Am J Physiol Regul Integr Comp Physiol 287: R262–R271, 2004;

Invited Review 10.1152/ajpregu.00183.2004.

Cardiac neuronal hierarchy in health and disease

J. Andrew Armour
Department of Pharmacology, Faculty of Medicine, University of Montréal, Montréal, Québec, H3C 3J7 Canada

Armour, J. Andrew. Cardiac neuronal hierarchy in health and disease. Am J

Physiol Regul Integr Comp Physiol 287: R262–R271, 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 inter-
connect 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

PREDICATED ON THE CONCEPT that the cardiac nervous system
offers as yet largely unrecognized opportunities to develop
novel therapeutic strategies to treat debilitating cardiac dis-
eases (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 ef-
ferent 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 post-
ganglionic neurons (99). The other efferent limb of this ner-
vous 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 sympa-
thetic efferent neurons, enhances cardiac indexes (119), the
other, represented by parasympathetic efferent neurons, de-
presses 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-
Address for reprint requests and other correspondence: J. A. Armour, Centre
de recherche, Hôpital du Sacré-Cœur de Montréal, 5400 boul. Gouin Ouest,
Montréal, Québec, H4J 1C5 Canada (E-mail: ja-armour@crhsc.umontreal.ca).
R262 0363-6119/04 $5.00 Copyright © 2004 the American Physiological Society
esis is that such interdependent modulation relies on central
neuronal interactions controlling cardiac adrenergic and cho-
linergic 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 reflexes involved de-
pend on specific linkages in the medulla, spinal cord, and
intrathoracic ganglia initiated by transduction of the cardiovas-
cular 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 cardiovascu-
lar status has been the subject of excellent reviews (2, 52, 96),
the intrathoracic nervous system is emphasized herein.
GENERAL PRINCIPLES OF NEUROCARDIOLOGY
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
http://www.ajpregu.org

CARDIAC NEURONAL HIERARCHY
throughout each cardiac cycle. An important anatomical fea-
ture of its intrathoracic component is that its widely distributed
neurons form linkages at specific nexus points. The relevance
of specific linkages interconnecting spatially distributed popu-
lations of neurons lies in the fact that they represent anatomi-
cally distinct loci where afferent and efferent neuronal ele-
ments functionally interact and, as such, are potential targets
for selective therapy (see below).
TRANSDUCTION OF THE CARDIOVASCULAR MILIEU
Overview
The milieu of diverse cardiac regions, the coronary vascu-
lature, 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 pred-
icated 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
Invited Review
R263
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
specific linkages
● such that each cell station is involved in temporally dependent cardio-
cardiac reflexes.
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 reflexes such that
● populations of CV neurons, acting in isolation,
● destabilize efferent neuronal control of regional cardiac electrical and/
or mechanical events.

Experimental evidence indicates that limited populations of

cardiac afferent neurons transduce purely mechanosensory or

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.

AJP-Regul Integr Comp Physiol • VOL 287 • AUGUST 2004 • www.ajpregu.org

Invited Review
R264 CARDIAC NEURONAL HIERARCHY
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 car-
diac afferents transduce multimodal stimuli in as much as they
can simultaneously sense local mechanical and chemical alter-
ations (17, 74, 97, 140). Anatomical and functional data indi-
cate that cardiovascular afferent neuronal somata are distrib-
uted 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 capa-
bilities 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 over-
comes the consequent lesser tension placed on its corda tendi-
nea 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 sys-
tolic pressure (74). Thus ventricular mechanosensory neurons
do not necessarily transduce ventricular dynamics in an alge-
braic fashion with respect to peak chamber pressure develop-
ment. That other ventricular mechanosensory neurons trans-
duce diastole (9, 140) indicates that collectively mechanosen-
sory 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 ves-
sels, particularly along the inner arch of the thoracic aorta and
at the bases of both vena cavae (7, 9, 10). They transduce with
AJP-Regul Integr Comp Physiol • VOL
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 mechan-
ics (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 con-
centration of each chemical that they are capable of transduc-
ing (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 individ-
ual 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
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 ␮m) neurons organized
as rosettes with central axo-dendritic and axo-somatic syn-
apses, as well as dendritic membrane specializations (20, 28,
47, 111, 113, 148). These features may represent the anatom-
ical substrate for two-way information processing within in-
trathoracic ganglia (8, 10, 12, 31, 72, 117, 137). Although
many short-loop intrathoracic cardio-cardiac reflexes appar-
ently 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 trans-
duction 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
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CARDIAC NEURONAL HIERARCHY
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 butyrylcholines-
terase-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, neu-
rons 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 atrioven-
tricular (AV) node (58, 114, 115). Neurons in the ventral
ventricular ganglionated plexus would selectively decrease
ventricular contractility (48). Attractive as this thesis of re-
gional 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
AJP-Regul Integr Comp Physiol • VOL
Invited Review
R265
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 ganglion-
ated 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 pericar-
dial sac (103), it may be difficult to attribute alterations in that
index to malfunction of a specific neuronal population (104).
INTERACTIVE HIERARCHICAL CONTROL
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 indi-
rectly to cardiac motor neurons and 2) the type and time scale
(latency of reflexes) 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 nic-
otine (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
identified in some of the 127 epicardial unipo-
lar electrograms recorded from the atria (top
shows changes in the areas subtended by local
electrograms reflecting modification of the re-
polarization phase) and in the 127 electrograms
recorded simultaneously from the ventricular
epicardium (bottom shows alterations in repo-
larization 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 mod-
ified, most of the ventricular epicardium under-
went electrical change. This representative fig-
ure is illustrative of the fact that right atrial
neurons influence adjacent atrial tissues as well
as distant atrial and ventricular regions. Ven-
tricular surfaces are depicted according to a
polar representation in which the outer circum-
ference represents the ventricular base and the
apex is at the center. lad, Left anterior descend-
ing; pda, posterior descending coronary artery.
This research was performed in collaboration
with René Cardinal and Michel Vermeulen.
287 • AUGUST 2004 • www.ajpregu.org
Invited Review
R266 CARDIAC NEURONAL HIERARCHY
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 coordina-
tion 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. Mech-
anosensory 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 defor-
mation 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 influ-
encing parasympathetic efferent neuronal control of the SA
node differentially throughout each cardiac cycle (90) to initi-
ate short-term heart rate variability (87). Some intrathoracic
sympathetic efferent neurons also display phase-related activ-
ity reflective of reflexes initiated by carotid artery, aortic, or
cardiac mechanosensory neurons (10, 16). Vena cava mech-
anosensory 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, chemosen-
sory-based reflexes can influence large numbers of cardiac
motor neurons over multiple cardiac cycles (12). For these
reasons it appears that intrathoracic sympathetic efferent post-
ganglionic neurons display either phase-related or stochastic
AJP-Regul Integr Comp Physiol • VOL
behavior predicated primarily on whether they transduce mech-
anosensory- vs. chemosensory-based inputs, respectively.
NEURONAL MEMORY
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 re-
quires 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 imme-
diate 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) indi-
cates that this capacity can reside solely within the intratho-
racic neuronal hierarchy.
REMODELING OF THE CARDIAC NEURONAL HIERARCHY
IN CARDIAC DISEASE
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 compro-
mised. This may be because the filtering capacity of its rela-
tively large intrathoracic local circuit neuronal population acts
to stabilize cardiac efferent neuronal function in the presence
of excessive sensory inputs arising from an ischemic myocar-
dium (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, hypo-
thalamus, insular cortex, etc.) and initiate symptoms (135).
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CARDIAC NEURONAL HIERARCHY
Central neuron-derived myocardial ischemia reflexes. Car-
diac parasympathetic and sympathetic efferent preganglionic
neurons become activated when sufficient populations of cen-
trally projecting cardiac afferent neurons transduce myocardial
ischemia to central neurons (101). Myocardial ischemia ini-
tiates 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 neu-
rons transducing such an event activate parasympathetic motor
neurons (2, 80). Ischemia-induced excitation of dorsal root
ganglion afferent neurons reflexly activates sympathetic effer-
ent 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 ventric-
ular 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) re-
mains unknown.
Ischemia-induced intrathoracic reflexes. Compromised re-
gional 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 ven-
tricular 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 trans-
mural 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 myo-
cardium modify local cardiac sensory neurite function (17, 29,
78, 97, 140). Many cardiac afferent neurons are further af-
fected on restoration of the arterial blood supply to their
sensory neurites during early reperfusion (19, 25, 54). Presum-
ably that is when the greatest concentration of locally accumu-
lated 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
AJP-Regul Integr Comp Physiol • VOL
Invited Review
R267
such an event (135). That their capacity to transduce myocar-
dial 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 remodel-
ing during the evolution of heart failure (126). Arterial barore-
flexes 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 ad-
renergic agonist becomes obtunded (32). Thus far heart failure
therapy involving adrenergic receptor blockade has been con-
sidered 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, ad-
renergic 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 ␤-ad-
renoceptor 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-
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.
287 • AUGUST 2004 • www.ajpregu.org
Invited Review
R268 CARDIAC NEURONAL HIERARCHY
tensin II receptor blockade reduces sympathetic efferent neu-
ronal 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 evo-
lution 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 parasym-
pathetic 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 trans-
duction of an ischemic myocardium can be overcome by
increasing their spinal cord neuronal inputs (93). Thus the
harmful consequences that activating large populations of in-
trinsic cardiac neurons consequent to their transducing regional
ventricular ischemia may be amenable to therapy.
Rate control. Activating select populations of intrinsic car-
diac 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 pres-
ence 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 ad-
jacent 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 popula-
tion 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 neu-
rons 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 vari-
AJP-Regul Integr Comp Physiol • VOL
able and even unexpected results among individuals (146). In
that regard, it should be recalled that activating select intratho-
racic 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 distrib-
uted collections of neurons displaying tightly coupled or sto-
chastic 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 cardio-
dynamics 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 success-
fully targeting its select components to retard disease progres-
sion.
GRANTS
The author gratefully acknowledges the support of the Canadian Institutes
of Health Research and the Heart and Stroke Foundation of Canada.
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