Syncope is defined as a sudden temporary loss of consciousness associated with a loss of postural tone with spontaneous recovery. Neurally mediated syncope is the term used to refer to syncope that results from reflex mechanisms associated with inappropriate vasodilatation and/or bradycardia. Head-up tilt (HUT) testing has assumed an important role in evaluating patients with unexplained syncope. Patients with a positive response can be classified into mixed, cardioinhibitory, and vasodepressor categories.

Currently, these responses are believed to have a common pathophysiological mechanism. Head-up tilt leads to pooling of venous blood in the lower limbs, resulting in decreased venous return. The normal compensatory response to head-up posture is reflex tachycardia, more forceful contraction of the left ventricle, and vasoconstriction. However, in individuals with neurally mediated syncope, this forceful ventricular contraction in the setting of a relatively empty cavity may activate the cardiac mechanoreceptors. An afferent pathway consisting of unmyelinated left ventricular vagal C fibers transmits signals to specific central nervous system sites. This reduces the efferent sympathetic tone and results in reflex hypotension and/or bradycardia (Bezold-Jarisch reflex).

However, provocation of syncope with HUT testing after heart transplantation has raised questions about this mechanism, because no evidence of reinnervation has been found in these patients. This suggests the existence of a peripheral element in the pathophysiology of neurally mediated syncope. Based on the central role of the autonomic nervous system in the genesis of neurally mediated syncope, heart rate variability analysis has been used to explore the cardiac autonomic tone in response to head-upright tilt in normal subjects, HUT results in a significant increase of the low frequency power spectrum in addition to withdrawal of the high frequency or parasympathetic tone. Controversial results have been obtained with heart rate variability analysis in neurally mediated syncope. Heart rate variability has been found to be decreased in normal adults and elderly people, while other investigators have found increased parasympathetic activity. We hypothesized that the response of the autonomic nervous system to head-up tilt is different in patients showing cardioinhibitory and vasodepressor responses. We, therefore, used heart rate variability analysis to explore the differential responses of cardiac autonomic tone to HUT in a group of patients with a positive non-pharmacological tilt-table test.

Twenty-four consecutive patients with a history of ?2 episodes of syncope were included in the study. Patients were sent from the Outpatient Clinic to the National Institute of Cardiology Electrophysiology Department for additional evaluation. The study group consisted of 14 male and 10 female patients aged 10 to 62 years. All had a positive response during a non-pharmacological HUT test, manifesting different types of syncope during the tilt test. The group showing a mixed response included eight patients (3 females and 5 males) whose mean age was 18 ± 8 years. The group showing a cardioinhibitory response consisted of nine patients (4 females and 5 males) whose ages averaged 17 ± 4 years. The group showing a vasodepressor response consisted of seven patients (3 females and 4 males) with a mean age of 52 ± 19 years.

Seven days before the study, all drugs with possible effects on the autonomous nervous system were withdrawn. After a thorough clinical assessment including a 12-lead electrocardiogram, 24-h ambulatory electrocardiogram monitoring, an echocardiogram and a neurologic evaluation, no evidence of heart disease and no apparent cause of syncope were found in any patient. Patients were submitted to a tilt test after an 8-h fast, between 10:00 a.m. and 1:00 p.m., in an isolated, dimly lit room. Normal saline solution (0.9%) was administered to maintain a permeable venous route, and patients were continuously monitored by electrocardiography. The tilt test was performed on an electrically driven tilt table capable of rotating from 0° to 90° on a horizontal line. Patients were placed in the supine position at 0° and remained in that position for 5 min. Afterward, the table was abruptly tilted to 70° in a standing position. Blood pressure was measured with a sphygmomanometer every 5 min and every minute after symptoms appeared. The test was interrupted when syncope or pre-syncope with hypotension occurred, at which time the patients were immediately returned to the supine position.

The ECG was obtained through continuous electrocardiographic recordings and stored in a personal computer. Heart rate variability was automatically analyzed by means of the Predictor program (Corazonix Corp., Oklahoma City, OK, USA) using Fast Fourier Transform (FFT) analysis. The time domain measures analyzed were the following: (a) mean R-R interval; (b) standard deviation of all R-R intervals (SDNN); (c) standard deviation of the averages of R-R intervals in all 5-min segments of the entire recording (SDANN) (normal >100); (d) square root of the mean of the sum of the squares of differences between adjacent R-R intervals (rMSSD) (normal range 1–25 msec); and (e) percentage of beats that differed more than 50 msec from the previous beat (pNN50) (normal range 10–20%).

Frequency domain measures were analyzed in 60-sec periods after 5 min of supine rest, following 1 min in a 70° upright position, 2 and 1 min before syncope, and finally, 1 and 5 min after syncope in the supine position. Power spectral density was calculated by a FFT algorithm producing a 512-point spectrum for the 0.01 to 1.0 Hz frequency band (total spectrum). The low frequency (0.04–0.15 Hz) and high frequency (0.15–0.4 Hz) bandwidth areas were calculated and power values were expressed as natural logarithm because they were not normally distributed. Clinical studies have shown that the power of the high-frequency component (0.15–0.4 Hz) reflects the parasympathetic input to the sinus node, whereas the low-frequency band (0.04–0.15 Hz) is modulated mainly by sympathetic impulses. Sympathovagal balance expressed as LF/HF ratio was also calculated in arithmetic power to cancel the influence of the parasympathetic activity on the LF spectral power.

Twenty-four patients showed a non-pharmacological positive test and were classified according to the hemodynamic and chronotropic responses observed during syncope:

1. Vasodepressor syncope—when heart rate increased initially but decreased afterward to less than 10% of the maximum peak with hypotension during syncope.

2. Cardioinhibitory syncope—when the heart rate decreased to <40 beats per minute (bpm) during syncope for more than 10 sec, or when asystole was observed for more than 3 sec, occurring concomitantly with hypotension.

3. Mixed syncope—when hypotension occurred prior to or concomitantly with bradycardia, and (a) heart rate increased before symptoms occurred, and decreased afterward, although it remained higher than 40 bpm; (b) heart rate was lower than 40 bpm for <10 sec; or (c) asystole occurred for <3 sec.

The study protocol was approved by the ethics committee and informed consent was obtained from all patients.