Journal of the Neurological Sciences 268 (2008) 6 – 11

www.elsevier.com/locate/jns

Review
Brain lateralization and sudden death: Its role in the
neurogenic heart syndrome
Ozcan Ozdemir ⁎, Vladimir Hachinski
University of Western Ontario London, ON: London Health Science Centre, Department of Neurological Sciences, Canada
Received 29 September 2007; accepted 15 November 2007
Available online 9 January 2008

Abstract

Sudden cardiac death is the leading cause of mortality, accounting for approximately 50% of all cardiovascular deaths and 12% deaths.
Although sudden deaths are commonly seen in patients with structural and ischemic heart diseases, some patients lack any evidence of
coronary atherosclerosis or structural heart abnormalities. In these patients mental stress and abnormal neurological conditions can produce
cardiovascular autonomic disturbances leading to life-threatening arrhythmias and sudden death. Emotional, physiological and physical stress
is associated with increased rates of cerebrovascular events and sudden deaths. Human studies in healthy individuals showed lateralization of
cardiovascular autonomic function exists in the forebrain, particularly the insular cortex.
Considerable evidence exists regarding the role of forebrain lateralization in cardiovascular autonomic regulation in patients with ischemic
and hemorrhagic stroke. Particularly insular cortex involvement is associated with more pronounced autonomic imbalance leading to life
threatening arrhythmias and sudden death. Left-handers may have a lower risk of sudden death compared with right-handers. Future studies
should focus on the association of handedness with cardiovascular autonomic networks and sudden death in different neurological diseases.
Identification of patients at risk for neurogenic sudden death by clinical characteristics and noninvasive diagnostic tools may help
implement prophylactic and therapeutic interventions that may reduce the mortality rate.
© 2007 Elsevier B.V. All rights reserved.

Keywords: Brain lateralization; Sudden death

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2. Pathophysiology in the neurogenic heart syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3. Lateralization of cardiovascular autonomic regulation in brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.1. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
3.2. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4. Cardiovascular reactivity and the role of the lateralization in the human brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4.1. Evidence for lateralization of brain function in patients with stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4.2. Hemorrhagic stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
5. Cerebral lateralization and sudden death in epileptic patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

⁎ Corresponding author. 339 Windermere Road, Room:A7-030 London ON Canada N6A5A5. Tel.: +1 519 6858500x35891; fax: +1 519 6633910.
E-mail address: ozcan_99@yahoo.com (O. Ozdemir).

0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2007.11.009
 O. Ozdemir, V. Hachinski / Journal of the Neurological Sciences 268 (2008) 6–11 7

6. Other neurological disorders, sudden death and brain lateralization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

7. Clinical implications and future direction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

1. Introduction
Sudden cardiac death, known as unexpected death is the
leading cause of mortality accounting for approximately 50% of
all cardiovascular mortality and 12% of all deaths [1]. Growing
evidence suggests a major role of the brain, particularly during
stress and in the presence of cerebral lesions in certain locations.
An acute stressor is associated with increased rates of
cardiovascular events and sudden death. Ventricular arrhyth-
mias more than doubled among implantable defibrillator
patients following the World Trade Center Attack [2]. The
number of deaths on the first day of missile strikes increased
significantly on Israeli cities during the Gulf War of 1991 [3].
Takotsubo cardiomyopathy or left ventricular ballooning, is
a clinical syndrome characterized by transient left ventricular
dysfunction that mimics myocardial infarction [4]. Although
its pathophysiological mechanisms are still unknown, cate-
cholamine-mediated cardiotoxicity is proposed as the leading
mechanism. Emotional and physical stress often precedes the
clinical syndrome in several case reports [5].

Fig. 1. A schematic diagram summarizing the concepts of brain-heart control under pathological states. PAG indicates periaqueductal gray; PB, parabrachial
nucleus; NTS, nucleus tractus solitarius; VLM, ventrolateral medulla; NA, nucleus ambiguus; LC, locus cereleus; DVN, dorsal vagal nucleus; IML,
intermediolateral column; AVN, atrioventricular node; SAN, sinuatrial node; ECG, electrocardiography; BP, blood pressure.
8 O. Ozdemir, V. Hachinski / Journal of the Neurological Sciences 268 (2008) 6–11

There is limited literature regarding the effect of emotional 3. Lateralization of cardiovascular autonomic regulation
stress on the rates of cerebrovascular events. Significant increase in brain
in the number of emergency department visits due to acute
stroke, TIA and myocardial infarctions was found on patients` 3.1. Animal studies
birthdays. Moreover the likelihood of having a vascular event
on a birthday is 27% higher than the expected average day [6]. Experimental studies helped to identify components of
Acute mental stress probably can stimulate many factors the cerebrogenic cardiovascular networks and the role of
that induce cardiovascular events and sudden death, includ- forebrain lateralization on cardiovascular autonomic regula-
ing myocardial ischemia, coronary vasoconstriction, transi- tion. Stimulation and electrophysiological studies in animals
ent endothelial dysfunction, platelet activation and
proarrhythmic changes, especially in patients with pre-
existing cardiac diease [7–11]. Although the greatest
incidence of sudden deaths occurs in patients with ischemic,
structural and non-structural heart disease, some persons do
not have postmortem evidence of coronary atherosclerosis or
recent myocardial infarction. In these patients mental stress
and abnormal neurological conditions can disturb the car-
diovascular functions and produce cardiovascular and auto-
nomic disturbances leading to neurogenic sudden death
(Fig. 1) [12,13]. We will summarize briefly the pathopysiol-
ogy of neurogenic heart damage and review the current
evidence regarding the role of brain lateralization, in the
generation of life-threatening arrhythmias leading to sudden
death. Furthermore we will summarize the role of right-
insular damage in the neurogenic-heart syndrome.

2. Pathophysiology in the neurogenic heart syndrome

The ischemic stroke and subarachnoid hemorrhage models

have provided important information regarding the pathophy-
siology of the neurogenic heart. Experimental occlusion of the
right middle cerebral artery causes an increase of neuropeptide
Y in the basolateral nucleus of the amygdala and leucine-
encephalin, dynorphin, neurotensin, tyrosine hydrolase in the
central nucleus [14]. Tyrosine hydrolase is important for the
production of catecholamines. In an experimental subarachnoid
model, Jacop et al. found hemodynamic and ultrastructural
effects similar that was seen with intravenous norepinephrine
injections [15]. Excessive sympathetic stimulation results in
accumulation of norepinephrine that becomes cardiotoxic.
Normally, activation of beta-adrenergic receptors leads to
production of 3′ -5′ cyclic adenosine monophosphate
(cAMP). Subsequently cAMP causes the opening of the cal-
cium channels resulting in the influx of calcium and efflux of
potassium ions. The increase in intracellular calcium promotes
actin–myosin interaction and finally muscle contraction. Sub-
sequently, with rapid sequestration of calcium ions, relaxation of
muscle occurs. In the presence of continuous beta-adrenergic
activation, the calcium channels may fail to close resulting in
intracellular metabolic derangement and subsequent cell death
in a hypercontracted state with prominent contraction bands.
Subendocardial hemorrhages with focal myocytolysis occurs
secondary to the above mechanism (Fig. 2) [16]. The sarco-
lemma, stroma, muscle nuclei and lipofuscin granules remain
relatively intact. These lesions may be surrounded by mono- Fig. 2. Pathophysiology of the neurogenic heart. CNS indicates central
nuclear cells. nervous system.
 O. Ozdemir, V. Hachinski / Journal of the Neurological Sciences 268 (2008) 6–11
demonstrated that the insular cortex plays an important role
in the control and representation of the cardiovascular
autonomic state. Ablation of the right posterior insular cortex
in anesthetized rodents increased the heart rate and blood
pressure [17]. In the urethane-anesthetized rat, the right
posterior insular lesions enhance cardiovascular sympathetic
tone without affecting baroreceptor gain whereas left
posterior insular cortex lesions increased baroreceptor gain
and did not affect baseline blood pressure [18].
Middle cerebral artery occlusion in animals results in an
increase in blood pressure, circulating norepinephrine levels,
sympathetic efferent nerve activity, myocytolysis and death
if the insular cortex is involved in the infarct. Furthermore
greater increase in arterial blood pressure, circulating nore-
pinephrine level was determined in animals with right
hemispheric infarction compared to the left [19].
3.2. Human studies
Sympathetic lateralization in the right hemisphere and
parasympathetic predominance and up-regulation of baror-
eceptor sensitivity in the left hemisphere was detected during
left and right intracarotid amobarbital injection in patients
with drug-refractory seizures [20].
Intraoperative electrical stimulation of the insula elicits
changes in cardiovascular function, which appear lateralized.
Tachycardia and hypertension result from stimulation of the
right insula, and bradycardia and hypotension from stimula-
tion of the left [21]. Baroreceptor stimulation lead to in-
creased neuronal activity within the insular cortex, greater on
the right side. Moreover a single left-handed subject in the
study had lateralization opposite to the right-handed indi-
viduals that may be related to asymmetry in forebrain car-
diovascular control centers [22].
In a healthy person, the hemispheric-specific influences
on sympathetic, parasympathetic, and baroreflex modula-
tion are in a balance that maintains equilibrium between the
right and left hemispheric sympathetic and left hemispheric
parasympathetic predominance and regular baroreceptor
sensitivity.
4. Cardiovascular reactivity and the role of the lateralization
in the human brain
The amygdala plays a crucial role in the control of car-
diovascular autonomic function and integrates autonomic
responses to emotional stimuli especially fear [23]. Some
evidence suggests the lateralization of emotional processing
in the amygdala [24]. Negative emotions lateralize towards
the right hemisphere and particularly the right amygdala,
which probably is involved in processing fearful stimuli and
mediating fear conditioning in humans [25].
A positron emission tomography (PET) study showed an
increase in regional blood flow in the right insula during
stressful tasks associated with sympathetic activation in healthy
volunteers [26]. Besides the forebrain, a right-lateralized
9
asymmetry in midbrain activity was shown during mental stress
in patients attending a cardiology clinic, which predispose them
to arrhythmias [27].
4.1. Evidence for lateralization of brain function in patients
with stroke
Ischemic stroke studies helped understand the concept of
neurogenic heart and the precise location of lesions gave us
an opportunity to investigate the lateralization of cardiovas-
cular function within the cortex.
Right hemispheric stroke increased nocturnal blood
pressure, reduced circadian blood pressure variability and
was associated with a higher norepinephrine level and reduced
heart rate variability compared with left hemisphere infarcts
indicating the role of lateralization of human forebrain in
cardiovascular autonomic control [28,29]. Recently 50 acute
stroke patients with increased serum cardiac troponin T levels
without apparent cause within 3 days of symptom onset and
control subjects with ischemic stroke without troponin T
elevation were studied to determine the association of specific
brain regions with myocardial injury. Each voxel of infarction
on diffusion-weighted images (DWIs), calculated voxel-wise
p values and a map of cerebral regions correlated with tro-
ponin elevation following stroke. Right insula (posterior,
superior, and medial areas) and the right inferior parietal lobule
involvement were significantly associated with cerebrogenic
myocardial injury [30].
A study in patients with first-ever acute ischemic stroke
and without pre-existing cardiac disease demonstrated a more
pronounced decrease in heart rate variability measurements
in patients with right-sided insular involvement indicating a
significant role for the right insular cortex in the pathogenesis
of cerebrogenic cardiac disturbance. Right insular damage
was associated with more complex arrhythmias including
ventricular tachycardia (VC), NSVT (non-sustained ventri-
cular tachycardia) and supraventricular tachycardia (SVT)
than any other localization [31]. A significant association was
found between right insular brain infarctions and 2-year all-
cause death and vascular death after adjustment for age, sex,
cardiovascular history, and disability at admission. Increased
QTc interval and left bundle branch block (LBBB) were
associated with higher mortality at 2-year follow-up in
patients with right insular infarctions. These findings could
support the necessity of intensive heart monitoring in patients
with right insular infarct [32]. In contrast to majority of the
studies, Laowattana et al. showed increased rates of cardiac
events (myocardial infarction, angina, congestive heart
failure, or sudden death) in patients with left insular infarction
compared with other strokes. This association was more
pronounced in stroke patients with no existing coronary
artery disease [33]. The potential importance of handedness
in sudden death is indicated in North American Symptomatic
Carotid Endarterectomy Trial (NASCET) that demonstrated
lower risk of sudden death in left-handed or ambidextrous
patients than right-handers [34].
10 O. Ozdemir, V. Hachinski / Journal of the Neurological Sciences 268 (2008) 6–11
4.2. Hemorrhagic stroke
ECG changes are observed in 40% to 70% of patients with
subarachnoid hemorrhage (SAH), 60% to 70% of patients
with intracerebral hemorrhage [35]. A study showed that 28%
of patients with SAH experienced either global or regional
left ventricular dysfunction especially during the first few
days after SAH [36]. High-grade SAH and elevated troponin
levels were associated independently with left ventricular
regional wall motion abnormalities [37]. Elevated values of
cardiac troponins were observed in 20% of patients with
supratentorial ICH [38]. The literature on lateralization of
brain on neurogenic cardiac arrhythmias in patients with ICH
and SAH is limited. SAH located in the right slyvian fissure
was independently associated with abnormal ECG changes.
This association was probably related to stimulation of the
insular cortex by SAH blood in the slyvian fissure [39].
Considerable evidence exists regarding the lateralization of
cardiovascular autonomic regulation within the forebrain,
especially the insular cortex in patients with both ischemic and
hemorrhagic stoke in whom the involvement of the insula may
play an important role in the generation of life-threatening
arrhythmias leading to sudden death. This vulnerable period
may exist over a long-term period after ischemic and hem-
orrhagic stroke in high-risk patients with insular involvement.
Regarding the majority of the current literature, this associa-
tion is even stronger when the right insula is damaged
secondary to ischemic or hemorrhagic stroke.
5. Cerebral lateralization and sudden death in epileptic
patients
Sudden unexpected death in epilepsy (SUDEP) is a major
cause of mortality for patients with epilepsy. The etiology for
SUDEP remains unknown and multifactorial, however, car-
diovascular autonomic dysregulation and cardiac arrhyth-
mias have been proposed as a leading cause of SUDEP [40].
Risk factors for SUDEP includes young age, intractable
epilepsy, high seizure frequency, long duration of epilepsy
and treatment with polytheraphy [41]. Half of the SUDEP
patients had cardiac rhythm or repolarization abnormalities
including sinus arrhythmia, atrial fibrillation and ST-segment
elevation during the ictal or postictal period [42]. Ictal
bradycardia was also reported in patients with partial sei-
zures originating from frontotemporal regions [43]. In res-
pect to current literature, some evidence supports the role of
cerebral lateralization in the manifestations of cardiovascular
autonomic system in epilepsy patients.
6. Other neurological disorders, sudden death and brain
lateralization
Several ECG changes and arrhythmias were detected in
patients with head injury, multiple sclerosis, brain tumors,
meningitis and encephalitis, migraine, cluster headache and
neurosurgical procedures [16,17]. Several studies showed
lateralization of autonomic function in patients with mi-
graine and cluster headaches [44,45]. Pain on the right side
resulted in more reduction in heart-rate variability compared
to left in patients with cluster headaches [44]. Given the
asymmetrical clinical and pathological involvement in neu-
rological degenerative diseases including Idiopathic Parkin-
son`s Disease and Alzheimer`s Disease, the lateralization of
the cardiovascular autonomic functions may be expected in
patients with these diseases. More studies with larger number
of patients with neurological diseases are needed to inves-
tigate the role of brain lateralization on cardiovascular auto-
nomic regulation.
7. Clinical implications and future direction
Awareness of a `neurogenic heart syndrome` and re-
cognition of right hemispheric involvement especially the
insular cortex is important. Early cardiac monitoring of these
patients may change the prognosis.
Combining clinical risk stratifiers (eg concomitant
cardiac disease for stroke, young age for epilepsy) with
noninvasive markers including increased QTc, the presence
of LBBB, T-wave alternans, a variety of HRV, baroreceptor
sensitivity and 2-dimensional echocardiogram may guide as
to identify the patients at risk for neurogenic life-threatening
arrhythmias and its lethal consequence sudden death.
We need pilot and randomized controlled trials to evaluate
the effectiveness of interventions including β-blockers, ACE
inhibitors to increase baroreceptor activity, prophylactic anti-
arrhythmic agents, inserting cardiac pacemaker or autonomic
defibrillator in the treatment and prevention of neurogenic
cardiovascular disturbances and sudden death in high risk
patients.
The identification of major stress, depression, anxiety and
other psychosocial risk factors and implementing behavioral
interventions in high-risk individuals for `neurogenic heart
syndrome` and cardiovascular disease may reduce the mor-
tality rate.
Left-handers may have a lower risk of sudden death,
explained with different organization of cardiovascular auto-
nomic networks in the brain compared to right-handers [31].
More work needs to delineate the relationship of handedness
with cardiovascular autonomic system and its role in sudden
death. Greater understanding of the role the brain in sudden
death could open new areas for treatment and prevention.
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