Can Adenosine 5′-Triphosphate Be Used to Select Treatment in Severe Vasovagal Syndrome?
Background Selection of treatment in vasovagal syndrome should be guided by the mechanism of symptoms. This study determined whether a simple drug test may assess one mechanism.
Methods and Results To identify patients at risk of severe cardioinhibitory response of vagal origin, we infused 20 mg ATP into 316 patients hospitalized for recurrent syncope (n=195) or presyncope (n=121) of unknown origin and into normal subjects (n=51). We then assessed the ECG and clinical responses to the drug, recommended therapy, and followed up the subjects chronically. A cardiac pause >10 seconds was seen in only 3 normal subjects (6%). Therefore, a pause ≤10 seconds yielded the ≈95th percentile of the normal range. ATP provoked a pause >10 seconds in 130 symptomatic patients (41%) and a pause ≤10 seconds in 186 symptomatic patients (59%). Thus, symptomatic patients with pauses >10 seconds were proposed for pacemaker implantation; all other patients and normal subjects were simply monitored. Among long-pause patients with follow-up, the observed recurrence rate for the 104 with pacemakers was one-third that for the 21 who were only monitored (P<.0001). Among followed-up short-pause patients, the rate in the 153 monitored-only patients did not differ from the 20 implanted patients (P=.432).
Conclusions The vagal effect of ATP may identify the subgroup of patients at high risk of severe cardioinhibitory response of vagal origin who likely will benefit from pacemaker therapy. This fast, uncomplicated test should be considered for further use in screening patients with vasovagal syndrome.
Vasovagal syndrome is the combination of vasodilation (systemic hypotension) and CI reflex (bradycardia or asystole). It is generally believed that this syndrome arises from a paradoxical interruption of the sympathetic activation that is associated with parasympathetic vagal excitation when the patient is upright, causing severe vasodilation and bradycardia. The most accepted mechanism underlying this abnormal reaction is excessive activation and possible hypersensitivity of the cardiac mechanoreceptors (vagal C fibers) excited by mechanical or chemical factors during a period of sympathetic excitation.1 2 Proving the vagal origin of a syncope is difficult even after a complete investigation.3 The head-up tilt test is effective for reproducing symptoms4 5 6 7 8 9 and for estimating the potential malignancy of about half of true vasovagal syndromes.10 11 12 However, even after the diagnosis is made, the therapeutic decision presents a dilemma: drugs, PM implantation, or no treatment.13 Several efficacious drugs have been proposed, but their long-term effectiveness is not evident, sometimes due to compliance problems.14 15 16 In severe vasovagal syndrome, dual-chamber PMs have been reported as being either more effective than drugs17 18 19 20 or useless.21 The lack of reliably effective therapy implies that this syndrome has multiple origins (including hypersensitivity of cardiovascular nerve endings) and variable clinical aspects due to the unpredictable relationship with its two components: vasodilation and the CI reflex.
General Overview of the Study
To identify patients with a high risk of severe CI response of vagal origin and thereby to provide an objective basis for a selected therapy, we used a simple pharmacological test to provoke a short and potent CI effect of vagal origin by injecting a 20 mg IV bolus of ATP, the same procedure that is used to terminate AV-nodal reentrant tachycardia.22 This test was evaluated in a clinical setting. We obtained ECG responses to ATP from a sample of asymptomatic subjects to determine the normal ECG responses to ATP. We also tested symptomatic vasovagal patients for ATP response; normal responders received the usual follow-up care, and abnormal responders received a PM. The therapy actually delivered to the patients was recorded, and the entire group was divided into four subgroups according to whether the individuals did or did not receive a PM and whether they had a short or long pause. Patients were followed up for recurrences for as long as 10 years; the recurrence rates for the four subgroups were analyzed to determine whether the abnormal ATP responders benefited from PMs more than the symptomatic but normal ATP responders.
To determine the normal range of the response to ATP, 51 asymptomatic patients hospitalized for routine check-ups were selected as normal subjects (Tables 1⇓ and 2⇓). Because our purpose was to estimate the range of “normal” ECG response to ATP, regardless of age or sex, the normal subjects’ age and sex did not match those of the symptomatic patients. Note that comparing the clinical outcomes of normal and symptomatic groups was not part of the study design.
All patients hospitalized for syncope or presyncope from March 1980 to December 1992 underwent physical, neurological, laboratory, and ECG (admission 12-lead ECG and 48-hour Holter or telemetry) testing. In 51% of the patients, electrophysiological testing was indicated by ECG (either excitability or conduction disturbances) or symptom modality. After eliminating patients with identifiable causes for their symptoms, including ECG abnormalities such as paroxysmal or permanent AF, sick sinus syndrome, carotid sinus syndrome, long PR interval (>300 ms), transient or permanent second-degree AV block, long HV interval (>60 ms), trifascicular block, or long QTc interval (>440 ms), the remaining 316 patients were further tested by using ATP. These patients, 195 hospitalized for syncope and 121 for presyncope, reported an average of 4.4±0.6 episodes before hospitalization, with an average of 7.2±1.5 months between episodes.
Syncope is defined as a transient loss of consciousness and presyncope as any of various subjective and objective signs of imminent syncope, including extreme weakness (almost syncopal) but with preserved audition and consciousness.
ATP, an endogenous purine nucleotide, produces in <30 seconds abrupt transient vagally mediated negative chronotropic and dromotropic vagal effects. Subsequently, it provokes a peripheral vasodilation, usually experienced as a generalized flush associated with reduced blood pressure.23 24 Its full negative chronotropic and dromotropic actions are attained with a dose of 0.3 mg/kg by using a commercially available solution (Striadyne, Wyeth Laboratories, 20 mg/2 mL) for a typical body weight of 67 kg. No special precautions are necessary except in asthmatic patients; the one observed severe bronchospastic reaction disappeared quickly with an infusion of hydrocortisone 250 mg IV.
After obtaining oral consent, the ATP test was initially performed during an electrophysiological study with available demand pacing and subsequently at bedside, between 4 and 6 pm, outside a period of dominant orthosympathetic activity. During testing, all patients were in sinus rhythm with a mean heart rate of 71.2±0.7 bpm and were free of antiarrhythmic drug therapy.
The patient rested in decubitus; a 5% dextrose infusion in the brachial vein was begun 1 hour before the test. A multichannel ECG was connected to the patient 10 minutes before the ATP injection. Arterial blood pressure was monitored by using an external automatic device (Dinamap). Because the patient must be relaxed during the test in order to exhibit the electrophysiological effects necessary for a valid test, the patient was kept unaware of the potential subjective effects following ATP injection to avoid any kind of anticipatory uncontrollable stress reaction. A 20-mg IV bolus (<2 seconds) of ATP in the brachial vein was followed by a 20-mL flush of a 5% dextrose solution, during which a continuous ECG recording at a speed of 25 mm/s was begun. Although clinical responses to ATP were recorded as well, only the ECG response distinguished severity of vagal sensitivity.
The ECG response consisted of five phases, irrespective of the patient’s group (Fig 1⇓). Phase I, a progressive slowing of the sinus rhythm, ends when either the PR interval prolongs abruptly (by at least 20%) or second-degree AV block occurs. This phase always occurs. Phase II, either first- or second-degree AV block, is always associated with increasing bradycardia. This phase ends either when a cardiac pause due to either a complete AV or SA block occurs or when the lower-degree block disappears. In a few instances this phase may not occur. In phase III, a cardiac pause of variable duration occurs due to complete AV or SA block. Even in symptomatic patients this phase may not occur at all (30% of the time in this study). During the cardiac pause, a few escape beats of various origins are usually observed, singly or in couplets (Fig 2⇓). In our experience, there is on average one escape beat every 5.4 seconds. If an escape rhythm occurred (ie, more than two escape beats with intervals <2.4 seconds), only the maximum time interval between two beats was used to measure the pause duration. Phase IV is marked by a return to the pretest rhythm via resumption of more rapid ventricular activity when phase III is present or a less severe AV block or bradycardia when it is not. Phase V is a reflex sympathetic sinus tachycardia. The total vagal effect is equal to the sum of phases II, III, and IV, but phase III represents its climax. In some patients, ATP may initiate transient AF, probably vagally mediated, starting as early as phase II and lasting for a few minutes only. In such cases, interpretation of the significance of phases IV and V becomes less clear. However, the duration of the cardiac pause is still used as the test criterion.
The clinical response to ATP varied and was independent of ECG response in all patient groups, ranging from a generalized flush to true syncope. Some syncopes were long enough to produce mild, transient neurological tonic reaction, but without biting of the tongue or spontaneous micturition. Some patients needed some cardiac massage before spontaneous resumption of consciousness. Although no severe effects resulted and no invasive procedures were needed, the usual cardiopulmonary resuscitation means were available since extended pauses may result from the test. After the test, the patient was asked to compare provoked with spontaneous symptoms. Because performing the test while the patient rested in decubitus attenuated the nature and severity of the provoked symptoms and the drop in blood pressure, reproduction of original symptoms was not expected.25 Therefore, only ECG results determined the final test assessment.
Therapeutic Strategy and Follow-Up
At the outset, we noted that ATP administration in the symptomatic patients provoked either bradycardia only or ventricular pause. Among patients with a pause, two distinct populations of pause durations were separated by a gap at 10 seconds. Although this natural divide disappeared as data accumulated, ultimately 94% of normal subjects had pauses ≤10 seconds (Fig 3⇓), indicating that a pause >10 seconds is an “abnormal” response to ATP. According to this definition, 41% of the symptomatic patients had an abnormal response. A PM implantation was recommended for this group (the long-pause patients), and simple monitoring was recommended (with or without drug therapy) for patients with shorter or absent pauses (the short-pause patients).
We initially recommended single-chamber PM devices; in 1985, we switched to dual-chamber devices. For drug treatment, we initially used long-acting atropine (1.0 to 1.5 mg/d) or ephedrine (50 mg/d); later, atenolol (200 mg/d) or sotalol (240 mg/d) was used. Patients were regularly followed up in clinics or by telephone every 6 months.
Age, CTR, phase duration, and weight are reported as mean±SEM; sex, structural cardiac disease, risk factors, presenting spontaneous symptoms, and symptom recurrences are described by frequency and percent relative frequency by respective groups. Differences between groups were tested with generalized linear or log-linear models. Associations between cardiac pause duration and symptoms during testing were estimated by using logistic regression. Cumulative recurrence-free survival from time of testing was estimated by using the Kaplan-Meier method. Recurrence-free survival distributions across ATP test result groups and PM treatment groups were compared by using Cox regression, adjusting for patient age, sex, weight, presenting symptoms, CTR, concomitant drug therapy, structural cardiac disease, and cardiovascular risk factors. Wald statistics employing a two-sided type I error rate of 5% were used for hypothesis testing. Computations were performed by using the statistical package SAS.26
After cross-classifying symptomatic patients into four subgroups by ATP test response (normal or abnormal) and PM implantation (yes or no), patients’ characteristics were compared with normal subjects’ and among subgroups (Tables 1⇑ and 2⇑). Symptomatic patients were older, more frequently female, and had higher CTRs and a higher frequency of cardiovascular risk factors than normal subjects. In addition, the long-pause patients were older, had larger CTRs, and more frequently had arterial disease than short-pause patients. Among long-pause patients, those with PMs did not differ from those without PMs; among short-pause patients, those with PMs differed only in having a higher frequency of cardiopathy than those without PMs, especially pertaining to ischemic disease.
For all subjects, the test itself took <5 minutes (Table 3⇓). Among the 316 symptomatic patients, ATP provoked a cardiac pause in 234 patients (74%) that was secondary to either third-degree AV block in 196 patients (84%) or SA block in 38 patients (16%). Irrespective of the spontaneous symptoms, 130 patients (41%) had a long pause (>10 seconds; mean duration, 20.5±0.7 seconds) and 186 (59%) had a short pause (≤10 seconds or no pause) (Table 3⇓). Among the 51 normal subjects, ATP provoked a cardiac pause in 23 subjects (45%) that was secondary to either third-degree AV block in 21 subjects (91%) or SA block in 2 subjects (9%). Only 3 normal subjects (6%) had a long pause (mean duration, 13.3±0.7 seconds); the 48 remaining normal subjects (94%) had a short pause (Fig 3⇑). This result implies a test specificity of 94%, assuming that the normal subjects were free of heart diseases and rhythm abnormalities. ATP initiated AF in 8 symptomatic (2.5%) and 3 (6%) normal subjects.
The average total duration of phases I and II was <26 seconds for all six groups of patients in Table 3⇑, a duration that is consistent with the 30 seconds reported in the literature and that indicates how rapidly vagal activity begins.
ATP reproduced presyncope (64 patients, or 53%) more often than syncope (59 patients, or 30%; Table 4⇓). Because the test was performed with the patients in decubitus, clinical responses were not expected to mimic ambulatory symptoms. Nevertheless, presyncope or syncope was associated with longer cardiac pauses (P=.0001); specifically, syncope was highly associated with the duration of the cardiac pause (P=.0001). Moreover, the distribution of pause duration during the test for patients presenting with syncope did not differ significantly from the distribution for the presyncopal patients (P=.60; Fig 3⇑). In the normal group, ATP provoked mild dizziness concomitant with simple sinus bradycardia in 3 patients (6%) and nonspecific flush in 48 patients (94%).
Of the 125 symptomatic long-pause patients with follow-up, 104 were implanted with PMs, and among them, symptoms recurred in 14 (14%) (Table 5⇓). Of the 173 symptomatic short-pause patients with follow-up, 153 received drug therapy or simple monitoring; among them, symptoms recurred in 32 (21%). The general strategy was not followed in 41 patients for different reasons: among long-pause patients, 21 (16%) refused PM implantation, and 10 had recurrences (48%); conversely, among short-pause patients, the treating physician elected a PM implantation in 20 patients (11%) with recurrences in 3 (15%). Normal subjects were followed up by telephone but were not treated.
Symptomatic patients were followed up approximately every 6 months for 49.7±33.5 (range, 1 to 163) months. Only 18 patients (6%) had no follow-up during this time. The Kaplan-Meier curves shown in Fig 4⇓ represent the cumulative recurrence-free survival from time of testing for the four subgroups of symptomatic patients: long-pause with PMs, long-pause without PMs, short-pause with PMs, and short-pause without PMs. Since patients were not randomly allocated to treatment, comparison of recurrence rates during the follow-up period are adjusted for age, sex, concomitant drug therapy, symptoms, underlying structural disease, and risk factors. Comparing all four survival curves after adjustment indicates significant differences between them (P=.0050).
Table 6⇓ shows the pairwise analysis comparing individual subgroups. The long-pause patients with PMs had significantly better survival than those without (P=.0001); treating long-pause patients with a PM decreased the rate of symptom recurrence by ≈84%. Short-pause patients with and without PMs had comparable symptom-free survival rates (P=.4029), which meant that the PM-treated long-pause patients had no different recurrence rates than either group of short-pause patients.
Patients with syncope or presyncope of unknown origin have historically been difficult to treat, even after diagnostic testing that clearly reproduces symptoms. Tools to identify potential causes of these symptoms could help the clinician select a treatment. Our results suggest that the ATP test defined in this study indicates objectively how severe the cardiac inhibition resulting from vagal stimulation of the heart can be in patients with vasovagal symptoms and identifies a subgroup that might benefit from cardiac pacing. This subgroup apparently has a more severe form of the syndrome, because the recurrence rate was higher among long-pause patients without PMs than among any other subgroup. Although most of its symptoms are relatively benign, vasovagal syndrome can be life-threatening in its more extreme manifestations, so treatment of this subgroup is critical.
Diagnostic procedures are often intended to reproduce the very symptoms that treatment seeks to ameliorate. However, identifying an underlying mechanism without necessarily provoking symptoms may indicate a therapy to address that mechanism. The ATP test need not reproduce spontaneous symptoms because it focuses instead on the ECG outcome during the test, ie, the duration of any provoked cardiac pause. Although the current study does not address mechanisms directly, the ATP test may uncover a mechanism (CI), thereby exposing the etiology and extent of the vasovagal syndrome.
ATP Test As an Indication for PM Therapy
Our hypothesis that the ATP test is indicative for PM therapy rests on the following three assertions.
ATP Produces a Predominant Vagal CI
Despite a wide array of studies in different species, the mechanism of cardiovascular actions of adenosine nucleotides are not fully known.24 27 28 29 30 However, there is reasonable evidence to support the assertion that ATP produces a predominant vagal CI. On the one hand, it is known that adenosine, the final product of the degradation of ATP, exerts direct negative chronotropic and dromotropic actions that are mediated by specific cell surface A1 adenosine receptors and inhibited by xanthines,30 but that it has no vagal activity. On the other hand, the cardiovascular actions of ATP are mediated by cell membrane P2 purinoceptors different from A1 adenosine receptors,28 by a triggered vagal reflex,28 30 and by its degradation to adenosine. Recently, Pelleg and others have demonstrated in the canine heart that only ATP triggers a vagal effect through the C fibers31 32 33 before its degradation and that the time to peak effect of ATP is half that of adenosine and significantly prolonged following vagotomy.28 29 Several authors have shown that in humans as well as animals atropine largely inhibits the vagal action of ATP but not of adenosine24 28 34 35 36 ; another study found different results.37
Although the present study was not designed to elucidate the mechanisms of action of ATP, two clinical observations may support the assertion that ATP acts mostly on the vagus system in both symptomatic and normal groups. First, ATP produced in all patients immediate (ie, <26 seconds) negative chronotropic and dromotropic effects that were identified by simple bradycardia or different degrees of AV or SA block. This short period could correspond to the initial vagal action of ATP before it degrades. Second, ATP induced an abrupt AF in 11 cases (3%), starting during phase II and disappearing quickly during the sympathetic rebound. AF induced by ATP (or by aconitine) has been observed in animals24 28 29 36 38 and by ATP in human clinical electrophysiology.39
In another study, ATP was used in normal subjects and those with neurally mediated syncope and sick sinus syndrome.40 However, the study was not conclusive about the usefulness of ATP in the diagnosis of vasovagal syndrome because the patients were preselected for sensitivity to carotid massage or tilt-table test and were not followed up prospectively.
There is some evidence that ATP and adenosine may suppress ventricular ectopic activity41 and thus contribute to increasing intersystolic intervals. Although it is plausible that some of the pauses seen in this study could be in part due to this suppressive effect, the study design does not allow us to test this theory.
Vagal CI of ATP Can Calibrate Cardiac Hypersensitivity
Our second assertion is that the vagal CI of ATP can calibrate hypersensitivity of the heart to vagal stimulation and indicate the likelihood of recurrent symptoms. While experimental and clinical observations suggest that ATP acts chiefly on the vagus system, our study shows that ATP acts more drastically in some patients (hypothetically, those with hearts more sensitive to vagal stimulation) than others. This hypersensitivity may be calibrated by the degree of CI provoked by ATP. Regardless of their spontaneous symptoms (Fig 3⇑), in 41% of symptomatic patients ATP caused a cardiac pause >10 seconds, ie, ≈95th percentile of the normal range. Exceeding this criterion indicates hypersensitivity of the heart to vagal stimulation; it occurred more frequently in the sicker and older population. The somewhat younger, healthier symptomatic patients with short or absent cardiac pauses may be considered to have a normal cardiac sensitivity to vagal stimulation. The ATP-indicated hypersensitivity of the heart to vagal activity may also indicate the likelihood of further symptoms predominantly due to cardiac pause, as opposed to symptoms due to vasodilation.
PMs Can Support Cardiac Output in Hypersensitive Patients
Finally, once symptomatic patients with hypersensitivity of the heart to vagal stimulation are identified, they can be considered for PM implantation to counteract future spontaneous pauses. Conversely, symptomatic patients with normal vagal sensitivity are unlikely to benefit from PM support. The therapeutic strategy can be independent of the type of symptoms, ie, spontaneous or provoked by ATP, once the underlying vagal hypersensitivity is uncovered.
Consistent with this strategy, the present study showed that for long-pause patients the recurrence rate was drastically lower in those with PMs compared with those without, even after controlling for confounding variables (Table 6⇑). For short-pause patients, PMs had no discernible effect.
There are three questions this study was not designed to address but that are related to the use of the ATP test. First, how reproducible is the ATP test from time to time within a patient? In a related ongoing study, the reproducibility of the test is being evaluated by readministering ATP within 1 to 10 days and within 3 to 4 years of the initial administration and comparing the results.42 In preliminary results, ECG outcomes had an initial and a late reproducibility of 88% and 68%, respectively, comparable to that for the tilt test.2 6 7 8 Second, how does the ATP test relate to the head-up tilt test? Unfortunately, no studies addressing this are yet available. Third, what is the sensitivity of the ATP test? Sensitivity is the proportion of diseased individuals responding positively to the test. This sensitivity depends on what disease is being targeted by the test. As Sutton indicated2 for the tilt test, there is no established provocative test for independently diagnosing CI response of vagal origin to serve as a diagnostic “gold standard”; hence, sensitivity cannot be reasonably based on such a disease. If, on the other hand, the disease is simply symptom recurrence, then the relative frequency of recurrent disease in the long-pause and short-pause patients must be estimated. However, the design of the study makes such estimation unreliable.
Like all observational studies, this one is limited by potential selection biases or confounding from unmeasured or uncontrolled factors (eg, diet or genetic predisposition). In addition, the treatment given to each patient was known to the follow-up evaluators, so potential unequal ascertainment of events arises. Randomly assigning treatments would eliminate the first limitation, and blinding the follow-up evaluators would reduce the potential for the second. However, the preliminary results of a pilot study43 among long-pause patients randomizing them to either PMs or usual care support the results of the present study.
Normal subjects were used to determine a cutoff criterion for the ATP test, so matching the normal subjects for age and sex to the symptomatic groups would strengthen the design. To illustrate: if the duration of cardiac pause usually were to increase physiologically with age, the normal range from younger subjects would inappropriately identify some members of the older group as “abnormal,” and treatment would have no or diminished apparent effect. However, mere association of a diagnostic measurement with age does not necessarily invalidate a uniform criterion (eg, blood pressure and hypertension). Indeed, the results of the present study suggest that the ≈95th percentile response of a group of normal subjects was an effective criterion for identifying among all symptomatic patients those with exceptionally higher recurrence rates that were treatable with cardiac pacing. Although a better cutoff criterion might be derived from a normal group matched in age and sex, the criterion used discriminated to a highly significant degree.
In summary, although ATP produced a potent vagal CI response, 94% of normal subjects had no cardiac pause or pauses ≤10 seconds. Using a 10-second pause as the criterion for discriminating normal from abnormal vagal sensitivity and comparing the effectiveness of pacing as a therapy in both groups showed pacing efficacy only in the abnormal (long-pause) group. The predictive usefulness of this criterion was independent of either presenting or provoked symptoms. We conclude that among patients suffering from syncope or presyncope of unknown origin, the ATP test identifies patients with severe vagal hypersensitivity of the heart by provoking a cardiac pause >10 seconds and that this identification provides an objective basis for PM implantation. This inexpensive, noninvasive, fast, and uncomplicated test may be performed at the patient’s bedside in a cardiology ward. For this reason, the results of this study strongly argue that the usefulness of the ATP test to select PM candidates in vasovagal syndrome should be studied in a randomized, multicenter clinical trial.
Selected Abbreviations and Acronyms
- Received January 9, 1997.
- Revision received March 6, 1997.
- Accepted March 9, 1997.
- Copyright © 1997 by American Heart Association
Abi-Samra FM, Maloney JD, Fouad-Tarazi FM, Castle LW. The usefulness of head-up tilt testing and hemodynamic investigations in the workup of syncope of unknown origin. PACE. 1988;11:1202-1214.
Brooks R, McGovern BA, Powell A, Garan H, Ruskin J. Day-to-day variability in the response to upright tilt table testing in patients with unexplained syncope. J Am Coll Cardiol. 1992;19:340A. Abstract.
Grubb B, Wolfe D, Temesy-Armos P, Hahn H, Elliott L. Reproducibility of head upright tilt table test: results in patients with syncope. PACE. 1992;15:1477-1481.
Kapoor WN, Brant N. Evaluation of syncope by upright tilt testing with isoproterenol: a nonspecific test. Ann Intern Med. 1992;116:358-363.
Maloney JD, Jaeger FJ, Fouad-Tarazi FM, Morris HH. Malignant vasovagal syncope: prolonged asystole provoked by head-up tilt. Cleve Clin J Med. 1988;55:542-548.
Sutton R. Vasovagal syndrome: could it be malignant? Eur J Card Pacing Electrophysiol. 1992;2:89. Abstract.
Dhala A, Blanck Z. Prognostic significance of asystole during head-up tilt testing. Circulation. 1993;88(suppl I):I-398. Abstract.
Natale A, Sra J, Dhala A, Wase A, Maglio C, Krebs A, Cudnohufsky S, Akhtar M. Clinical follow-up in 327 patients with positive head-up tilt: how should appropriate therapy be chosen? Circulation. 1993;88(suppl I):I-398. Abstract.
Abi-Samra FM, Davison NM, Gohn DC, Vincent KA. Long-term effectiveness of beta-blockers for the treatment of recurrent vasodepressor syncope. J Am Coll Cardiol. 1992;19:339A. Abstract.
Natale A, Sra J, Dhala A, Wase A, Jazayeri M, Deshpande S, Blanck Z, Akhtar M. Efficacy of different treatment strategies for neurocardiogenic syncope. PACE. 1995;18:655-662.
Linzer M, Wang PJ, Mandalakas N, Comegno A, Butts L, Colburn C, Clyne C, Estes AM III. Beta blockade is not effective in treating neurally mediated syncope. J Am Coll Cardiol. 1992;19:339A. Abstract.
Fitzpatrick AP, Theodorakis G, Ahmed R, Williams T, Sutton R. Dual chamber pacing aborts vasovagal syncope induced by head-up 60° tilt. PACE. 1991;14:13-19.
Moya A, Permanyer-Miralda G, Sagrista J, Mont L, Rius T, Soler-Soler J. Response to dual chamber pacing in patients with syncope and positive tilt test with cardio-inhibitory response. PACE. 1993;16(pt II):936. Abstract.
Hughes FC, Jan Y, Bors V, Baubion N. Etude de l’action chronotrope de l’ATP chez l’homme. Coeur Méd Intern. 1980;19:227-234.
Puech P, Sassine A, Munoz A, Masse C, Zettelmaier F, Leenhardt A, Yoshimura H. Electrophysiologic effects of purine: clinical applications. In: Zipes D, Jalife J, eds. Cardiac Electrophysiology and Arrhythmias. Orlando, Fla: Grune and Stratton; 1985:443-450.
Moller M, Oxho H, Mickley H, Hansen KN. Posture-dependent chronotropic effect of carotid sinus massage. PACE. 1987;10:1191-1193.
SAS/STAT User’s Guide. version 6. Cary, NC: SAS Institute; 1989:261-268.
Drury AN, Szent-Gyorgy I. The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol (Lond). 1929;68:213-226.
Pelleg A, Belardinelli L. Cardiac electrophysiology and pharmacology of adenosine: basic and clinical aspects. Cardiovasc Res. 1993;27:54-61.
Pelleg A, Hurt CM, Soler-Baillo JM, Polansky M. Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in dogs. Am J Physiol. 1993;265(Heart Circ Physiol. 34):H681-H690.
Sharma AD, Rinne C, Klein GJ, Yee R, Szabo T. Negative chronotropic effects of adenosine triphosphate on the sinus node are mediated by muscarinic cholinergic and not purinergic receptors. J Am Coll Cardiol. 1988;11:227A. Abstract.
Armour JA, Huang MH, Pelleg A, Sylvén C. Responsiveness of in situ canine nodose ganglion afferent neurons to epicardial mechanical or chemical stimuli. Cardiovasc Res. 1994;28:1218-1225.
Hurt CM, Wang L, Xu J, Sterious W, Pelleg A. Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in dogs, II: vagal afferent traffic. Am J Physiol. 1994;267:H1093-H1097.
Burnstock G. Purinergic receptors in the heart. Circ Res. 1980;46(suppl I):I-175-I-182.
Munoz A, Sassine A, Lehujeur C, Koliopoulos N, Puech P. Mode d’action des substances purinergiques dérivées de l’adénine sur la conduction auriculo-ventriculaire: etude expérimentale chez le chien. Arch Mal Coeur. 1985;78:143-150.
Lechat P, Tonet JL, Fontaine G, Frank R, Grosgogeat Y. Etude des effets de l’aminophylline et de l’atropine sur le bloc nodal induit par l’adenosine triphosphate. Thérapie. 1984;39:609-617.
Scherf D. Studies on auricular tachycardia caused by aconitine administration. Proc Soc Exp Biol Med N Y. 1947;64:233-239.
Coumel P, Leclercq JF, Attuel P, Lavallée JP, Flammang D. Autonomic influences in the genesis of atrial arrhythmias: atrial flutter and fibrillation of vagal origin. In: Narula OS, ed. Cardiac Arrhythmias: Electrophysiology, Diagnosis and Management. Baltimore, Md: Williams and Wilkins; 1979:243-255.
Brignole M, Menozzi C, Alboni P, Oddone D, Gianfrachi L, Gaggioli G, Lolli G, Paparella N. The effect of exogenous adenosine in patients with neurally-mediated syncope and sick sinus syndrome. PACE. 1994;17:2211-2216.
Flammang D, Waynberger M, Chassing A. Reproducibility of adenosine-5′-triphosphate test used for diagnosing vaso-vagal syndrome. Eur J Card Pacing Electrophysiol. 1994;4:219. Abstract.
Flammang D, Waynberger M, Chassing A. ATP (adenosine-5′-triphosphate) test: an effective tool for optimizing the treatment of recurrent vaso-vagal syncopes. Eur J Card Pacing Electrophysiol. 1994;4:152. Abstract.