Europace Advance Access originally published online on August 22, 2008
Europace 2008 10(10):1170-1175; doi:10.1093/europace/eun217
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Syncope
Impaired arterial baroreflex function before nitrate-induced vasovagal syncope during head-up tilt test
Cardiology Unit, Emergency and Organ Transplantation Department, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy
Manuscript submitted 28 April 2008. Accepted after revision 1 August 2008.
* Corresponding author. Tel: +39 080 5478622; fax: +39 080 5478796. E-mail address: massimo.iacoviello{at}cardio.uniba.it
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Abstract |
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Aims: The aim of this study was to evaluate arterial baroreflex control of heart rate immediately before head-up tilt test (HUT)-induced vasovagal syncope (VVS).
Methods and results: We enrolled 97 otherwise healthy subjects with recurrent unexplained syncope. After 10 min of rest in supine position, they underwent a passive HUT potentiated with nitroglycerin administration after 20 min. Beat-to-beat heart rate and systolic blood pressure were continuously recorded. Sequence method was used to measure two complementary parameters reflecting arterial baroreflex control of heart rate: the baroreflex sensitivity (BRS) and the baroreflex effectiveness index (BEI). Twenty-one patients fainted before nitrate administration (HUT+) and 37 after nitrate administration (NTG+). Immediately before syncope, the NTG+ patients showed significantly lower BRS values than those observed at the end of the test in the patients without syncope (5.5 ± 2.8 vs. 7.7 ± 3.4 ms/mmHg; P = 0.004) and a significantly lower BEI (30 ± 20% vs. 53 ± 24%; P < 0.001). The HUT+ patients did not show any significant differences in BRS and BEI before syncope from the values observed during the corresponding tilt period in the other groups.
Conclusion: A significant depression in BRS and BEI occurs immediately before syncope in patients who faint after nitrate administration, thus suggesting that arterial baroreflex dysfunction plays a role in mediating nitrate-induced VVS.
Key Words: Vasovagal syncope, Tilt table test, Baroreceptor reflex
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Introduction |
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The complex pathophysiology of vasovagal syncope (VVS) has not yet been fully elucidated, although the occurrence of hypotension and/or bradycardia at the time of VVS suggests that the reflexes involved in controlling heart rate, cardiac contractility, and vascular tone (i.e. the arterial and cardiopulmonary reflexes) may play a role.1
Most studies have not found any clear evidence of alterations in the arterial baroreflex control of heart rate in subjects with tilt-induced syncope,2–7 and a few have reported a reduction8–10 or an increase in baroreflex activity.11,12 These discrepancies may be partially due to differences in methods (with or without an external stimulus) and/or in the assessment of arterial baroreflex function at different phases of a head-up tilt test (HUT): i.e. at baseline, during, or after HUT, immediately before VVS or not. Finally, there are few data concerning the relationship between baroreflex function and the administration of the drugs currently recommended to potentiate HUT and increase the sensitivity of the test.13
In order to clarify the role of arterial baroreflex function in VVS, the sequence method of measuring baroreflex function offers a number of advantages: it is based on evaluating spontaneous oscillations in systolic arterial pressure (SAP) and the RR interval (RRI) without the use of external stimulus, can be used to evaluate short periods (and thus allows the analysis of all of the phases of HUT, including those before syncope), and makes it possible to assess two complementary aspects of arterial baroreflex function: baroreflex sensitivity (BRS), which provides qualitative information, and the baroreflex effectiveness index (BEI), which quantifies the number of times the baroreflex is effective in driving the sinus node.14
The aim of this study was to evaluate the arterial baroreflex control of heart rate before syncope in patients with HUT-induced VVS, with and without nitrate administration, using the sequence method.
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Methods |
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Study population
We studied consecutive patients with a history of suspected VVS occurring in the 2 months preceding enrolment. The exclusion criteria were a history of cardiovascular disease, carotid sinus syndrome, or any disease that might affect the autonomic nervous system, and the use of any medication affecting the cardiovascular system. The study complied with the Declaration of Helsinki was approved by our local Ethics Committee, and all of the subjects gave their written informed consent.
Tilt test protocol
Head-up tilt test was performed in accordance with the current guidelines.13 Briefly, the tests took place between 9:00 and 11:00 a.m. in a temperature-controlled room (23°C). After 10 min of supine rest, the subjects were tilted to 70° using an electronically operating tilt table with a footboard. If VVS had not occurred after 20 min, 300 µg of nitroglycerin (NTG) was administered sublingually, and HUT was continued for a further 20 min.13 The syncope was classified by two of us (C.F. and M.I.) on the basis of the modified Vasovagal Syncope International Study (VASIS) classification as type 1 (mixed), type 2A (cardioinhibition without asystole), type 2B (cardioinhibition with asystole), or type 3 (vasodepressive).
Cardiovascular parameters
Beat-to-beat SAP, RRI, stroke volume (SV), and total peripheral resistance (TPR) were continuously monitored and recorded using a Task Force Monitor (CNSystems, Graz, Austria). Continuous SAP was obtained using the finger vascular downloading technique15 and was automatically and continuously corrected to the oscillometric values obtained from the contralateral arm (brachial artery). Real-time beat-to-beat SV was estimated using an improved method of transthoracic impedance cardiography15–17 in which changes in thoracic electrical impedance are used to estimate changes in blood volume in the aorta and changes in fluid volume in the thorax.17 Left ventricular SV was calculated by measuring the maximum rate of thoracic electrical impedance during ventricular ejection and dividing it by the base impedance multiplied by left ventricular ejection time and a chest volume constant (determined by age, weight, height, and body surface area).17 Total peripheral resistance was calculated on the basis of Ohm’s law.17 Six-channel ECG was included to determine the RRI.17
Data analysis
The recorded SAP, RRI, SV, and TPR data were analysed off-line using software written in Visual Basic by one of us (P.G.) (Microsoft Access, Microsoft Corp., Redmond, WA, USA). Mean values were calculated for each of the following periods: the baseline 10 min in a supine position; the first and last 3 min of passive HUT; and the first and last 3 min after NTG administration. In the case of patients with a positive syncope response, the final 3 min were those preceding but not including the syncope; if the syncope occurred before 6 min, the initial and final phases were obtained by splitting the period into two equal parts.
Arterial baroreflex sensitivity
The SAP time series were scanned in order to identify ramps of four or more consecutive beats characterized by a progressive increase (up-ramp) or reduction (down-ramp) of at least 1 mmHg. Spontaneous sequences were identified as SAP ramps followed by concomitant and concordant RRI lengthening/shortening of at least 5 ms.18 The sequences were scanned with a lag order of 0, 1, and 2 including each sequence only once. The slope of the regression line between the RRI and SAP values was computed for each sequence and was considered reliable when the correlation coefficient was >0.80. Baroreflex sensitivity was computed as the average of all baroreflex sequences, and the BEI was defined as the percentage ratio between the number of sequences and the total number of SAP ramps.14
Statistical analysis
The data are given as mean values ± SD unless otherwise specified. Categorical variables are described as frequencies and percentages. Within-group comparisons were made using the Student t-test for dependent variables, and between-group comparisons by means of the Student t-test for independent samples or analysis of variance followed by the Newman–Keuls multiple comparison. Two-way ANOVA was used to evaluate baroreflex sensitivity immediately before syncope by VASIS classification and on the basis of NTG administration. The homogeneity of the variances was assessed using the F test. Frequencies were compared by means of the 
2 test. The primary study endpoint was to compare the baroreflex control of heart rate in patients with induced VVS in comparison with those without syncope. Considering a P-value of <0.05 as statistically significant, under a hypothesized standard deviation of 3 ms/mmHg evaluated using the same method in a similar population during HUT,19 the sample size provided a power >80% to detect a difference of >3 ms/mmHg in BRS between groups. Statistical power was analysed using STATISTICA Power Analysis (StatSoft Inc., Tulsa, OK, USA), and the statistical analyses were made using STATISTICA 6.1 software (StatSoft Inc.).
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Results |
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Vasovagal syncope was observed in 58 (60%) of the 97 enrolled patients: 21 of them fainted during passive HUT (HUT+) and 37 after NTG administration (NTG+); and 39 patients did not faint (NTG–). Table 1 shows the demographic and baseline clinical characteristics of the three groups. The patients who fainted during the passive phase of HUT were characterized by higher baseline BEI values than those without syncope, and the patients who were positive after NTG administration had a lower BMI, and higher baseline BRS and BEI values than those without syncope. There were no between-group differences in age, gender distribution, SAP, RRI, SV, or TPR (Table 1).
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Time to syncope was significantly (P = 0.022) different: the HUT+ patients fainted a median of 10 min [inter-quartile range (IQR) 5–16] after the start of the test, whereas the NTG+ patients fainted a median of 6 min (IQR 5–9) after nitrate administration. The variability of time to syncope was significantly greater in the HUT+ than in the NTG+ group (SD: 6 vs. 3 min; P < 0.001 by the F test). The VASIS classification distribution was not different between the HUT+ and NTG+ groups (Table 1).
Table 2 shows the mean SAP, RRI, SV, and TPR values during the different phases of HUT in the three groups, and Figure 1 shows the mean number of SAP ramps (standardized per 100 heart beats) and the mean BEI and BRS values during the different phases of the tilt test.
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In the NTG– group, SAP significantly decreased during the NTG phase, whereas RRI and SV significantly decreased during HUT and remained unchanged after NTG (Table 2). Total peripheral resistance significantly decreased after NTG administration. There was a significant increase in SAP ramps during the pharmacological phase (Figure 1A). BRS significantly decreased after NTG administration, and then remained stable until the end of the test (Figure 1C), whereas BEI significantly increased (Figure 1B).
In the HUT+ group, SV significantly decreased during HUT, with lower SAP values than in the other groups at the beginning of HUT (P = 0.005 vs. NTG–) and immediately before syncope (P < 0.001 vs. NTG–, and P < 0.001 vs. NTG+). There was a significant reduction in the BEI (Figure 1B) but not in the BRS (Figure 1C) before syncope, but the BEI was not significantly different from that observed in the other groups during the same tilt period.
In the NTG+ group, SAP and TPR significantly decreased immediately before syncope; RRI and SV significantly decreased during HUT, and further decreased after NTG and before syncope (Table 2). Immediately before syncope, mean RRI (P < 0.001), SV (P = 0.014), and TPR (P = 0.012) were all lower than in the NTG– group (Table 2). SAP ramps significantly increased during HUT and, as in the NTG– group, there was a further increase after nitrate administration (Figure 1A). This group also showed a marked reduction in the BEI before syncope (Figure 1B), whereas BRS significantly and progressively decreased during the passive phase (Figure 1C) and further decreased immediately before syncope (Figure 1C). At the end of the test, the NTG+ patients had significantly lower BEI and BRS values than the NTG– patients (Figure 1), and also significantly lower BRS (but not BEI) than those observed before syncope in the HUT+ group.
Figure 2 shows BRS and BEI immediately before VVS in the patients who fainted before and after nitrate administration by their VASIS classification. Two-way ANOVA showed that VASIS classification had no significant effect on either BRS or BEI (respectively, P = 0.29 and P = 0.11); nitrate administration had a significant effect on BRS (P = 0.013) but not on BEI (P = 0.14).
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Discussion |
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The main finding of our study is that subjects with recurrent unexplained syncope who are prone to experience VVS during HUT after nitrate administration are characterized by a qualitative (BRS) and quantitative (BEI) impairment in their arterial baroreflex control of heart rate immediately before VVS.
The relevance of the arterial baroreflex in the pathophysiology of VVS is not very clear, and it has not been assessed in patients fainting during a tilt test potentiated by drug administration. We studied a homogeneous population of otherwise healthy subjects with a history of recent unexplained syncope who were not taking any medication. The arterial baroreflex was measured using the sequence method, whose advantages include the possibility of assessing two parameters that provide complementary information concerning the baroreflex control of heart rate: BRS offers qualitative information about baroreceptor sensitivity by measuring the magnitude of the reflex changes in RRI in relation to the amplitude of the changes in the SAP input, but only when this drive is effective; the BEI provides quantitative information about arterial baroreflex function by quantifying the number of times the baroreflex is effective in driving the sinus node.14 The sequence method also makes it possible to estimate the blood pressure variability leading to baroreceptor activation and deactivation by calculating SAP ramps.
Our findings show that there was a significant increase in SAP ramps after nitrate administration in the patients who did and did not faint, and this can be considered an expression of the increased variability in blood pressure previously proposed as a marker of maladaptive arterial baroreflex control during orthostatic stress.20–21 Although the effect of nitrate administration was similar in the two groups, the response of the patients with syncope to the more frequent baroreceptor stimulation and deactivation was a marked reduction in both BRS and BEI, whereas the patients without VVS showed only a slight and non-significant decrease in BRS and a progressive improvement in BEI. These different reductions are even more evident when we consider the baseline BRS and BEI values which, as has been previously demonstrated,18 were greater in the patients who fainted than in those who did not.
The simultaneously impaired BRS and BEI suggest that nitrate administration in patients who are prone to faint induces a qualitative and quantitative worsening in arterial baroreflex function. This could favour the occurrence of VVS by leading to an unstable relationship between SAP and RRI22 due to the failure of effective arterial baroreflex control over the greater variability in blood pressure. On the other hand, the greater effectiveness of the baroreflex in patients with a negative HUT response may play a compensatory role by reducing the probability of VVS during HUT.
On the basis of these findings demonstrating a significant relationship between nitrate administration, impaired baroreflex function, and the occurrence of VVS, it is possible to make some speculations concerning the mechanisms by which nitroglycerin increases the positive rate of HUT. It is believed that NTG potentiates orthostatic stress by enhancing venous pooling in the upright posture, thus facilitating the onset of the Bezold-Jarish reflex. However, the effects of NTG (particularly those on arterial baroreflex function) may also be related to its effects on the autonomic nervous system.23 Nitroglycerin is a nitric oxide donor that not only induces marked venodilatation, but also neuromodulation at the level of the peripheral and central nervous systems,23,24 and experimental models have shown that nitric oxide has a direct effect on the central nervous system that generally leads to sympathetic inhibition.24 However, it has also been demonstrated that, at the level of nucleus tractus solitarii, it mediates the angiotensin II effect of reducing cardiac baroreceptor reflex gain,25 which may explain our results.
Finally, it is worth noting that we also observed significantly lower TPR values before syncope in the patients who fainted after NTG, thus suggesting the possible co-existence of a cardiopulmonary reflex impairment that can be mediated by nitrate administration. However, TPR only provides indirect information about the cardiopulmonary reflex and so no definite conclusions can be drawn.
We found that the patients who fainted during passive HUT did not show any significant impairment in arterial baroreflex function before syncope. Although a significant reduction in BEI was observed from the start of the HUT, there were no significant differences in BRS or BEI from those observed in the other groups during the same tilt period. There may be various reasons for this. It has been previously suggested that patient heterogeneity and the multiplicity of mechanisms leading to VVS26–27 may contribute to the differences in the behaviour of the arterial baroreflex between those who faint before and after nitrate administration. In our case, this hypothesis seems to be strengthened by the fact that the variability in the time to the occurrence of VVS in our NTG+ patients was significantly less than in our HUT+ patients. In most cases, syncope occurred during the first few minutes after nitrate administration, thus suggesting a similar mechanism leading to syncope. On the other hand, the greater variability in the occurrence of syncope in the HUT+ patients suggests the possible presence of heterogeneous mechanisms leading to VVS. Furthermore, we cannot exclude the possibility that the changes in baroreflex function in the patients who fainted before nitrate administration are so fast that they cannot be detected by analysing the 3 min before syncope.
We also evaluated the interaction between nitrate administration and VASIS classification by means of ANOVA, which clearly showed that the effect of nitrates on BRS did not depend on the type of syncope. However, further studies are required to clarify the relationships between the different VASIS classifications, nitrate administration, and baroreflex function because our study was not powered to test this hypothesis.
In conclusion, subjects with recurrent unexplained syncope who are prone to experience VVS during HUT after nitrate administration are characterized by the qualitative and quantitative impairment of the baroreflex control of heart rate before syncope, thus suggesting the involvement of arterial baroreflex dysfunction in the pathophysiology of nitrate-induced VVS.
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This study was partially supported by a grant from the University of Bari.
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Acknowledgements |
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The authors would like to thank Mr Cataldo Balducci, Mrs Mariella Vitone and Mrs Margherita Sarlo for their helpful cooperation.
Conflict of interest: none declared.
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Footnotes |
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These two authors equally contributed to this paper. 
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