Endogenous Circadian Rhythm in Vasovagal Response to Head-Up TiltClinical Perspective
Background—The incidence of syncope exhibits a daily pattern with more occurrences in the morning, possibly as a result of influences from the endogenous circadian system and/or the daily pattern of behavioral/emotional stimuli. This study tested the hypothesis that the circadian system modulates cardiovascular responses to postural stress, leading to increased susceptibility to syncope at specific times of day.
Methods and Results—Twelve subjects underwent a 13-day in-laboratory protocol in which subjects' sleep-wake cycles were adjusted to 20 hours for 12 cycles. A 15-minute tilt-table test (60° head-up) was performed ≈4.5 hours after scheduled awakening in each cycle so that 12 tests in each subject were distributed evenly across the circadian cycle. Of 144 tests, signs/symptoms of presyncope were observed in 21 tests in 6 subjects. These presyncope events displayed a clear circadian rhythm (P=0.028) with almost all cases (17/21) occurring in the half of the circadian cycle corresponding to the biological night (10:30 pm to 10:30 am). Significant circadian rhythms were also observed in hemodynamic and autonomic function markers (blood pressure, heart rate, epinephrine, norepinephrine, and indices of cardiac vagal tone) that may underlie the circadian rhythm of presyncope susceptibility.
Conclusions—The circadian system affects cardiovascular responses to postural stress, resulting in greater susceptibility to presyncope during the night. This finding suggests that night-shift workers and people with disrupted sleep at night may have greater risk of syncope as a result of their exposure to postural stress during the biological night.
Syncope is a sudden and transient loss of consciousness caused by transient global cerebral hypoperfusion.1 A common presenting problem in healthcare settings, syncope accounts for ≈1% of emergency room visits.1,2 Syncope may cause major morbidity such as fractures and motor vehicle accidents (≈6% of patients) and minor injuries such as laceration and bruises (≈29% of patients).1 The impacts of syncope on public safety (eg, syncope while driving) have also attracted recent interest.3,4
Clinical Perspective on p 970
The most common type of syncope is vasovagal syncope (VVS), which is associated with hypotension and/or bradycardia and is neurally mediated by vagal excess and sympathetic withdrawal.1,5 VVS accounts for >77% of reported syncope episodes and occurs more frequently in young individuals.2 The incidence of VVS displays a daily pattern with a broad peak in the morning (6 am to noon).6,–,8 The peak conceivably could be caused by the day/night distribution of behavioral stressors that may trigger VVS such as standing up in the morning after an overnight sleep with nocturnal diuresis and redistribution of body fluids.9 Alternatively, the daily pattern of syncope could be influenced by the circadian pacemaker that coordinates/generates endogenous rhythms of ≈24 hours in numerous neurophysiological processes, including cardiac autonomic function,10,11 possibly making the cardiovascular system more vulnerable to stressors at specific circadian times. Hossmann et al12 explored this possibility by examining sympathetic and adrenergic vascular responses of 5 healthy subjects every 3 hours across a 24-hour period. Their study clearly demonstrated 24-hour rhythms in sympathetic responses to tilt with greater responses at 9 am and 9 pm.12 However, the observed rhythms were likely a combined effect of the endogenous circadian cycle and the sleep-wake cycle because these rhythms are usually synchronized and because the subjects were allowed to sleep between 11 pm and 7 am, were awakened only ≈5 minutes before each test so that the influences of sleep or sleep inertia cannot be excluded.13 Therefore, the independent influences of the endogenous circadian system on vasovagal response are still unknown.
An important tool for the diagnosis of the VVS susceptibility is the head-up tilt-table test.1 By introducing orthostatic stress, the tilt-table test is widely used to reproduce syncope in patients susceptible to hypotension and bradycardia.1 Autonomic cardiovascular regulation plays a major role in the pathogenesis of VVS.14 We hypothesize that the endogenous circadian system contributes to the daily pattern of vasovagal episodes via influences on the autonomic control, resulting in different physiological responses to the same postural stressor at different circadian times. To test this hypothesis, we examined symptomatic, hemodynamic, and autonomic responses to tilt-table testing at different circadian times (see Methods).
We studied 12 healthy subjects (aged 20 to 42 years, 6 women) who had no history of medical disorders, syncopal attacks, orthostatic hypotension (OH), or impaired autonomic function (see further details in the Methods section in the online-only Data Supplement). Subjects were recruited through advertisements for healthy volunteers in local New England newspapers. To ensure regular oscillations of the circadian pacemaker, we excluded subjects who reported shift work within the prior 3 years or crossing >1 time zone within the prior 3 months. Additionally, subjects maintained regular sleep-wake cycles with 8-hour sleep opportunities per night for 2 to 3 weeks before undergoing a 13-day in-laboratory protocol. Subjects were free of drugs (including caffeine, alcohol, and nicotine) before and throughout the study. The study was approved by the local Institutional Review Board. Subjects provided informed consent before participation.
To assess endogenous circadian influences on vasovagal responses, we used a “forced desynchrony” protocol with each subject living in a private and constant-temperature laboratory room free of time cues (Figure 1). After 2 baseline days (the same sleep-wake schedule as the preceding 2 to 3 weeks at home), subjects underwent twelve 20-hour sleep-wake cycles (forced desynchrony phase) with 6 hours 40 minutes of scheduled sleep each cycle. This protocol during the forced desynchrony phase was performed in dim light (≈0 lux during scheduled sleep and ≈1.8 lux during wakefulness) to avoid circadian-phase resetting effects of light. Thus, the circadian pacemaker oscillates at its inherent rate (≈24 hours), decoupled from the 20-hour sleep-wake cycles. The same behaviors, including tilt-table testing and mild steady-state cycle exercise, were repeated in each sleep-wake cycle so that all behaviors became uniformly distributed across the circadian cycle by the end of the protocol. The responses to exercise across the circadian cycle in these subjects have been published elsewhere.15
A 15-minute passive head-up tilt test was performed at ≈4.5 hours after scheduled waking for each sleep-wake cycle. Before the test, subjects remained in bed in the semirecumbent position (45° upper body) for ≈4 hours, during which time the subjects ate breakfast (≈3 hours before tilt), rested, and completed computerized questionnaires/tests. Thereafter, subjects were gently slid from the bed to the adjacent tilt table and remained relaxed in the horizontal and supine position throughout a 25-minute baseline period. Then, subjects were tilted to 60° from the horizontal position (head-up with foot plate support) with a motorized tilting mechanism (model T7605, Metron Medical Australia Pty Ltd, Carrum Downs, Victoria, Australia) and maintained this posture for up to 15 minutes. Note that there was a tilt test during the baseline day so that subjects were partially habituated before the forced desynchrony phase.
The safety procedures involved monitoring: (1) systolic blood pressure (SBP) via an oscillometric arm cuff sphygmomanometer (Dinamap, Critikon Inc, Tampa, FL) at least every 3 minutes during the tilt phase, (2) beat-to-beat SBP changes from finger plethysmography (Portapres, TNO-Biomedical, Amsterdam, Netherlands), (3) ECG for heart rate (HR) and arrhythmias, and (4) symptoms (see Data Acquisition). Tests were aborted whenever any of the following signs and/or symptoms appeared (criteria for presyncope): (1) sustained low SBP of <80 mm Hg (detected via sphygmomanometer) or 15 mm Hg below baseline (excluding cases with stable SBP >100 mm Hg); (2) precipitous SBP decrease of >15 mm Hg in <60 seconds (detected via finger plethysmography), leading to low SBP <80 mm Hg or 15 mm Hg below baseline; (3) HR decrease >20 bpm from baseline (bradycardia) or asystole for ≥5 seconds (no such case occurred); or (4) other symptoms of imminent syncope, including feeling faint, feeling nauseous, experiencing tunnel vision/blacking out, and being unresponsive to questions, or the subject's request to be tilted down because of these symptoms.
In case of presyncope, the table was rapidly lowered to the horizontal position and the subject was maintained in the supine posture. If vital signs did not normalize immediately or symptoms did not disappear within 30 minutes after tilting down, medical assistance would be called (no such case occurred).
Blood pressure (BP) was continuously measured with finger plethysmography. This device cannot accurately estimate absolute levels of brachial artery pressure, and a cross-reference was made to a more accurate automatic oscillometric cuff sphygmomanometer every 5 minutes during baseline and at least every 3 minutes during tilt.
ECG waveforms were continuously recorded at 256 Hz with an ambulatory recording device (Vitaport, Temec Instruments, Kerkrade, the Netherlands) to assess autonomic nervous system activity.
Core body temperature was sampled every minute throughout with a rectal temperature sensor (Yellow Springs Instrument Company, Yellow Springs, OH) to provide a marker of the circadian phase.
Blood was sampled via an indwelling catheter in a forearm vein that was in place throughout the entire study. Only 5 cm3 blood was drawn each time. Epinephrine and norepinephrine were measured, from blood samples collected after ≈10 minutes of baseline and after 5 to 10 minutes of tilt in each test, with chemiluminescent assays (sensitivity=1 pg/mL and 40 pg/mL for epinephrine and norepinephrine, respectively) as markers of sympathetic activity.
The degrees of nausea, “feeling hot,” and general discomfort were rated separately by subjects at least every 3 minutes during tilt using an 11-point rating scale with 0 indicating no symptoms and 10 indicating extreme symptoms. In each test, the maximum scores were used as indices of the subjective tilt response.
To assess tilt responses, cardiovascular variables during baseline and the stable tilt conditions were compared. Data during the first minute after tilting up and the last minute before tilting down were excluded to avoid influences from the postural transitions.
Circadian Phase Estimation
The endogenous circadian cycle affects core body temperature with a period of ≈24 hours and thus can be estimated by nonlinear regression of individual core body temperature recordings (Figure I in the online-only Data Supplement).16 Using the obtained circadian period of each subject (mean, 24.09 hours; range, 23.8 to 24.6 hours) and assigning phase 0° to the time of each subject's minimum core body temperature (mean, ≈4:30 am), all data were assigned the respective circadian phases (0° to 360°; Figure II in the online-only Data Supplement).
HR Variability Analysis
To assess autonomic nervous system activity, the time-domain HR variability analysis was performed. R waves in the ECG were identified with a QRS wave detector based on amplitude and the first derivative of the ECG waveform17 and were visually scanned by a trained technician to ensure that only normal R waves were included. Mean and SD of normal-to-normal (SDNN) beat intervals were calculated, along with the following indices of cardiac parasympathetic tone: square root of the mean of squares of differences between adjacent normal-to-normal intervals (RMSSD), and percentage of differences between adjacent normal-to-normal intervals that are >50 ms (pNN50). The frequency-domain HR variability analysis was also performed (Methods and Figures III and IV in the online-only Data Supplement).
With the use of Beatscope Software (version 1.1, Finapres Medical Systems, Amsterdam, the Netherlands), beat-to-beat SBP, diastolic BP (DBP), HR, stroke volume (SV), cardiac output (CO), ejection time, and total peripheral resistance (TPR) were derived from BP waveforms (finger plethysmography). The low-frequency power of SBP was obtained as an additional index of sympathetic activity changes (Materials and Figures V and VI in the online-only Data Supplement).
All tilt tests for a subject were treated as repeated measures without causal relationship among adjacent tests with the assumption that 20 hours is sufficient for full recovery should presyncope have occurred in a prior test. Four types of statistical analyses were performed. First, to address the primary goal of assessing the circadian distribution of presyncope events, a generalized linear mixed model was used with presyncope as the response (present or absent), circadian bin as a fixed effect (divided into six 60° bins), and subject as a random factor for intercept (Table I in the online-only Data Supplement). In this primary analysis, test outcomes of all subjects (144 tests) were included. Next, in a secondary analysis, subjects were divided into 2 groups: those with presyncope (presyncopal group) and those who did not experience presyncope (nonpresyncopal group). To assess the effects of tilt, group, and their interactions on continuous physiological variables, mixed-model ANOVAs were performed with subject as a random effect for intercept (Table II in the online-only Data Supplement). Third, similar mixed models were applied to assess different tilt responses between trials with and without presyncope within the presyncopal group (72 tests; Table III in the online-only Data Supplement). Finally, cosinor analyses18 using mixed models were applied to test the effects on physiological variables of circadian phase and its interactions with tilt (see Methods and Table IV in the online-only Data Supplement). Actual circadian phases of data (instead of 60° bins) were used in the cosinor analyses.
Presyncope During Tilt-Table Testing
Twenty-one cases of presyncope occurred in 6 subjects. In all 21 cases, signs/symptoms of presyncope disappeared almost instantaneously after tilting down, and BP and subjective symptoms normalized within 3 minutes after tilting down. No cases of fully developed syncope occurred, presumably because the tests were aborted when clear signs/symptoms of presyncope appeared. Figure 2 shows a typical presyncope event that is clearly a vasovagal event, indicated by a delayed and precipitous decrease in SBP occurring after ≈12 minutes of tilt, along with bradycardia at the end of the test. In other presyncope events, the phase of reflex bradycardia and/or vasodepressor effects accompanying VVS were not always as pronounced because we aborted the tests early to avoid syncope and to reduce the burden on the volunteers during this prolonged and intensive study. In addition to the SBP decrease, significant falls in SV and CO, without a fall in TPR, were observed just before presyncope occurred (Figure XII in the online-only Data Supplement).
Endogenous Circadian Rhythm in Presyncope Events
The 21 presyncope events did not occur randomly across the circadian cycle but displayed a significant circadian rhythm (generalized linear mixed model, P=0.028; Figure 3B) with a peak at the circadian phase bin centered around 0° (corresponding to ≈4:30 am). Figure 3A shows an example subject with tilt tests aborted consistently during the biological night, and Figure 3B shows the group average probability of presyncope occurrence at different circadian phases. From the model output, the mean probability across the biological night and early morning (270° to 90°; corresponding to 10:30 pm to 10:30 am) is ≈16.8%, ≈9 times the probability from the other half of the circadian cycle (Figure 3B). There was no training effect on presyncope occurrences throughout the protocol (11 presyncope events in the first 6 cycles and 10 in the last 6 cycles). The distribution of presyncope events at different cycles confirmed a strong circadian influence indicated by 2 peaks located at cycles 3 and 9 when tilt tests were performed during the biological night (Figure VII in the online-only Data Supplement).
Classification of Presyncope Events
The presyncope events could be divided into 2 categories. In the first category, 17 cases were associated with a precipitous SBP drop (detected with finger plethysmography) leading to 15 mm Hg below baseline (detected with sphygmomanometry; 4 cases), SBP <80 mm Hg alone (1 case), or both (12 cases). Sphygmomanometric SBP within 2 minutes before tilting down was 81.1±5.1 (mean±SE) mm Hg in these 17 trials (baseline SBP, 99.8±3.2 mm Hg). Twelve of these 17 cases (including the one with only SBP <80 mm Hg) were also associated with symptoms of imminent syncope (criterion 4). In the second category, 4 cases were associated with only symptoms of imminent syncope without hypotension, ie, SBP of 89.0±4.6 mm Hg when being tilted down (baseline SBP, 97.4±2.1 mm Hg). No presyncope cases were based on a sustained low SBP (15 mm Hg below baseline and <100 mm Hg) (criterion 1). No cases of serious arrhythmias or asystole occurred.
Both VVS and syncope resulting from OH can be triggered by orthostatic stress, and their manifestations often overlap.1 We classified all 21 presyncope events as vasovagal presyncope rather than OH for the following reasons. First, from a pathophysiological point of view, the difference between VVS and OH is that OH is due to autonomic function failure1,19 and VVS is due to intermittently inappropriate cardiovascular reflexes in response to a trigger. Here, all subjects were healthy adults without a history of OH or impaired autonomic function. Thus, OH was not expected in this group. Second, all presyncope events occurred after >4 minutes of tilt (mean±SE, 10.7±0.6 minutes; Figure VIII in the online-only Data Supplement). This is different from classic OH-induced syncope/presyncope that occurs within 3 minutes of standing or tilt.1 Third, delayed OH can cause syncope/presyncope after 3 minutes of tilt. However, delayed OH is characterized by progressive decreases of SBP and TPR after tilt-up,20 whereas none of 21 cases in the current study fit such a description of delayed OH.
Cardiovascular Responses to Head-Up Tilt
To determine whether there were any underlying physiological differences that could explain the sporadic occurrence of presyncope, comparisons were performed between nonpresyncopal and presyncopal subjects and between the 21 presyncope trials and the 51 trials without presyncope in presyncopal subjects. The following results reflect only the responses during the stable tilt period.
General Effects of Head-Up Tilt
In responses to tilt, subjects showed decreased SBP, increased DBP, increased HR, increased sympathetic activity (epinephrine and norepinephrine levels), and decreased vagal tone (SDNN, RMSSD, and pNN50; Figure 4). The tilt effects on autonomic nervous activity were confirmed by the frequency-domain HR variability analysis and the SBP spectral analysis (Figures III and V in the online-only Data Supplement).
Presyncopal subjects had reduced tilt responses in all variables except epinephrine and HR compared with the nonpresyncopal subjects (see the P values for tilt by group in Figure 4). There were no significant differences in group means of all variables except that SBP was lower in the presyncopal group.
Physiological Responses in Presyncope Trials
Within the presyncopal subjects, the SBP drop during the presyncope trials was larger than that during the trials without presyncope (Figure 5A). The tilt-induced increases in DBP and norepinephrine were less in the presyncope trials although the reductions did not reach significance (DBP: mixed-model ANOVA, P=0.05; norepinephrine: P=0.08; Figure 5D and 5E).
There were overall (both conditions) significant circadian rhythms in all reported physiological variables: SBP, HR, epinephrine, and norepinephrine were lowest and cardiac parasympathetic markers (SDNN, pNN50, and RMSSD) were highest during the biological night (285° to 45° or ≈11:30 pm to 7:30 am; Figure 6 and the Table). The circadian influences were smaller than the tilt effects on all variables except SBP, which yielded similarly sized effects.
During the biological night, the tilt-induced epinephrine increase was smaller and the tilt-induced decreases in RMSSD and pNN50 were larger than during the biological day (Figure 6). For instance, the epinephrine increase at 330° (≈15.0 pg/mL) was much smaller than the increase at ≈200° (≈33.1 pg/mL).
Subjective Responses to Head-Up Tilt
A different subjective scoring system was used in the first 2 subjects (1 presyncopal and 1 nonpresyncopal), so those results were excluded from the group analyses of subjective tilt responses. There were no group mean differences between presyncopal and nonpresyncopal subjects in their maximum scores of nausea, feeling hot, and general discomfort (Figure XIII in the online-only Data Supplement). Within the presyncopal subjects, all subjective responses were significantly higher when presyncope occurred: nausea, 0.9±0.5 (mean±SE) without presyncope versus 4.6±0.6 for presyncope trials; feeling hot, 1.6±0.5 versus 4.1±0.6, respectively; general discomfort, 1.1±0.5 versus 4.6±0.6, respectively (mixed-model ANOVA, P<0.0001 for all 3 measures). Significant circadian rhythms were observed in all subjective measures with a trough at ≈130° to 200° (≈1:10 to 5:50 pm) and a peak at ≈340° to 10° (≈3:10 to 5:10 am). These circadian rhythms showed no significant group differences except that nausea displayed a larger circadian variation in the presyncopal group (cosinor analyses, P=0.0017; Figure XIII in the online-only Data Supplement).
We found in healthy subjects that the susceptibility to presyncope due to head-up tilt was much higher during circadian phases corresponding to the biological night (equivalent to ≈10:30 pm to 10:30 am in these subjects). The symptoms of nausea and general discomfort during tilt also became worse across the biological night. These findings provide strong evidence that the circadian system modulates vasovagal responses, yielding different responses to the same stressor at different circadian times. We also found significant circadian rhythms in indices of hemodynamics and autonomic activity such as SBP, DBP, HR, epinephrine, norepinephrine, and HR variability–derived parasympathetic markers that likely underlie the circadian modulation of vasovagal responses.
BP Regulation During Tilt-Table Testing
Arterial BP while upright is maintained predominantly through the regulation of the sympathetic outflow, leading to increased HR, cardiac contractility, and peripheral vasoconstriction. We found that SBP was lower in presyncopal subjects than nonpresyncopal subjects (Figure 4A), suggesting a threshold effect whereby lower baseline SBP is more likely to be associated with presyncope. Moreover, SBP is lower during the biological night, thereby increasing the likelihood of presyncope at that time. A previous study suggested that a steep fall in CO is the main mechanism in the initiation of a vasovagal faint.21 Our study supports such a CO-mediated mechanism for the initiation of hypotension because CO and SV decreased significantly while TPR showed no significant decrease before tilt-down before the occurrences of presyncope (Figure XII in the online-only Data Supplement).
Changes in neurohumoral factors can be important mechanisms underlying development of syncope/presyncope during head-up tilt. As demonstrated in this study, circadian influences on epinephrine and norepinephrine may contribute to the observed circadian rhythm of presyncope, eg, lower epinephrine during the biological night when presyncope occurred more frequently. The mechanistic link between endogenous circadian rhythms of neurohumoral factors and presyncope is yet to be elucidated.
Tilt-Table Test Reproducibility
The head-up tilt-table test is widely used to diagnose VVS.1 However, reproducibility of the test is still a concern. The long-term reproducibility of positive tilt responses (with presyncope/syncope) varies from 62% to 85%,22 and 1-day reproducibility may be as low as 35%.23 The present study likely represents one of the best-controlled tilt-table data sets because all tests were performed at the same time after waking up, with all scheduled events rigorously controlled for all test cycles. We showed that the circadian time when tests are performed is a very important source of variation; eg, the chance of experiencing presyncope at the circadian phase 0° (≈4:30 am) was >20 times larger than that at 180° (≈4:30 pm). Thus, nocturnal tilt tests could potentially be a sensitive method to reveal individuals at higher risks for syncope. The observed presyncope events might be interpreted as “false-positive” responses because these subjects had no history of syncope. However, other studies have suggested that vasovagal susceptibility is probably present in all healthy humans.24 Thus, it is possible that these subjects might be asymptomatic mostly because they have never previously experienced orthostatic stress during nighttime.
Although an endogenous circadian rhythm in presyncope susceptibility is very clear, there are certain limitations regarding the underlying mechanism. First, we studied healthy young subjects without a history of syncope. Although VVS can occur in young and ostensibly healthy people,5 it is important to validate our findings in populations more susceptible to VVS. Second, the underlying mechanism causing presyncope/syncope may be different during passive postural changes (as in this study) compared with standing up actively when the leg muscle contractions help maintain venous return and SBP.25 Third, the 4 presyncope events based on only symptoms of imminent syncope without hypotension might not have developed into syncope. However, the circadian rhythm of presyncope events remains after exclusion of the 4 cases (Figure IX in the online-only Data Supplement). Fourth, it is conceivable that more presyncope/syncope events would have occurred if tilt were extended beyond 15 minutes. However, the peak of presyncope incidence occurred at 11 to 12 minutes of tilt (Figure VIII in the online-only Data Supplement). Thus, the choice of the maximum tilt duration is unlikely to have affected the observed circadian rhythm of presyncope events. Fifth, among our criteria for presyncope, using a relatively arbitrary absolute SBP threshold for aborting the tilt test (criterion 2, SBP <80 mm Hg) could artificially introduce more aborted tests when baseline SBP was lower. However, this is unlikely because only 1 presyncope event was based on this threshold criterion alone, and this 1 case did not occur in the biological night. Additionally, the subjective responses during the stable tilt condition displayed circadian rhythms with greater responses at the circadian time corresponding to the peak of presyncope occurrences. Thus, the circadian rhythm of presyncope distribution is likely to reflect a real effect of the circadian system on VVS susceptibility.
This study provides direct evidence that the circadian pacemaker influences vasovagal responses to head-up tilt, leading to higher susceptibility to presyncope overnight. Such a vulnerable time window may not be a concern for people with normal sleep-wake schedules who would sleep through the vulnerable period without exposure to postural stressors. However, the vulnerable time window may have a greater impact on individuals who have to remain awake or wake up during the nighttime such as shift workers, military personnel, emergency workers, airline pilots, truck drivers, parents of infants, and people with nocturia, insomnia, or other sleep disorders. Such populations may be at a higher risk for syncope, which could have important consequences on personal and public safety.
Although most syncope events occur during the daytime, previous studies also documented VVS during the normal hours of sleep (eg, 10 pm to 7 am) in nonintoxicated adults who wake up feeling faint and may briefly lose consciousness in bed or immediately on standing.26 The occurrence of such nocturnal syncope (called sleep syncope) has been a puzzle. Jardine et al27 hypothesized that sleep syncope may be linked to different cardiovascular responses to afferent stimuli during sleep (eg, the centrally mediated increase in vagal activity during the deeper phases of non–rapid-eye-movement sleep). Our finding of the highest presyncope risk at ≈4:30 am mediated by the circadian system (Figure 3B) suggests that the endogenous circadian system also may be mechanistically involved in the pathophysiology of sleep syncope. The possible underlying mechanisms include the observed circadian-modulated increase in parasympathetic nervous activity, decreased sympathetic nervous system activity, decreased SBP (Figure 6), and decreased CO (Figure XI in the online-only Data Supplement) during the biological night.
Sources of Funding
This research was supported by National Institutes of Health grants R01-HL76409, K24-HL76446, NCRR-GCRC-MO1-RR02635, P30-HL101299, and K99HL102241 and a KL2 Medical Research Investigator Training (MeRIT) grant (5 KL2 RR025757-02) awarded via Harvard Catalyst/The Harvard Clinical and Translational Science Center.
We thank Dr Wei Wang for statistical consultation.
Guest Editor for this article was Julian M. Stewart, MD, PhD.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.110.943019/DC1.
- Received April 21, 2010.
- Accepted January 5, 2011.
- © 2011 American Heart Association, Inc.
The European Society of Cardiology Guidelines for the diagnosis and management of syncope reviewed by Angel Moya, MD, FESC, Chair of the Guideline Taskforce with J. Taylor, MPhil. Eur Heart J. 2009;30:2539–2540.
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Vasovagal syncope, the most common type of syncope, displays a daily pattern with more occurrences during the morning (6 am to noon). This pattern could be caused by the daily distribution of behavioral/emotional stimuli and/or modulation of physiological responses by the endogenous circadian system (“body clock”). The present study provides strong evidence that the circadian system could contribute to the daily pattern of vasovagal syncope via its influences on hemodynamic and autonomic responses to tilt stressor. We found that the vulnerability to presyncope caused by head-up tilt has a strong endogenous circadian rhythm, with susceptibility 9 times greater at the circadian times between 10:30 pm and 10:30 am compared with between 10:30 am and 10:30 pm. This finding highlights the importance of performing tilt-table tests at similar circadian times when comparing responses of different individuals or the same person before and after treatments for syncope. Additionally, a higher sensitivity may be achieved by performing tilt-table testing during early morning hours or the nighttime. The identified vulnerable period may have relevance to individuals who remain awake or wake up frequently during the nighttime such as night-shift workers, parents feeding their infants, and elderly people with increased nocturia and insomnia. These people may be at higher risk for syncope as a result of their exposure to postural stress during the nighttime. Moreover, the morning broad peak of vasovagal syncope observed in the epidemiological studies might be a combined effect of the endogenous circadian system and daily patterns of external behavioral stimuli.