CLINICAL STUDIES: SYNCOPE
Provocation of neurocardiogenic syncope by clomipramine administration during the head-up tilt test in vasovagal syndrome
George N. Theodorakis, MD*,
Manolis Markianos, MD ,
Elias Zarvalis, MD*,
Efthimios G. Livanis, MD*,
Panagiota Flevari, MD* and
Dimitrios Th Kremastinos, MD*
* Onassis Cardiac Surgery Center, Second Department of Cardiology, Eginition Hospital, Athens University Medical School, Athens, Greece
Laboratory of Neurochemistry, Eginition Hospital, Athens University Medical School, Athens, Greece
Manuscript received September 28, 1999;
revised manuscript received January 21, 2000,
accepted March 27, 2000.
Reprint requests and correspondence: Dr. George N. Theodorakis, Onassis Cardiac Surgery Center, 356 Sygrou Avenue, 17674 Athens, Greece
elbee{at}ath.forthnet.gr
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Abstract
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OBJECTIVES
We sought to test the hypothesis that activation of the serotonergic system in patients with vasovagal syndrome during the head-up tilt test provokes syncope.
BACKGROUND
Central serotonergic activation participates in the pathogenesis of neurocardiogenic syncope. Drugs increasing serotonin (5-HT) in the central nervous system have not been tested as drug challenges during the head-up tilt test with clomipramine (Clom-HUT).
METHODS
The serotonergic re-uptake inhibitor clomipramine was infused (5 mg in 5 min) at the start of Clom-HUT in 55 patients (mean age 40 ± 17 years) with a positive history of recurrent neurocardiogenic syncope and in 22 healthy control subjects (mean age 46 ± 15 years). Blood samples were taken at 0, 5, 10 and 20 min for estimation of plasma prolactin and cortisol as neuroendocrine indicators of central serotonergic responsitivity. All subjects had been previously tested with a basic 60° head-up tilt test (B-HUT) for 30 min, and if negative, isoproterenol infusion was given at the end of the test.
RESULTS
Twenty-nine (53%) of the 55 patients and none of the 22 control subjects had a positive result in the B-HUT. With Clom-HUT, the proportion of patients who experienced a positive response increased to 80% (n = 44), although this happened to only one control subject. Prolactin and cortisol plasma levels increased significantly in the positive Clom-HUT patient group only.
CONCLUSIONS
The results indicate an increased responsitivity of the central serotonergic neural system in subjects with vasovagal syndrome, the activation of which leads to sympathetic withdrawal. The use of clomipramine infusion with the tilt test seems to considerably improve its diagnostic value.
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Abbreviations and Acronyms
| | B-HUT | = basic head-up tilt | | Clom-HUT | = head-up tilt test with clomipramine | | ECG | = electrocardiographic | | 5-HT | = serotonin |
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Neurally mediated syncope is one of the most common types of syncope (1–3). Head-up tilt testing with or without drugs is the clinical tool of choice for the diagnosis of this syndrome (4).
Although a number of central mechanisms may play a role in neurally mediated syncope, no drug acting on the central nervous system has been tested as a challenge during head-up tilt testing. In a previous study, we found increases in plasma prolactin and cortisol after a vasovagal reaction during the head-up tilt test, suggesting participation of central serotonergic activation (5). In a recent study, we found that patients with a positive history of neurocardiogenic syncope had higher prolactin and cortisol responses to clomipramine infusion compared with normal subjects, indicating a more sensitive central serotonergic system in the former group (6). Acute clomipramine administration blocks the reuptake of serotonin (5-HT) in the synapse space and increases stimulation of the 5-HT receptors. Hypothalamic pituitary-adrenal axis hormones and prolactin secretion are in part regulated by 5-HT inputs, and their responses to early administration of 5-HT agents are mediated, at least in part, by 5-HT mechanisms (7,8).
The purpose of our study was to test the hypothesis that an increase of 5-HT in the central nervous system can facilitate syncope during head-up tilt testing in patients with a history of neurocardiogenic syncope. For this purpose, we
used intravenous clomipramine administration during the head-up tilt test in an attempt to investigate the usefulness of this new test in patients with a history of neurocardiogenic syncope. To evaluate the central serotonergic responsivity, we measured plasma prolactin and cortisol in samples taken during the test.
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Methods
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Patients.
The study group consisted of 77 subjects. Fifty-five of them (mean age 40 ± 17 years, 23 men) had a positive history of neurocardiogenic syncope (patient group). We considered as a positive history of recurrent neurocardiogenic syncope the presence of two or more syncopal spells in association with symptoms of autonomic dysfunction such as pallor, nausea or sweating. The mean number of syncopal episodes during the last six months was 3.7 ± 2. All patients with a positive history were seen in the outpatient clinic for the evaluation of their syncopal episodes. A thorough clinical evaluation, 12-lead electrocardiography, echocardiography and electrophysiologic study, when needed, ruled out any structural heart disease, whereas neurologic diagnostic procedures (i.e., electroencephalography, computed tomography) performed when clinically indicated ruled out any neurologic disease in patients with neurocardiogenic syncope.
A group of 22 control subjects (mean age 46 ± 15 years, 12 men) with nonspecific symptoms, no history of syncopal attacks in their medical records and no evidence of structural heart disease served as the control group.
Protocol.
All patients were tested with no medical treatment for at least one week. All patients underwent two consecutive head-up tilt tests, with a 24-h interval between the tests. The first basic head-up tilt test (B-HUT) was performed using the protocol currently used for the evaluation of neurocardiogenic syncope in our Cardiology Clinic (9), and the second head-up tilt test included intravenous clomipramine administration (Clom-HUT). All tilt table tests were performed between 8:00 AM and 1 PM, after the subjects had been fasting for at least 12 h. The subjects were connected to a standard electrocardiographic (ECG) monitor for continuous observation of heart rate and rhythm. Arterial blood pressure was also continuously monitored with a Finapress noninvasive blood pressure system. An automatic arterial blood pressure sphygmomanometer was also used to confirm the blood pressure measures every 5 min throughout the test and continuously during symptoms. Thirty minutes before the test, a venous cannula was inserted into a forearm vein.
The subjects were placed in the supine position for 10 min for baseline ECG and blood pressure recordings and then tilted to a head-up position at 60° for 30 min on a foot plate support (passive phase). If a positive response to the upright tilt test occurred during the initial upright tilt, patients were returned to the supine position and the test was terminated. If 30 min of passive tilt testing was completed without a positive response, patients were returned to the supine position for 10 min and upright tilting was repeated for 15 min with intravenous infusion of isoproterenol (infusion rate 2 µg/min, increased until the heart rate reached the target of 130 beats/min).
The second day, all subjects underwent a second test at 60° for 20 min, after a 10-min rest in the supine position. At the start of the tilt test, intravenous infusion of 5 mg of clomipramine was given over the first 5 min.
Blood samples from the venous cannula, for the estimation of cortisol and prolactin plasma levels, were taken at baseline and at 5, 10 and 20 min during Clom-HUT.
The hormone levels were estimated using commercially available radioimmunoassay kits (Serono Diagnostics [Rome, Italy] for prolactin and Diagnostic System Laboratories [Texas] for cortisol). The interassay and intra-assay coefficients of variation for all estimations were <5%.
A test was regarded as positive if it succeeded in reproducing the patient’s syncope or presyncope, associated with an abrupt fall in systolic blood pressure <80 mm Hg or concomitant bradycardia (heart rate <50 beats/min), or both. The test was regarded as negative if it was completed with no symptoms. Positive responses were classified into vasodepressor (defined as hypotension, without significant bradycardia) cardioinhibitory (bradycardia, without associated hypotension) and mixed type (hypotension, followed by bradycardia).
All subjects were informed of the experimental nature of the study and gave their written consent. Two of the authors were included in the control group. The Ethics Committee of the Hospital approved the study protocol.
Statistical analysis.
Two-way analysis of variance with repeated measures was used for statistical evaluation of the hormone responses, followed by planned comparisons (STATISTICA, version 5.0). A value of p < 0.05 was considered significant.
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Results
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B-HUT.
Twenty-nine (53%) of the 55 subjects in the patient group had a positive response during B-HUT (19 during the passive tilt test and 10 during tilt testing with isoproterenol). The mean time to syncope was 15 ± 10 min (minimum 2 min, maximum 30 min) during the passive tilt test and 5 ± 2 min during tilt testing with isoproterenol (minimum 3 min, maximum 12 min). The type of the positive response was cardioinhibitory in 8 patients, vasodepressor in 8 and mixed in the remaining 13. None of the 22 control subjects had a positive B-HUT.
Head-up tilt test with clomipramine.
Forty-four (80%) of the 55 subjects in the patient group had a positive response during Clom-HUT. The mean time to syncope in patients with a positive Clom-HUT response was 9 ± 3 min (minimum 5 min, maximum 17 min). The type of the positive response was cardioinhibitory in 9 patients, vasodepressor in 13 and mixed in the remaining 22. One subject of the 22 in the control group had a positive Clom-HUT response of the vasodepressor type.
Comparison between the two test responses.
A comparison of the results of the two tests in the patient group is shown in Figure 1. Twenty-one control subjects had a negative response during both B-HUT and Clom-HUT.
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Figure 1 Results of B-HUT and Clom-HUT in the 55 subjects in each group. Twenty-five subjects in the patient group had a positive response during both B-HUT and Clom-HUT. Seven subjects in the patient group had a negative response during both B-HUT and Clom-HUT. Nineteen subjects in the patient group with a negative B-HUT response had a subsequent positive Clom-HUT response. Four subjects in the patient group with positive B-HUT had negative Clom-HUT response.
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Comparison between the types of responses in the positive tests.
Sixteen (64%) of 25 subjects in the patient group reproduced positive responses in both tests, with the same response modality (2 [25%] of 8 patients with a cardioinhibitory type, 9 [69%] of 13 with a mixed type and 5 [63%] of 8 with a vasodepressor type).
Hormonal responses during the clomipramine test.
During the clomipramine test, blood samples for cortisol and prolactin plasma levels estimations were drawn from 61 subjects (41 from the patient group and 20 from the control group). The remaining subjects refused blood sampling.
The patients who had syncope (n = 32) during Clom-HUT showed a significant increase in plasma levels of both hormones, as compared with the control subjects with a negative Clom-HUT response (n = 20) and the patients with a negative Clom-HUT response (n = 9). The patterns of prolactin and cortisol responses during Clom-HUT in the three groups are shown in Figure 2, and the statistical evaluation is shown in Table 1.
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Figure 2 Plasma levels (mean ± SE) of prolactin (PRL) and cortisol (CORT) at baseline and at 5, 10 and 20 min during Clom-HUT. Line with solid circles = patient group with a positive Clom-HUT response; line with open circles = patient group with a negative Clom-HUT response; line with solid triangles = control group with a negative Clom-HUT response. Analysis of variance with repeated measures was applied for statistical analysis. Planned comparisons: *Significant increases as compared with both other groups. #Significant increases as compared with the control group only.
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View this table:
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Table 1 Statistical Evaluation of Prolactin and Cortisol Response to the Head-Up Tilt Test With Clomipramine in the Three Groups of Subjects
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Discussion
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This study shows that Clom-HUT is a promising technique, because the sensitivity of the test might be increased as compared with B-HUT, without a loss of specificity and without the need for prolonged titration and time-consuming procedures. The mean time to a positive response was reduced from 15 ± 10 min in the passive tilt test to 9 ± 3 min in the clomipramine test. In addition, there was no need for isoproterenol infusion. The duration of a negative basic tilt test was 55 min, whereas that of the clomipramine test was only 20 min. We believe that 20 min is a sufficient duration for the clomipramine test, because that time is two standard deviations away from the mean time to positive responses.
Reproducibility of upright tilt testing has been reported to be adequate, ranging from 67% to 85%, which is in favor of our study, as one can assume that performing the clomipramine test on the first day could have increased the sensitivity of this test and decreased the sensitivity of the basic tilt test (10–14). Twenty-five (86%) of the 29 patients with a positive basic tilt test also reproduced a positive response with the clomipramine test. The sensitivity and specificity of this test in evaluating neurocardiogenic syncope, compared with existing tests, is worth studying in future large-scale trials with greater numbers of patients and control subjects.
Central serotonergic activity and syncope.
The central nervous system plays a major role in the homeostasis of the cardiovascular system. Medullary nuclei contain the major excitatory (pressor) and inhibitory (depressor) regions (15). The functional role of the nucleus tractus solitarius and other brain stem nuclei is significant in the cardiovascular control of peripheral vascular resistance and heart rate. Serotonergic receptors are found in the nucleus tractus solitarius, in the raphe nuclei and within the ventrolateral area (16–18).
In humans, drugs that enhance central serotonergic activity, such as clomipramine, fenfluramine and 5-hydroxytryptophan, have been shown to increase the plasma levels of prolactin and cortisol and have been used as a probe to assess the reactivity of the system (19–23). It has been proven that as low as 10 mg of clomipramine administered intravenously leads to an increase in plasma prolactin and cortisol concentrations, suggesting that even small doses can be used as a useful probe of serotonergic function in humans (24). In our study, we administered only 5 mg intravenously, because we assumed that the increase of 5-HT in the central nervous system, along with orthostatic stress, would be sufficient to provoke syncope in patients with neurocardiogenic syncope.
In a previous study, we have shown that plasma levels of cortisol and prolactin increased during the tilt test in subjects who developed syncope (5). In the present study, the statistically significant increased plasma levels of cortisol and prolactin during syncope confirmed the findings of our previous study. In another study, we found that after an intravenous infusion of 25 mg of clomipramine in patients in the supine position, those with a history of recurrent neurocardiogenic syncope had higher cortisol and prolactin plasma levels than did normal control subjects, indicating an increased responsiveness of the central serotonergic system to this agent (6). Heart rate and blood pressure were not different in the supine position in that study, although a different serotonergic response was found. It could be assumed from these previous studies that central serotonergic activation is involved in the pathogenesis of neurocardiogenic syncope. Because the central serotonergic system is in part a regulator of heart rate and blood pressure homeostasis, syncope development is also dependent on the feedback of peripheral and cortical inputs.
Conclusions.
The results of our study show that central serotonergic activation is a major component of neurocardiogenic syncope. Clomipramine infusion during head-up tilt testing can reliably reproduce syncope by enhancing serotonergic activity in the central nervous system. The head-up tilt test with clomipramine may prove to be a valuable, time-saving test for the evaluation of patients with neurocardiogenic syncope.
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