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(Circulation. 1997;96:2509-2513.)
© 1997 American Heart Association, Inc.

Articles

Vagal and Sympathetic Mechanisms in Patients With Orthostatic Vasovagal Syncope

Carlos A. Morillo, MD; Dwain L. Eckberg, MD; Kenneth A. Ellenbogen, MD; Larry A. Beightol, MS; Jeffrey B. Hoag, MS; Kari U.O. Tahvanainen, MS; Tom A. Kuusela, PhD; ; André M. Diedrich, MD

From the Medical College of Virginia, Virginia Commonwealth University, and Hunter Holmes McGuire Department of Veterans Affairs Medical Center, Richmond, Va (C.A.M., D.L.E., K.A.E., L.A.B., J.B.H.); the Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland (K.U.O.T.); the University of Turku (Finland) (T.A.K.); and DLR, Institute of Aerospace Medicine, Cologne, Germany (A.M.D.).

Correspondence to Dwain L. Eckberg, MD, Hunter Holmes McGuire Department of Veterans Affairs Medical Center, Richmond, VA 23249. E-mail deckberg{at}aol.com

	Abstract

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Background Autonomic and particularly sympathetic mechanisms play a central role in the pathophysiology of vasovagal syncope. We report direct measurements of muscle sympathetic nerve activity in patients with orthostatic vasovagal syncope.

Methods and Results We studied 53 otherwise healthy patients with orthostatic syncope. We measured RR intervals and finger arterial pressures and in 15 patients, peroneal nerve muscle sympathetic activity before and during passive 60 degree head-up tilt, with low-dose intravenous isoproterenol if presyncope did not develop by 15 minutes. We measured baroreflex gain before tilt with regression of RR intervals or sympathetic bursts on systolic or diastolic pressures after sequential injections of nitroprusside and phenylephrine. Orthostatic vasovagal reactions occurred in 21 patients, including 7 microneurography patients. Presyncopal and nonsyncopal patients had similar baseline RR intervals, arterial pressure, and muscle sympathetic nerve activity. Vagal baroreflex responses were significantly impaired at arterial pressures below (but not above) baseline levels in presyncopal patients. Initial responses to tilt were comparable; however, during the final 200 seconds of tilt, presyncopal patients had lower RR intervals and diastolic pressures than nonsyncopal patients and gradual reduction of arterial pressure and sympathetic activity. Frank presyncope began abruptly with precipitous reduction of arterial pressure, disappearance of muscle sympathetic nerve activity, and RR interval lengthening.

Conclusions Patients with orthostatic vasovagal reactions have impaired vagal baroreflex responses to arterial pressure changes below resting levels but normal initial responses to upright tilt. Subtle vasovagal physiology begins before overt presyncope. The final trigger of human orthostatic vasovagal reactions appears to be the abrupt disappearance of muscle sympathetic nerve activity.

Key Words: baroreflex • sympathetic nerve activity • vagal

	Introduction

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Orthostatic vasovagal syncope is the most common form of syncope.¹ Bradycardia is vagally mediated, because it can be corrected by administration of atropine.² Hypotension is not vagally mediated, because it occurs in the absence of bradycardia and persists despite restoration of heart rate to usual (or higher) levels by atropine, or electronic pacing.³ Lewis² suggested that hypotension during vasovagal reactions occurs because of vasodilation. We report direct measurements of muscle sympathetic nerve activity in patients who did or did not faint during passive upright tilt.

	Methods

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We studied 53 patients (23 women) with two or more episodes of orthostatic syncope during the preceding 6 months. Patients' average age (±SEM) was 48±3 years (range, 12 to 82). No patient had evidence of structural heart disease or diabetes. All patients (or their parents) gave written informed consent before this approved study.

We recorded the ECG, photoplethysmographic arterial pressure (Finapres, Ohmeda 2300), respiration (pneumobelt in 11 microneurography patients), and multiunit postganglionic peroneal nerve muscle sympathetic activity (in 15 patients).⁴ The filtered nerve signal was amplified, rectified, and integrated by a Nerve Traffic Analyzer (model 662C-3, University of Iowa Bioengineering). We digitized all signals at 250 Hz with commercial hardware and software (WINDAQ, Dataq Instruments).

RR interval, systolic pressure, respiration, and integrated muscle sympathetic nerve activity spectral powers were estimated with fast Fourier transforms.⁵ We normalized muscle sympathetic bursts with signal-to-noise ratios >3:1 by determining average burst areas during the initial supine rest period and dividing this number by the area of subsequent bursts. We calculated coherence between diastolic pressure and muscle sympathetic nerve activity with cross-spectral analysis and considered these signals to be related significantly when coherence was 0.50.⁶

We measured vagal arterial baroreflexes with regression of RR intervals on systolic pressures after sequential intravenous injections of 0.15 mg nitroprusside followed 60 seconds later by 0.15 mg phenylephrine and by phenylephrine followed by nitroprusside.⁷ We also estimated vagal baroreflex gain from the square root of the ratio of fast Fourier transform systolic pressure and RR interval power spectra in time series with coherence 0.5, at frequencies between 0.04 and 0.15 Hz.⁶ We measured sympathetic baroreflex responses with regression of sympathetic bursts integrated over 3 mm Hg pressure ranges on average diastolic pressures within each pressure range.

We made control recordings for 7 minutes, did pharmacological baroreflex testing, and, when all measurements had returned to baseline levels, began tilt table testing. We tilted subjects abruptly to a 60 degree head-up position on an electrically driven table with a foot support. If presyncope did not occur by 15 minutes, we gave 1 to 2 µg/min intravenous isoproterenol to increase baseline heart rate by 20%.⁸ We returned patients to the supine position immediately if syncope or presyncope occurred, systolic pressure fell to <70 mm Hg, or heart rate fell to <40 bpm. Patients did not control their breathing.

We used the unpaired t test (with normally distributed data) or the Wilcoxon signed ranks test to identify differences between baseline measurements and baroreflex slopes. We used a repeated-measures mixed model analysis⁹ to detect group differences and trends at the beginning and end of tilt, with time as a covariant. We assumed differences to be significant at P.05.

	Results

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Twenty-one of the 53 patients, including 7 of the 15 microneurography patients, experienced presyncope during upright tilt. All except two presyncopal patients in the microneurography group were given isoproterenol. Age, the proportion of women, RR intervals, and systolic and diastolic pressures during supine rest were comparable (P>.14) in patients with ("presyncopal") and without presyncope ("nonsyncopal"). In the subgroup of patients studied with microneurography, mean (±SEM) echocardiographic left ventricular ejection fractions were identical (68±2%), and baseline muscle sympathetic nerve activity, however expressed, was comparable in presyncopal and nonsyncopal groups.

Vagal baroreflex gain during pressure reductions and elevations provoked by nitroprusside-phenylephrine sequences was significantly less in presyncopal than nonsyncopal patients (4.4±0.8 versus 8.5±1.3 ms/mm Hg, P=.029; 4.2±1.5 versus 11.0±1.5 ms/mm Hg, P=.019) but was comparable (P.471) after phenylephrine-nitroprusside sequences. Increases of muscle sympathetic nerve activity after injections of nitroprusside tended to be less in presyncopal than nonsyncopal patients (-0.0069±0.0121 versus -0.054±0.0195 arbitrary units/mm Hg, P=.073). Three presyncopal patients and one nonsyncopal patient had concordant sympathetic responses (reductions of muscle sympathetic nerve activity during reductions of arterial pressure). Arterial pressure elevations after phenylephrine injections silenced muscle sympathetic nerve activity and are not reported.

The remaining experimental results are from microneurography patients. In 12 of these 15 patients, the quality of sympathetic nerve recordings was maintained throughout the experiment. In one patient, the recording site was lost at the beginning of tilt. In two patients, sympathetic activity disappeared at the onset of presyncope and did not reappear after they were returned to the horizontal position. We suspect but cannot prove that loss of sympathetic activity in these two patients was due to vasovagal physiology. Accordingly, we excluded their recordings from analyses of data obtained during the last minutes of tilt.

Mean RR interval and systolic and diastolic pressure spectral power in 0.05 to 0.15 and 0.15 to 0.4 Hz ranges and their ratios were comparable (P.524) in presyncopal and nonsyncopal microneurography patients. Muscle sympathetic nerve activity spectral power, however, was substantially and significantly lower in presyncopal than nonsyncopal groups, in both 0.10 Hz and respiratory frequency ranges (2.8±1.2 versus 11.7±2.3 Hz, P=.006; 0.5±0.2 versus 5.6±2.1 Hz, P=.026). Respiratory spectral power in the 0.05 to 0.15 Hz range was comparable (P=.21) in presyncopal and nonsyncopal patients. Significant (.50) coherence between diastolic pressure and muscle sympathetic nerve activity was present before tilt in only one presyncopal patient and one nonsyncopal patient.

During the first minutes of tilt (Fig 1), RR interval decreases and systolic and diastolic pressure and muscle sympathetic nerve increases were comparable in presyncopal and nonsyncopal patients (P.275) and had no significant trends. During the 200 seconds before the onset of presyncope, however, average RR intervals in the presyncopal group were lower (0.53±0.09 versus 0.75±0.08 ms, P=.036) and systolic and diastolic pressures and muscle sympathetic nerve activity were comparable (P.214). Breathing frequency before, during the early minutes of tilt, at the onset of isoproterenol infusion, and at the end of tilt was comparable in presyncopal and nonsyncopal patients (P.11). Although there was no significant trend of breathing frequency during tilt in either group, one nonsyncopal patient increased his breathing frequency from 21 breaths per minute during isoproterenol infusion to 37 by the end of tilt.

View larger version (55K): [in this window] [in a new window]   Figure 1. Mean (±SEM) RR intervals, arterial pressure, and muscle sympathetic nerve activity (integral of normalized burst areas/5 seconds) for all 14 patients who maintained sympathetic neurograms during upright tilt. (Nerve recording sites were lost in two presyncopal patients at the onset of presyncope.) Horizontal lines define average steady-state values obtained from nonsyncopal patients. Statistical comparisons for the two left panels were made from 5-second averages, beginning 2 minutes after the beginning of tilt and continuing for 5 minutes. Statistical comparisons for the two right panels were made from 5-second averages, beginning at -200 seconds and continuing until the onset of presyncope (or until the same average time after the onset of tilt in nonsyncopal patients).

During 100 seconds before the onset of presyncope, systolic and diastolic pressures and muscle sympathetic nerve activity tended to decline (P=.015, .054, and .19) and RR intervals tended to increase. An iterative least-squares regression algorithm¹⁰ defined the point at which these trends began. Reduction of systolic pressure began first (at -121±15 seconds, at a rate of 0.32 mm Hg/s). Reduction of diastolic pressure (at -101±21 seconds; 0.01 mm Hg/s) and muscle sympathetic nerve activity (at -89±21 seconds; 0.01 arbitrary units/s) followed. Barely perceptible RR interval lengthening began last (at -69±16 seconds; 0.44 ms/s). At the onset of presyncope (Fig 1), average muscle sympathetic nerve activity and arterial pressure declined sharply and RR intervals lengthened dramatically.

Fig 2 depicts fast Fourier transforms of 64 seconds of muscle sympathetic nerve activity, moved by 32-second steps through a recording obtained from one patient. Muscle sympathetic nerve activity at the cardiac frequency increased in parallel with heart rate. Isoproterenol further increased sympathetic nerve activity and heart rate. Low-frequency sympathetic nerve activity was prominent throughout the record.

View larger version (58K): [in this window] [in a new window]   Figure 2. Entire record from one presyncopal patient from before the beginning of upright tilt until after he had been returned to the horizontal position. At the onset of presyncope (last vertical dashed line, top three panels), sympathetic nerve activity disappeared at all frequencies. After the patient had been returned to the horizontal position, normal levels of muscle sympathetic activity returned. The record indicates that sympathetic activity oscillated at very low (bottom margin of bottom panel), low (0.05 Hz), respiratory, and cardiac frequencies (peaks from middle of left margin, moving toward the upper right margin). Prominent low-frequency rhythms were present also in nonsyncopal patients.

At the onset of presyncope, muscle sympathetic nerve activity disappeared at all frequencies, systolic pressure plummeted, and RR intervals increased. (The patient was returned to the horizontal position at the time the large fluctuations of RR intervals began.)

Low-frequency (0.05 to 0.15 Hz) RR interval, arterial pressure, respiration, and muscle sympathetic nerve activity rhythms, measured with moving fast Fourier transform power spectra, were similar in both groups and constant. Spontaneous vagally mediated arterial baroreflex gain⁶ was comparable in presyncopal and nonsyncopal patients during supine rest (13.5±1.9 versus 9.5±1.9 ms/mm Hg, P=.287) and did not change systematically during the last 200 seconds before the onset of presyncope (or the same interval after tilt in nonsyncopal patients).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Our study defines orthostatic vasovagal mechanisms. Patients destined to experience orthostatic presyncope have impaired vagal and normal muscle sympathetic baroreflex responses to arterial pressure changes below baseline levels. Presyncopal patients have normal reductions of RR intervals and increases of systolic and diastolic pressure and muscle sympathetic nerve activity during the early minutes of tilt but subtle evidence for vasovagal physiology in the minutes preceding presyncope. The full-blown orthostatic vasovagal reaction, which is not preceded by changes of low-frequency sympathetic or vagal rhythms¹¹ or spontaneous vagal baroreflex gain,¹² is ushered in by abrupt cessation of sympathetic nerve traffic to skeletal muscle.

Our findings refute the notion that vasovagal hypotension reflects vasodilation secondary to increased sympathetic nerve traffic. In all except one patient who experienced orthostatic vasovagal reactions, muscle sympathetic nerve activity disappeared (Figs 1 and 2). In one patient, sympathetic activity was declining abruptly as she was being returned to the horizontal position. Our findings do not exclude vasodilation secondary to increased levels of circulating epinephrine or vasodilator substances. We are aware of only two published case reports involving direct measurements of muscle sympathetic nerve activity during orthostatic vasovagal reactions.^{13 14} However, there are several case reports of muscle sympathetic nerve activity recorded in supine subjects during vasovagal reactions induced by lower body suction, hemodialysis, or nitroprusside.^{15 16 17 18 19 20} Regardless of body position, all published recordings document disappearance of muscle sympathetic nerve activity at the beginning of vasovagal reactions. Disappearance of sympathetic vasoconstrictor nerve traffic to the skeletal muscle vascular bed is sufficient to explain vasovagal reactions, since skeletal muscle comprises more than 40% of human body mass.

We have no explanation for our unique observation that supine patients who subsequently experience vasovagal reactions during upright tilt have major reductions of muscle sympathetic nerve spectral power at low and respiratory frequencies.

Data recorded during the final 200 seconds of upright tilt before the onset of vasovagal reactions (Fig 1) suggest that vasovagal physiology begins before it becomes apparent clinically. Our patients experienced subtle but steady reductions of arterial pressure and muscle sympathetic nerve activity and increases of RR intervals before the overt event. Arterial pressure reductions preceded sympathetic nerve activity reductions and, as reported earlier by Sra and coworkers,³ RR interval prolongations. However, during this period, when the trends were paradoxical, mean RR intervals were significantly shorter (not longer²¹ ), and mean muscle sympathetic nerve activity was insignificantly greater in presyncopal than nonsyncopal patients.

The major limitation of our study is that all our subjects were patients referred because they had experienced orthostatic syncope. We defend our selection of subjects on two counts. First, we wanted to evaluate the range of patients with clinical orthostatic vasovagal reactions; we thought it unlikely that we could conduct our invasive study in asymptomatic volunteers whose ages were similar to those referred to us for evaluation (12 to 82 years). More importantly, orthostatic vasovagal syncope is not necessarily a disease. Reductions of renal sympathetic nerve activity in animals²² and plasma norepinephrine levels in humans²³ occur physiologically during reductions of arterial pressure, and vasovagal reactions occur in virtually everyone, if the stress is great enough.^{24 25}

In summary, we measured arterial baroreflex function and directly recorded muscle sympathetic nerve activity in patients who did or did not experience vasovagal reactions during passive head-up tilt, with or without isoproterenol infusion. We found that patients destined to experience vasovagal reactions have subnormal vagal baroreflex responses to pressure changes below baseline. We found also that subtle vasovagal physiology is present before it becomes apparent clinically, and that the full blown vasovagal reaction is ushered in by abrupt disappearance of muscle sympathetic nerve vasoconstrictor traffic. Mechanisms responsible for the gradual and then sudden switching from hemodynamic compensation to vasovagal physiology remain to be determined.

	Acknowledgments

 
This study was supported by grants and contracts from the Department of Veterans Affairs, the National Institutes of Health (HL-22296), and the National Aeronautics and Space Administration (NAG 2-408 and NAS-17720). We thank our patients and Dr I-Li Lu, who performed statistical analyses.

Note Added in Proof

In the June 1997 issue of the Journal of Clinical Investigation (1997;99:2736-2744), Mosqueda-Garcia and colleagues report responses of 57 subjects (including 14 studied with sympathetic microneurography) to passive upright tilt. They studied three groups, including patients with clinical orthostatic vasovagal syncope, and healthy subjects with no history of syncope who did or did not faint during tilt. Mosqueda-Garcia's study and ours differ in important respects. His protocol was different (tilt was graded, and nitroprusside and phenylephrine were given as infusions rather than boluses, after rather than before tilt). Moreover, his subjects were younger than ours, and importantly, had orthostatic hypotension (ours did not). Although there are also differences in the results that merit close scrutiny (including particularly vagal and sympathetic baroreflex malfunction during tilt, which Mosqueda-Garcia found and we did not), the main conclusion of the two studies is the same: Clinical orthostatic vasovagal reactions are ushered in by disappearance of muscle sympathetic nerve traffic.

Received June 23, 1997; revision received August 21, 1997; accepted August 21, 1997.

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