(Circulation. 1999;99:1318-1324.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Induction of Neurally Mediated Syncope With Adenosine
From the Department of Medicine, Division of Cardiology, New York Hospital-Cornell University Medical Center, New York, NY.
Correspondence to Bruce B. Lerman, MD, Division of Cardiology, New York Hospital-Cornell Medical Center, 525 E 68th St, Starr 4, New York, NY 10021. E-mail blerman{at}mail.med.cornell.edu
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Abstract |
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Background—Tilt testing is used to establish the diagnosis of neurally mediated syncope. However, applicability of the tilt test is limited by test sensitivity and length of time required to perform the test. We hypothesized that adenosine could facilitate the induction of neurally mediated syncope through its sympathomimetic effects and therefore could be used as an alternative to routine tilt testing.
Methods and Results—In protocol 1, the yield of adenosine tilt testing (12 mg while upright, followed by 60° tilt for 5 minutes) and a 15-minute isoproterenol tilt test were compared in 84 patients with a negative 30-minute drug-free tilt test. In protocol 2, 100 patients underwent an initial adenosine tilt test followed by our routine tilt test (30-minute drug-free tilt followed by a 15-minute isoproterenol tilt). Six additional control patients underwent microneurography of the peroneal nerve to compare the sympathomimetic effects during bolus administration of adenosine and continuous infusion of isoproterenol. In protocol 1, the yields of adenosine (8 of 84, 10%) and isoproterenol (7 of 84, 8%) tilt testing were comparable (P=NS). In protocol 2, the yields of adenosine (19 of 100, 19%) and routine (22 of 100, 22%) tilt testing were also comparable (P=NS). Although the yield of adenosine tilt testing was comparable in both protocols, patients with a negative adenosine tilt test but a positive routine tilt test usually required isoproterenol to elicit the positive response. Microneurography confirmed discordant sympathetic activation after adenosine and isoproterenol administration.
Conclusions—Adenosine is effective for the induction of neurally mediated syncope, with a diagnostic yield comparable to routine tilt testing. However, the discordant results obtained with adenosine and the isoproterenol phase of routine tilt testing suggest that adenosine and isoproterenol tilt testing may have complementary roles in eliciting a positive response. Therefore, a tilt protocol that uses an initial adenosine tilt followed, if necessary, by an isoproterenol tilt would be expected to increase the overall yield and reduce the duration of tilt testing.
Key Words: adenosine • syncope • tests
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Over the past decade, tilt testing has become a widely accepted diagnostic tool for the evaluation of neurally mediated syncope.1 2 3 Syncope during orthostatic stress is thought to be initiated by venous pooling, with a subsequent reduction in central blood volume and stroke volume and a compensatory increase in sympathetic activity. In susceptible individuals, the increase in sympathetic activity may trigger the Bezold-Jarisch reflex,4 which results in bradycardia and/or hypotension.
Despite its clinical acceptance as a test to diagnose neurally mediated syncope, tilt testing continues to be limited in use partly because of (1) concerns over the sensitivity of the test, (2) the lack of a standardized test protocol, and (3) the lengthy duration of a complete study. In those patients with a negative drug-free tilt test who require pharmacological tilt testing, the total test duration may approach 2 hours.5
Recently, adenosine has been proposed to be an endogenous modulator of neurally mediated syncope.6 It is also possible that exogenous adenosine, like isoproterenol, is a facilitator of neurally mediated syncope through its sympathomimetic effects. In contrast to the well-characterized inhibitory cardiovascular actions of adenosine, including depression of sinoatrial and AV nodal activity, attenuation of the stimulatory effects of catecholamines, and inhibition of norepinephrine release from nerve terminals,7 8 it also has a sympathoexcitatory effect mediated via baroreflex and peripheral chemoreceptor activation.9 10 11
We hypothesized that adenosine could facilitate the induction of neurally mediated syncope through its sympathomimetic effects and therefore could be used as an alternative to routine tilt testing. The use of adenosine during tilt testing would offer several potential advantages over routine tilt testing: (1) ease of administration, (2) short drug half-life, and most importantly (3) a marked reduction in the time needed to perform tilt testing. Therefore, we sought to contrast the safety and diagnostic yield of adenosine tilt testing with routine tilt testing.
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Methods |
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Patient Selection
We prospectively evaluated 255 consecutive patients referred for tilt testing between August 1996 and October 1997 to evaluate unexplained presyncope and/or syncope despite appropriate medical and/or neurological evaluation.
Fifty-four patients were excluded from the analysis, including 24 patients taking ß-blockers at the time of the tilt test. Other reasons for exclusion included history of asthma (n=5), orthostatic hypotension (n=5), inability to administer isoproterenol because of concomitant angina (n=3) or aortic stenosis (n=2), patient refusal (n=1), and miscellaneous reasons that precluded completion of the entire protocol (n=14). Of the last group, 4 patients were excluded from analysis because carotid sinus massage subsequent to the tilt test reproduced their clinical symptoms.
Study Protocol
All patients were studied in the fasting state after informed
written consent was obtained. Patients were monitored via a Passport
recorder (Datascope Corp). The recorder permitted continuous
heart rate monitoring and automatic noninvasive measurements of blood
pressure at 60-second intervals.
We evaluated 3 protocols over the course of the study. The first 101
patients were enrolled in protocol 1, which compared the
diagnostic yield of adenosine and isoproterenol
tilt testing in patients with an initial negative drug-free tilt test
(Figure 1
). Resting supine blood pressure
and heart rate measurements were obtained over 15 minutes. Patients
were subsequently tilted upright at a 60° angle for 30 minutes on a
tilt table with a footboard. If the patient's clinical episodes of
presyncope and/or syncope were reproduced, the patient was returned to
the supine position and the test was terminated. The remaining patients
with a negative drug-free tilt test received while remaining upright a
bolus of 12 mg adenosine IV (Adenocard, Fujisawa) followed by a
10-cm3 flush of isotonic saline and were observed
for up to 5 minutes. After development of initial bradycardia and/or AV
block, all patients developed a reflex sinus tachycardia.
In susceptible patients, this was followed by a vasovagal response
(Figure 2). These patients were
classified as having a positive adenosine tilt test (see
below). It is important to emphasize that a positive response occurred
only after development of sinus tachycardia and was not
temporally associated with the preceding sinus slowing or AV block.
After returning to the supine position, all patients with a negative
drug-free tilt test, regardless of their response to adenosine,
underwent isoproterenol tilt testing. Isoproterenol infusion was begun
at 1 µg/min and titrated over 15 minutes until supine heart rate
increased by 20% over baseline or a maximum dose of 5 µg/min was
reached. Patients were then tilted upright for 15 minutes. Patients who
completed the entire protocol without a vasovagal response were
classified as having a negative study.
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Protocol 2 compared the efficacy of an adenosine tilt test with
our routine tilt test, with and without isoproterenol, in 100 patients
(Figure 3). Resting supine blood pressure
and heart rate measurements were obtained over 5 minutes in protocol 2
patients. Patients were tilted upright at a 60° angle and immediately
given adenosine as previously described. After 5 minutes of
observation, patients were returned to the supine position, and our
standard tilt test protocol was performed. Regardless of the response
to adenosine, all patients underwent our routine tilt test.
Resting supine blood pressure and heart rate measurements were obtained
for 15 minutes. As previously described, this was followed by 30
minutes of drug-free tilt testing and, if necessary, 15 minutes of tilt
testing during isoproterenol infusion.
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The initial dose of adenosine was 150 µg/kg (
12 mg). If an
adenosine effect (a transient decrease in heart rate by 
20%
compared with baseline or transient AV block) was not demonstrated, the
patient was returned to the supine position. After 5 minutes, the
patient was retilted and given an incremental dose of adenosine
(an additional 75 µg/kg). The process was repeated until an
adenosine effect was observed.
Protocol 3 was designed to compare and contrast the patterns of muscle
sympathetic nerve activity (MSNA) between adenosine and
isoproterenol. Six control patients (2 men; age, 37±11 years) without
significant cardiovascular history underwent
microneurography while supine according to methods previously
described.11 After a 20-minute rest period following
identification of the peroneal nerve, 5 minutes of baseline
recordings was obtained (Figure 4A). Subsequently, isoproterenol (1±1
µg/min) was infused to increase resting heart rate by 20%. After 5
minutes to reach a steady state at the desired isoproterenol dose, an
additional 5 minutes of recordings was obtained (Figure 4B) and analyzed at 1-minute intervals. Isoproterenol
infusion was then discontinued. After a 30-minute washout period and a
1-minute baseline recording period (Figure 4C), all
patients received a bolus administration of 150 µg/kg (13±4 mg)
adenosine and underwent an additional 3-minute
recording period. These data were analyzed in 10-second
intervals and then normalized to 1-minute intervals to allow comparison
with the isoproterenol data. After adenosine administration,
all patients developed initial transient AV block (Figure 4D)
followed by sinus tachycardia (Figure 4E).
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Definitions
Presyncope was defined as the induction of symptoms of imminent
syncope. Presyncope was considered a positive end point only in
patients being evaluated for clinical presyncope. Syncope was defined
as the transient loss of consciousness. Our routine tilt test was a
drug-free tilt test (60° for 30 minutes); if necessary, this was
followed by an isoproterenol tilt test (60° for 15 minutes). A
positive tilt test was defined as the reproduction of clinical
presyncope or syncope, after either an adenosine or routine
tilt test accompanied by relative bradycardia (20% decrease in heart
rate compared with baseline) and/or hypotension (systolic blood
pressure 
80 mm Hg).
Statistical Analysis
All continuous variables are expressed as mean±SD. Group
comparisons of continuous and dichotomous variables were calculated
by use of Student's t test and Fisher's exact test,
respectively. Comparisons of diagnostic yields in matched
patients were made using McNemar's 
2 test.
Comparison of repeated measures was performed by within-group ANOVA
with the use of prespecified contrasts to compare results during or
after adenosine or isoproterenol infusion with those obtained
during multiple control intervals (Crunch 4.0, Crunch Software Corp).
For all comparisons, P<0.05 was considered statistically
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Demographics
The mean age of the 201 patients was 55±20 years. The study population consisted of 81 men (40%) and 120 women (60%). Patients were referred for the evaluation of syncope (66%), presyncope (19%), or both (15%). The first episode prompted evaluation in 50 patients (25%); 31 patients (15%) had 2 episodes, and 118 patients (60%) had
3 episodes. Left ventricular (LV) ejection fraction was
known for 115 patients (57%) and was normal in 100 of these patients
(88%). History of cardiac disease was noted in 36% of the patients.
This included hypertension (21%), coronary artery disease
(13%), congestive heart failure (3%), and
cardiomyopathy (2%). In 5% of the patients,
ventricular pacing was available via a permanent pacemaker
or internal defibrillator.
Protocols 1 and 2 were performed in 101 and 100 patients, respectively.
No significant differences were observed between patients in protocols
1 and 2 with respect to age, sex, number of clinical episodes before
tilt testing, indication for tilt testing, and LV systolic
function (the Table).
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ECG
A baseline 12-lead ECG was available in all patients and was
normal in 158 (79%). Abnormalities on the ECG included a rhythm other
than sinus, including sinus bradycardia (heart rate <50 bpm) in 5%,
atrial fibrillation or flutter in 3%, ventricular pacing
in 4%, first-degree AV block in 4%,
intraventricular conduction delay in 9%,
ventricular hypertrophy in 3%, and/or evidence
of prior Q-wave myocardial infarction in 5%.
Adenosine Administration
Adenosine was well tolerated. The most frequent symptoms
associated with adenosine were flushing, diaphoresis,
light-headedness, and shortness of breath. In 2 patients, syncope
developed in the setting of prolonged AV block (>10 seconds)
immediately after infusion of 12 mg adenosine. These patients
were returned to the supine position before adenosine-mediated
tachycardia developed and were among those patients
excluded from analysis because of an uninterpretable
adenosine tilt test. All effects of adenosine were
self-limited; no patient required pharmacological intervention as a
result of adenosine administration. In addition, no patient
developed atrial fibrillation after adenosine infusion.
The most common ECG effect of adenosine, observed in 67% of patients, was development of transient AV block. The mean duration of AV block was 4±3 seconds (maximum, 14 seconds). Less common effects included sinus pauses in 18% and sinus bradycardia in 15%. The mean duration of sinus pause was 4±2 seconds (maximum, 10 seconds). In all patients with a positive adenosine tilt test, the vasovagal response occurred within 2 minutes of the resolution of AV block after adenosine administration.
Protocol 1
Seventeen (17%) patients developed a vasovagal response during
the initial drug-free tilt test (Figure 5). The mean time to a vasovagal response
was 16±11 minutes. According to protocol, the remaining 84 patients
underwent a pharmacological tilt test. After administration of
adenosine, 8 patients (10%) developed a vasovagal response. A
positive response was similarly observed in 7 patients (8%,
P=NS) after administration of isoproterenol 2±1 µg/min.
The mean time to a vasovagal response was 6±2 minutes during
isoproterenol infusion. Concordant positive responses to
adenosine and isoproterenol were observed in 3 patients, and
discordant responses were seen in 9 (Figure 6).
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Protocol 2
Nineteen patients (19%) developed a vasovagal response after
administration of adenosine (Figure 7). As described earlier, all patients
then underwent a routine tilt test regardless of their response to
adenosine. A drug-free tilt test was positive in 11 patients
(11%). Of the 89 patients with a negative drug-free tilt test, an
additional 11 (12%) had a positive response to tilt testing during
infusion of isoproterenol 2±1 µg/min. The mean time to a vasovagal
response was 16±11 minutes for patients with a positive drug-free tilt
test. During isoproterenol infusion, the mean time to a vasovagal
response was 8±4 minutes. There was no significant difference between
the overall positive yields of an adenosine tilt test (19%)
and the routine tilt test (22%) (P=NS).
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A positive tilt test with adenosine or during the routine
protocol was observed in 31 patients. Nine patients were
adenosine positive only; 12 patients were positive only during
the routine tilt test protocol; 10 patients had a concordant positive
response. Therefore, the concordance and discordance rates were 79%
(79 of 100) and 21% (21 of 100), respectively, between
adenosine and routine tilt testing (Figure 8). An example of a discordant response
is shown in Figure 2
, which depicts an ECG recording
during adenosine tilt testing from a patient with a lifelong
history of "seizures" precipitated by emotional distress and
accompanied by nausea and light-headedness. However, extensive
neurological testing, including MRI and electroencephalography, was
normal. The patient had been treated unsuccessfully with anticonvulsant
medications for several years. Although a subsequent routine tilt test,
with and without isoproterenol, was normal, the adenosine tilt
test was markedly positive and reproduced her clinical
"seizures."
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Of the 10 patients who were positive during both the adenosine
and routine tilt tests, 8 (80%) did not require isoproterenol for a
positive response during the routine tilt test. In contrast, of the 12
patients who were positive during the routine tilt test protocol but
negative during adenosine tilt testing, 9 (75%) required
isoproterenol to produce a positive response (P=0.03, Figure 8).
Adenosine Administration
The mean adenosine dose in these patients was 11.5±3.4 mg
(range, 6 to 24 mg). Only 6 patients required additional
adenosine because the initial dose failed to result in an
adenosine effect. Of these patients, 2 developed syncope in
response to a larger dose of adenosine after an earlier dose
failed to cause sinus slowing or AV block or to produce a vasovagal
response. No patient who failed to demonstrate an initial negative
chronotropic or dromotropic response with a given dose of
adenosine developed a positive adenosine tilt test at
that dose. Figure 9 is a
recording from a patient who received sequential doses of
adenosine. After doses of 12 and 18 mg adenosine, there
was neither an adenosine effect nor a vasovagal response.
However, after receiving 24 mg of adenosine, the patient
developed transient AV block, consistent with an
adenosine effect, which was followed by
adenosine-mediated sinus tachycardia and a
vasovagal response, which reproduced the patient's clinical episode.
According to protocol, the patient underwent a routine tilt test. After
a negative drug-free tilt test, a vasovagal response was reproduced
during the isoproterenol phase of the tilt protocol.
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Predictors of a Positive Test
A positive tilt test could not be predicted from baseline
demographic variables, including age, sex, indication for tilt
testing, LV ejection fraction, and history of cardiac disease. In
addition, baseline ECG abnormalities were not predictive of a positive
tilt test. However, the likelihood of a positive tilt test increased
with the number of clinical episodes. A positive routine tilt test was
observed in 7%, 19%, and 31% (P=0.02) of patients with 1,
2, and 3 clinical episodes, respectively, before tilt testing. A
similar trend, 8%, 14%, and 18%, was observed with adenosine
tilt testing (P=NS).
Protocol 3 (Microneurography)
Adenosine was associated with transient AV block, which
resulted in bradycardia and hypotension (Figure 10A and 10B). This period was
characterized by marked sympathetic activation as reflected by an
increase in MSNA by as much as 360% (19±3 to 52±17 bursts per
minute; Figure 10C). On resolution of AV block, there was
transient sinus tachycardia (10 seconds) followed by a
return of heart rate and blood pressure to baseline. Concomitantly,
MSNA decreased by as much as 67% compared with baseline (19±3 to 9±3
bursts per minute) and remained significantly depressed for an
additional 90 seconds. No significant differences in root mean square
successive differences12 were observed between baseline
and the 3-minute period after resolution of adenosine-induced
AV block. In contrast, isoproterenol infusion was associated with sinus
tachycardia, a decrease in mean arterial
pressure, and an 100% sustained increase in MSNA (14±2 to 26±1
bursts per minute; Figure 10D through 10F).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The principal finding of this study is that adenosine is a safe and effective pharmacological agent for the provocation of neurally mediated syncope in susceptible individuals. The positive yield of adenosine tilt testing is similar to isoproterenol tilt testing in patients with a negative drug-free tilt test and, more importantly, is similar to the overall yield of routine tilt testing (drug-free tilt followed by an isoproterenol tilt). These findings have significant clinical implications because in a heterogeneous population referred for tilt testing to evaluate unexplained presyncope and/or syncope, a single bolus dose of adenosine can provide a positive yield comparable to a routine tilt test protocol in <10 minutes.
Despite the similar overall yield, a 21% discordance rate was observed between adenosine and routine tilt testing. Among the 31 patients with a positive tilt test, 9 were positive only during adenosine tilt and 12 were positive only during routine tilt test. Of these latter 12 patients, 9 required isoproterenol to produce a positive response, suggesting that adenosine and isoproterenol tilt testing may have complementary roles in the evaluation of patients with neurally mediated syncope.
Effects of Adenosine
The pharmacological effects of adenosine are mediated via
various effectors.7 8 In addition to its cardiac effects
mediated by the A1 receptor (negative chronotropy
and dromotropy as well as an antiadrenergic
effect), binding of adenosine to the A2
receptor results in coronary and systemic vasodilatation. This
effect, in part, mediates sustained hypotension in anesthetized
patients.9 10 11 In contrast, adenosine infusion in
conscious patients results in sympathetic activation, characterized by
an increase in systolic blood pressure, heart rate, and
ventilation, effects mediated by baroreflex and peripheral
chemoreceptor activation.
The hemodynamic effects of bolus doses of adenosine, as performed in our study, are less well characterized than the effects during continuous infusion of adenosine. In a recent report, bolus doses of adenosine were associated with a triphasic hemodynamic response. There was an immediate hypertensive response, suggesting sympathetic activation, followed by hypotension (related to vasodilatation) and finally sinus tachycardia (likely caused by baroreceptor unloading). In susceptible individuals, vasovagal syncope occurred after this last response.6
Although adenosine causes a dose-dependent decrease in blood
pressure and heart rate when injected into the nucleus
solitarius,13 it is unlikely that exogenous
adenosine, at the doses given in our study (150 µg/kg),
crosses the blood-brain barrier.14 Therefore, a more
likely explanation for the response to exogenous adenosine is
that it increases sympathetic activation through unloading of
baroreceptors and arterial chemoreceptor activation, which
then triggers a vasovagal event in susceptible individuals. Thus,
exogenous adenosine can be considered a means by which to
increase sympathetic activation during orthostatic
stress.
There are several possible explanations for the discordance between the
results of adenosine and isoproterenol tilt testing in
individual patients. In some patients, the discordance may be due to
the delivery of a subdiagnostic adenosine dose. We
believe that demonstrating an adenosine effect (transient sinus
slowing or AV block) is required to confirm that an adequate dose was
given. In most patients, a dose of 150 µg/kg (12 mg) is
sufficient. Higher doses of adenosine rarely are required.
Failure to achieve an adenosine effect may result in a
false-negative adenosine-based tilt test.
Additionally, discordance may reflect differential patient
sensitivities related to the mechanisms of sympathetic activation by
adenosine (chemoreceptor activation and unloading of
baroreceptors) and isoproterenol (direct ß-adrenergic stimulation and
unloading of baroreceptors). To clarify this issue, we performed
microneurography and examined the differences in the pattern of
sympathetic activation after adenosine and isoproterenol
infusion. In contrast to the effects of continuous adenosine
infusion, the effects on MSNA after bolus doses of adenosine
have not previously been reported.10 11 In our study,
bolus doses of adenosine were associated with initial
sympathetic activation, as reflected by a marked increase in MSNA (as
much as 360% relative to baseline), followed by prolonged (90
seconds) sympathetic withdrawal, as reflected by a decrease in MSNA (as
much as 67% relative to baseline). The absence of a significant change
in root mean square successive differences suggests that the decrease
in MSNA reflects sympathetic withdrawal rather than augmented vagal
tone. Presumably, in susceptible individuals, there is continued
sympathetic withdrawal that results in vasovagal syncope. In contrast,
continuous isoproterenol infusion was associated with a sustained
increase in MSNA. However, the maximum increase in MSNA in response to
isoproterenol was less than one third that associated with
adenosine. Therefore, adenosine results in an initial
rapid and large increase in sympathetic activation followed by a rapid
decline, whereas isoproterenol produces a more modest but sustained
increase in MSNA.
Finally, discordance may reflect a false-positive response to either adenosine or isoproterenol. In the absence of a true gold standard, it is not possible to determine the actual sensitivity and specificity of tilt testing with or without pharmacological provocation. The most applicable surrogate is the reproduction of the patient's clinical episode with a concordant hemodynamic response. Because this was our end point for determination of a positive tilt test, we do not believe that discordance reflects a false-positive response.
Study Limitations
A possible limitation of our study is that we did not test the
adenosine or routine tilt test protocol in a control population
of subjects without a history of presyncope or syncope. However, the
specificity of both adenosine and routine tilt testing with a
protocol similar to ours has previously been reported. The 12-mg
adenosine bolus dosing regimen during tilt testing has a
specificity of 93%,6 similar to the specificity of
low-dose isoproterenol tilt testing with a 60° protocol
(88%).15 Because previous studies have already
demonstrated an acceptable specificity for both adenosine and
routine tilt testing, the primary aim of our study was to compare
adenosine with isoproterenol and routine tilt testing. A second
potential limitation is that the order in which the
diagnostic tests were performed (eg, adenosine
versus isoproterenol and adenosine versus routine tilt testing)
was not systematically varied, so the possibility that the results of
the adenosine stage may have affected the results of the
subsequent stages cannot be excluded. Finally, the discordant effects
of adenosine and isoproterenol on MSNA may reflect differences
in their mode of administration and/or differences in the
hemodynamic response induced by these drugs.
Specifically, the greater increase in MSNA with adenosine may
reflect the effect of bolus administration of adenosine (versus
continuous isoproterenol infusion), which may result in a greater
degree of hypotension and baroreceptor unloading.
Implications
Using our findings and bearing in mind the discordance between
adenosine and routine tilt testing, we propose a simplified,
more efficient tilt test protocol. Patients would initially undergo
adenosine tilt testing (with a weight-adjusted dose of
adenosine). A positive adenosine tilt test would
obviate the need for further testing, providing a substantial time
savings for the patient and physician. Patients with a negative
adenosine tilt test would then undergo a 15-minute
isoproterenol tilt phase. This recommendation is based on our
observation that patients with a negative adenosine but a
positive routine tilt test usually require isoproterenol to yield a
positive response during tilt testing. Compared with current clinical
tilt test protocols that use an initial drug-free tilt test followed by
pharmacological provocation with isoproterenol, this protocol may offer
a more efficient and sensitive means for diagnosing neurally mediated
syncope.
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Acknowledgments |
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This work was supported in part by grants from the National Institutes of Health (RO1 HL-56139 and MO1 RR-00047), the Rosenfeld Foundation, and the Michael Wolk Foundation.
Received June 5, 1998; revision received November 30, 1998; accepted December 7, 1998.
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 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]
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G.N. Theodorakis, E.G. Livanis, D. Leftheriotis, P. Flevari, M. Markianos, and D.Th. Kremastinos Head-up tilt test with clomipramine challenge in vasovagal syndrome--a new tilt testing protocol Eur. Heart J., April 1, 2003; 24(7): 658 - 663. [Abstract] [Full Text] [PDF]
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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]
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 A. Y. Saadjian, S. Levy, F. Franceschi, I. Zouher, F. Paganelli, and R. P. Guieu Role of Endogenous Adenosine as a Modulator of Syncope Induced During Tilt Testing Circulation, July 30, 2002; 106(5): 569 - 574. [Abstract] [Full Text] [PDF]
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 S. Mittal, S. C. Hao, S. Iwai, K. M. Stein, S. M. Markowitz, D. J. Slotwiner, and B. B. Lerman Significance of inducible ventricular fibrillation in patients with coronary artery disease and unexplained syncope J. Am. Coll. Cardiol., August 1, 2001; 38(2): 371 - 376. [Abstract] [Full Text] [PDF]
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Task Force on Syncope, European Society of Cardiol, M Brignole, P Alboni, D Benditt, L Bergfeldt, J.J Blanc, P.E Bloch Thomsen, J.G van Dijk, A Fitzpatrick, S Hohnloser, et al. Guidelines on management (diagnosis and treatment) of syncope Eur. Heart J., August 1, 2001; 22(15): 1256 - 1306. [Abstract] [PDF]
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 M Brignole, G Gaggioli, C Menozzi, A Del Rosso, S Costa, A Bartoletti, N Bottoni, and G Lolli Clinical features of adenosine sensitive syncope and tilt induced vasovagal syncope Heart, January 1, 2000; 83(1): 24 - 28. [Abstract] [Full Text] [PDF]
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