that during the evolution of cardiac disease, Intrinsic cardiac neurons may undergoing pathological changes. The transduction of altered CV status to the cardiac neuronal hierarchy affects its spatially and temporally organized reexes such that populations of CV neurons, acting in isolation, destabilize efferent neuronal control of regional cardiac electrical and/ or mechanical events.

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). Afferent Neuronal Transduction of the Cardiac and Intrathoracic Vascular Milieu Experimental evidence indicates that limited populations of cardiac afferent neurons transduce purely mechanosensory or

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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 reexes. 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. AJP-Regul Integr Comp Physiol VOL
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chemosensory signals. Mechanosensory afferent neurons are dened 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 outow 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) reective 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 outow 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 Signicant 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
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considerable precision phasic mechanical changes that the underlying vascular wall undergoes during each cardiac cycle (7). For instance, the activity generated by aortic ones reects 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 (0.11 Hz), reective 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 reect 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 efciency of information transduced to second-order neurons by such a limited population.
LOCAL CIRCUIT NEURONS IN CARDIAC CONTROL

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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 inuence 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 m) 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 reexes 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 insignicant loss in their overall function (12). That some intrinsic cardiac neurons project axons to not
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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).
MOTOR CONTROL OF CARDIAC FUNCTION

Intrathoracic cardiac neurons that express catecholaminergic phenotypic properties (55, 66, 72), when excited, increase heart rate, dromotropism, and force of contraction. That occurs when populations of intrinsic cardiac neurons are exposed to locally applied adrenergic agonists or nicotine (12). Intrinsic cardiac neurons that express acetylcholinesterase- or butyrylcholinesterase-like activities, when activated, reduce these cardiac indexes (46). It has been assumed by some authors that neurons in one intrinsic cardiac ganglionated plexus exert motor control solely over adjacent cardiac regions. In such a scenario, neurons in the right atrial ganglionated plexus solely regulate adjacent SA nodal tissue, whereas those in the inferior vena cava-inferior atrial ganglionated plexus control the atrioventricular (AV) node (58, 114, 115). Neurons in the ventral ventricular ganglionated plexus would selectively decrease ventricular contractility (48). Attractive as this thesis of regional control is, nothing could be farther from what neurons in each major intrinsic cardiac ganglionated plexus are capable of doing. 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 reexly 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 difcult to attribute alterations in that index to malfunction of a specic neuronal population (104).
INTERACTIVE HIERARCHICAL CONTROL

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Sensory data arising from the heart (7, 9) and major vessels (84, 141) initiate central (2, 52, 145) and peripheral (11) reexes 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 reexes) of information transduced to such neurons.
Fig. 2. Atrial and ventricular electrical events affected by neurons within a locus in the right atrial ganglionated plexus (RAGP). When nicotine (100 M, 0.1 ml) was applied locally to neurons in the caudal portion of the RAGP of an anesthetized open-chest dog, changes were identied in some of the 127 epicardial unipolar electrograms recorded from the atria (top shows changes in the areas subtended by local electrograms reecting modication 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 modied, most of the ventricular epicardium underwent electrical change. This representative gure is illustrative of the fact that right atrial neurons inuence 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 Rene Cardinal and Michel Vermeulen.

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As some intrathoracic neurons are sensitive to excitatory or inhibitory amino acids (75), these reexes 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 Reexes The short-term scaling properties of fast-responding cardiac mechanosensory neurons generate short-latency reexes that exert rapid control over select populations of cardiac motor neurons. Their relatively short distance to rst synapse permits differential activation of cardiac motor neurons during specic phases of the cardiac cycle (8) to exert beat-to-beat coordination of heart rate and regional contractility (22). These shortloop mechanosensory-based reexes are under central neuronal control (12). Mechanosensory-Based Vascular-Cardiac Reexes Arterial-cardiac reexes 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 delity (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 phaserelated activity reecting arterial events (8, 85), thereby inuencing 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 reective of reexes initiated by carotid artery, aortic, or cardiac mechanosensory neurons (10, 16). Vena cava mechanosensory afferent neurons also modulate cardiac efferent neurons via intrathoracic reexes (16). Chemosensory-Based Cardio-Cardiac Reexes Populations of afferent neurons transduce the cardiac and arterial blood chemical milieu to intrathoracic and higher center neurons, doing so over longer timescales reective 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 reexes can inuence 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
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behavior predicated primarily on whether they transduce mechanosensory- vs. chemosensory-based inputs, respectively.
NEURONAL MEMORY

In the context of this review, memory can be dened 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 reex based (8). As mentioned above, cardiac chemosensory neurons display working memory reective in part of a changing local cardiac chemical milieu (81) such that, once the stimulus is removed, behavioral modication frequently persists (138). Such thresholded adaptation reective 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

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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 ltering 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 sufciently activated to inuence suprabulbar neurons (e.g., the limbic system, hypothalamus, insular cortex, etc.) and initiate symptoms (135).
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Central neuron-derived myocardial ischemia reexes. Cardiac parasympathetic and sympathetic efferent preganglionic neurons become activated when sufcient populations of centrally projecting cardiac afferent neurons transduce myocardial ischemia to central neurons (101). Myocardial ischemia initiates cardiac depressor or augmentor reexes, 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 sufcient 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 reexly activates sympathetic efferent neurons innervating the heart and systemic vasculature (8, 97) to initiate arterial hypertension (133). Regional myocardial ischemia can also inuence ascending spinal cord pathways to affect medullary cardiomotor neurons (2), yet another cardiocardiac reex. Given the multiplicity of these reexes, it is difcult to sustain the thesis that select heart rate changes can be ascribed to reexes initiated from a specic left ventricular region. Rather, anatomical (69) and functional (17, 74, 138) data indicate that central reexes initiated by regional ventricular ischemia induce regionally specic or global (cardiac and systemic vasculature) effects depending on how that event is transduced throughout the entire cardiac neuroaxis (21, 106). How these reexes act to stabilize or destabilize cardiac control in the presence of altered baroreceptor sensitivity (152) remains unknown. Ischemia-induced intrathoracic reexes. Compromised regional coronary arterial blood ow can affect intrinsic cardiac neuronal function and initiate intrathoracic reexes. 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 reexes so initiated modulate not only cardiodynamics (15), but also regional coronary arterial blood ow (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
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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 baroreexes 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 sufcient 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, angio-

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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.
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tensin 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 brillation can occur when sufcient 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 brillation (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 variAJP-Regul Integr Comp Physiol VOL

able 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). Perspectives 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 delity 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.
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