Vasovagal syncope is a common and
potentially dangerous clinical problem that can
be provoked by passive head-up tilt. Although
previous investigations have focussed primarily
on cardiac and vascular responses preceding
vasovagal syncope, changes in breathing patterns
may also occur before fainting. Subjects have
been observed to
yawn, sigh,
or hyperventilate before syncope, suggesting
that alterations in respiration may accompany
sudden changes in autonomic control of the heart
and vasculature. In a previous study, we
demonstrated vasomotor instability preceding
syncope and showed that it is probably not
related to respiration. However, to our
knowledge, the relation between respiration and
cardiovagal activity in neurally mediated
syncope has not been previously
investigated.
Frequency domain (Fourier) analysis of
cardiac interbeat interval (R-R) variability has
been widely used to assess autonomic control of
cardiovascular function," Highfrequency
variability in the range of 0.15 to 0.45 Hz
results almost exclusively from
respiration-related vagal modulation of heart
rate, and its amplitude has been used as an
index of vagal tone. Low frequency variability
between 0.04 and 0.15 Hz probably reflects the
effects of both respiration and
bamreflex-mediated sympathetic outflow on the
heart. Fourier analysis of R-R interval
variability is appealing for the assessment of
autonomic mechanisms underlying syncope;
however, its interpretation is confounded by
alterations in respiratory frequency and
amplitude that may precede the development of
symptoms. Furthermore, this technique cannot be
used to assess sudden, time-dependent changes in
the amplitude of a particular frequency.
Recently, the technique of complex demodulation
has been developed to provide a continuous
assessment of the amplitude of cardiovascular
variabilities and thereby identify changing
autonomic responses to cardiovascular events. We
used this method to investigate alterations in
cardiac interbeat interval and respiratory
dynamics preceding vasovagal syncope and their
relation to each other. Since vasovagal syncope
is thought to be due to a sudden increase in
vagal outflow from the central nervous system,
we hypothesized that there would be a marked
increase in high frequency R-R interval
variability
Discussion
Principal Findings
The principal results of this study are as
follows: (1) Healthy subjects with tilt-induced
vasovagal syncope experience increases in
respiratory amplitude beginning 3 minutes before
systolic BP reaches 80 mm Hg and syncope is
imminent. The increase in respiratory amplitude
begins at the time that blood pressure begins to
fall. Because respiratory frequency remains
unchanged during this time period, the subjects
are probably hyperventilating. (2) At
approximately 90 seconds before syncope there is
a sudden prolongation of R-R interval and
increase in high and low frequency R-R interval
amplitude that indicates an abrupt enhancement
of vagal tone. (3) The increase in respiratory
amplitude between 180 and 90 seconds before
syncope is not accompanied by changes in
R-R interval or R-R interval variability,
suggesting there is dissociation between
respiration and the vagaily-mediated
"respiratory sinus arrhythmia." This finding is
reinforced by the coherence analysis, which
showed fewer syncope subjects with coherence
between respiratory and R-R interval
variabilities before the end of tilt and lower
transfer magnitudes in syncope subjects compared
with control subjects during this time
period.
Although BP fell during the last 3 minutes
before syncope, there was no significant change
in low or high frequency BP amplitude during
this time period. This may be due to the
counterbalancing effect of large respiratory
amplitudes on BP, thus masking the decline in
low frequency BP fluctuations (Mayer waves) that
would otherwise be expected to occur as
sympathetic activity is withdrawn from the
vasculature.
Several previous studies have used time and
frequency domain analyses of heart rate
variability to determine whether subjects who
are prone to vasovagal syncope have an increase
in baseline vagal tone. The results of these
studies are conflicting; some show increases in
heart rate variability, whereas others show no
difference" or in syncopal subjects compared
with control subjects. The advantage of complex
demodulation over previous methods is that it
permits the continuous assessment of changes in
autonomic control of cardiovascular function
during dynamic conditions that precipitate
syncope. Our results indicate that baseline
cardiovagal tone is not different between
syncopal and nonsyncopal subjects but that vagal
tone suddenly increases just before the
fainting. Thus vasovagal syncope may not be due
to an underlying state of hypervagotonia but to
the sudden onset of a vagal reflex precipitated
by preload reduction and possibly
hyperventilation.
Potential Mechanisms and Effects of
Hyperpnea Before Syncope
Although hyperpnea has been observed in
individual patients before syncope,' and is
popularly known to produce syncope not been
widely recognized as a typical physiological
response preceding a vasovagal faint. Hyperpnea
may be a primary or secondary event. It may
result from autonomic outflow to the lungs from
brain centers that are stimulated at the onset
of vasovagal syncope. Or, it may be a secondary
response to the vasodilatation and hypotension
that also precedes syncope. Hyperpnea can
generate large negative intrathoracic pressures
that may act as a "respiratory pump" to enhance
venous return. This may account for the large
respiratory and BP fluctuations seen in the
syncope patient shown in Figure 2. The
respiratory pump might prevent syncope unless
such large pressures are generated that
intrathoracic veins actually collapse." Although
large intrathoracic pressures might explain the
sudden cardiovascular collapse that occurred
when respiratory amplitude reached its peak, it
is unlikely that sufficiently large pressures
were generated to produce syncope.
Alternatively, a respiratory alkalosis
associated with hyperventilation may cause
cerebral vasoconstriction. The consequent
reduction in cerebral blood flow could
predispose to the development of syncope.
Unfortunately, we were unable to measure pH,
PCO2, or cerebral blood flow during the
study.
Potential Mechanism of Dissociation
Between Respiration and R-R Interval
Variability
Respiration is usually closely coupled to
heart rate, producing the respiratory sinus
arrhythmia (RSA). However, our data suggest that
respiratory and cardiac interval oscillations
can also occur independently. During conditions
when vagal tone remains constant, increases in
tidal volume have been shown to increase the
amplitude of the RSA. Our results during the 5
minutes before the time of syncope show that
respiratory amplitude increases for at least 1.5
minutes before there is any change in R-R
interval variability. Furthermore, during this
increase in respiratory amplitude the transfer
magnitude between respiration and R-R interval
is low. When vagal tone later increases, as is
evident by an increase in R-R interval just
before syncope, the amplitude of RSA also
increases, along with further increases in
respiratory amplitude. It is not clear whether
respiration becomes coupled with cardiovagal
activity at this point or whether these two
systems continue to operate relatively
independently.
There are several possible explanations for
the dissociation between respiration and R-R
interval variability. First, high sympathetic
tone during tilt may suppress RSA until
sympathetic withdrawal before syncope allows RSA
to increase. This hypothesis is supported by the
finding in rats that noradrenaline stimulation
of aqueductal gray matter inhibits vagal-induced
bradycardia. Furthermore, in humans, heightened
(3-adrenergic activity during exercise reduces
RSA, whereas (3-blockade may enhance it.
A second possible explanation for the
dissociation between respiratory and R-R
interval variability before syncope is that
hyperventilation may suppress RSA.
Hyperventilation abolishes the bradycardia
induced by electrical stimulation of the carotid
sinus nerve in dogs." By augmenting central
inspiratory drive and increasing the activity of
pulmonary stretch receptors, hyperventilation
reduces the excitability of cardiac vagal
motoneurons. The decoupling of respiration and
RSA during hyperventilation may permit
respiratory pumping without inspiratory cardiac
slowing, thereby partially counteracting preload
reduction during head-up tilt.
Third, it is possible that the increase in
respiratory tidal volume did not produce a
detectable change in RSA until it reached a
critical threshold. Eckbere has shown that a 50%
increase in tidal volume increases the average
R-R interval amplitude by only 15%. Data from
Hirsh and Bishop suggest that changes of <1 L
in tidal volume at respiratory frequencies
>0.15 Hz have relatively little effect on RSA
(<5 bpm). Therefore we may not be able to
detect changes in RSA until tidal volume
increases substantially.
Finally, it is possible that during
baroreflex suppression of vagal outflow in
response to head-up tilt, respiratory gating has
a minimal effect on cardiac vagal motoneuron
activity. Saut et al showed that the transfer
magnitude of respiration to heart rate is lower
during upright posture compared with supine
posture. Therefore respiratory and cardiac
interval oscillations could be relatively
independent of one another until vagal tone
increases before syncope. This possibility
requires further study.
Limitations
There are several limitations to this study.
First, we were unable to measure sympathetic
nervous system activity directly and therefore
do not know whether high sympathetic tone
suppressed the respiratory sinus arrhythmia or
whether a sudden reduction in sympathetic tone
preceded syncope. Also, because we did not
measure arterial PCO2 and pH, we cannot confirm
the presence of hyperventilation or whether
hyperventilation produced a respiratory
alkalosis and associated hemodynamic collapse.
Although the primary study variables
(respiration, R-R interval, and BP) were the
same for both groups until 3.5 minutes before
the end of tilt, the absence of other
hemodynamic measurements makes it difficult to
know for sure whether the two study groups
experienced the same orthostatic stress. Because
the resolution of complex demodulation is
approximately 30 seconds, we cannot ascertain
the exact timing of autonomic changes before
syncope. Nevertheless, complex demodulation
enabled us to identify distinct changes in
respiratory and cardiac interval dynamics before
syncope that previous studies have been unable
to address. Finally, we studied healthy subjects
with no recent history of spontaneous syncope.
Therefore our findings may not be generalizable
to patients who are seen by physicians for the
evaluation of spontaneous syncope.
In otherwise healthy subjects, tilt-induced
vasovagal syncope appears to be preceded by a
period of hyperpnea that is followed by an
abrupt increase in cardiovagal tone. Whether
prevention of the hyperpneic response will
prevent the development of syncope requires
further investigation.
