|
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
|
|
|
|||||||||
|
|||||||||||
|
J Am Coll Cardiol, 2003; 41:93-98 © 2003 by the American College of Cardiology Foundation |
* Ospedali del Tigullio, Lavagna, Italy
Ospedale S. Maria Nuova, Reggio Emilia, Italy
Ospedale Civile, Cento, Italy
Ospedale S. Pietro Igneo, Fucecchio, Italy
Manuscript received May 24, 2002; revised manuscript received September 5, 2002, accepted September 13, 2002.
* Reprint requests and correspondence: Dr. Michele Brignole, Department of Cardiology, Ospedali Riuniti, I-16032 Lavagna, Italy.
mbrignole{at}ASL4.liguria.it
 |
Abstract |
|---|
 Top Abstract MethodsResultsDiscussionReferences |
|---|
6 s after an intravenous bolus of 20 mg ATP). BACKGROUND: Patients with unexplained syncope tend to have more positive ATP tests results than those without syncope.
METHODS: An implantable loop recorder (ILR) was inserted in 36 ATP-positive patients (69 ± 10 years; 22 women; median of 6 syncopal episodes); 15 of them also had a positive response to tilt testing.
RESULTS: During the follow-up of 18 ± 9 months, 18 patients (50%) had syncopal recurrence and 16 (44%) had an electrocardiographically documented episode: AV block (n = 3: paroxysmal in 2 and permanent in 1), AV block followed by sinus arrest (n = 1), sinus arrest (n = 5), sinus bradycardia <40 beats/min (n = 2), normal sinus rhythm (n = 2), sinus tachycardia (n = 1), rapid atrial fibrillation (n = 1), and ectopic atrial tachycardia (n = 1). Bradycardia was documented in a total of 11 cases (69%), and a long ventricular pause (4 to 29 s) was present in eight cases (50%). All three patients with ILR-documented AV block had previously had a negative tilt test, whereas seven of eight with ILR-documented sinus bradycardia or sinus arrest had previously had a positive tilt test.
CONCLUSIONS: In patients with adenosine-sensitive syncope, the mechanism of syncope is heterogeneous, although bradycardia is the most frequent finding. Adenosine triphosphate–induced AV block predicts AV block as the mechanism of spontaneous syncope in only a few tilt-negative patients.
| ||||||||||
|
Methods |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
Patients were considered eligible if they were >40 years old, had previously had three or more syncopal episodes with an interval of >6 months between the first and last episode, and had a clinical presentation severe enough (because of a high number of spells or high risk) to require treatment, if any was available. Patients were included in the study only if a careful history, physical examination, baseline ECG, carotid sinus massage, echocardiogram, and 24-h ambulatory recording were not diagnostic of the etiology of syncope. Any other test necessary for a definitive diagnosisof the cause of syncope was performed when clinically indicated. In particular, an electrophysiologic study was performed in the case of cardiac abnormalities or a history of palpitations.
Because of the overlap between adenosine-sensitive syncope and tilt-induced syncope (5,6), all patients underwent tilt testing. The tilt-test protocol always included a 20 min passive phase and a subsequent 15 min phase with nitroglycerin provocation, according to the Italian protocol (7). Patients with positive response to both ATP and tilt testing were included in the study.
Protocol of the ATP test
The ATP test consisted of injecting a 20-mg bolus (<3 s) of ATP dissolved in 10 ml of saline solution into a brachial vein, followed by a 20-ml flush of dextrose solution (1,2). During injection, patients remained supine, and continuous ECG recordings were made just before and 2 min after drug administration. Blood pressure was monitored non-invasively. Interpretation of the test result was based exclusively on the duration of the maximum ventricular pause (maximum RR interval). A value 6 s was defined as abnormal (2). In a previous study (2), this value was found in 28% of patients with syncope of unknown origin and in 5% of control subjects without syncope.
End point
When patients were deemed eligible, an ILR (Reveal, Medtronic) was implanted subcutaneously. The recommended program mode was one event, 21 min before activation and 1 min after activation. Patients were instructed to activate the device after every episode of syncope or pre-syncope. The records of all episodes were retrieved, printed, and analyzed. The primary end point of this study was the analysis of the ECG tracing obtained during the first syncopal episode that was correctly recorded by the device.
Control group
As control group, 15 patients (61 ± 13 years; 10 men) who had negative ATP and tilt tests were evaluated. They were all consecutive patients who had received an ILR device during the same period of recruitment because of unexplained syncope; they had received the same workup as described for the study patients. An ATP injection had induced a pause of 2.6 ± 0.8 s.
Statistical methods
A comparison between groups was carried out by means of the Student t test for continuous variables and the Fisher exact test for proportions. The time to onset of events was analyzed by means of Kaplan-Meier survival curves.
|
Results |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
|
Primary end point. An ILR-documented syncopal event occurred in 16 adenosine-sensitive patients (44%) after a median nine months (interquartile range 3 to 13) (Table 2). Two other patients were unable to activate the device at the time of their syncopal relapse. Atrioventricular block was recorded in three cases (19%) (paroxysmal in two and permanent in one), AV block followed by sinus arrest in one case, sinus arrest in five cases (mostly preceded by progressive bradycardia and/or tachycardia), progressive sinus bradycardia <40 beats/min in two cases, normal sinus rhythm in two cases, progressive sinus tachycardia in one case, rapid atrial fibrillation in one case, and ectopic atrial tachycardia in one case. Bradycardia was documented in 11 cases (69%), and a long ventricular pause (4 to 29 s) was present in eight cases (50%). The ATP test results were similar in the patients who had syncopal recurrence and in those who did not (maximum pause of 8.4 vs. 8.2 s, respectively) and also in the subgroup who had recurrence due to bradycardia (maximum pause of 8.6 s).
|
|
|
|
|
Multiple syncopal episodes occurred in six patients (Patients no. 5, 6, 7, 8, 9, and 11; Table 2). In all patients, very similar findings were observed during their second events, and in one patient during his third event.
No patient suffered severe injury due to syncopal relapse, and none died. An interview of a witness to the episode recorded in Patient no. 15 suggested a diagnosis of an epileptic attack. As a consequence of the results of the study, seven patients had a permanent pacemaker implanted, one underwent transcatheter ablation, and one received anti-epileptic therapy. No therapy was undertaken in the other patients.
|
Discussion |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
At the time of ILR-documented syncope, about half of the patients showed long pauses, and two-thirds had severe bradycardia. Sinus arrest or bradycardia was more frequent in patients who had an associated positive response during tilt testing. This finding is consistent with that observed in a previous study in patients with tilt-positive syncope (8). The finding of progressive sinus bradycardia frequently followed by sinus arrest has been regarded as highly suggestive of a neurally mediated mechanism. The association between AV block and sinus arrest, as in Patient no. 4, also suggests a neurally mediated mechanism (8). On the other hand, AV block without sinus bradycardia or arrest occurred in three (37%) of the eight patients with adenosine-sensitive syncope and a negative tilt test. In a previous study (8), AV block was shown to be a very uncommon mechanism in patients with unexplained isolated syncope and in patients with tilt-positive syncope. Atrioventricular block was also uncommon in the control group in the present study. Therefore, 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 an intrinsic AV conduction disease (9) and argues against a neurally mediated mechanism.
On the basis of the high percentage of ILR-documented bradycardic episodes, one could suggest that the ATP test is useful in predicting bradycardia in general, even if not AV block specifically. Actually, other authors have claimed that the ATP test is useful in identifying patients with severe vasovagal syncope who might benefit from pacing therapy (1,10). In the present study, the positivity of tilt testing, rather than the positivity of the ATP test, seems better able to predict subsequent cardio-inhibitory vasovagal syncope. Moreover, in a large population of patients with unexplained, isolated syncope (8), and in the control group of the present study, bradycardia was found as frequently as in adenosine-sensitive patients, suggesting that bradycardia is a frequent cause of syncope, regardless of the results of the ATP test. 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 previously.
Although the receptors are different, the cardiac actions of adenosine are remarkably similar to those of the neurotransmitter acetylcholine (11). 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 norepinephrine and epinephrine on adenyl cyclase (cyclic adenosine monophosphate–dependent effect) (3,11). 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 (12,13). The injection of ATP or adenosine causes hypotension. The role of hypotension in the mechanism of syncope is unclear. A consequence might be that vasovagal syncope could be facilitated by an increased susceptibility to adenosine, and that adenosine-sensitive syncope could be facilitated by increased vagal outflow. Interestingly, in support of this supposed synergic effect, the mechanism of syncope was bradycardic in seven (87%) of eight patients in whom both the ATP and tilt test were positive.
A positive response to the ATP test has been shown to be associated with typical clinical features (6) that were consistently observed in the present study in the three patients who had ILR-documented AV block. Typically, adenosine-sensitive syncope first manifests itself in middle or old age and is more common in females. Because 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 this form and clearly differentiate it from vasovagal syncope. Despite the old age of patients, structural heart disease is usually absent or, if present, mild and mainly due to a long history of hypertension. Adenosine-sensitive syncope is rare, accounting for about 3% of patients referred for investigation of syncope (6).
Study limitations. The results of the study are hampered by the small number of patients in various groups, reflecting the relative rarity of severe adenosine-sensitive syncope. Thus, the results should be regarded as intermediate pending larger trials. Although the follow-up duration (18 ± 9 months) was longer than that of similar studies with ILR, it is likely that longer observations would be of considerable interest.
Practical consequences
Because of its low positive predictive value, the ATP test has little value in evaluating patients with unexplained syncope and in selecting treatment. The favorable outcome we observed suggests the strategy of postponing treatment, pacemaker therapy in particular, until a definite diagnosis can be made by documenting a spontaneous syncopal relapse. In accordance with this approach, only nine patients (25%) underwent ILR-guided specific therapy immediately after their first syncopal documentation; no therapy was undertaken in the others. Many other patients would probably have had a documented syncopal recurrence if the monitoring phase had been prolonged. The usefulness of a very prolonged monitoring phase and the efficacy of therapy in preventing further syncopal recurrences remain to be proved in prospective therapy trials. Moreover, the benign nature of the clinical syndrome, which is similar to that of neurally mediated syncope, suggests that ILR implantation should be done only when its clinical presentation is severe enough (because of high number or high risk) to require treatment.
|
References |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  M. Brignole, F. Giada, A. Raviele, and J. J. Blanc Pacing for syncope: what role? which perspective? Eur. Heart J. Suppl., December 1, 2007; 9(suppl_I): I37 - I43. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Authors/Task Force Members, P. E. Vardas, A. Auricchio, J.-J. Blanc, J.-C. Daubert, H. Drexler, H. Ector, M. Gasparini, C. Linde, F. B. Morgado, et al. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in Collaboration with the European Heart Rhythm Association Europace, October 1, 2007; 9(10): 959 - 998. [Full Text] [PDF]
|
|
|
|
 |
|
 Authors/Task Force Members, P. E. Vardas, A. Auricchio, J.-J. Blanc, J.-C. Daubert, H. Drexler, H. Ector, M. Gasparini, C. Linde, F. B. Morgado, et al. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in Collaboration with the European Heart Rhythm Association Eur. Heart J., September 2, 2007; 28(18): 2256 - 2295. [Full Text] [PDF]
|
|
|
|
|
|
R. Maggi, C. Menozzi, M. Brignole, C. Podoleanu, M. Iori, R. Sutton, A. Moya, F. Giada, S. Orazi, and N. Grovale Cardioinhibitory carotid sinus hypersensitivity predicts an asystolic mechanism of spontaneous neurally mediated syncope Europace, August 1, 2007; 9(8): 563 - 567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Fragakis, I. Iliadis, E. Sidopoulos, A. Lambrou, E. Tsaritsaniotis, and G. Katsaris The value of adenosine test in the diagnosis of sick sinus syndrome: susceptibility of sinus and atrioventricular node to adenosine in patients with sick sinus syndrome and unexplained syncope Europace, August 1, 2007; 9(8): 559 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Brignole, R. Sutton, C. Menozzi, R. Garcia-Civera, A. Moya, W. Wieling, D. Andresen, D. G. Benditt, N. Grovale, T. De Santo, et al. Lack of correlation between the responses to tilt testing and adenosine triphosphate test and the mechanism of spontaneous neurally mediated syncope Eur. Heart J., September 2, 2006; 27(18): 2232 - 2239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. W. Parry, S. Nath, J. P. Bourke, R. S. Bexton, and R. A. Kenny Adenosine test in the diagnosis of unexplained syncope: marker of conducting tissue disease or neurally mediated syncope? Eur. Heart J., June 2, 2006; 27(12): 1396 - 1400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-C. Deharo, C. Jego, A. Lanteaume, and P. Djiane An Implantable Loop Recorder Study of Highly Symptomatic Vasovagal Patients: The Heart Rhythm Observed During a Spontaneous Syncope Is Identical to the Recurrent Syncope But Not Correlated With the Head-Up Tilt Test or Adenosine Triphosphate Test J. Am. Coll. Cardiol., February 7, 2006; 47(3): 587 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Perennes, M. Fatemi, M. L. Borel, Y. Lebras, C. L'Her, and J.-J. Blanc Epidemiology, Clinical Features, and Follow-Up of Patients With Syncope and a Positive Adenosine Triphosphate Test Result J. Am. Coll. Cardiol., February 7, 2006; 47(3): 594 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Task Force members, M. Brignole, P. Alboni, D. G. Benditt, L. Bergfeldt, J.-J. Blanc, P. E. B. Thomsen, J. G. van Dijk, A. Fitzpatrick, S. Hohnloser, et al. Guidelines on management (diagnosis and treatment) of syncope - Update 2004: The task force on Syncope, European Society of Cardiology Eur. Heart J., November 2, 2004; 25(22): 2054 - 2072. [Full Text] [PDF]
|
|
|
|
|
|
Guidelines on Management (diagnosis and treatment) of syncope - update 2004: The Task Force on Syncope, European Society of Cardiology Europace, January 1, 2004; 6(6): 467 - 537. [Full Text] [PDF]
|
|
|
|
|
|
M. Brignole, P. Donateo, and C. Menozzi The diagnostic value of ATP testing in patients with unexplained syncope Europace, January 1, 2003; 5(4): 425 - 428. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
80 beats/min and then suddenly falls at the time of syncope. (B) Expanded electrocardiographic recording at the time of the syncopal event. The onset of atrioventricular block is sudden, with no change in the PP interval; the main pause lasted 12 s.
