(Circulation. 1997;96:1201-1208.)
© 1997 American Heart Association, Inc.
Articles |
Can Adenosine 5'-Triphosphate Be Used to Select Treatment in Severe Vasovagal Syndrome?
From Angouleme General Hospital (D.F., M.W., A.C.), Saint Michel, France; Medtronic Pacing Division (T.C., M.A.), Minneapolis, Minn; and the Division of Environmental and Occupational Health (T.C.), School of Public Health, University of Minnesota, Minneapolis.
Correspondence to Daniel Flammang, MD, Department of Cardiology, Angouleme General Hospital, 16470 Saint Michel, France.
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Abstract |
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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.
Key Words: syncope • adenosine • phosphates • vagus nerve
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Introduction |
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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.
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Methods |
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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.
Population
Normal Subjects
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.
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Symptomatic Patients
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
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.
Test Procedure
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.
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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).
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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.
Statistical Methods
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
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Results |
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ATP Test
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.
ECG Response
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.
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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.
Clinical Response
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%).
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Therapeutic Strategy
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.
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Follow-up Results
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).
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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.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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.
Related Questions
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.
Limitations
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.
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Selected Abbreviations and Acronyms |
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Received January 9, 1997; revision received March 6, 1997; accepted March 9, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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