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J Am Coll Cardiol, 2006; 48:516-522, doi:10.1016/j.jacc.2006.04.073 (Published online 11 July 2006).
© 2006 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: AUTONOMIC FUNCTION

Norepinephrine Transporter Inhibition Prevents Tilt-Induced Pre-Syncope

Christoph Schroeder, MD*, Andreas L. Birkenfeld, MD*, Antje F. Mayer*, Jens Tank, MD*, Andre Diedrich, MD, PhD{dagger}, Friedrich C. Luft, MD* and Jens Jordan, MD*,*

* Franz-Volhard Clinical Research Center, Medical Faculty of the Charité and HELIOS Klinikum, Berlin, Germany
{dagger} Autonomic Dysfunction Service, Vanderbilt University, Nashville, Tennessee

Manuscript received January 25, 2006; revised manuscript received March 10, 2006, accepted April 10, 2006.

* Reprint requests and correspondence: Dr. Jens Jordan, Franz-Volhard Clinical Research Center, Charité Campus Buch, Wiltbergstr. 50, Haus 129, 13125 Berlin, Germany (Email: jordan{at}fvk.charite-buch.de).


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We tested the hypothesis that pharmacological norepinephrine reuptake transporter (NET) inhibition delays the onset of head-up tilt-induced presyncope in healthy subjects.

BACKGROUND: Treatment of neurally mediated syncope is unsatisfactory. In a previous study in a small number of healthy subjects, pharmacologic NET inhibition delayed the onset of head-up tilt-induced pre-syncope.

METHODS: We combined data sets from 3 substudies comprising 51 healthy subjects without a history of syncope. In a double-blind, randomized, cross-over fashion, subjects underwent 2 head-up tilt tests, once with placebo and once with a NET inhibitor (sibutramine or reboxetine). Tilt testing was prematurely ended when pre-syncopal symptoms such as dizziness, nausea, or visual disturbances occurred together with a decrease in blood pressure and/or heart rate.

RESULTS: The mean tolerated tilt test duration was 29 ± 2 min with placebo and 35 ± 1 min with NET inhibition (p = 0.001). The odds ratio for premature abortion of head-up tilt testing was 0.22 (95% confidence interval 0.09 to 0.55, p < 0.001) in favor of NET inhibition. Norepinephrine reuptake transporter inhibition elicited a pressor response and increased upright heart rate.

CONCLUSIONS: In healthy subjects, NET inhibition prevents tilt-induced neurally mediated (pre)syncope. Therefore, NET inhibition may be a worthwhile target of drug intervention for larger trials in highly symptomatic patients with neurally mediated syncope.

Abbreviations and Acronyms
  DHPG = dihydroxyphenylglycol
  HR = heart rate
  NET = norepinephrine reuptake transporter

Treatment of neurally mediated syncope is unsatisfactory. Patients with rare syncopal episodes may respond to reassurance, increased fluid and sodium intake, and physical countermeasures (1). Highly symptomatic patients would qualify for more aggressive treatment. Numerous drugs have been proposed for this indication. Given the questionable efficacy, current guidelines do not recommend a particular drug for the use in neurally mediated syncope (1). Furthermore, recent trials showed that pacemaker therapy in patients with neurally mediated syncope are of no value (2,3). This state of affairs may be explained by the fact that the underlying pathophysiology of neurally mediated syncope is still obscure (4). The "ventricular theory" proposed that activation of ventricular stretch receptors through forceful contractions of an "empty" ventricle triggers bradycardia and vasodilatation (5). However, the left ventricle is not empty during syncope onset (6), and neurally mediated syncope can occur in cardiac transplant patients with a denervated heart (7). Furthermore, careful physiological studies in animals question the existence of ventricular receptors that respond to physiological changes in stretch (8,9). Excessive cardiac sympathetic activation was also implicated earlier, giving rise to the widespread use of beta-blockers. However, a number of studies failed to show efficacy of beta-blockers in neurally mediated syncope (10–14). In contrast, yohimbine-induced sympathetic activation improved, rather than worsened, orthostatic tolerance in highly selected syncope patients (15). Perhaps cardiac sympathetic activation is beneficial in neurally mediated syncope. Inhibition of the neuronal norepinephrine transporter (NET) results in a more selective increase in cardiac sympathetic drive (16). In a small number of healthy subjects, pharmacological NET inhibition delayed the onset of head-up tilt-induced pre-syncope (17). We combined data sets from our current and earlier studies to confirm and to extend the observation in a larger number of subjects.


   Methods
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Study population.   We studied healthy volunteers without a history of spontaneous syncope. Table 1 summarizes the study population of the 3 substudies. The combined data set comprised 51 individuals.


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  		Table 1. Study and Subject Characteristics
 
Study design.   All studies were conducted in a double-blind, placebo-controlled, cross-over fashion. Subjects were tested twice, once with placebo, and once with a NET inhibitor. Treatment sequence was randomized. The duration of NET inhibitor treatment, the NET inhibitor used, and the head-up tilt protocol differed between studies (Table 1). Reboxetine is a selective inhibitor of NET that is used for treatment of depression (18,19). In the first study, subjects ingested 8 mg reboxetine or matching placebo 13 and 1 h before testing (17). In the second study, a single dose of 8 mg reboxetine or placebo was given 90 min before the tilt test. In the third study, subjects were treated with the norepinephrine and serotonin transporter inhibitor sibutramine (20). The drug is widely used for the treatment of obesity. Subjects took 10 mg sibutramine 26 and 14 h, and 20 mg sibutramine 2 h before testing or a matching placebo (21).

All head-up tilt studies were conducted after an overnight fast and a baseline period of at least 30 min in the supine position. In studies 1 and 3, we conducted a graded head-up tilt test. Subjects were subjected to 3 min each at 15°, 30°, 45°, and 60° head-up tilt, before the final tilt angle of 75° was achieved. Subjects remained at 75° head-up tilt for 30 min. Maximal tilt time in studies 1 and 3 was 42 min (17,21). In study 2, subjects underwent a 45° head-up tilt for maximal 30 min. Tilt testing was aborted prematurely by the experimenters (C.S. and A.L.B.) when the subjects reported intolerable orthostatic symptoms such as dizziness, nausea, or visual disturbances. Neurally mediated (pre)syncope was defined as either combined (vasovagal) type (progressive decrease in blood pressure and heart rate [HR] of at least 30 mm Hg and 20 beats/min, respectively) or vasodepressor type (isolated progressive decrease in blood pressure of at least 20 mm Hg). In all studies, blood pressure was continuously monitored by a finger servoplethysmomanometer (2300 Finapres, Ohmeda, GE Healthcare, Waukesha, Wisconsin) that was kept at heart level throughout the experiments. In addition, blood pressure was measured by an automated oscillometric sphygmanometer (Dinamap, Critikon, GE Healthcare) at regular intervals. Heart rate was monitored continuously by electrocardiogram (Viridia CMS, Hewlett Packard, Palo Alto, California).

Catecholamine determinations.   Plasma catecholamine concentrations were determined by a modified high-pressure liquid chromatographic method (22) from blood samples drawn after 30 min of supine rest and at the end of head-up tilting.

Statistics.   The primary outcome variable was the tolerated tilt duration in minutes with placebo and with NET inhibition in the combined data set. The null hypothesis was that the tilt test duration with placebo and with NET inhibition is equal. We compared variances between the groups by using the F test. Student paired t test or Wilcoxon matched pairs test was used to compare parametric and non-parametric data, respectively. The odds ratio was calculated using a 2-by-2 table. Two-way analysis of variance was used to test for sequence and treatment effects and possible interactions. Kaplan-Meier curves were compared using the log-rank test. All statistical tests were 2-tailed. A value for p < 0.05 was considered significant. All data are expressed as mean ± SEM.


   Results
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Discussion
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Of the 51 subjects, 27 received placebo on the first study day, followed by NET inhibition on the second day. The remaining 24 subjects received study drugs in the reversed order. The mean tolerated tilt test duration was 29 ± 2 min with placebo and 35 ± 1 min with NET inhibition (p = 0.001). We did not find an effect of treatment sequence on tolerated tilt test duration (p = 0.5 for the interaction of sequence and treatment response). The odds ratio for premature abortion of head-up tilt testing was 0.22 (95% confidence interval: 0.09 to 0.55, p < 0.001) in favor of NET inhibition compared with placebo. Figure 1 shows individual differences in tolerated head-up tilt duration between placebo and NET inhibition with reboxetine or sibutramine. The improvement in tolerated tilt test duration was consistent between studies (p = 0.9 for the interaction between study and treatment response). The average improvement in tolerated tilt test time was 6 ± 3 min in study 1 (p < 0.05), 6 ± 2 min in study 2 (p < 0.05), and 4 ± 3 min in study 3 (p = 0.11). With placebo, 26 subjects (51%) completed tilt testing without symptoms. Twenty-five subjects (49%) experienced (pre)syncope either of the combined type (n = 23) or the vasodepressive type (n = 2) during head-up tilt testing on the placebo day. With pharmacologic NET inhibition, 42 subjects (82%) completed the test without symptoms. In 9 subjects (18%), tilt testing was aborted prematurely, due to (pre)syncope of the combined type (n = 2) or intolerable orthostatic symptoms without bradycardia or hypotension (n = 7).


Figure 1
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  		Figure 1 Individual differences in tolerated time during head-up tilt testing between norepinephrine reuptake transporter (NET) inhibition and placebo treatment. In subjects who tolerated the full duration of the tilt study, both on placebo and during NET inhibition, the difference is 0. The solid vertical lines indicate the mean value and the boundaries of the 95% confidence interval.

 
Of the 25 individuals who developed (pre)syncope during head-up tilt testing on the placebo day, 16 completed the tilt test with NET inhibition without symptoms. All subjects who experienced pre-syncope on both study days withstood the orthostatic stress for a longer time after NET inhibition than with placebo (mean increase in orthostatic tolerance with NET inhibition 9 ± 3 min compared with that of placebo). Three subjects developed pre-syncope during head-up tilt only with NET inhibition and had no symptoms on the placebo day. Figure 2 shows Kaplan-Meier plots for "tilt-test survival" for all 3 studies. "Tilt-test survival" was significantly improved with NET inhibition in studies 1 and 2 and borderline in significance for study 3.


Figure 2
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  		Figure 2 Kaplan-Meier plots for "tilt-test survival" with placebo (broken lines) and norepinephrine reuptake transporter (NET) inhibition (solid lines) for all 3 studies separately.

 
Blood pressure and HR responses in the supine position and with head-up tilt are given in Table 2. In each study, NET inhibition raised supine blood pressure and supine HR. In the combined data set, blood pressure was 117 ± 2/66 ± 1 mm Hg with placebo and 128 ± 2/69 ± 1 mm Hg with NET inhibition (p < 0.0001 for systolic and <0.01 for diastolic blood pressure). Supine HR was 62 ± 1 beats/min with placebo and 67 ± 1 beats/min with NET inhibition (p < 0.0001). In patients who completed head-up tilt testing without pre-syncope, HR towards the end of tilt testing was profoundly increased with NET inhibition (112 ± 3 beats/min with NET inhibition, 87 ± 3 beats/min with placebo, p < 0.0001). Individual HR and blood pressure data at the end of head-up tilt testing in (pre)syncopal patients are illustrated in Figure 3. These measurements correspond to the last 10 s before the test had to be aborted. Both blood pressure and HR at the end of head-up tilt were significantly higher in NET inhibition subjects compared with those of placebo-treated subjects. Figure 4 shows representative blood pressure and HR tracings over the entire head-up tilt test in 1 subject with placebo and with NET inhibition.


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  		Table 2. Systemic Hemodynamics in the Supine and Upright Position and Mean Tilt Duration
 

Figure 3
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  		Figure 3 Individual data of blood pressure and heart rate in (pre)syncopal patients on norepinephrine reuptake transporter (NET) inhibition and on placebo immediately before tilt testing had to be aborted. bpm = beats/min.

 

Figure 4
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  		Figure 4 Original beat-by-beat tracings of finger blood pressure (BP) (upper tracings) and heart rate (HR) (lower tracings) in a representative subject on placebo (left) and on norepinephrine reuptake transporter (NET) inhibition with reboxetine (right). On placebo, the patient experienced a typical neurally mediated pre-syncope with a sudden decrease in HR and BP after 24 min of head-up tilt (asterisk). On NET inhibition, upright HR was markedly increased. The subject was able to complete the tilt protocol (42 min) without pre-syncope. bpm = beats/min.

 
Plasma concentrations of catecholamines are given in Table 3. Compared with placebo, NET inhibition decreased concentrations of norepinephrine and its main degradation product, dihydroxyphenylglycol (DHPG), in the supine position. During head-up tilt, DHPG concentrations were markedly reduced with NET inhibition, while norepinephrine concentrations tended to be increased (p = 0.07). The catecholamine profile in the supine position did not differ between (pre)syncopal subjects and subjects who completed head-up tilt testing. With placebo, epinephrine concentrations in the upright position were 2-fold higher in (pre)syncopal subjects (115 ± 20 pg/ml) compared with individuals who completed head-up tilting without symptoms (63 ± 7 pg/ml, p < 0.01). With NET inhibition, there was no difference in upright epinephrine concentrations in (pre)syncopal and asymptomatic subjects (63 ± 15 pg/ml vs. 55 ± 5 pg/ml, respectively, p = 0.5).


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  		Table 3. Supine and Upright Catecholamines With Placebo and With NET Inhibition
 

   Discussion
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We tested the hypothesis that short-term NET inhibition prevents head-up tilt-induced neurally mediated pre-syncope or syncope. To address the issue in a sensitive fashion, we combined the data set from 3 separate double-blind, randomized, placebo-controlled studies in healthy subjects. Two of these studies have been previously published (17,21). Norepinephrine reuptake transporter inhibition was remarkably effective in delaying or preventing neurally mediated pre-syncope or syncope. Even in subjects who experienced (pre)syncope, blood pressure and HR were higher during NET inhibition compared with those seen with placebo. Our findings may have important pathophysiological and clinical implications.

In contrast with selective NET inhibition with reboxetine, sibutramine attenuates both neuronal norepinephrine and serotonin uptake (23). Thus, sibutramine could influence sympathetic regulation through changes in norepinephrine turnover, changes in serotonin turnover, or both mechanisms combined. Whether serotonin is involved in the pathophysiology of neurally mediated syncope is still under debate (4,9). Paroxetine, a serotonin reuptake blocker, has been shown to be effective in treating neurally mediated syncope in a single study (24). However, in anesthetized rabbits, selective inhibition of neuronal serotonin uptake had no effect on HR, arterial pressure, post-ganglionic renal sympathetic nerve activity, and norepinephrine spillover (25). Thus, changes in autonomic cardiovascular regulation with sibutramine in our study are probably related to changes in norepinephrine uptake rather than an effect on serotonin turnover.

Norepinephrine reuptake transporter has a central role in norepinephrine turnover. Throughout the body, approximately 80% of released norepinephrine is taken up from the synaptic cleft through NET and either repackaged or metabolized (26). Systemic NET inhibition is associated with complex changes in the regulation of the sympathetic nervous system. In peripheral tissues, NET inhibition tends to raise synaptic norepinephrine concentrations (16). In the brain, NET inhibition has a sympatholytic effect presumably through activation of alpha-2 adrenoreceptors (16,27,28). The balance between peripheral sympathetic stimulation and central sympathetic inhibition differs between organs. For example, in the kidney and in the forearm, NET inhibition attenuates norepinephrine spillover (16). In contrast, NET inhibition substantially increases cardiac norepinephrine spillover (16). In the heart, pre- and post-synaptic membranes are located particularly close to each other (26). The anatomical feature makes the heart more dependent on NET for removal of norepinephrine from the synaptic cleft. Thus, a larger proportion of the released norepinephrine is taken up through NET in the heart compared with other organs (29). Genetic NET deficiency (30) and pharmacologic NET blockade (17) induce an increase in HR, particularly with standing. Indeed, NET deficiency is a rare cause of the postural tachycardia syndrome. Thus, NET inhibitors are particularly suitable to selectively increase adrenergic drive to the heart.

The orthostatic tachycardia with NET inhibition is mediated through beta-adrenoreceptor stimulation (21). The increased upright HR with NET inhibition in our study is consistent with increased cardiac beta-adrenoreceptor stimulation. If neurally mediated syncope was mediated through excessive cardiac sympathetic stimulation, one would expect to observe worsening in orthostatic tolerance with NET inhibition. We found the opposite. Similarly, systemic sympathetic activation with yohimbine improved orthostatic tolerance in highly selected patients with neurally mediated syncope (15). All these findings challenge the concept that excessive adrenergic stimulation of the heart sets off neurally mediated syncope. Therefore, it is not surprising that beta-blockers are not efficacious in syncope treatment (10–14).

During neurally mediated syncope, sympathetic activity decreases suddenly resulting in vasodilatation and bradycardia (5). It has been suggested that epinephrine released before the onset of the hypotension may trigger neurally mediated syncope (31). Similar to previous studies (5,31–33), epinephrine concentrations in the upright position were markedly increased in (pre)syncopal subjects on placebo. Norepinephrine reuptake transporter inhibition "normalized" upright epinephrine concentrations in these subjects. It is possible that the beneficial effect of NET inhibition on orthostatic tolerance is explained, in part, by attenuated epinephrine release. Another possible explanation for the beneficial effect of NET inhibition is that higher synaptic norepinephrine concentrations are maintained even when sympathetic efferent activity shuts off. Possibly, NET inhibition interferes with the still unknown neural pathways that induce sympathetic withdrawal. Earlier pacemaker studies addressed the issue of bradycardia directly; however, the results were disappointing (2). In an accompanying editorial to that study, the issue was raised if there is an effective treatment for neurally mediated syncope (34). Our study cannot answer that question. Nevertheless, we believe that we have made a step in the right direction.

The major limitation of our work is that we studied "false-positive" subjects without a history for spontaneous syncope. The mechanism leading to bradycardia and hypotension may differ between "false-positive" subjects and syncope patients. Even between different subsets of syncope patients, the mechanism may not be the same (35). For example, in a subset of older syncope patients with very frequent syncopal spells, sympathetic activity fails to increase properly with upright posture resulting in a more gradual depressor response (5). In other patients, sympathetic activity is not reduced until the actual onset of syncope (36). Given the heterogeneity of sympathetic regulation, our results may not be simply extrapolated to all syncope patients. Yet the underlying neural mechanism appears to be similar in a larger proportion of syncope patients and in "false-positive" control subjects. We determined the response to short-term NET inhibition. Thus, we cannot exclude the possibility that the effect of NET inhibition on neurally mediated syncope abates over time. Finally, the high occurrence of tilt-induced (pre)syncope in our study population of healthy volunteers is somewhat surprising. In fact, the percentage of false-positive results of head-up tilt testing in healthy controls varies extremely. This heterogeneity may be explained, in part, with differences in tilt testing protocols (37,38). One possible explanation for the large number of false-positive tilt tests in our study is the instrumentation with intravenous catheters.

Despite these issues, we suggest that NET may be involved in the pathogenesis of neurally mediated syncope. Norepinephrine reuptake transporter inhibition may be a worthwhile target of drug intervention for larger trials in highly symptomatic patients with neurally mediated syncope. However, given the benign prognosis of the condition, a potentially beneficial effect has to be weighed against a significant increase in blood pressure and HR.


   Footnotes
 
This work was supported, in part, by a Deutsche Forschungsgemeinschaft grant. Dr. Jordan received lecture fees from Abbott Pharmaceuticals.


   References
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 Abstract
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 Results
 Discussion
 References
 

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