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DOI 10.1212/WNL.0000000000000605
2014;83;261-271 Published Online before print June 13, 2014Neurology Jose-Alberto Palma and Eduardo E. Benarroch
correlations
Neural control of the heart: Recent concepts and clinical
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CLINICAL
IMPLICATIONS OF
NEUROSCIENCE
RESEARCH
Section Editor
Eduardo E.
Benarroch, MD
Jose-Alberto Palma, MD,
PhD
Eduardo E. Benarroch,
MD
Correspondence to
Dr. Palma:
josealberto.palmacarazo@nyumc.
org
Neural control of the heart
Recent concepts and clinical correlations
Areas distributed throughout the neuraxis, includ-
ing the anterior insula, anterior cingulate cortex
(ACC), amygdala, hypothalamus, periaqueductal
gray matter, parabrachial nucleus, and several re-
gions of the medulla, exert a beat-to-beat control
on cardiac function. These areas are critically
involved in emotional behavior, stress responses,
and homeostatic reflexes and exert their influence
on heart rate (HR) and cardiac contractility via the
sympathetic and parasympathetic nervous systems.
Over the past several years, advances in neuroana-
tomical, neurophysiologic, and functional imaging
studies have provided insight into the central and
peripheral mechanisms of neural control of cardiac
function in humans. Whereas some issues, such as
lateralization of this central control, remain unre-
solved, the adverse cardiac consequences of a wide
variety of neurologic disorders emphasize the need
to better understand the functional anatomy and
neurochemical mechanisms of the neural control
of the heart. Important examples are severe arrhyth-
mias and myocardial injury in the setting of neuro-
logic catastrophes and sudden unexplained death in
epilepsy. This review will focus on some of the cur-
rent experimental and clinical information related to
these relevant issues for the neurologist.
INTRINSIC ELECTROPHYSIOLOGIC PROPERTIES
OF THE HEART The heart has a pacemaker activ-
ity, which originates in specialized cardiomyocytes
from the cardiac intrinsic conduction system. This
comprises the sinoatrial (SA) node, the atrioven-
tricular (AV) node, the bundle of His, and the
Purkinje fiber network.
1
The HR, excitability,
and contractile function of the cardiomyocytes
depend on the interplay between their intrinsic
properties and their regulation by the vagus and
sympathetic nerves via the intrinsic cardiac gangli-
onated plexuses.
Heart rate. In normal conditions, the spontaneous
depolarization (automatism) of the SA node deter-
mines the HR (chronotropism). This is under the
control of a “voltage clock,”which depends on cyclic
activation and deactivation of different membrane ion
channels, and a calcium (Ca
21
) clock, triggered by
rhythmic Ca
21
release from the sarcoplasmic reticu-
lum. One important determinant of the voltage clock
is the hyperpolarization-activated pacemaker current
I
f
, which is a mixed sodium (Na
1
)-potassium (K
2
)
inward current carried by hyperpolarization-activated
cyclic nucleotide-gated (HCN) channels; HCN4 is
the most abundant isoform and is activated by
cyclic adenosine monophosphate (cAMP).
2
The
Ca
21
clock depends on spontaneous release of Ca
21
from the sarcoplasmic reticulum via the ryanodine
receptor 2 (RYR2); rhythmic increase of cytosolic
Ca
21
activates the Ca
21
-Na
1
exchanger current
leading to depolarization.
3,4
Cardiac action potential. The initial event in the car-
diac cycle is spreading of depolarization via connexin
channels from neighboring cardiomyocytes, which is
followed by opening of voltage-gated Na
1
(primarily
Na
v
1.5) channels. Depolarization rapidly inactivates
voltage-gated Na
1
channels and activates both L-type
calcium channels responsible for the plateau of the
action potential the conduction, and voltage-gated K
1
channels responsible for repolarization, including the
slowly activating I
Ks
channels. The balanced activity
of these channels determines the velocity of AV
conduction, or dromotropism (PR interval), the
duration of the cardiac action potential (QT interval),
GLOSSARY
ACC 5anterior cingulate cortex; AF 5atrial fibrillation; AV 5atrioventricular; BP 5blood pressure; BRS 5baroreflex
sensitivity; cAMP 5cyclic adenosine monophosphate; CeA 5central nucleus of the amygdala; DMH 5dorsomedial nucleus
of hypothalamus; GABA 5g-aminobutyric acid; HCN 5hyperpolarization-activated cyclic nucleotide-gated; HF 5high fre-
quency; HR 5heart rate; HRV 5heart rate variability; IC 5insular cortex; ICN 5intrinsic cardiac nervous system; IML 5
intermediolateral; LF 5low frequency; NAmb 5nucleus ambiguus; NE 5norepineph rine; NTS 5nucleus of the solitary tract;
PD 5Parkinson disease; PKA 5protein kinase A; QTc 5corrected QT; RSA 5respiratory sinus arrhythmia; RVLM 5rostral
ventrolateral medulla; RYR2 5ryanodine receptor 2; SA 5sinoatrial; SAH 5subarachnoid hemorrhage; SERCA 5sarcoen-
doplasmic reticulum Ca2
1
-ATPase.
From the Dysautonomia Center (J.-A.P.), Department of Neurology, New York University Medical Center, NY; and Department of Neurology
(E.E.B.), Mayo Clinic, Rochester, MN.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, ifany, are provided at the end of the article.
© 2014 American Academy of Neurology 261
and the excitability of the His-Purkinje system
(bathmotropism).
Excitation-contraction coupling. Calcium released from
the sarcoplasmic reticulum through the RYR2 binds
to the troponin complex and activates the contractile
apparatus resulting in systolic contraction (inotropism).
Cellular relaxation during diastole (lusitropism) occurs
upon removal of cytosolic Ca
21
by the smooth endo-
plasmic reticulum Ca
21
uptake pump (SERCA), which
is negatively regulated by the protein phospholamban.
5
CARDIAC INNERVATION The neural control of the
heart involves areas distributed throughout the neur-
axis (figure). The cardiac nervous system includes
intrinsic and extrinsic components.
6,7
The intrinsic
cardiac nervous system (ICN) is a complex neural net-
work composed of ganglionated plexuses embedded in
the epicardial fat pads and the heart wall.
8,9
The func-
tion of the ICN is controlled by extrinsic influences
mediated by the vagus and sympathetic nerves.
Cardiac ganglia. Ganglion cells are grouped into 5
major locations, including the superior and posterior
right atrium; the superior left atrium; adventitia
around the aorta and pulmonary trunk; AV groove;
and interatrial septum. The ICN contains a heteroge-
neous population of neurons that include afferent,
efferent, and local circuit neurons. Most ganglion
cells utilize acetylcholine as their primary transmitter;
others contain somatostatin, vasoactive intestinal pep-
tide, or nitric oxide synthase. The cardiac ganglia are
sites of signal integration; ganglion neurons are highly
interconnected and have intrinsic activity that is mod-
ulated by sympathetic or vagal inputs.
Sympathetic output. The sympathetic innervation of
the heart originates in a subgroup of neurons of the
intermediolateral (IML) cell column of the spinal
cord (figure); these neurons receive tonic excitatory
glutamatergic inputs from neurons in the rostral ven-
trolateral medulla (RVLM). The cardiac pregangli-
onic sympathetic neurons are cholinergic and send
small myelinated axons that synapse on noradrenergic
neurons of the superior, middle cervical and cervico-
thoracic (stellate) ganglia; these ganglia innervate the
heart via the superior, middle, and inferior cardiac
nerves.
10
The left-to-right distribution of sympathetic
nerves is asymmetrical and shows interindividual
variability; this may explain their heterogeneous
influence on electrophysiologic properties of the
heart. Whereas the primary neurotransmitter of
cardiac sympathetic neurons is norepinephrine (NE),
some also release adenosine triphosphate, calcitonin
gene-related peptide, and neuropeptide Y.
Parasympathetic output. The vagus nerve provides the
parasympathetic innervation of the heart (cardiovagal
innervation). The preganglionic cardiovagal neurons are
primarily located in the nucleus ambiguus (NAmb),
11
and to a lesser extent in the dorsal motor nucleus of the
vagus.
12
Theseneuronsarecholinergicandtheiraxons
reach the cardiac ganglia via superior cervical, inferior
cervical thoracic rami, which anastomose with cardiac
sympathetic nerves to form the cardiac plexus. Most of
the vagal nerve fibers innervate the atrium and SA and
AV nodes
13
; some branches also innervate the wall of the
ventricles.
14
EFFECTS OF THE AUTONOMIC OUTPUT ON
CARDIAC FUNCTION Sympathetic effects. Sympa-
thetic activation elicits an increase in automatism
of the SA node, conduction through the AV node,
excitability of the His-Purkinje system, force of
contraction during systole, and speed of relaxation
of the cardiac muscle cells during diastole.
15
These
effects are primarily mediated by NE acting via
b
1
-adrenoreceptors, leading to cAMP production
and activation of protein kinase A (PKA). PKA-
mediated phosphorylation activates L-type calcium
channels resulting in increased duration of the
plateau phase of the cardiac action potential; this
effect is limited by PKA-induced activation of I
Ks
currents, which prevents an excessive prolongation of
the action potential (QT interval). Phosphorylation of
RYR2 promotes Ca
21
release from the sarcoplasmic
reticulum and thus excitation-contraction coupling;
phosphorylation of phospholamban promotes Ca
21
uptake via the SERCA, accelerating diastolic relaxation.
Parasympathetic effects. The main effects of the vagus,
via the cholinergic neurons of the cardiac ganglia, are
inhibition of the pacemaker activity of the SA node
(decrease in HR), reduced AV conduction, and
decreased excitability of the His-Purkinje system.
These effects are mediated by muscarinic M
2
receptors, which are coupled to G
i/o
transduction
pathways. Via b/gsubunits, M
2
receptors activate
G protein–coupled inwardly rectifying K
1
channels
leading to hyperpolarization of the SA node.
16
M
2
receptors also inhibit cAMP production and activate
nitric oxide signaling, which inhibit L-type calcium
channels.
17
Interactions between vagal and sympathetic influences on
the heart. In resting conditions, tonic vagal influence
on the automatism of the SA node predominates over
that of the sympathetic system. The HR has a circa-
dian pattern; it increases in early morning as a conse-
quence of surges in sympathetic activity and decreases
during sleep, particularly during non-REM sleep
due to vagal predominance. Phasic transient vagal
interruption and sympathetic activation result in HR
surges during REM sleep.
18
The vagal control of the
HR is modulated on a beat-to-beat basis by respiration;
262 Neurology 83 July 15, 2014
cardiovagal activity is reduced during inspiration and
increased during expiration, a physiologic phenomenon
known as respiratory sinus arrhythmia (RSA).
19
RSA is
an important measure of cardiovagal output and
cardiovascular health, and decreases linearly with age.
There is a rapid reduction of vagal activity, together
with increased sympathetic influence, in response to
orthostatic stress, hypovolemia, or exercise. In
conditions with very low basal HR (e.g., athletes,
during non-REM sleep, or patients with sinus
bradycardia), vagal stimulation may paradoxically
increase HR by shortening the time between atrial
depolarizations. Responses to vagal stimulation,
particularly in the ventricles, are higher in the setting
of prominent concurrent sympathetic stimulation; this
so-called “accentuated antagonism”depends on
presynaptic inhibition of sympathetic transmission.
HR variability. HR variability (HRV) is the variation
in the beat-to-beat time interval (RR interval) or
Figure Efferent and afferent control of cardiac function
Neural control of the heart is integrated at all levels of the neuraxis. Several forebrain areas, including the insular cortex, anterior cingulate cortex (ACC),
central nucleus of the amygdala, and several hypothalamic nuclei project to medullary and spinal nuclei controlling cardiac function; these projections
are either direct or via a relay in the periaqueductal gray (PAG). Sympathetic activation is triggered by neurons of the rostral ventrolateral medulla, which
send excitatory projections to preganglionic sympathetic neurons of the intermediolateral (IML) cell columns of the spinal cord. These neurons activate non-
adrenergic neurons of the stellate and other paravertebral ganglia, which send axons that contribute to the cardiac plexuses innervating the heart. Para-
sympathetic output is mediated by vagal neurons located in the ventrolateral portion of the nucleus ambiguus and, to a lesser extent, the dorsal motor
nucleus of the vagus. These neurons send preganglionic axons that synapse on cholinergic and noncholinergic neurons located in the cardiac ganglia. Inputs
from cardiac receptors are conveyed by spinal afferents that follow the trajectory spinal nerves and have their cell body in the dorsal root ganglia (DRG), or
by vagal afferents with cell bodies in the nodose ganglion (NG). Spinal afferents relay on second-order neurons of lamina I, which project to the thalamus,
parabrachial nucleus, PAG, and other brainstem and hypothalamic targets (not shown). Cardiac vagal afferents, together with carotid baroreceptor affer-
ents, provide inputs to the nucleus of the solitary tract. This nucleus initiates a variety of cardiovascular reflexes and also conveys cardiovascular receptor
information to the thalamus and parabrachial nucleus. The parabrachial nucleus is a site of integration of spinal and brainstem afferents and conveysthis
information to the thalamus, amygdala, and hypothalamus. The thalamic relay nuclei receiving information from cardiovascular receptors project to the pos-
terior insular cortex; the dorsal ACC may also receive inputs related to cardiac pain. The catecholaminergic neurons of the A1/C1 group of the ventrolateral
medulla send a parallel viscerosensory pathway to the hypothalamus, PAG, and locus ceruleus (LC). DVN 5dorsal vagal nucleus; PG 5petrosal ganglion.
Neurology 83 July 15, 2014 263
instantaneous HR that results from interactions
between the vagal and sympathetic influences on
the SA node. HRV can be assessed during
autonomic testing, particularly by assessing the HR
response to deep breathing and during the Valsalva
maneuver. There are several indices of HRV in the
time and frequency domains.
20,21
Time-domain
analysis is derived from the RR intervals; frequency-
domain (i.e., spectral) analysis provides information on
how the power of HRV is distributed as a function of
frequency. The high-frequency (HF) component
(0.15–0.4 Hz) represents the vagal influence and
reflects respiratory modulation of cardiovagal output;
the low-frequency (LF) component (0.05–0.15 Hz)
probably depends on a mixture of sympathetic and
vagal influences and has been correlated with baroreflex
sensitivity (BRS) (see below). Although the LF/HF ratio
is frequently referred to as “sympathovagal balance,”it
rather represents the mutual relationship between BRS
and vagal influence.
MEDULLARY CONTROL OF THE AUTONOMIC
OUTPUT TO THE HEART Rostral ventrolateral
medulla. The RVLM contains premotor glutamatergic
sympathoexcitatory neurons that tonically activate the
cardiac preganglionic sympathetic IML neurons and
serve as a common effector of descending and reflex
pathways controlling blood pressure (BP) and cardiac
function
22
; some of these neurons also synthesize epi-
nephrine (C1 group). RVLM neurons are activated by
psychological stress, pain, hypoxia, hypovolemia, and
hypoglycemia both directly and via descending inputs
from the forebrain and are inhibited on a beat-to-beat
basis by the baroreflex via disynaptic inhibition from the
nucleus tractus solitarii (nucleus of the solitary tract;
NTS), mediated by g-aminobutyricacid(GABA)ergic
neurons of the caudal ventrolateral medulla (see below).
22
Nucleus ambiguus. The NAmb contains the majority
of cardioinhibitory vagal motoneurons that control
SA automatism and AV node conduction.
23
These
neurons are activated by glutamatergic inputs from
barosensitive neurons of the NTS and inhibited by
local GABAergic neurons and by GABAergic neurons
of the medullary ventral respiratory group that are
active during inspiration. The Hering-Breuer reflex
triggered by pulmonary mechanoreceptors via the
NTS may also contribute to the RSA. Neurons in
the dorsal vagal nucleus contribute to cardiac
innervation and mediate small effects on HR, AV
conduction, and contractility.
Nucleus of the solitary tract. The NTS is the first relay
station of visceral afferent information. The caudal por-
tion of the NTS receives afferents from baroreceptors,
cardiac receptors, chemoreceptors, and pulmonary
receptors, primarily via vagal and glossopharyngeal
afferents,
24
and is the first central relay for all medullary
reflexes, including the baroreflex and cardiac reflexes
controlling BP and HR.
25
Cardiovascular reflexes. Baroreflex. The baroreceptor
reflex (baroreflex) is a crucial BP buffering mechanism
and is triggered by mechanical deformation of the ves-
sel wall in the carotid sinus and aortic arch during sys-
tole. Increase in BP activates baroreceptor afferents of
the glossopharyngeal and vagus nerves, which provide
monosynaptic excitatory input to the NTS. Barosensi-
tive NTS neurons initiate sympathoinhibitory and car-
dioinhibitory response via 2 different pathways.
25
The
sympathoinhibitory pathway controls total peripheral
resistance via disynaptic inhibition of RVLM neurons
mediated by GABAergic neurons of the caudal ventro-
lateral medulla; the cardioinhibitory pathway elicits a
decrease in HR via direct excitatory inputs from the
NTS to cardiovagal neurons of the NAmb.
25
BRS is a
measure of baroreflex function that assesses primarily the
cardiovagal component; it is defined as changes in beat-
to-beat interval per unit change in BP and can be as-
sessed using pharmacologic or noninvasive methods.
20,21
Cardiac reflexes. Afferents from the heart and coro-
nary and pulmonary arteries trigger a variety of cardi-
ovascular reflexes.
26
Cardiac afferents include
unmyelinated afferents with cell bodies in thoracic
dorsal root ganglia that follow the trajectory of the
sympathetic nerve trunks (these spinal afferents are
thus mislabeled as “sympathetic”afferents) and pro-
vide inputs to the dorsal horn (particularly lamina I)
and intermediate gray matter of the spinal cord, and
myelinated and unmyelinated vagal afferents with cell
bodies in the nodose ganglion that provide inputs to
the NTS. Atrial distension in the setting of increased
blood volume activates myelinated vagal afferents,
which trigger reflex activation of sympathetic input
to the SA node and thus increase in HR, as well as
inhibition of renal sympathetic activity and arginine
vasopressin release, promoting sodium and water
excretion. Unmyelinated spinal and vagal afferents
innervating the ventricles are activated by strong
mechanical or chemical stimuli, including products
of ischemia or inflammations such as adenosine tri-
phosphate, serotonin, and prostanoids. Spinal affer-
ents elicit, via spinothalamic projections from lamina
I neurons, the sensation of cardiac pain; these affer-
ents can also trigger excitatory cardiac reflexes via
local interneurons projecting to the IML (the so-
called “cardio-cardiac reflex”). In response to chemi-
cal stimulation of myocardial injury, unmyelinated
vagal afferents in the ventricles may trigger a decrease
in BP and HR (Bezold-Jarisch reflex). Stimulation of
pulmonary arterial baroreceptors at physiologic pres-
sures causes reflex vasoconstriction and respiratory
stimulation, and could have an important role in
264 Neurology 83 July 15, 2014
cardiovascular control during exercise or in hypoxic
conditions.
26
FOREBRAIN CONTROL OF CARDIAC FUNCTION
Several forebrain areas form a reciprocally intercon-
nected network that initiates integrated autonomic,
endocrine, and behavioral responses to emotionally
relevant or stressful stimuli. They include the insular
cortex (IC), ACC, central nucleus of the amygdala
(CeA), and several hypothalamic nuclei (figure).
These forebrain regions project to medullary and
spinal nuclei controlling cardiac function; these pro-
jections are either direct or via a relay in the periaque-
ductal gray. Afferent cardiovascular information
conveyed by dorsal horn (layer I) or NTS neurons
reaches cortical areas via the thalamus; visceral affer-
ent input is also conveyed to the parabrachial nucleus
of the pons, which relays the information to the thal-
amus, hypothalamus, and amygdala, and by catechol-
aminergic neurons of the A1/C1 group of the
ventrolateral medulla. Despite the large body of
experimental information about the role of these areas
in control of cardiac function,
27–33
their contribution
to cardiovascular control in humans is yet poorly
understood. For example, the hemispheric lateraliza-
tion of cardiovascular control is still an unresolved
issue. Several approaches have been used to address
this issue, including functional neuroimaging includ-
ing fMRI,
34–39
microstimulation during surgery for
intractable epilepsy,
40,41
and, more recently, concur-
rent microelectrode recordings of sympathetic out-
flow to either muscle or skin with fMRI.
42
Insular cortex. The IC is a complex structure that has
been implicated in a large number of functions and in
the pathophysiology of a variety of neurologic disor-
ders.
43
From the cytoarchitectural, connectivity, and
functional standpoint, it is subdivided into dorsocau-
dal and rostroventral zones. The dorsocaudal zone
comprises several areas that receive inputs from dif-
ferent subnuclei of the thalamus that relay gustatory,
viscerosensory, somatosensory, pain, and vestibular
sensations. The rostroventral zone is interconnected
with the ACC and the amygdala and is primarily
involved in emotional processing. According to
Craig,
44,45
the posterior, middle, and anterior IC repre-
sent 3 consecutive steps of integration and process-
ing.
44,45
The posterior IC receives thalamic inputs
relaying converging pain, temperature, and visceral sen-
sory information and provides primary interoceptive
representation; the middle IC integrates this informa-
tion with inputs from high-order polysensory cortex,
ACC, and amygdala and then conveys this integrated
input to the anterior IC, which represents the neural
substrate of awareness of the internal bodily state
and is a key component of emotional experience.
44,45
Consistent with this proposal, similar regions of the
IC and adjacent inferior frontal operculum were
activated when subjects monitored their own HR and
rated their own emotional responses.
46
Electrical stimulation of the insula in patients
undergoing surgical treatment for intractable epilepsy
elicits a variety of visceromotor phenomena, includ-
ing changes in BP and HR.
40,41,47
In one study, stim-
ulation of the left IC more frequently elicited a small
decrease in HR and BP whereas stimulation of the
right IC elicited the opposite effects.
41
This has led to
the suggestion that the left IC primarily regulates the
parasympathetic and the right IC the sympathetic
influence on the heart.
48
This appears to be supported
by fMRI studies showing a correlation between left
IC activation and HF (vagal) modulation of HRV,
36
and lateralization of insular activation during the Val-
salva maneuver, cold pressor test, and handgrip maneu-
ver.
49
However, this may be an oversimplification.
For example, concomitant fMRI and microelectrode
recordings show that resting muscle sympathetic nerve
activity coincides with activation of the left IC whereas
skin sympathetic activity coincides with activation of
the left posterior and right anterior insula.
42
Anterior cingulate cortex. The ACC integrates auto-
nomic responses with behavioral arousal via its exten-
sive connections with the IC, prefrontal cortex,
amygdala, hypothalamus, and brainstem autonomic
nuclei. The nomenclature of the ACC is confusing,
because different functional regions have received dif-
ferent names in the anatomical and functional neuro-
imaging literature.
50
The rostral (or ventral) ACC is
involved in emotional responses and includes a subge-
nual region that has strong connections with the CeA,
lateral hypothalamus, and parabrachial nucleus, and a
pregenual region that is involved in emotional behavior
but lacks these direct connections. The “caudal”or
“dorsal”ACC is also referred to as midcingulate cortex
49
and is involved in cognitive functions, including conflict
resolution and attention-to-action, via its connections
with the prefrontal cortex. Functional MRI studies
indicate that the ventral ACC is part of the brain
“default mode network”that is active in the resting
state in conditions of self-monitoring; the dorsal ACC,
togetherwiththeanteriorIC,isacorecomponentof
the so-called “salience network”and is primarily
engaged during tasks that demand cognitive control,
including conflict resolution.
35,51,52
Dorsal ACC
activation during these tasks is associated with an
increase in sympathetic drive, resulting in HR
increase. In contrast, the subgenual ACC and adjacent
ventromedial prefrontal cortex become inactivated
duringthesetasks;thisisconsistent with experimental
evidence showing projections of these regions to
cardiac parasympathetic nuclei.
53,54
Pharmacologic and
Neurology 83 July 15, 2014 265
neuroimaging studies show that subgenual ACC activity
is associated with vagally mediated HRV,
38
particularly
in the right hemisphere.
55
Amygdala. The amygdala provides emotional valence
to sensory stimuli and is involved in mechanisms of
fear conditioning.
56
The amygdala comprises several
subnuclei, including the basolateral nuclear complex
and the CeA, which includes lateral and medial sub-
divisions. The medial subdivision of the CeA projects
to the hypothalamus and brainstem and triggers the
autonomic, endocrine, and motor manifestations of
the fear responses; sympathoexcitatory responses
involve excitatory connections to the RVLM, and
inhibition of barosensitive neurons of the NTS.
57,58
Functional neuroimaging studies consistently found
coactivation of the lateral and medial amygdala in
relationship to changes in HRV both at rest and dur-
ing emotional tasks.
29,36
The orbitofrontal and ven-
tromedial prefrontal cortices exert an inhibitory effect
on the amygdala via GABAergic neurons in the lateral
CeA and in the intercalate nucleus between the baso-
lateral amygdala and the CeA; these prefrontal influ-
ences underlie mechanisms of emotional regulation,
including fear extinction.
59
Thus, in addition to pro-
moting vagal output, these prefrontal areas may ton-
ically inhibit sympathoexcitatory responses initiated
in the amygdala.
38
Hypothalamus. The hypothalamus controls auto-
nomic output to the heart via inputs that originate
primarily from the paraventricular nucleus, dorsome-
dial nucleus of hypothalamus (DMH), and lateral
hypothalamic area
27,60
; these hypothalamic projections
reach the periaqueductal gray parabrachial nucleus,
RVLM, NAmb, dorsal motor nucleus of the vagus,
NTS, and IML.
27,60
Sympathoexcitatory responses
during stress are mediated by projections from the
paraventricular nucleus, DMH, or lateral hypothala-
mus to the RVLM or IML.
61,62
Hypothalamic inputs
also modulate the baroreflex via their effects on the
NTS
63
or affect cardiovagal responses via inputs to
the NAmb.
64–66
The DMH may contribute to reduced
HRV and BRS via influence on the NTS in the setting
of anxiety-like states.
67
Experimental studies indicate
that the inputs from the IC to the hypothalamus are
mostly ipsilateral; this may also be the case in humans,
as shown by coactivation of the left dorsomedial
hypothalamus and left IC during spontaneous bursts
of muscle sympathetic nerve activity at rest.
42
CLINICAL IMPLICATIONS Cardiac manifestations of
neurologic disorders. Reduced HRV. Reduced HRV and
reduced BRS are relevant markers of cardiovascular risk,
including predisposition toward ventricular arrhythmias
in patients with primary cardiac disease.
68,69
They may
reflect abnormalities in forebrain vagal or sympathetic
drive, brainstem reflexes, or vagal or sympathetic output
(asoccursindiabeticoramyloidneuropathy).For
example, reduced HRV, primarily at the expense of
decreased HF (vagal) component and sometimes asso-
ciated with indices of increased sympathetic activity, has
been reported in patients with ischemic stroke,
70–73
epi-
lepsy,
74
multiple sclerosis,
75
and Parkinson disease
(PD).
76,77
Cardiac arrhythmias. Central autonomic disorders
may manifest with a wide spectrum of cardiac
arrhythmias, some of them life-threatening. Sympa-
thetic hyperactivity triggers both supraventricular and
ventricular tachycardia; vagal hyperactivity leads to bra-
dyarrhythmias, including AV block, and sympathetic
or vagal hyperactivity may lead to atrial fibrillation
(AF).
7,78,79
In the ventricles, sympathetic activity is
proarrhythmic and vagal activation is antiarrhythmic.
Sympathetically triggered activation of L-channels pro-
longs the plateau of the cardiac action potential; in this
setting, inability to activate repolarizing K
1
currents
(due to drug effects or channelopathies) may lead to
QT prolongation, which predisposes to polymorphic
ventricular tachycardia (torsades de pointes) and ven-
tricular fibrillation.
Myocardial injury and Takotsubo cardiomyopathy.
Acute neurologic insults leading to sympathetic
hyperactivity may trigger reversible myocardial
injury, as reflected by T-wave inversion and serum
troponin elevation. Takotsubo cardiomyopathy (also
known as apical ballooning syndrome) is a reversible
cardiomyopathy that primarily affects the left ventri-
cle; it has a typical echocardiographic pattern charac-
terized by wall motion abnormalities with apical
akinesis, basal hyperkinesis, and frequently resolves
within 2 to 4 weeks.
80
The postulated pathogenesis
of Takotsubo cardiomyopathy is direct myocardial
injury by excessive epinephrine and NE.
81
Excessive
catecholamines may also induce coronary artery spasm
and microvascular dysfunction, causing myocardial
stunning. Takotsubo cardiomyopathy may be trig-
gered by insular and vertebrobasilar stroke,
82
limbic
encephalitis,
83
subarachnoid hemorrhage (SAH),
84
seizures,
85
or brainstem lesions affecting the NTS.
86
Specific disorders associated with cardiac complications.
Epilepsy. There are several links between seizures and
cardiac dysfunction; these include cardiac arrhythmias
as a localizing ictal event, seizures and cardiac arrhyth-
mias as coincident manifestations of channelopathies,
and cardiovascular dysregulation and ictal arrhythmias
as a mechanism of sudden unexpected death in epi-
lepsy. Cardiac arrhythmias are the most common ictal
events, but they do not help to localize the hemisphere
of seizure onset.
87–89
Sinus tachycardia occurs in 80%
to 100% of patients before, during, or after a temporal
lobe seizure
90–93
; paroxysmal AF, supraventricular or
266 Neurology 83 July 15, 2014
ventricular tachycardia, and ventricular fibrillation may
also occur.
94
Temporal lobe seizures may lead to ictal
bradycardia and asystole
88,95
; cardiac sympathetic
denervation may constitute a risk factor for this man-
ifestation.
96
Seizures can also lead to alterations of car-
diac repolarization as manifested by acute changes in
corrected QT (QTc) duration,
97
which may be in part
related to ictal hypoxemia.
98
Abnormal QT prolonga-
tion may be more common in patients with left-sided
seizures.
99
Mutations in genes encoding Na
1
or K
1
channels are associated with coexistence of long QT
syndrome or Brugada syndrome and epilepsy.
100,101
Autonomic cardiovascular manifestations of seizures
may have a role in the pathophysiology of sudden
unexpected death in epilepsy, but this causal relation-
ship is yet to be established.
102
Ischemic stroke. Ischemic or hemorrhagic strokes,
particularly those involving the IC, can manifest with
cardiac arrhythmias or myocardial injury that may be
potential causes of sudden death.
47,103
In general, evi-
dence suggests that right insular ischemic strokes are
more frequently associated with cardiac complications,
including reduced HRV, increased QT interval, car-
diac arrhythmias (such as AF or premature ventricular
contractions), AV block, and T-wave inversion than
left insular strokes.
48,104–107
These changes can be inde-
pendent predictors of all-cause vascular mortality.
Reduced HRV may also be a marker of subacute post-
stroke infections
108
and a predictor of poor functional
neurologic recovery.
109
Insular strokes can also lead to
myocardial injury but the lateralization of this effect is
inconsistent; right-sided strokes were more frequently
associated with elevation of troponin
110
and left-sided
strokes with elevation of B-type natriuretic peptide and
poor cardiac outcome.
111
Hemorrhagic stroke. Lobar and basal ganglia hemor-
rhages may trigger ECG changes and indices of myo-
cardial injury that have prognostic implications.
112–115
Repolarization changes are most characteristic and
include QTc prolongation, nonspecific ST changes,
andinvertedTwaves.ProlongedQTcisfrequently
associated with hydrocephalus and IC involvement.
115
SAH is the prototype of an acute neurologic catastrophe
associated with massive sympathoexcitation,
116
which
typically occurs in the first 24 to 48 hours after the
event. The acute sympathoadrenal excitation may pro-
duce ECG changes in up to 90% of patients; these
include T-wave changes, waves, and prolonged
QT.
117–119
The most common arrhythmias are sinus
tachycardia and AF. Ventricular tachycardia, torsades
de pointes, ventricular fibrillation, and asystole are more
likely to occur in the setting of prolonged QT and
hypokalemia.
116,117
The presence of ECG abnormalities,
particularly repolarization changes and sinus arrhyth-
mias, is associated with poor outcome and sudden
death.
116,119
There is a relationship between the clinical
severity of the SAH and the presence of myocardial
injury and regional left ventricular wall motion abnor-
malities, including Takotsubo cardiomyopathy.
120–123
Neurodegenerative diseases. Neurodegenerative disor-
ders affecting the brainstem, spinal, or peripheral
autonomic output, such as multiple system atrophy
or PD, manifest primarily with orthostatic hypoten-
sion, gastrointestinal dysmotility, or bladder dysfunc-
tion; however, they may also affect cardiac function.
Cardiac abnormalities in PD may represent a combi-
nation of peripheral sympathetic denervation, as
documented with cardiac neuroimaging, and central
mechanisms; they include inability to increase the
HR during exercise (chronotropic insufficiency),
reduced HRV, particularly during sleep, and QT pro-
longation.
124–126
QT prolongation may also occur in
multiple system atrophy and may be related to the
increased incidence of sudden cardiac death in these
patients.
127
Patients with prion diseases have altered
HRV during sleep, but the anatomical substrate and
clinical significance of this finding is yet
undetermined.
128
PERSPECTIVE In 1942, Walter B. Cannon pub-
lished a remarkable paper entitled “Voodoo Death,”
in which he compiled experiences of death from
fright. Cannon postulated that those deaths were
caused “by a lasting and intense action of the
sympatho-adrenal system”with devastating effects on
the heart. Since then, our knowledge about the neural
control of the heart has advanced remarkably. Current
evidence clearly indicates that dysfunction of the
autonomic nervous system due to damage to the
central autonomic network is a common phenomenon
that links the major cardiac pathologies seen in
neurologic disorders. These profound effects on the
heart may contribute to the mortality rates of many
neurologic conditions such as SAH, ischemic stroke,
and epilepsy. These phenomena may also be
important in the pathogenesis of sudden cardiac death.
AUTHOR CONTRIBUTIONS
Jose-Alberto Palma: drafting/revising the manuscript, study concept or
design. Eduardo Benarroch: drafting/revising the manuscript, study con-
cept or design, analysis or interpretation of data, study supervision.
STUDY FUNDING
No targeted funding reported.
DISCLOSURE
J.-A. Palma reports no disclosures. E. Benarroch receives a stipend in his
capacity as section editor of Clinical Implications of Neurologic Research
for Neurology
®
. Go to Neurology.org for full disclosures.
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Neurology 83 July 15, 2014 271
DOI 10.1212/WNL.0000000000000605
2014;83;261-271 Published Online before print June 13, 2014Neurology Jose-Alberto Palma and Eduardo E. Benarroch
Neural control of the heart: Recent concepts and clinical correlations
This information is current as of June 13, 2014
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