Can ATP Be Used to Select Treatment in Severe Vasovagal Syndrome?
ABSTRACT & COMMENTARY
Synopsis: Data suggests that intravenous ATP testing can identify patients who will benefit with permanent pacemaker therapy during long-term follow-up.
Source: Flammang D, et al. Circulation 1997;96: 1201-1208.
Flammang and associates tested the hypothesis that intravenous infusion of adenosine triphosphate (ATP) would identify patients with unexplained syncope or presyncope who would benefit from permanent pacemaker insertion. The study group included 195 patients hospitalized for syncope and 121 patients with presyncope. Patients with obvious causes of syncope as determined by physical examination, neurologic or laboratory testing, or ECG monitoring were excluded. A control group of 51 patients without symptoms also received ATP infusions. ATP, which in the bloodstream is rapidly broken down to adenosine, was injected as a single 20 mg intravenous bolus into a brachial vein. Continuous ECG recordings were made after the infusion. The ECG response showed the typical pattern of sinus slowing with varying degrees of atrioventricular block followed by recovery and then a reflex sympathetically mediated sinus tachycardia. The criterion for a positive response used by Flammang et al was a ventricular pause of greater than 10 seconds at any time after the infusion. Permanent pacemaker implantation was recommended for patients who had pauses of longer than 10 seconds, whereas patients with shorter pauses were managed at the investigators’ discretion. Control group patients were followed on no therapy.
Among the 316 symptomatic patients, 130 had a pause of greater than 10 seconds duration in response to 20 mg of intravenous ATP. One hundred eighty-six patients had a shorter pause or no pause at all. Among the 51 normal subjects, only three had a pause of greater than 10 seconds duration. Permanent pacemakers were implanted in 104 of 125 long-pause patients, with a subsequent recurrence rate of 14%. Among the 173 symptomatic patients with short pauses in response to ATP, 153 were followed on either drug therapy or no therapy and in this group, symptoms recurred in 21%. None of the normal subjects developed syncope or presyncope during follow-up. Flammang et al conclude that their data suggest that intravenous ATP testing can identify patients who will benefit with permanent pacemaker therapy during long-term follow-up. They attribute the effects of ATP to a vagally mediated cardioinhibitory effect. They propose this test as a simple bedside method for evaluating patients with unexplained syncope.
COMMENT BY JOHN P. DiMARCO, MD, PhD
This paper presents an interesting hypothesis. Flammang et al propose that by subjecting patients to an ATP infusion, they can identify patients in whom prior symptoms were due to long pauses. They describe this as a "severe vasovagal" syndrome, but this may not be precisely true. After injection in man, ATP is rapidly broken down to adenosine. Adenosine interacts with a purinergic adenosine A1 receptor that produces effects on several cardiac ionic channels. The effects are similar to those produced by muscarinic cholinergic stimulation, but a different receptor is involved since adenosine’s effects are being blocked by aminophylline but not by atropine. In some species, particularly canines, ATP does interact with vagal receptors, but this is probably not the case in humans. Therefore, it is not precisely correct to refer to this as a test of vagal sensitivity, and I would not describe this finding as supportive of a diagnosis of a "severe vasovagal" syndrome.
A number of other investigators have looked at the effects of adenosine in patients with neurally mediated syncope and/or sick sinus syndrome. Brignole et al (PACE Pacing Clin Electrophysiol 1994;17:2211-2216) infused ATP in patients with either neurally mediated syncope or documented sick sinus syndrome. Patients with both these conditions were more sensitive to adenosine than were the control patients. Saito et al reported marked inhibition of sinus node automaticity in patients with sick sinus syndrome after infusion of 10 mg of ATP (Arzneimittel-Forschung 1993;43:13-16). In contrast, Lai et al (Chest 1991;99:887-891) found that intravenous aminophylline had no effect on sinus cycle length in patients with known sinus node dysfunction. Thus, the role of adenosine as a mediator of sinus node dysfunction, or vasovagal syncope remains controversial.
In this study, the symptomatic patients were considerably older than the control group (73.6 + vs 56.2 + 2.5 years of age), suggesting that at least some of these may have had both intrinsic sinus node dysfunction as well as a vasodepressor syndrome. It would have been interesting to repeat the ATP infusions after administration of either aminophylline, atropine, or both to try to determine which receptor type was actually involved. No matter what the mechanism, this report suggests that adenosine or ATP infusion may provide additional justification for a trial of pacemaker therapy in patients with recurrent unexplained syncope or presyncope.
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