mise à jour du
5 février 2006
1998; 98; 977-983
Complex demodulation of cardiorespiratory
dynamics preceding vasovagal syncope
Lipsitz L, Hayano J, Sakata S, Okada A, Morin R
Harvard Medical School, Boston, USA


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
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.
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.