Neurocardiogenic Syncope and Related Disorders of Orthostatic Intolerance

Article (PDF Available)inCirculation 111(22):2997-3006 · July 2005with73 Reads
DOI: 10.1161/CIRCULATIONAHA.104.482018 · Source: PubMed
The ANS is both complex and diverse and is involved in essentially every organ system and in the majority of disease processes. Disruptions in this system can be incredibly diverse in presentation, yet often culminate in a failure to maintain normotension, with resultant near syncope and syncope. A working knowledge of these disorders is required for both their recognition and their management. Further investigations will aid in our understanding of this wide range of disorders and at the same time identify better diagnostic and therapeutic modalities.
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DOI: 10.1161/CIRCULATIONAHA.104.482018
2005;111;2997-3006 Circulation
Blair P. Grubb
Neurocardiogenic Syncope and Related Disorders of Orthostatic Intolerance
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Neurocardiogenic Syncope and Related Disorders of
Orthostatic Intolerance
Blair P. Grubb, MD
“We shall not cease from exploration
and the end of all our exploring
will be to arrive where we started
and know the place for the first time”
—T.S. Eliot, Four Quartets
yncope, defined as transient loss of consciousness and
postural tone with spontaneous recovery, has both chal-
lenged and perplexed physicians since the dawn of recorded
time. The earliest written accounts come from Hippocrates,
and the word syncope itself is derived from an old Greek term
meaning “to cut short” or “interrupt.” Recurrent episodes of
syncope may result from a large number of different disor-
ders, all of which cause a transitory reduction in cerebral
blood flow sufficient to disturb the normal functions of the
brain. Over the last 2 decades, considerable attention has been
given to types of syncope that occur due to a centrally
mediated (or “reflex”) fall in systemic blood pressure, a
condition that has been referred to as vasovagal (and later
neurocardiogenic) syncope. However, research into the na-
ture of this disorder revealed that it is but one aspect of a
broad and varied group of disturbances in the normal func-
tioning of the autonomic nervous system (ANS), each of
which may result in orthostatic intolerance, hypotension, and
ultimately syncope. Continued investigations into the nature
of these similar yet different disorders has led to the devel-
opment of a system of classification that attempts to more
accurately reflect our understanding of these conditions and
their interrelationships.
The present system of classification has proven both
functional and clinically relevant and includes a group of
disorders that most investigators have thought to be princi-
pally autonomic in nature. Because both the cardiologist and
the cardiac electrophysiologist frequently are expected to
both diagnose and treat these conditions, the following review
is designed to provide a basic framework for understanding
their causes, clinical presentations, diagnosis, and
Autonomic Nervous System
To survive in the world, all animals must possess the ability
to make moment by moment alterations that permit their
internal environment to remain stable despite dramatic
changes in their external environment. This includes not only
changes in ambient temperature, humidity, and barometric
pressure but also the ability to react quickly to the presence of
perceived danger. The principal neural mechanisms by which
this “homeostasis” is maintained and regulated are governed
by the hypothalamus via its 2 effector systems, which include
the ANS and the endocrine system.
Although the adoption of upright posture represents one of
the defining moments in human development, it nonetheless
provided a unique challenge to a blood pressure control
system that had principally evolved to meet the needs of
animals who spent the majority of their time in a dorsal
1– 4
The ANS provides the principal means for both
the short- and long-term responses to changes in position (the
renin-angiotensin-aldosterone system also plays a role but
over a longer time frame).
In the normal person, approxi-
mately 25% to 30% of blood volume is located in the thorax
when they are supine. On standing, there is a gravity-
mediated downward displacement of roughly 300 to 800 mL
of blood to the vasculature of the abdomen and lower
This represents a volume drop of between 25%
and 30%, half of which occurs within the first few minutes of
standing. This sudden redistribution of blood results in a fall
in venous return to the heart. Because the heart can only
pump the blood that it receives, this causes a fall in stroke
volume of 40% and a decline in arterial pressure. The
reference point around which these changes occur is called
the venous hydrostatic indifference point (HIP) and is defined
as the site in the vascular system where pressure is indepen-
dent of posture (the venous HIP is around the diaphragm, the
arterial HIP is near the level of the left ventricle).
with the arterial HIP, the venous HIP is dynamic in nature and
is influenced by factors such as the degree of vascular
compliance, intravascular volume, and muscular activity.
While standing, contractions of the leg muscles (in conjunc-
tion with the venous valve system) actively pump blood back
to the heart and move the venous HIP closer to the level of the
right atrium.
In addition, standing produces a substantial increase in the
transmural capillary pressure present in the dependent areas
of the body, which causes a rise in fluid filtration into tissue
spaces. This process reaches a steady state after 30 minutes
Received September 14, 2004; revision received January 31, 2005; accepted March 9, 2005.
From the Cardiology Department of Medicine, the Medical University of Ohio, Toledo, Ohio.
Correspondence to Blair P. Grubb, MD, Cardiology, Medical University of Ohio, 3000 Arlington Ave, Toledo, OH 43614. E-mail
(Circulation. 2005;111:2997-3006.)
© 2005 American Heart Association, Inc.
Circulation is available at DOI: 10.1161/CIRCULATIONAHA.104.482018
Contemporary Reviews in Cardiovascular Medicine
of upright posture and can produce a decline in plasma
volume of up to 10%.
Successful maintenance of upright posture (and cerebral
perfusion) requires the interplay of several cardiovascular
regulatory systems. Orthostatic stabilization occurs within 1
minute. The exact response to postural change differs with
standing (an active process) compared with responses seen
during head-up tilt (a more passive process). Wieling and van
have described 3 phases of orthostatic response.
These consist of (1) the initial response (during the first 30
seconds), (2) the early steady state alteration (at 1 to 2
minutes), and finally (3) the prolonged orthostatic period
(after at least 5 minutes upright).
Immediately after head-up tilt, cardiac stroke volume
remains normal despite the decline in venous return (believed
to occur due to blood left in the pulmonary circulation). This
is followed by a gradual fall in both arterial pressure and
cardiac filling. This causes activation of 2 different groups of
pressure receptors consisting of the high-pressure receptors of
the carotid sinus and aortic arch and the low-pressure recep-
tors of the heart and lungs.
Within the heart, there are
mechanoreceptors linked by unmyelinated vagal afferents in
all 4 cardiac chambers. These mechanoreceptors produce a
tonic inhibitory effect on the cardiovascular control centers of
the medulla, in particular on the nucleus tractus solitarii. The
baroreceptive neurons of the nucleus tractus solitarii directly
activate cardiovagal neurons of the nucleus ambiguous and
dorsal vagal nucleus while inhibiting the sympathoexcitatory
neurons of the rostral ventrolateral medulla.
The reduced venous return and fall in filling pressure that
occur during upright posture reduce the stretch on these
receptors. As their firing rates decrease, there is a change in
medullary input, which triggers an increase in sympathetic
outflow. This causes a constriction not only of the systemic
resistance vessels but of the splanchnic capacitance vessels as
well. In addition, there is a focal axon reflex (the venoarter-
iolar axon reflex) that can constrict flow to the skin, muscle,
and adipose tissue. This may contribute up to 50% of the
increase in limb vascular resistance seen during upright
During head-up tilt, there is also activation of the high-
pressure receptors in the carotid sinus. The carotid sinus
contains a group of baroreceptors and nerve endings located
in the enlarged area of the internal carotid artery, just after its
origin from the common carotid artery. Here, the mechano-
receptors are located in the adventitia of the arterial wall.
The afferent impulses generated by stretch on the arterial wall
are then transmitted via the sensory fibers of the carotid sinus
nerve that travels with the glossopharyngeal nerve. These
afferent pathways terminate in the nucleus tractus solitarii in
the medulla, near the dorsal and ambiguous nuclei.
initial increase in heart rate seen during tilt is thought to be
modulated by a decline in carotid artery pressure. The slow
rise in diastolic pressure seen during upright tilt is believed to
be more closely related to a progressive increase in peripheral
vascular resistance.
The circulatory changes seen during standing are some-
what different from those seen during tilt. Standing is a much
more active process that is accompanied by contractions of
muscles of both the leg and abdomen, which produces a
compression of both capacitance and resistance vessels and
results in an elevation in peripheral vascular resistance. This
increase is sufficient to cause a transient increase in both right
atrial pressure and cardiac output, which in turn causes an
activation of the low-pressure receptors of the heart. This
provokes an increase in neural traffic to the brain, with a
subsequent decrease in peripheral vascular resistance, which
can fall as much as 40%.
This can allow a fall in mean
arterial pressure of up to 20 mm Hg that can last for up to 6
to 8 seconds. The decline in pressure is then compensated for
by the same mechanisms as during head-up tilt.
The early steady state adjustments to upright posture
consist of an increase in heart ate of 10 to 15 bpm, an
increase of 10 mm Hg, and little or no change in systolic
blood pressure.
At this point, compared with supine posture,
the blood volume of the thorax has fallen by 30%, cardiac
output has increased by 30%, and heart rate is 10 to 15 bpm
Continued upright posture also activates a series of neuro-
hormonal changes, the exact extent of which depend on the
patient’s volume status. The greater the volume depletion, the
greater the degree of activation of the renin-angiotensin-al-
dosterone system (and vasopressin). However, one of the
most important aspects of the body’s ability to compensate
for continued orthostatic stress is the influence of arterial
baroreceptors (particularly the carotid sinus) on peripheral
vascular resistance. At any given moment, 5% of the
body’s blood is in the capillaries, 8% is in the heart, 12% is
in the pulmonary vasculature, 15% is in the arterial system,
and 60% is in the venous system.
The inability of any one of
these mechanisms to operate adequately (or in a coordinated
manner) may result in a failure of the body to compensate to
either an initial or prolonged orthostatic challenge. This, in
turn, would result in systemic hypotension, which, if suffi-
ciently profound, could lead to cerebral hypoperfusion and
subsequent loss of consciousness.
Conditions That Occur as a Result of Disturbances
in Orthostatic Control
A growing number of autonomic disturbances of orthostatic
regulation have been identified. Although in many ways
similar, each has features that make it unique. In attempting
to classify them into a useful system, one should remember
that when we look at nature, in many ways we see what we
wish to see that fits what we know about it at that moment.
Conditions such as supraventricular tachycardia and long-QT
syndrome were each first thought to be a single entity but
with time were found to be composed of a variety of
subgroups. To attempt to make sense of the apparent chaos of
nature, we try to organize and classify it into a coherent
framework and system that fits with both our knowledge and
our expectations.
Thus, any system of classification is in
many ways arbitrary, subject to debate, and in a constant
process of revision and refinement. The system presented in
the Figure follows that developed by the American Auto-
nomic Society and attempts to represent our current under-
standing of these disorders in a clinically useful framework.
In some ways, all autonomic disturbances can be thought of
2998 Circulation June 7, 2005