© 2003 by European Society of Cardiology
EDITORIAL
The diagnostic value of ATP testing in patients with unexplained syncope
1Arrhythmologic Centre, Department of Cardiology, Ospedali del Tigullio Lavagna, Italy; 2Interventional Cardiology, Department of Cardiology, Ospedale S Maria Nuova Reggio Emilia, Italy
Manuscript submitted 14 January 2003. Accepted after revision 22 June 2003.
Correspondence: Michele Brignole, MD, Department of Cardiology, Ospedali del Tigullio, I-16032 Lavagna, Italy. Tel.: +39-0185-329569; Fax: +39-0185-306506. E-mail: mbrignole{at}asl4.liguria.it
Abstract
A minority of patients with unexplained syncope has an increased susceptibility to adenosine triphosphate (ATP) injection. In these ‘hypersensitive’ patients, owing to its powerful cardiac and hypotensive effects, endogenous adenosine released under physiological and pathological conditions could trigger bradycardia and/or hypotension and cause syncope. This hypothesis still needs to be proven. However, there is some evidence that the ATP test identifies a group of patients with otherwise unexplained syncope with definite clinical features, absence of structural heart disease and benign prognosis. The mechanism of syncope is heterogeneous; indeed, in cases of electrocardiographic documentation of spontaneous syncope, either a long ventricular pause (mainly due to paroxysmal atrioventricular (AV) block) or no rhythm variations or even tachycardia were documented. ATP-positive patients have clinical features and mechanisms of syncope which are different from tilt-positive patients. Owing to its low positive predictive value, the ATP test is of little value in selecting treatment. A favourable outcome suggests a strategy of postponing treatment, in particular pacemaker therapy, until a definite diagnosis can be made by documenting a spontaneous syncopal relapse.
Key Words: Unexplained syncope, ATP, ADP, vasovagal syncope
Introduction
Patients with unexplained syncope are reported to show greater susceptibility to intravenous injection of adenosine triphosphate (ATP) than those without syncope[1,
2]. Therefore ATP testing has been proposed as an investigative tool in patients with unexplained syncope[1,2]. In predisposed patients with unexplained syncope, the cardiac action of adenosine, which has a powerful dromotropic effect on the atrioventricular (AV) node[3], causes prolonged ventricular pauses due to AV block, which are suspected of being responsible for spontaneous attacks. The action of ATP is due to its rapid catabolism to adenosine and the subsequent action of adenosine at purinoceptor sites. ATP and adenosine have similar effects in humans[3] even if some vagal effect may be exerted by ATP but not by adenosine in the canine heart[4].
Protocol of the ATP test
The protocol proposed by Flammang et al.[1] consists of the injection in a brachial vein of a bolus (<3 s) of 20 mg of ATP followed by a 20 ml flush of dextrose solution or dissolved in 10 ml of saline solution. Blood pressure is monitored non-invasively. The maximum bradycardiac effect following a bolus of ATP usually occurs after 10–20 s (which is the latency time necessary for the drug to reach the heart); this persists for up to 20 s and is followed by sinus tachycardia for up to 2 min; hypotension occurs during and immediately after the bradycardiac phase and is sometimes followed by moderate hypertension.
Interpretation of the result of the test is exclusively based on the duration of the cardiac ‘pause’. A value of >6 s ventricular asystole due to complete AV block[2] or >10 s phase III response (defined as the total duration of complete AV block or sino-atrial block even if interrupted by some escape beats)[1] are defined as abnormal. In an intrapatient comparison performed on 43 patients, a >6 s ventricular asystole was always present in the seven patients who had also a >10 s phase III, whereas a >6 s ventricular asystole was also present in 14 patients who did not have >10 s phase III (personal communication). However defined, such abnormal responses were chosen because these were observed in about 5% of control subjects without syncope[1,2].
In patients with abnormal responses, reproducibility was approximately 80% both in the short- and the long-term[2,5].
ATP and adenosine have similar effects in humans, but adenosine is more stable at room temperature[3]. In an intrapatient randomized crossover comparison, ATP 20 mg i.v. was compared with adenosine 20 mg i.v. in 13 patients with unexplained syncope. The maximum cardiac pause was 4.7±2.6 s with ATP and 5.0±2.7 s with adenosine (coefficient of correlation, r=0.67, P=0.01) (personal communication). Thus adenosine can be used in place of ATP.
Relationship between ATP test and spontaneous syncope
In patients with syncope of unknown origin, the ATP test was abnormal in 28 and 41% of the patients in two series[1,2]. Moreover, in a small group of patients with syncope electrocardiographically documented to be caused by a transient pause, ATP test reproduced AV block with a pause >6 s in 53% of the patients with documented spontaneous AV block but in none of those with sinus arrest[2]. The interpretation of these studies is that some patients with unexplained syncope show an increased susceptibility to ATP in comparison with those without syncope. The ATP test is able to reproduce AV block, and suggests the mechanism, in patients with spontaneous paroxysmal AV block. The logical inference is that the ATP test should be able to identify patients with syncope due to transient AV block even when the electrophysiological findings and other conventional tests are unremarkable. Furthermore, as a logical consequence, cardiac pacing therapy has been proposed by Flammang et al.[1].
Unfortunately the results were not confirmed in a small prospective follow-up study[6] in 21 patients with unexplained syncope after completely negative cardiological investigation who had received an Implantable Loop Recorder. During the follow-up of 18±9 months, eight (38%) patients had an ECG-documented episode: sudden onset AV block without changes in heart rate in three (37%) cases (paroxysmal in two and permanent in one), sinus arrest in one (12%) case, normal sinus rhythm in two (25%) cases, sinus tachycardia in one (12%) case and ectopic atrial tachycardia in one (12%) case. Thus, the mechanism of syncope was heterogeneous and an ATP-induced AV block predicted AV block as the mechanism of the spontaneous syncope only in a few patients. Different results were found in 15 other patients who had had positive responses to both the ATP test and tilt testing. Of these, eight patients had syncopal recurrence during which sinus arrest was documented in five, sinus bradycardia in two and sinus tachycardia in one.
Despite the low prevalence of AV block, this was higher than that observed in a control group of patients with tilt-induced vasovagal syncope or ATP-negative unexplained syncope (37 vs 8%) (P=0.02); conversely, progressive sinus bradycardia often followed by sinus arrest was more frequent in the control group (92 vs 12%) (P=0.02). This finding might not be fortuitous. The feature of sudden onset of AV block with no change in sinus rate or with an increase in heart rate resembles that observed in patients with bundle branch block who have intrinsic AV conduction disease[7] and argues against a neurally mediated mechanism. Conversely, progressive sinus bradycardia frequently followed by sinus arrest was typically observed in a previous study in patients with vasovagal syncope[8] and has been regarded as highly suggestive of a neurally mediated mechanism.
In brief, it seems that the test is able to identify a few patients with syncope due to transient AV block even when electrophysiological findings and other conventional tests are unremarkable. Unfortunately, due to the high rate of false positive results, the test yields a low positive predictive value and is of little value in selecting treatment.
Adenosine-sensitive syncope: does it exist?
Some authors[9–11] have hypothesized that adenosine could be an important modulator in triggering a vasovagal response in susceptible patients. Indeed, the injection of a bolus of adenosine during tilt testing has been seen to provoke a vasovagal response in susceptible patients with syncope with a positivity rate comparable with that of isoprenaline[10,11]. The ATP test has been suggested as a useful tool to identify a subgroup of patients at high risk of severe cardioinhibitory responses of vagal origin[11].
Nevertheless, ATP-positive patients and tilt-positive patients show several clinical differences. Firstly, as discussed in the previous section, the ECG-documented mechanism of syncope is quite different from that observed in patients with a positive response to tilt testing. Secondly, the patients with a positive response to the ATP test show typical clinical features[12]. Syncope first manifests in middle or old age. There is a small female predominance. Vasovagal syncope can occur at any age; typically it begins in the teenage years and there may be a long period of life without recurrences[13]. As the attacks nearly always occur in the standing position, and warning symptoms are frequently absent, loss of consciousness often results in falls that cause injury. The lack of historical findings of vasovagal or situational episodes and the absence of triggering factors characterize the ATP-sensitive form and clearly differentiate it from vasovagal syncope. Despite the old age of patients, structural heart disease is usually absent or, if present, is mild and mainly due to a long history of hypertension. Pure ATP hypersensitive patients are rare, accounting for about 3% of patients referred for investigation of syncope[12].
Nevertheless, some overlap exists between ATP-positive and tilt-positive patients which makes it likely that some common physiopathological pathways exist[9,12]. In a study[12], about one-fourth of the patients with tilt-induced syncope also had an adenosine-sensitive syncope, and the ATP test was positive in 15% of the patients with a history of syncope suggestive of a neurally mediated mechanism. The clinical features of the patients who had both tilt and ATP tests positive differed both from the patients with tilt-induced syncope alone and from those with adenosine-sensitive syncope alone; thus, these patients had clinical features that were atypical both of the vasovagal syndrome and the adenosine-induced syncope. This fact suggests that, in this particular population, more complex, multiple mechanisms are responsible for syncope and that syncopal attacks can be caused alternatively by a vasovagal mechanism or an adenosine-mediated mechanism or both.
How to explain all those findings on a pathophysiological basis? In ‘hypersensitive’ patients, owing to ATP's powerful cardiac and hypotensive effects, endogenous adenosine, released under physiological and pathological conditions, could trigger bradycardia and/or hypotension and cause syncope. In a recent study[14], endogenous adenosine plasma levels were higher in patients with a positive tilt test than in patients with a negative test and they increased during tilt-induced syncope. These observations suggest that adenosine release may be involved in the triggering mechanism of syncope induced during tilt testing. Although the receptors are different, the cardiac actions of adenosine are remarkably similar to those of the neurotransmitter acetylcholine[3]. Both acetylcholine and adenosine produce the same effects and share similar receptor–effector coupling systems. A major role of acetylcholine and adenosine, in addition to their direct effect, is to function in parallel to oppose the cardiac stimulatory action of the sympathetic neurotransmitters noradrenaline and adrenaline on adenylcyclase (cAMP-dependent effect)[3,15]. Thus, adrenergic, cholinergic and purinergic outflows are integrated at the level of the receptor–effector coupling system, and the final cardiac effect results from the sum of these excitatory and inhibitory effects. In addition to its cardiac effects, adenosine also promotes vasodilation, decreases central and peripheral sympathetic efferent nerve activity and inhibits renin release[10,11]. The injection of ATP or adenosine causes hypotension. The role of hypotension in the mechanism of syncope is unclear. A consequence might be that a vasovagal syncope could be facilitated by an increased susceptibility to adenosine, and that an adenosine-sensitive syncope could be facilitated by an increased vagal outflow.
The cause of the hypersensitivity in the patients with adenosine-sensitive syncope is not clear. There are several potential explanations: increased density of adenosine receptors; increased coupling efficacy of the receptors; increased density of Ik-adenosine; increased release of adenosine (i.e. increased interstitial levels of adenosine); decreased degradation of adenosine[3]. Nevertheless, we cannot exclude the possibility that, in a few patients, unknown AV conduction abnormalities not recognizable by means of standard clinical and electrophysiological evaluation, or a non-specific susceptibility of the AV node to different triggers (for example vagal hyperactivity as discussed above), could constitute the substrate responsible for the hypersensitivity to adenosine.
In conclusion, the patients with a hypersensitive ATP response are different from those with a positive tilt test response and, in general, from the patients affected by the typical vasovagal syncope. However, these findings are insufficient to identify a new syndrome, the ‘adenosine-sensitive syncope’. Whether this latter syndrome exists still remains a matter of discussion.
Treatment
Theophylline is a specific adenosine-receptor antagonist. In a small observational study a low recurrence rate was observed in patients treated with this drug[2]. Nevertheless, the potential role of this drug must be evaluated in a randomized trial.
Other authors have found a low recurrence rate of syncope after pacing therapy[1,16]. Nevertheless, in the prospective validation study[6], only half of the patients with isolated adenosine-sensitive syncope showed bradycardia at the time of ILR-documented syncope. Thus, in at least half of the adenosine-sensitive patients, cardiac pacing therapy lacks a pathophysiological background. Admittedly, sinus arrest or bradycardia were more frequent in patients in whom both the ATP and tilt test were positive; indeed, in these latter patients the mechanism of syncope was mostly due to sinus bradycardia or sinus arrest[6]. Thus, the positivity of tilt testing, rather than the positivity of ATP test, seems better able to predict a subsequent cardioinhibitory vasovagal syncope. Moreover, in a large population of patients with isolated unexplained syncope bradycardia was found in two-thirds of patients, suggesting that bradycardia is a frequent cause of syncope regardless of the results of the ATP test[8]. The results of pacing therapy are also inconclusive. Indeed, in one large non-controlled study[1], syncope recurred in 13 and 15% of paced patients with positive and negative ATP test results, respectively. This suggests that the beneficial effect of pacing is independent of the result of the test and rather reflects the high prevalence of syncope due to bradycardia, as shown above.
In the Loop Recorder study[6], no patient suffered severe injury due to syncopal relapse and none died. As a consequence of the results of the study, only 25% of the patients received therapy after their syncopal relapse: seven patients had a permanent pacemaker implanted, one patient underwent transcatheter ablation and one patient received antiepileptic therapy. No therapy was undertaken in the other patients. Owing to the benign nature of the syndrome and its favourable outcome a strategy of postponing treatment seems to be safe and feasible.
Conclusions
A minority of patients with unexplained syncope shows an increased susceptibility to ATP injection. In these ‘hypersensitive’ patients, owing to its powerful cardiac and hypotensive effects, endogenous adenosine, released under physiological and pathological conditions, could trigger bradycardia and/or hypotension and cause syncope. This hypothesis still needs to be proven. However, there is some evidence that the ATP test identifies a group of patients with otherwise unexplained syncope with definite clinical features, absence of structural heart disease and benign prognosis albeit with a heterogeneous mechanism of syncope. ATP-positive patients have clinical features and mechanisms of syncope different from tilt-positive patients.
Adenosine-mediated paroxysmal AV block is regarded as the more specific mechanism of syncope in this group of patients, but this finding is observed only in a minority. Owing to its low positive predictive value, ATP testing is of little value in selecting treatment. The favourable outcome suggests the strategy of postponing treatment, in particular pacemaker therapy, until a definite diagnosis can be made by documenting a spontaneous syncopal relapse. Moreover, the benign nature of the clinical syndrome, which is similar to that of neurally mediated syncope, suggests implantation of a Loop Recorder only when its clinical presentation is severe enough (high number of syncopes or occurrence in high-risk situations) to require treatment.
References
[1] Flammang D, Church T, Waynberger M, Chassing A, Antiel M. Can adenosine 5'triphosphate be used to select treatment in severe vasovagal syndrome? Circulation 1997; 96: 1201–1208.
[2] Brignole M, Gaggioli G, Menozzi C, et al. Adenosine-induced atrioventricular block in patients with unexplained syncope. The diagnostic value of ATP test. Circulation 1997; 96: 3921–3927.
[3] Belardinelli L, Linden J, Berne RM. The cardiac effects of adenosine. Prog Cardiovasc Dis 1989; 22: 73–97.
[4] Pelleg A, Hurt CM, Soler-Baillo JM, Polansky M. Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in dogs. Am J Physiol 1993; 265: 681–690.
[5] Flammang D, Chassing A, Donal E, Hamani D, Erickson M, McCarville S. Reproducibility of the adenosine 5'triphosphate test in vasovagal syndrome. J Cardiovasc Electrophysiol 1998; 9: 1161–1166.[Web of Science][Medline]
[6] Donateo P, Brignole M, Menozzi C, et al. Mechanism of syncope in patients with positive adenosine triphosphate test. J Am Coll Cardiol 2003; 41: 93–98.
[7] Brignole M, Menozzi C, Moya A, et al. The mechanism of syncope in patients with bundle branch block and negative electrophysiologic test. Circulation 2001; 104: 2045–2050.
[8] Moya A, Brignole M, Menozzi C, et al. Mechanism of syncope in patients with isolated syncope and in patients with tilt-positive syncope. Circulation 2001; 104: 1261–1267.
[9] Flammang D, Erickson M, McCarville S, Church T, Hamani D, Donal E. Contribution of head-up tilt testing and ATP testing in assessing the mechanisms of vasovagal syndrome. Preliminary results and potential therapeutic implications. Circulation 1999; 99: 2427–2433.
[10] Shen WK, Hammil S, Munger T, et al. Adenosine: potential modulator for vasovagal syncope. J Am Coll Cardiol 1996; 28: 146–154.[Abstract]
[11] Mittal S, Stein K, Markowitz S, Slotwiner D, Rohatgi S, Lerman B. Induction of neurally mediated syncope with adenosine. Circulation 1999; 99: 1318–1324.
[12] Brignole M, Gaggioli G, Menozzi C, et al. Clinical features of adenosine sensitive syncope and tilt-induced vasovagal syncope. Heart 2000; 83: 24–28.
[13] Sutton R. Vasovagal syncope: clinical features, epidemiology, and natural history. In Blanc JJ, Benditt D, Sutton R (Eds.). Neurally Mediated Syncope: Pathophysiology, Investigations, and Treatment 1996; Armonk, NY Futura pp. 71–76.
[14] Saadjian AY, Levy S, Franceschi F, Zouher I, Paganelli F, Guieu RP. Role of endogenous adenosine as a modulator of syncope induced during tilt testing. Circulation 2002; 106: 569–574.
[15] Lerman B and Belardinelli L. Cardiac electrophysiology of adenosine. Basic and clinical concepts. Circulation 1991; 83: 1499–1508.
[16] Flammang D, Antiel M, Church T, et al. Is a pacemaker indicated for vasovagal patients with severe cardioinhibitory reflex as identified by ATP test? Europace 1999; 1: 140–145.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||