Sleep syncope is a recently described form of vasovagal syncope that interrupts sleep. The pathophysiology of this condition is uncertain but a ‘central’ non-baroreflex-mediated trigger has been suggested. In the present study, we tested the hypothesis that patients with sleep syncope have abnormal sympatho-vagal responses to non-baroreflex, but normal responses to baroreflex stimuli. We collected historical data from SS patients (patients with vasovagal syncope with sleep syncope; n=16) and NSS patients (patients with vasovagal syncope without sleep syncope; n=35), including demography, and triggers and symptoms during syncope. MBP (mean blood pressure), HR (heart rate) and MSNA (muscle sympathetic nerve activity) in SS patients were compared with NSS patients and matched controls (n=16) during HG (handgrip), CPTs (cold pressor tests), HUT (head-up tilting) and tilt-induced pre-syncope. Patients and controls were of similar age and gender distribution [SS patients, age 46.0±4 years (69% female); NSS patients, 47.3±4 years (63% female); controls, 43.7±5 years (69% female)]. Compared with NSS patients, SS patients reported more fainting episodes: (i) triggered by phobias (75 compared with 37%; P=0.001); (ii) while in the horizontal position (44 compared with 6%; P=0.001); and (iii) associated with abdominal symptoms (69 compared with 9%; P=0.001). Compared with controls, the MBP response to HG was attenuated in SS patients (P=0.016), and MSNA (burst frequency and incidence) responses to CPT were attenuated in both syncope groups (SS, P=0.011 and 0.003 respectively; NSS, P=0.021 and 0.049 respectively). MSNA responses to HUT did not differ. For both non-baroreflex and baroreflex responses, there were no differences in any of the MSNA indices between the syncope groups. Patients with vasovagal syncope, with or without sleep syncope, have very similar sympatho-vagal responses to both non-baroreflex and baroreflex stimuli. This is consistent with sleep syncope being a subform of vasovagal syncope. Attenuation of sympathetic responses to non-baroreflex pathways may be important in the mechanism of vasovagal syncope.

INTRODUCTION

Vasovagal syncope is usually triggered by emotional or postural stimuli and generally occurs when the patient is conscious and the body is upright. Emotions are thought to act via ‘central’ non-baroreflex pathways which inhibit the brainstem [1], whereas upright posture offloads the baroreceptors and disinhibits sympathetic output [2]. Exactly how these mechanisms lead to syncope is poorly understood. Haemodynamic studies have demonstrated that patients with vasovagal syncope initially respond normally to the orthostatic stress of tilting, but subsequently develop an exaggerated fall in cardiac output, probably secondary to increased venous (splanchnic) pooling of blood [35]. Sympathetic withdrawal and bradycardia occur later. Healthy humans will also eventually develop a vasovagal reaction depending on the degree of orthostatic stress and their vasoconstrictor reserve [6]. This has lead to the view that recurrent fainters should be regarded as normal variants, at the lower end of the spectrum of orthostatic tolerance [7]. But do all fainters fit this spectrum?

We have described previously a group of 13 patients who complained of syncope interrupting nocturnal sleep [8]. They woke up feeling faint, and lost consciousness either in bed or immediately upon standing. Most remembered abdominal discomfort at the onset of the attack. We have termed this condition ‘sleep syncope’. These patients also fainted in response to emotional and postural stimuli in the course of daily living, and during HUT (head-up tilting) in the laboratory. We therefore suggested that sleep syncope should be regarded as a new type of vasovagal syncope [9]. The number of patients reported to date is small, and the sleep episodes usually occur sporadically, so no BP (blood pressure) and very few ECG recordings have been undertaken during attacks. Furthermore, no detailed laboratory results have been published.

We therefore decided to undertake autonomic studies on sleep syncope patients, particularly MSNA (muscle sympathetic nerve activity) responses to both non-baroreflex and baroreflex stimuli. MSNA is a reliable index of vasoconstrictor tone. Non-baroreflex pathways are thought to drive the initial pressor responses to HG (handgrip) [10,11] and CPTs (cold pressor tests) [12,13]. Arterial and cardiopulmonary baroreflexes are off-loaded during HUT and hypotension, and MSNA normally increases [14,15]. We assessed non-baroreflex control from responses to HG and hand-in-ice, and baroreflex control from responses to HUT and tilt-induced syncope. We compared non-baroreflex and baroreflex responses in SS patients (patients with vasovagal syncope with sleep syncope) with those of NSS patients (patients with vasovagal syncope without sleep syncope) and controls. As described above, vasovagal reactions can be triggered by phobic reactions via inhibitory non-baroreflex pathways or baroreflex unloading via orthostatic stress. While supine, baroreflex unloading is an unlikely trigger for a vasovagal reaction. We therefore hypothesized that SS patients would have altered responses to tests that assess non-baroreflex pathways controlling BP compared with control subjects and NSS patients. Furthermore, sympathetic responses to HUT would be similar in all three groups and responses to tilt-induced hypotension would be similar in SS and NSS patients.

MATERIALS AND METHODS

Subjects

Patients were enrolled consecutively over a 4-year period (2002–2006) from the syncope clinic at Christchurch Hospital, Christchurch, New Zealand. Referrals were made by neurologists, cardiologists and general practioners. After providing written informed consent, patients underwent autonomic and tilt testing according to a protocol approved by the Canterbury District Health Board Ethics Committee. All patients were initially assessed in the clinic and were asked to fill out a questionnaire detailing the history of their episodes of syncope. This included when the episodes started, their frequency and duration, associated symptoms, exact sequence of a typical episode, possible triggers (including specific phobic reactions), posture at the time of syncope, medical conditions and medication. ECGs were undertaken on all patients and were examined for conduction abnormalities. Patients with epilepsy, hypertension, heart failure and cerebrovascular disease were excluded. Only patients with a history typical for recurrent vasovagal syncope were accepted.

On the basis of the history, 26 patients with suspected vasovagal syncope and a life-long history of two or more episodes of sleep syncope were assigned to the SS group, and 64 patients with suspected vasovagal syncope and no sleep episodes were assigned to the NSS group. We selected 22 control volunteers (mainly hospital staff with no history of syncope), who were age- and gender-matched to both of the syncope groups. For analysis, we retrospectively selected only tilt-positive patients (48 out of 64 patients) from the NSS group. We subsequently rejected 10, 13 and six patients from the SS, NSS and control groups respectively, because of unsatisfactory MNSA recordings.

Protocol

On the morning of tilting, all medication was withheld, and patients were allowed a light caffeine-free breakfast. All studies took place at 08.00 hours in the same room at the same temperature (20°C). Patients were positioned supine on a hydraulic tilt table in the horizontal position. Three ECG electrodes were applied to the chest. Respiratory rate was monitored using thoracic impedance derived from the ECG signal. A 3-French cannula was inserted into the right brachial artery. Tungsten electrodes (1–5 μm in diameter) were placed in the right leg for microneurographic recordings of the superficial peroneal nerve according to the methods described by Hagbarth and Vallbo [16]. The signal was amplified (×1000), filtered between 700 and 2000 Hz, and integrated (0.1 s) for the purpose of counting multi-fibre bursts. Bursts were accepted provided they were pulse-synchronized, inversely related to BP during deep breathing, and had a signal-to-background ratio >3. Burst frequency (bursts/min) and burst incidence (bursts/100 heart beats) were counted. Burst area was measured (arbitrary units) using custom-made analysis software. All data were recorded continuously using analogue-to-digital conversion software.

Autonomic tests

After ensuring recordings were stable for 20 min, baseline values for MBP (mean BP), HR (heart rate) and MSNA (burst frequency, burst incidence and burst area) were calculated from 5-min averages immediately before each manoeuvre with the patient always resting supine in the horizontal position. We ensured baseline values were consistent by allowing at least 10 min between tests and performing the tests in the same order as listed below.

Non-baroreflex responses

First, maximal voluntary (HG) contraction capacity was measured using a dynamometer and the patient was asked to grip at 30% of maximal value for 60 s using the left hand [10]. Secondly, a cold pressor stimulus was achieved by submerging the left hand in a bucket of ice water for 60 s [13]. MBP, HR and MSNA responses to HG and CPT were assessed by averaging levels over the final 20 s of the (60 s) stimulus. Previous studies have shown that, for HG, this period includes major incremental changes in MBP and HR but not MSNA, particularly during the first minute of stimulus, whereas reflex MSNA, driven by muscle metaboreceptors, is more important thereafter [10,11]. For CPT, however, major increases in all variables occur during the first minute [12,13]. Variability in sympathetic baseline levels and responses may occur secondary to age and gender [17,18], and pre-existing cardiovascular disease [1921]. As described above, we avoided individual variability by screening out hypertension, heart failure and cerebrovascular disease, and ensuring that baseline levels were achieved before each stimulus. We did not measure muscle bulk or match the groups for arm dominance. Most patients found it difficult to comply with both tests beyond the first 60 s, and after this MSNA recordings were often corrupted by motor unit activity.

Baroreflex responses

Finally, patients were tilted to the head-up 60° position with a foot support (HUT), fixing the right leg to the table in a partially flexed position so that it was non-weight-bearing, thus protecting the nerve recording field during tilt-up and pre-syncope. MBP, HR and MSNA levels were averaged over the third minute of tilting. If the patient was stable after 20 min, 0.4 mg of nitrolingual spray [GTN (glyceryl trinitrate)] was given sublingually. Twenty-second averages of all indices were taken during pre-syncope before tilt-down. Pre-syncope was defined as a fall in MBP to 80 mmHg or less, associated with the onset of hypotensive symptoms. When this occurred, patients were immediately tilted back to the horizontal position before loss of consciousness. This usually avoided bradycardia and vagal symptoms, allowing continuous MSNA recordings throughout pre-syncope and recovery. The maximum tilt time for patients and controls was 40 min.

Statistics

Comparisons among the three or two groups were undertaken using ANOVA or χ2 tests as appropriate. Changes within groups were tested using paired Student's t tests, and comparisons of these changes were made using repeated-measures ANOVA.

RESULTS

Patients and subjects

Descriptive features of the patient and control groups are listed in Table 1. Both groups of syncope patients were of similar age and gender to the controls. In the SS group, the average number of sleep episodes was 7.0 over a lifetime (range, 1–20) and 2.5 over the previous year (range, 1–10). Compared with the NSS group, SS patients more often reported a life-time history of fainting (episodes started in childhood, 63 compared with 20%; P=0.003), total loss of consciousness in the horizontal position (44 compared with 6%; P=0.001), and fainting triggered by phobic reactions to blood, crowds and enclosed places (75 compared with 37%; P=0.01). Abdominal discomfort, either pain or the urge to defaecate, was more common during sleep episodes (69 compared with 9%; P=0.001). Nearly all of the patients in the SS group were tilt-positive (88 compared with 100%; P=0.094), and tilt times (i.e. time to pre-syncope) were similar to the NSS group (P=0.67). GTN was administered during tilting in 69% of both syncope groups (P=1.0). None of the control group fainted during tilting. Medication in the SS group was metoprolol (n=2), oral contraceptive (n=2), aspirin (n=2), antidepressants (n=1), statins (n=1) and omeperazole (n=1); and in the NSS group was metoprolol (n=4), antidepressants (n=5), statins (n=3), oral contraceptive (n=2) and aspirin (5).

Table 1
Descriptive results for the syncope patients and controls

Values are means (range) or absolute numbers (%). Total sleep, lifetime number of episodes of sleep syncope; SS episodes, number of sleep syncope episodes during the previous year; duration of hx, time between first syncope episode and the study; syncope horizontal, number of patients reporting syncope onset whilst horizontal; abdominal symptoms, number of patients who reported abdominal symptoms (pain or the urge to defaecate) during syncope episodes; lifelong syncope, number of patients who reported episodes starting in childhood; phobic reactions, number of patients who reported syncope in response to crowds, enclosed spaces and the sight of blood; tilt-positive, number of patients who were tilt positive; tilt time, total time from head-up tilting to the end of tilting (onset of pre-syncope for SS and NSS groups and 40 min of tilting for controls) immediately before tilting back to the horizontal. *P values refer to between-group comparisons for all three groups for age and gender, and between syncope groups for the remainder.

CharacteristicSS patients (n=16)NSS patients (n=35)Controls (n=16)P value*
Age (years) 46.0 (20–71) 47.3 (61–85) 43.6 (16–77) 0.78 
Gender (% female) 68.8 62.9 68.0 0.88 
Total sleep (n7 (2–20) − − 
SS episodes (n2.5 (1–10) − − 
Duration of hx (years) 17.9 (1–40) 3.9 (0.3–20) − 0.001 
Syncope horizontal (n7 (44%) 2 (6%) − 0.001 
Abdominal symptoms (n11 (69%) 3 (9%) − 0.001 
Lifelong syncope (n10 (63%) 7 (20%) − 0.001 
Phobic reactions (n12 (75%) 13 (37%) − 0.012 
Tilt-positive (n14 (88%) 35 (100%) − 0.094 
Tilt time (min) 24.8 (19–40) 23.9 (8–37) 40 0.67 
CharacteristicSS patients (n=16)NSS patients (n=35)Controls (n=16)P value*
Age (years) 46.0 (20–71) 47.3 (61–85) 43.6 (16–77) 0.78 
Gender (% female) 68.8 62.9 68.0 0.88 
Total sleep (n7 (2–20) − − 
SS episodes (n2.5 (1–10) − − 
Duration of hx (years) 17.9 (1–40) 3.9 (0.3–20) − 0.001 
Syncope horizontal (n7 (44%) 2 (6%) − 0.001 
Abdominal symptoms (n11 (69%) 3 (9%) − 0.001 
Lifelong syncope (n10 (63%) 7 (20%) − 0.001 
Phobic reactions (n12 (75%) 13 (37%) − 0.012 
Tilt-positive (n14 (88%) 35 (100%) − 0.094 
Tilt time (min) 24.8 (19–40) 23.9 (8–37) 40 0.67 

Autonomic function tests

Haemodynamic and MSNA results at baseline and at the end of the tilting are shown in Table 2. Values did not differ among the three groups apart from MBP at the end of tilting, which was lower in the syncope groups (P=0.001). There were no differences between the two syncope groups.

Table 2
Haemodynamic and MSNA results for syncope patients and controls at baseline and at the end of tilting

Values are means±S.E.M. *P values refer to ANOVA between all three groups. MSNA burst area values are not listed because the between-group comparisons of individual time points were not valid.

ParameterSS patients (n=16)NSS patients (n=35)Control (n=16)P value*
Baseline     
 MBP (mmHg) 99±6 113±3 113±3 0.09 
 HR (beats/min) 67±3 65±2 68±2 0.43 
 MSNA (bursts/min) 27±3 29±2 29±2 0.87 
 MSNA (bursts/100 beats) 41±4 46±3 42±3 0.65 
End of tilting     
 MBP (mmHg) 73±4 69±2 102±4 0.001 
 HR (beats/min) 82±6 81±4 90±5 0.35 
 MSNA (bursts/min) 36±4 44±3 52±6 0.053 
 MSNA (bursts/100 beats) 44±5 57±4 58±4 0.10 
ParameterSS patients (n=16)NSS patients (n=35)Control (n=16)P value*
Baseline     
 MBP (mmHg) 99±6 113±3 113±3 0.09 
 HR (beats/min) 67±3 65±2 68±2 0.43 
 MSNA (bursts/min) 27±3 29±2 29±2 0.87 
 MSNA (bursts/100 beats) 41±4 46±3 42±3 0.65 
End of tilting     
 MBP (mmHg) 73±4 69±2 102±4 0.001 
 HR (beats/min) 82±6 81±4 90±5 0.35 
 MSNA (bursts/min) 36±4 44±3 52±6 0.053 
 MSNA (bursts/100 beats) 44±5 57±4 58±4 0.10 

Haemodynamic responses to HG, CPT, HUT and pre-syncope are shown in Figures 1 and 2. During HG, MBP (P=0.001) and HR (P=0.001) increased in all groups, but the MBP response was attenuated in the SS group (100±6 to 110±6 mmHg) compared with controls (114±3 to 133±5 mmHg; P=0.016). During CPT, MBP increased in all groups (P=0.001; between group, P=0.32), whereas HR remained constant (P=0.32). There were no differences between the syncope groups. During HUT, MBP was maintained in all groups during early tilting, but at end of tilting fell below baseline in controls (113±3 to 102±4 mmHg; P=0.001) and syncope groups (SS group, 99±6 to 73±4 mmHg; P=0.001; and NSS group, 113±3 to 69±2 mmHg; P=0.001). The fall in MBP was greater in both syncope groups than controls (SS group, P=0.01; and NSS group, P=0.001), and was greater in the NSS group than the SS group (P=0.031). In all groups, HR increased during early tilting (P=0.001) and was sustained at the end of tilting (P=0.001; between group, P=0.35).

MBP and HR responses to HG and CPTs

Figure 1
MBP and HR responses to HG and CPTs

*Significant difference from baseline within groups; †significant differences in response compared with control. SS patients, n=16; NSS patients, n=35; controls, n=16.

Figure 1
MBP and HR responses to HG and CPTs

*Significant difference from baseline within groups; †significant differences in response compared with control. SS patients, n=16; NSS patients, n=35; controls, n=16.

MBP and HR before and after HUT and at the end of tilting

Figure 2
MBP and HR before and after HUT and at the end of tilting

*Significant difference from baseline within groups; †significant difference in response compared with control. SS patients, n=16; NSS patients, n=35; controls, n=16.

Figure 2
MBP and HR before and after HUT and at the end of tilting

*Significant difference from baseline within groups; †significant difference in response compared with control. SS patients, n=16; NSS patients, n=35; controls, n=16.

MSNA responses to HG, CPT and HUT are shown in Figures 3 and 4. During HG, all indices of MSNA increased (P=0.001) in all groups (P=0.2, 0.57 and 0.54 respectively). During CPT all indices increased (P=0.001), but compared with control (burst frequency, 27±2 to 45±2 burst/min; and burst incidence, 42±4 to 70±5 bursts/100 beats) responses were relatively attenuated in both syncope groups (SS patients, 27±3 to 42±3 bursts/min and 41±5 to 54±5 bursts/100 beats, P=0.011 and 0.003; and NSS patients, 29±2 to 49±2 bursts/min and 46±3 to 64±3 bursts/100 beats, P=0.021 and 0.049). During early tilting, all of the MNSA indices increased similarly in all of the groups (P=0.001; between group, P=0.13, 0.35 and 0.35). At the end of tilting, the burst frequency and burst incidence remained above baseline in the control (52±6 bursts/min and 58±4 bursts/100 beats) and NSS (44±3 bursts/min and 57±4 bursts/100 beats; P=0.001) groups, and fell back to baseline in the SS group (36±4 bursts/min and 44±5 bursts/100 beats; P=0.14 and 0.706). Burst frequency fell more in the SS group than control group (P=0.035), and tended to fall in the NSS group (P=0.078). For other MSNA indices, there were no differences between the syncope and control groups. For both non-baroreflex and baroreflex responses, there were no differences in any of the MSNA indices between the syncope groups.

MSNA burst frequency, burst incidence and burst area/min responses to HG and CPTs

Figure 3
MSNA burst frequency, burst incidence and burst area/min responses to HG and CPTs

*Significant change from baseline within groups; †significant difference in response compared with control. SS patients, n=16; NSS patients, n=35; controls, n=16. b/100 beats, bursts/100 beats; ba/min, burst area/min (%).

Figure 3
MSNA burst frequency, burst incidence and burst area/min responses to HG and CPTs

*Significant change from baseline within groups; †significant difference in response compared with control. SS patients, n=16; NSS patients, n=35; controls, n=16. b/100 beats, bursts/100 beats; ba/min, burst area/min (%).

MSNA burst frequency, burst incidence and burst area/min before and after HUT and at the end of tilting

Figure 4
MSNA burst frequency, burst incidence and burst area/min before and after HUT and at the end of tilting

*Significant change from baseline within groups; †significant difference in response compared with control. SS patients, n=16; NSS patients, n=35; controls, n=16.

Figure 4
MSNA burst frequency, burst incidence and burst area/min before and after HUT and at the end of tilting

*Significant change from baseline within groups; †significant difference in response compared with control. SS patients, n=16; NSS patients, n=35; controls, n=16.

DISCUSSION

The results of the present study can be summarized as follows: (i) both groups of syncope patients (with and without sleep syncope) have decreased sympathetic responses to non-baroreflex stimuli; and (ii) sympatho-vagal responses in syncope patients with and without sleep syncope are similar, with a trend towards further attenuation in the sleep group. These findings support the hypothesis that sleep syncope is a form of vasovagal syncope and may be triggered via a non-baroreflex pathway. The laboratory findings were consistent with the patients' histories: those with sleep syncope reported vasovagal episodes at other times in response to non-baroreflex (emotional) and baroreflex (postural) stimuli. Furthermore, vasovagal symptoms occurred during sleep episodes (e.g. nausea, feeling hot, sweating and light headedness). Finally, nearly all SS patients had a vasovagal reaction during tilt testing.

Unfortunately, because of the episodic nature of sleep syncope, we have been unable to capture a continuous BP recording during an episode, and, until this is achieved, our understanding of this condition is dependent on careful history taking, ECG event monitoring and post-hoc laboratory investigations [9]. Previously, many laboratory studies have been performed in patients with vasovagal syncope during tilt-induced syncope to assess BP, ECG and MSNA continuously and dissect out the sequence of events. The assumption is that tilt-induced syncope is the physiological equivalent of vasovagal syncope [14,22,23]. To date, no study has used standard autonomic tests for comparing haemodynamic and sympathetic nerve responses in vasovagal patients with controls [24]. BP responses to HG have traditionally been criticized because of poor reproducibility; however, a substantial part of the variation can be eliminated by using continuous BP monitoring, as in the present study, instead of intermittent arm-cuff inflations [25]. There is a major variation in baseline MSNA between individuals and with age [17,18]. Furthermore, MSNA responses to CPT are lower in women [26]. We overcame this potential limitation by matching the control group for age and gender. Hence we were able to demonstrate the similarity between the syncope groups over a wide range of autonomic tests. Our results for HG and CPT were plausible in that MBP changes were generally concordant with all indices of MSNA (with the exception of burst area in HG), the maximal level was always greatest in controls and least in the SS group. It is possible that our present study was under-powered to detect a significant difference between the syncope groups for some MSNA indices. Patient numbers were limited by the relatively low prevalence of sleep syncope and technical difficulties achieving satisfactory nerve recordings. Thus even though there was a trend for MSNA responses to be relatively more attenuated in the SS group, we emphasize that the pattern of response was always similar in the syncope groups, particularly when they both deviated from controls during CPT. The normal initial response to HUT observed in the present study confirms previous studies: BP was maintained in both syncope groups by similar increases in HR and MSNA, indicating no obvious abnormality in baroreflex control [22,23,27]. As expected, at the end of tilting, MSNA remained increased in controls, but tended to fall back to baseline levels in the syncope groups. MSNA withdrawal was more apparent in the SS group, but, again, the pattern of response was similar in the two syncope groups across most MSNA indices, moving in the opposite direction to controls. MSNA withdrawal may have been harder to demonstrate in some patients, because we tilted them back to the horizontal as soon as they became hypotensive, i.e. before complete withdrawal and increased vagal tone [22,27]. This was undertaken in the interests of patient comfort and to preserve the sympathetic recording field. The rapid return of MSNA activity immediately after returning the subject to the horizontal position is the only way to be sure that the fall off in bursts is real rather than a loss of the recording field [14]. Consequently, we did not reproduce any of the abdominal symptoms reported by patients during their sleep episodes.

Our present finding that MSNA responses to non-baroreflex pathways are decreased in patients with vasovagal and sleep syncope is novel. It may provide an explanation as to the mechanism for vasovagal syncope in the horizontal position when central blood volume is full. In this position, the baroreceptors are relatively loaded, making it unlikely that decreased vasoconstrictor reserve, impaired baroreflex function or even a paroxysmal cardio-inhibitory reflex could be the mechanism [28,29]. In patients with vasovagal syncope, some studies have demonstrated attenuation of baroreflex function, including cardiopulmonary baroreflex control of vasoconstriction [30], and arterial baroreflex control of vasoconstriction or HR [14,31]. However, others have found exaggerated (cardiopulmonary and arterial) baroreflex control of vasoconstriction or HR [3234]. Therefore the importance of cardio-inhibitory reflexes in humans is uncertain [35,36]. Despite the often quoted ‘biphasic fainting response’, there is very little evidence that exaggerated sympathetic reactions to non-baroreflex or baroreflex stimuli are important [37,38]. Other mechanisms with the potential to temporarily impair sympathetic output (and hence vasoconstrictor reserve) need to be considered. During the first minute of static HG, BP is increased primarily by central command. Descending cortical pathways inhibit cardiovagal activity in the brainstem thus increasing HR and cardiac output. During the second minute, BP increases further, but more in response to MSNA via the muscle metaboreflex [11]. We found that, in sleep syncope patients, BP response was attenuated during the first minute, but the exact mechanism for this was unclear. The cold pressor response is primarily an increase in vasoconstrictor MSNA activity, following stimulation of thermoreceptor fibres in the skin which connect to the CNS (central nervous system) via spinothalamic afferents [12,13]. In addition, a central response to pain (via nociceptors) may contribute to the increase in MBP by maintaining cardiac output [39]. Although baroreflex control of MSNA persists during cold stimulation, severe hypertension is not sufficient to eliminate the pressor response [40]. This reflex therefore operates via a very potent central pathway for the rapid stimulation of MSNA. We found it was decreased in both syncope groups. We suggest that attenuated non-baroreflex responses may therefore predispose patients to vasovagal and sleep syncope. This is consistent with studies showing that HG and cold pressor stimuli may increase orthostatic tolerance in some, but not all, individuals [41,42].

Non-baroreflex mechanisms may be particularly important for maintaining BP during sleep when baroreflex function is altered; it has been demonstrated that, during slow-wave sleep, MSNA decreases simultaneously with a fall in BP, but that arousal stimuli are able to increase BP rapidly, via sudden increments of MSNA [43]. Furthermore, recent studies have shown that sudden bursts of MSNA in response to noxious arousal stimuli may be impaired in (awake) phobic patients with vasovagal syncope [44]. This may explain the association we found in the present study between sleep and phobia-triggered syncope. Patients may be predisposed to both forms of syncope because their non-baroreflex excitatory pathways are unable to override progressive hypotension during slow-wave sleep and in response to fear. Thus, in certain situations, these pathways may be as crucial for maintaining MSNA as the baroreflexes.

In conclusion, the results of the present study demonstrate that patients with sleep vasovagal syncope and patients with daytime vasovagal syncope have similar responses to sympatho-vagal function tests. Compared with matched control subjects, they have decreased responses to non-baroreflex-mediated function tests. The trend towards lower responses in sleep syncope patients is consistent with the hypothesis that sleep syncope is at the end of the normal spectrum of vasovagal susceptibility, in which syncope can occur in the supine position despite normal baroreflex function.

FUNDING

C. T. P. K. was supported by the Netherlands Heart Foundation Dr E. Dekker Stipend [grant number 2004/T2007].

Abbreviations

     
  • BP

    blood pressure

  •  
  • CPT

    cold pressor test

  •  
  • GTN

    glyceryl trinitrate

  •  
  • HG

    handgrip

  •  
  • HR

    heart rate

  •  
  • HUT

    head-up tilting

  •  
  • MBP

    mean BP

  •  
  • MSNA

    muscle sympathetic nerve activity

  •  
  • NSS

    vasovagal syncope without sleep syncope

  •  
  • SS

    vasovagal syncope with sleep syncope

References

References
1
Engel
 
G. L.
 
Psychologic stress, vasodepressor (vasovagal) syncope and sudden death
Ann. Intern. Med.
1978
, vol. 
89
 (pg. 
403
-
412
)
2
Burke
 
D.
Sundlof
 
G.
Wallin
 
G.
 
Postural effects on muscle nerve sympathetic activity in man
J. Physiol.
1977
, vol. 
272
 (pg. 
399
-
414
)
3
Stevens
 
P.
 
Cardiovascular dynamics during orthostasis and the influence of intravascular instrumentation
Am. J. Cardiol.
1966
, vol. 
17
 (pg. 
211
-
218
)
4
Stewart
 
J. M.
McLoed
 
K. J.
Sanyal
 
S.
Herzberg
 
G.
Montglomery
 
L. D.
 
Relation of postural vasovagal syncope to splanchnic hypervolemia in adolescents
Circulation
2004
, vol. 
110
 (pg. 
2575
-
2581
)
5
Weissler
 
A. M.
Warren
 
J. V.
Estes
 
E. H.
McIntosh
 
H. D.
Leonard
 
J. J.
 
Vasodepressor syncope. Factors influencing cardiac output
Circulation
1957
, vol. 
15
 (pg. 
875
-
882
)
6
Fu
 
Q.
Witkowski
 
S.
Levine
 
B. D.
 
Vasoconstrictor reserve and sympathetic neural control of orthostatsis
Circulation
2004
, vol. 
110
 (pg. 
2931
-
2937
)
7
Alboni
 
P.
Brignole
 
M.
Uberti
 
E. C.
 
Is vasovagal syncope a disease?
Europace
2007
, vol. 
9
 (pg. 
83
-
87
)
8
Krediet
 
C. T. P.
Jardine
 
D. L.
Cortelli
 
P.
Visman
 
A. G.
Wieling
 
W.
 
Vasovagal syncope interrupting sleep?
Heart
2004
, vol. 
90
 pg. 
e25
 
9
Jardine
 
D. L.
Krediet
 
C. T. P.
Cortelli
 
P.
Wieling
 
W.
 
Fainting in your sleep?
Clin. Auton. Res.
2006
, vol. 
16
 (pg. 
76
-
78
)
10
Mark
 
A. L.
Victor
 
R. G.
Nerhed
 
C.
Wallin
 
B. G.
 
Microneurographic studies of the mechanisms of sympathetic nerve responses to static exercise in humans
Circ. Res.
1985
, vol. 
57
 (pg. 
461
-
469
)
11
Victor
 
R. G.
Pryor
 
S. L.
Secher
 
N. H.
Mitchell
 
J. H.
 
Effects of partial neuromuscular blockade on sympathetic nerve responses to static exercise in humans
Circ. Res.
1989
, vol. 
65
 (pg. 
468
-
476
)
12
Victor
 
R. G.
Liembach
 
W. N.
Seals
 
D. R.
Wallin
 
B. G.
Mark
 
A. L.
 
Effects of the cold pressor test on muscle sympathetic nerve activity in humans
Hypertension
1987
, vol. 
9
 (pg. 
429
-
436
)
13
Fagius
 
J.
Karhuvaara
 
S.
Sundlof
 
G.
 
The cold pressor test: effects on sympathetic nerve activity in human muscle and skin fasicles
Acta Physiol. Scand.
1989
, vol. 
137
 (pg. 
325
-
334
)
14
Mosqueda-Garcia
 
R.
Furlan
 
R.
Fernandes-Violante
 
R.
Desai
 
T.
Snell
 
M.
Jarai
 
Z.
Ananthram
 
V.
Robertson
 
R. M.
Robertson
 
D.
 
Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt
J. Clin. Invest.
1997
, vol. 
99
 (pg. 
2736
-
2744
)
15
Fadel
 
P. J.
Stromstad
 
M.
Hansen
 
J.
Sander
 
M.
Horn
 
K.
Ogoh
 
S.
Smith
 
M. L.
Secher
 
N. H.
Raven
 
P. B.
 
Arterial baroreflex control of sympathetic nerve activity during acute hypotension: effect of fitness
Am. J. Physiol. Heart Circ. Physiol.
2001
, vol. 
280
 (pg. 
H2524
-
H2532
)
16
Hagbarth
 
K. E.
Vallbo
 
A. B.
 
Pulse and respiratory grouping of sympathetic impulses in human muscle nerves
Acta Physiol. Scand.
1968
, vol. 
74
 (pg. 
96
-
108
)
17
Sundlof
 
G.
Wallin
 
G.
 
The variability of muscle sympathetic nerve activity in resting and recumbent man
J. Physiol.
1977
, vol. 
272
 (pg. 
383
-
397
)
18
Sundlof
 
G.
Wallin
 
B. G.
 
Human muscle nerve sympathetic activity at rest. Relationship to blood pressure and age
J. Physiol.
1978
, vol. 
274
 (pg. 
621
-
637
)
19
Anderson
 
E. A.
Sinkey
 
C. A.
Lawton
 
W. J.
Mark
 
A.
 
Elevated sympathetic nerve activity in borderline hypertensive humans
Hypertension
1989
, vol. 
14
 (pg. 
177
-
183
)
20
Leimbach
 
W. N.
Wallin
 
G.
Victor
 
R. G.
Aylward
 
P. E.
Sundlof
 
G.
Mark
 
A.
 
Direct evidence from interaneuaral recordings for increased central sympathetic outflow in patients with heart failure
Circulation
1986
, vol. 
73
 (pg. 
913
-
919
)
21
Mizushima
 
T.
Tajima
 
F.
Nakamura
 
T.
Yanamoto
 
M.
Lee
 
K. H.
Ogata
 
H.
 
Muscle sympathetic nerve activity during cold pressor test in patients with cerebrovascular accidents
Stroke
1998
, vol. 
29
 (pg. 
607
-
612
)
22
Morrillo
 
C. A.
Eckberg
 
D. L.
Ellenbogen
 
K. A.
Beightol
 
L. A.
Hoag
 
J. B.
Tahvanainen
 
K. U. O.
Kuusela
 
T. A.
Diedrich
 
A. M.
 
Vagal and sympathetic mechanisms in patients with orthostatic syncope
Circulation
1997
, vol. 
96
 (pg. 
2509
-
2513
)
23
Kamiya
 
A.
Hayano
 
J.
Kawada
 
T.
Michikami
 
D.
Yamamoto
 
K.
Ariumi
 
H.
Shimizu
 
S.
Uemura
 
K.
Miyamoto
 
T.
Aiba
 
T.
, et al 
Low-frequency oscillation of nerve activity decreases during development of tilt-induced syncope preceding sympathetic withdrawal and tachycardia
Am. J. Physiol. Heart Circ. Physiol.
2005
, vol. 
298
 (pg. 
H1758
-
H1769
)
24
Van den Berg
 
M. P.
Smit
 
A.
 
Bedside autonomic function testing in patients with vasovagal syncope
Pacing Clin. Electrophysiol.
1997
, vol. 
20
 (pg. 
2039
-
2042
)
25
Kowalewski
 
M. A.
Urban
 
M.
 
Short- and long-term reproducibility of autonomic measures in supine and standing positions
Clin. Sci.
2004
, vol. 
106
 (pg. 
61
-
66
)
26
Shoemaker
 
J. K.
Hogeman
 
C. S.
Khan
 
M.
Kimmerly
 
D. S.
Sinoway
 
L. I.
 
Gender affects sympathetic and hemodynamic response to postural stress
Am. J. Physiol. Heart Circ. Physiol.
2001
, vol. 
281
 (pg. 
H2028
-
H2035
)
27
Jardine
 
D. L.
Ikram
 
H.
Frampton
 
C. M.
Frethey
 
R.
Bennett
 
S. I.
Crozier
 
I. G.
 
The autonomic control of vasovagal syncope
Am. J. Physiol. Heart Circ. Physiol.
1998
, vol. 
274
 (pg. 
H2110
-
H2115
)
28
Glick
 
G.
Yu
 
P.
 
Hemodynamic changes during spontaneous vasovagal reactions
Am. J. Med.
1963
, vol. 
34
 (pg. 
42
-
51
)
29
Hainsworth
 
R.
 
Pathophysiology of syncope
Clin. Auton. Res.
2004
, vol. 
14
 
Suppl. 1
(pg. 
18
-
24
)
30
Bechir
 
M.
Binggeli
 
C.
Corti
 
R.
Chenevard
 
R.
Spieker
 
L.
Ruschitzka
 
F.
Luscher
 
T. F.
Noll
 
G.
 
Dysfunctional baroreflex regulation of sympathetic nerve activity in patients with vasovagal syncope
Circulation
2003
, vol. 
107
 (pg. 
1620
-
1625
)
31
Wahbha
 
M. M.
Morley
 
C. A.
Al-Shamma
 
M. H.
Hainsworth
 
R.
 
Cardiovascular reflex responses in patients with unexplained syncope
Clin. Sci.
1989
, vol. 
77
 (pg. 
547
-
553
)
32
Sneddon
 
J. F.
Counihan
 
P. J.
Bashir
 
Y.
Haywood
 
G. A.
Ward
 
D. E.
Camm
 
A. J.
 
Assessment of autonomic function in patients with neurally mediated syncope: augmented cardiopulmonary baroreceptor responses to graded orthostatic stress
J. Am. Coll. Cardiol.
1993
, vol. 
21
 (pg. 
1193
-
1198
)
33
Pitzalis
 
M.
Parati
 
G.
Massari
 
F.
Guida
 
P.
Di Rienzo
 
M.
Rizzon
 
B.
Castiglioni
 
P.
Iacoviello
 
M.
Mastropasqua
 
F.
Rizzon
 
P.
 
Enhanced reflex response to baroreceptor deactivation in subjects with tilt-induced syncope
J. Am. Coll. Cardiol.
2003
, vol. 
41
 (pg. 
1167
-
1173
)
34
Adler
 
P. S.
France
 
C.
Ditto
 
B.
 
Baroreflex sensitivity at rest in individuals with a history of vasovagal syncope
J. Psychosom. Res.
1991
, vol. 
35
 (pg. 
591
-
597
)
35
van Lieshout
 
J.
Wieling
 
W.
Karemaker
 
J.
 
Neural circulatory control in vasovagal syncope
Pacing Clin. Electrophysiol.
1997
, vol. 
20
 (pg. 
753
-
763
)
36
Scherrer
 
U.
Vissing
 
S.
Morgan
 
B. J.
Hanson
 
P.
Victor
 
R. G.
 
Vasovagal syncope after infusion of a vasodilator in a heart transplant recipient
N. Eng. J. Med.
1990
, vol. 
323
 (pg. 
602
-
604
)
37
Graham
 
D. T.
 
Prediction of fainting in blood donors
Circulation
1961
, vol. 
23
 (pg. 
901
-
906
)
38
Sarlo
 
M.
Buodo
 
G.
Munafo
 
M.
Stegagno
 
L.
Palomba
 
D.
 
Cardiovascular dynamics in blood phobia: evidence for a key role of sympathetic activity in vulnerability to syncope
Psychophysiology
2008
, vol. 
45
 (pg. 
1038
-
1045
)
39
Peckerman
 
A.
Huwitz
 
B. E.
Saab
 
P. G.
Llabre
 
M. M.
McCabe
 
P. M.
Schneiderman
 
N.
 
Stimulus of the cold pressor test and the associated patterns of cardiovascular disease
Psychophysiology
1994
, vol. 
31
 (pg. 
282
-
290
)
40
Cui
 
J.
Wilson
 
T. E.
Crandall
 
C. G.
 
Baroreflex modulation of muscle sympathetic nerve activity during cold pressor test in humans
Am. J. Physiol. Heart Circ. Physiol.
2002
, vol. 
282
 (pg. 
H1717
-
H1723
)
41
Brignole
 
M.
Croci
 
F.
Menozzi
 
C.
Solano
 
A.
Donateo
 
P.
Oddone
 
D.
Puggioni
 
E.
Lolli
 
G.
 
Isometric arm counter-pressure maneouvers to abort impending vasovagal syncope
J. Am. Coll. Cardiol.
2002
, vol. 
40
 (pg. 
2053
-
2059
)
42
Fu
 
Q.
Arbab-Zadeh
 
A.
Perhonen
 
M. A.
Zhang
 
R.
Zuckerman
 
J. H.
Levine
 
B. D.
 
Hemodynamics of orthostatic intolerance: implications for gender differences
Am. J. Physiol. Heart Circ. Physiol.
2004
, vol. 
286
 (pg. 
H449
-
H457
)
43
Somers
 
V. K.
Dyken
 
M. E.
Mark
 
A. L.
Abboud
 
F. M.
 
Sympathetic activity during sleep in normal subjects
N. Eng. J. Med.
1993
, vol. 
328
 (pg. 
303
-
307
)
44
Donadio
 
V.
Liguori
 
R.
Elam
 
M.
Karlsson
 
T.
Montagna
 
P.
Cortelli
 
P.
Baruzzi
 
A.
Wallin
 
G.
 
Arousal elicits exaggerated inhibition of sympathetic nerve activity in phobic syncope patients
Brain
2007
, vol. 
130
 (pg. 
1653
-
1662
)