Download Provocation of sudden heart rate oscillation with adenosine exposes

Clinical research
European Heart Journal (2006) 27, 469–475
doi:10.1093/eurheartj/ehi460
Provocation of sudden heart rate oscillation with
adenosine exposes abnormal QT responses in patients
with long QT syndrome: a bedside test for diagnosing
long QT syndrome
Sami Viskin1*, Raphael Rosso1, Ori Rogowski1, Bernard Belhassen1, Aviva Levitas2,
Abraham Wagshal2, Amos Katz2, Dana Fourey1, David Zeltser1, Antonio Oliva3, Guido D. Pollevick3,
Charles Antzelevitch3, and Uri Rozovski1
1
Department of Cardiology, Tel-Aviv Sourasky Medical Center, Sackler-School of Medicine, Tel Aviv University, Weizman 6,
Tel Aviv 64239, Israel; 2 Soroka University Medical Center, Ben-Gurion University, Beer Sheva, Israel; and 3 The Masonic
Medical Research Laboratory, Utica, New York, USA
Received 8 July 2005; accepted 25 July 2005; online publish-ahead-of-print 16 August 2005
KEYWORDS
Long QT syndrome;
Adenosine;
Torsade de pointes;
Electrocardiogram
Aims As arrhythmias in the long QT syndrome (LQTS) are triggered by heart rate deceleration or acceleration, we speculated that the sudden bradycardia and subsequent tachycardia that follow adenosine
injection would unravel QT changes of diagnostic value in patients with LQTS.
Methods and results Patients (18 LQTS and 20 controls) received intravenous adenosine during sinus
rhythm. Adenosine was injected at incremental doses until atrioventricular block or sinus pauses
lasting 3 s occurred. The QT duration and morphology were studied at baseline and at the time of
maximal bradycardia and subsequent tachycardia. Despite similar degree of adenosine-induced bradycardia (longest R–R 1.7 + 0.7 vs. 2.2 + 1.3 s for LQTS and controls, P ¼ NS), the QT interval of LQT
patients increased by 15.8 + 13.1%, whereas the QT of controls increased by only 1.5 + 6.7%
(P , 0.001). Similarly, despite similar reflex tachycardia (shortest R–R 0.58 + 0.07 vs. 0.55 + 0.07 s
for LQT patients and controls, P ¼ NS), LQTS patients developed greater QT prolongation
(QTc ¼ 569 + 53 vs. 458 + 58 ms for LQT patients and controls, P , 0.001). The best discriminator
was the QTc during maximal bradycardia. Notched T-waves were observed in 72% of LQT patients but
in only 5% of controls during adenosine-induced bradycardia (P , 0.001).
Conclusion By provoking transient bradycardia followed by sinus tachycardia, this adenosine challenge
test triggers QT changes that appear to be useful in distinguishing patients with LQTS from healthy
controls.
Introduction
The diagnosis of the long QT syndrome (LQTS) is straightforward when torsade de pointes is documented at the time of
symptoms in a patient with obvious prolongation of the QT
interval.1,2 More often, however, diagnosing an LQTS is problematic for several reasons. First, arrhythmic symptoms
related to an LQTS occur infrequently, making it difficult
to document torsade de pointes. Secondly, considerable
overlapping in the duration of the QT interval exists
between carriers of LQTS mutations and healthy controls.3,4
Hence, a common scenario is the referral of patients with
borderline or slightly prolonged QT segment who have symptoms suggestive of arrhythmias but no arrhythmia documentation. Thirdly, although genetic testing may confirm the
* Corresponding author. Fax: þ972 3 6974416.
E-mail address: [email protected]
diagnosis when a cardiac channel malfunction is identified,
this testing may take months to conclude and is performed
only in specialized centres. Moreover, failing to identify a
mutation does not exclude the diagnosis of LQTS.5 Thus,
diagnosing a congenital LQTS remains a clinical challenge.1
Sudden changes in heart rate affect the QT segment of
patients with LQTS profoundly.6 In fact, sudden acceleration, or sudden deceleration, of the heart rate can trigger
torsade de pointes. In the first scenario, sinus tachycardia
(as seen during stress) leads to T-wave alternans7 and ultimately triggers ‘adrenergic-dependent’ (tachycardiadependent) torsade de pointes.8 Similarly, sudden heart
rate slowing (as during post-extrasystolic pauses)1,9 leads
to post-pause ‘U-wave augmentation’9,10 and eventually
causes ‘pause-dependent’ (bradycardia-dependent) torsade
de pointes.11,12
The adenosine compounds [adenosine and adenosine
triphosphate (ATP)] are nucleotides that, when injected
& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: [email protected]
470
intravenously, block atrioventricular (AV) nodal conduction
for a few seconds. Physicians take advantage of this property to terminate supraventricular tachycardias13 or to
identify the presence of dual AV node physiology or accessory pathways.14,15 When injected during sinus rhythm,
the adenosine compounds cause dose-dependent bradycardia either due to sinus pauses or due to transient AV block.
This short-lasting bradyarrhythmia is soon followed by
marked sinus tachycardia.16 We aimed to take advantage
of the sudden deceleration–acceleration sequence that
invariably follows the injection of adenosine during sinus
rhythm to evaluate whether these heart rate oscillations
would unravel pathologic QT changes in patients with LQTS.
Methods
Patient groups
The ‘LQTS group’ consisted of patients with ‘definite LQTS’ or ‘high
probability for LQTS’. Patients with high probability of LQTS are
patients with ‘International LQTS Registry Score’ of 4 points.17
Patients with definite LQTS have, in addition, documented torsade
de pointes and/or an LQTS mutation. The ‘control group’ consisted
of consecutive patients prospectively undergoing an adenosine or
ATP challenge test for identifying the presence of dual AV node physiology or concealed accessory pathway as previously described.14,15
None of the controls had a history of syncope or a familial history
even reminiscent of LQTS, none were receiving medications known
to impair myocardial repolarization and none of them had evidence
of organic heart disease including left ventricular hypertrophy.
Patients and controls provided informed consent according to the
study protocol reviewed by our Institutional Review Committee. A
history of bronchial asthma was an exclusion criterion.
Interventions
LQTS patients and controls underwent the adenosine or ATP test as a
bedside test during continuous electrocardiographic recording. ATP
(Striadyne, Ayerst Laboratories, France) or adenosine (Adenocor,
Sanofi-Winthrop) was injected through an antecubital vein as a
rapid bolus, followed by a 20 mL flush of normal saline. The initial
dose was 10 mg of ATP or 6 mg of adenosine. Repeated injections
(using 10 mg or 6 mg increments, for ATP or adenosine, respectively)
were given until one of the following events occurred: (i) transient
AV nodal block of second or third degree, (ii) sinus bradycardia or
sinus arrest leading to 3 s asystole, (iii) the patient requested termination of the test because of side effects, or (iv) a maximal dose
of 40 mg ATP or 24 mg adenosine was reached. Only patients developing bradycardia (as described earlier) were included in the final
analysis.
Measurements
To avoid reader bias, one investigator first photocopied and coded
four electrocardiograms for each patient that were recorded at
the following points in time: (i) at baseline, (ii) at the time of
maximal bradycardia, (iii) at the time of maximal tachycardia,
and (iv) at the maximal QT effect (at the time of the most obvious
changes in T-wave morphology during the reflex tachycardia
phase). All the coded electrocardiograms (four traces per patient)
were then presented in random order to a second investigator
who performed the QT measurements. Thus, the ‘QT reader’ was
unaware not only of the patient allottment but also of the patient’s
baseline QT when measuring the QT interval recorded during
adenosine-induced bradycardia or tachycardia. The following
measurements were made in all 12 leads at each point in time:
(i) QT and QT(peak) (the intervals from the onset of the QRS to
S. Viskin et al.
the end of the T-wave and to the peak of the T-wave, respectively);
(ii) QT(peak-end) [the difference between QT and QT(peak)];
(iii) QTc [the mean QT (of 12 leads) divided by the root square of
the preceding R–R interval]; (iv) the presence of abnormal
T-waves (T-wave inversion and notched T-waves) and the amplitude
of all the T-wave components were noted: T2 signifies that there
were notched or double T-waves, T2 . T1 signifies that the second
T-wave component was taller than the first component by any
value and T2 T1 signifies that T2 was considerably taller than
T1 (by .0.1 mV).
Statistics
Data are displayed as mean + SD for continuous variables and as
number and percentage for categorical variables. To examine the
hypothesis that administrating adenosine influences the QT parameters of LQT patients and controls differently, ANOVA in a
mixed inter–intra model was performed twice, with the QT and
the QTc as the dependent variables, and with two independent variables: (i) the stage in relation to adenosine injection (i.e. baseline,
maximal bradycardia, maximal tachycardia, and maximal QT effect)
was entered as a repeated measure variable and (ii) the subject’s
status (LQTS or control) was entered as a between-subject variable.
Contrast analysis was then performed to compare QT parameters in
relation to baseline, separately for the LQTS and the control groups.
Finally, discriminant analysis was performed to examine the best separation solution between the two groups. For this purpose, 70% of the
total sample was randomly selected and a discriminant U function
was applied in a stepwise method, i.e. only variables that minimized
the lambda score were entered. The results were then applied to all
cases to examine how good the model performs. For all categorical
variables, the x2 phi and Cramer’s V statistics were used. Twotailed P-value 0.05 was considered significant. The SPSS statistical
package was used to perform all statistical evaluation (SSPS Inc. V12
Chicago, IL, USA).
Results
Twenty patients with LQTS and 22 controls agreed to participate in the study. One LQT patient developed cough and
mild expiratory wheezing (that resolved without therapy).
A second patient, as well as two controls, withdrew their
consent to participate after the first or second dose of adenosine. These patients were excluded from further analysis
because the adenosine doses given failed to provoke any
bradycardia. Thus, the effects of adenosine were evaluated
in 18 patients with LQTS and 20 controls. All but one of the
LQT patients had LQTS score17 4 (mean score 5.1 + 1).
The only patient with LQTS score ,4 (3 points) has an
LQT2 mutation. Seven patients were genotyped: five
patients have LQT2, one has LQT1, and one has LQT3. The
LQTS group includes six patients with documented torsade
de pointes or ventricular fibrillation and seven patients
with a history of syncope.
Patients and controls were similar in terms of their demographic and electrocardiographic characteristics except for
the QT interval, which (as expected) was longer in patients
with LQTS (Table 1 ). It should be noted that 10 (56%) of the
LQT patients had a mean QTc ,460 ms, whereas seven of
the controls had a mean QTc .410 ms. Thus, 17 (45%) of
the study population had QTc values that would be considered ‘borderline’ because, in large genotyped populations, such QT intervals can be seen in LQTS-mutation
carriers or healthy individuals.3,18 In addition, the adenosine doses administered to both patient groups were
similar. Moreover, the sudden changes in heart rate that
Adenosine test for diagnosing LQTS
471
Table 1 Baseline characteristics and response to adenosine in
the study group
Age (years)
Male gender (%)
Baseline R–R (ms)
Baseline QTc (ms)
Adenosine dosea (mg)
Longest R–Rb (ms)
Shortest R–Rb
LQTS
(n ¼ 18)
Control
(n ¼ 20)
P-value
32.7 + 15.8
7 (39)
870 + 150
454 + 24
11.7 + 6
1670 + 670
580 + 70
31.4 + 12.2
10 (50)
840 + 220
399 + 29
14.1 + 5.3
2240 + 1270
550 + 70
0.76
0.49
0.63
,0.001
0.19
0.09
0.187
a
Some patients received ATP: 10, 20, 30, and 40 mg of ATP were
counted as 6, 12, 18, and 24 mg of adenosine, respectively.
b
The longest R–R and the shortest R–R denote the maximal bradycardia
and the maximal tachycardia responses seen after adenosine administration, respectively.
were induced by adenosine were of similar magnitude in
both groups (Table 1 ).
patients and six (32%) controls (P ¼ NS) at the time of
maximal effect. In contrast, double T-waves (T-wave
notches) were noted in at least one lead in 10 (56%) of
LQT patients and two (10%) of controls (P ¼ 0.003) at baseline. Moreover, during the bradycardia phase of the adenosine challenge, the percentage of patients with double
T-waves increased to 72% among LQT patients but decreased
to 5% in controls (P , 0.001). During the tachycardia phase,
72% of LQT patients and 30% of controls had notched
T-waves. However, T2 . T1 was seen in 12 (67%) of LQT
patients but in only two (10%) of controls (P , 0.001) and
T2 T1 was seen at the time of maximal effect in eight
(44%) of LQT patients and in only one (5%) of controls
(P ¼ 0.004). One LQT patient developed ventricular extrasystoles that appeared to represent triggered activity from
early after-depolarizations because they were pause-dependent and originated from the terminal part of the QT
segment (Figure 4, bottom trace) and one LQT patient
developed T-wave alternans during the tachycardia phase
of the test (Figure 5 ).
Safety
Bradycardia-induced QT changes
Despite similar degrees of adenosine-induced bradycardia
(Figure 1 ), there were striking differences in the response
of the QT interval between the two groups: During
maximal bradycardia, the QT interval of controls increased
by only 1.5 + 6.7%, whereas a 15.8 + 13.1% increment in
QT interval was seen among LQT patients (P , 0.001)
(Figures 1–3 ). Because of the marked increase in R–R interval, the QTc of both groups actually decreased during bradycardia, yet significantly less among LQT patients (the QTc
shortened by 13 + 18 and by 32 + 17% for LQT patients
and controls, respectively, P ¼ 0.002). At the time of
maximal bradycardia, the QT was 366 + 39 ms for controls
and 487 + 69 ms for LQT patients (P , 0.001), and the QTc
was 269 + 69 ms for controls and 395 + 79 ms for LQT
patients (P , 0.001) (Figure 1 ).
Tachycardia-induced QT changes
The adenosine-induced transient bradycardia was invariably
followed by sinus tachycardia that reached a maximal rate
21 + 9 s after the deepest bradycardia. The maximal heart
rate during the tachycardia phase was similar for LQT
patients and controls (R–R interval 582 + 70 ms for LQTS
vs. 543 + 67 ms for controls, P ¼ NS). The maximal changes
in T-wave morphology and QT duration were not seen at the
time of maximal tachycardia but rather 11 + 9 s later, when
the sinus rate began to return towards the baseline rate.
Although the heart rate at the time of maximal T-wave
changes was similar between LQTS patients and controls
(Figure 1 ), the QT and the QTc of LQT patients were
much longer than those of the controls (QT ¼ 458 + 55
vs. 348 + 57 ms, P , 0.001 and QTc ¼ 569 + 53 vs.
458 + 58 ms, P , 0.001, for LQT patients and controls,
respectively) (Figures 1 and 4 ).
Adenosine-induced changes in T-wave morphology
T-wave inversion following adenosine injection was of no
diagnostic value because it occurred in five (28%) LQT
All patients experienced the usual side effects of adenosine:
chest pain, dyspnoea, and/or flushing and, as mentioned
earlier, three patients requested termination of the study
because of these side effects, whereas in one patient, we
terminated the study prematurely because of short-lasting
wheezing. All the side effects terminated within seconds
without intervention.
Diagnostic value of the adenosine challenge
Adenosine challenge resulted in dissimilar response in LQT
patients and controls. This was evident from the significant
interaction between stage (baseline, bradycardia, tachycardia, and maximal effect) and patients’ group (LQTS vs.
control) for both QT and QTc: (F(3,108) ¼ 6.764, P , 0.0001
for QT and F(3,108) ¼ 3.745, P ¼ 0.013 for QTc). Contrast
analysis revealed that the difference in QT and QTc
between subjects with LQTS and controls was larger at all
the three stages that followed adenosine injection (i.e.
maximal bradycardia, maximal tachycardia, and maximal
effect) than at baseline. The largest difference was seen
during maximal bradycardia, where the difference
between the mean QT values of the two groups was
121 ms (vs. a 59 ms difference at baseline) and the difference between the mean QTc values of the two groups was
125 ms (vs. a 55 ms difference at baseline) (Figure 1 ).
To reduce the influence of outliers, the median values of
LQT patients and controls were also compared. Again, the
best separation between groups was evident in the QTc at
maximal bradycardia, where the difference between
medians was 135 ms (vs. 67 ms at baseline). Because the
QT of controls hardly changed while the R–R interval suddenly increased during adenosine-induced bradycardia, the
QTc of controls actually shortened (Figure 1 ). On the basis
of the current sample, the parameter that best distinguishes
between two groups is the QTc measured during bradycardia. A QTc ,250 ms during maximal bradycardia nearly
excludes LQTS, whereas QTc .380 ms during bradycardia
strongly implies LQTS. This is because only 5% of LQTS
had a QTc 250 ms, whereas 95% of controls have QTc
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S. Viskin et al.
Figure 1 Response of the R–R, QT, QTc, and QT(peak-end) to intravenous adenosine injection during sinus rhythm in patients with LQTS (black bars) and controls
(white bars). All graphs show the mean (horizontal line) and SD (bar) during baseline, at the time of maximal adenosine-induced bradycardia, and the time that
the maximal effect on the QT interval was observed during adenosine-induced tachycardia. QT(peak-end) is the interval between the peak of the T-wave and the
end of the QT interval. P , 0.01, P , 0.001.
Figure 2 Typical response of the QT interval to sudden changes in heart rate provoked by adenosine in a control. Following the injection of 18 mg adenosine,
there is transient complete AV block leading to 3.5 s of ventricular asystole. Despite the marked bradycardia, there is little change in the QT duration and morphology. Ten seconds later, reflex sinus tachycardia occurs. The amplitude of the T-wave slightly decreases during tachycardia but the T-wave morphology remains
normal.
,380 ms at this stage. The second best distinguishing
parameter was the QTc at the time of maximal QT effect.
At this stage, a QTc ,490 ms nearly excludes LQTS (only
5% of LQTS had a QTc ,490 ms during this stage), whereas
a QTc .620 ms strongly implies LQTS (95% of controls have
QTc ,620 ms during this stage).
The area under the curve of the receiver operating
characteristics (ROC) curves ranged between 0.933 and
0.969 for the QT measures at baseline, maximal effect,
and maximal bradycardia values, and between 0.881 and
0.933 for the QTc measures at the same time points. From
the ROC curve analysis, a QT of 0.41 s at maximal bradycardia time point had a sensitivity of 0.94 and a specificity
of 0.9 to detect LQTS. At the time of maximal effect
of adenosine on T-wave morphology, a QTc of 0.49 has a
sensitivity of 0.94 and a specificity of 0.85 for detecting
LQTS.
To build a predicting, explanatory model, we first
randomly selected 70% of the sample and then applied discriminant analysis for both QT and QTc. For the QT,
only the QT interval at maximal effect entered the
final equation, with a lambda score of 0.366. This model
correctly predicted 92.6% of the randomly selected cases
(25/27 cases) and 89% (10/11 cases) of the remaining 30%.
For the QTc, both QTc at maximal tachycardia and QTc at
baseline entered the model, with a total lambda score of
0.25. This model correctly predicted 96.3% of the selected
cases (26/27) as well as all the unselected cases (11/11).
Adenosine test for diagnosing LQTS
473
Figure 3 Response of the QT interval to adenosine-induced bradycardia in two patients with LQTS. The top trace is from a 40-year-old female. Her baseline QTc
is 480 ms and her T-waves have normal morphology. Following injection of 30 mg ATP, she developed 4 s of AV block (P-waves are marked with arrowheads). During
the bradycardia, the T-wave become notched (T2 T1). The bottom trace is from a 22-year-old female. Her baseline QTc is 500 ms. The T-wave in lead V2 is
followed by a second wave that most probably represents a ‘physiologic U-wave’10 because it is well defined, of small amplitude, and terminates much after the
end of the QT interval defined from other leads (arrow). The maximal bradycardia, maximal tachycardia, and the maximal effects on the QT interval occur 20, 40,
and 55 s after the ATP injection, respectively. During bradycardia, she develops notched T-waves in V2 [the amplitude of the second component increased and
now terminates synchronously with the QT interval ends in other leads (arrow)]. During tachycardia, the T-wave assumes a bizarre morphology in lead V2,
whereas abnormal ‘typical notched T-waves’ (T2 . T1) are noticed during tachycardia in lead V4.
Figure 4 Response of the QT interval to adenosine-induced tachycardia in three patients with LQTS. In the top trace (female, 47 years old), the QT interval not
only fails to shorten during tachycardia but actually lengthens to the point that the end of the T-wave almost reaches the following P-wave. The middle trace is
from a 50-year-old female with asymptomatic LQT2 mutation. Her QTc is only 430 ms at baseline and the T-wave morphology is normal. However, during the
tachycardia phase of adenosine, the QT actually prolongs from 400 to 480 ms, the T-wave becomes frankly abnormal ( ), and the QTc increases from 430 to
550 ms. The bottom trace is from a 56-year-old male. His baseline QT is only 420 ms. During the tachycardia phase of adenosine, he first developed notched
abnormal T-waves ( ) and eventually develops ventricular ectopy that looks typical of LQTS-related arrhythmias because the extrasystoles arise from the terminal
part of the QT interval. Note that post-extrasystolic pauses trigger bizarre T-wave changes ( ). The QTc reached a maximum of 560 ms before the onset of
ventricular ectopy.
Discussion
Accurate diagnosis of the LQTS is imperative because this
is a potentially lethal disorder for which effective therapy
exists. Among the numerous diagnostic tests proposed over
the years,1 the two most commonly used tests, exercise19,20
and epinephrine challenge,21–23 take advantage of the poor
accommodation of the QT interval in response to heart rate
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S. Viskin et al.
Figure 5 Provocation of T-wave alternans with adenosine. Adenosine test in an asymptomatic patient is considered to be an ‘obligatory carrier’ of LQTS because
her mother and daughter have obvious LQTS with documented torsade de pointes (her daughter has been reported elsewhere).32 The QTc at baseline is borderline
for a female (QTc ¼ 450 ms). During the tachycardia phase of the adenosine challenge, she develops T-wave alternans (arrows).
acceleration to improve the diagnosis of the LQTS. We report,
for the first time, that the behaviour of the QT interval markedly differs between LQT patients and controls during the
bradycardia- and the tachycardia-phase that follow an
adenosine challenge test.
Diagnostic value of the adenosine challenge test
Because this is the first use of adenosine to diagnose LQTS,
we only studied patients with ‘definite’ or ‘high probability’
for LQTS and ‘definitively healthy’ controls (proof of
concept design). As a consequence of this design, the QT
parameters of the two groups were already dissimilar at
baseline, making it more challenging to demonstrate the
diagnostic value of the new diagnostic test. Nevertheless,
the different response of the QT interval to the sudden
heart rate changes provoked by adenosine augmented the
difference between LQT patients and controls. The best discriminator proved to be the QTc measured during maximal
bradycardia and the second best discriminator was the QTc
at the time when the maximal effects of adenosine on QT
morphology were evident during tachycardia. The magnitude of the difference between LQT patients and controls
at any of these two stages was significantly larger than any
difference noticeable at baseline. During maximal bradycardia, QTc cut-off points of 250 ms and 620 ms provided
excellent discrimination between LQTS and controls
because only 5% of LQTS (but almost 40% of controls) had
QTc ,250 ms, whereas ,5% of controls (but 60% of LQTS)
had QTc .620 ms. It should be noted that the best model
that resulted in correct prediction of almost all the sample
tested, including LQT patients and controls, was achieved
by using both the baseline QTc and the QTc at maximal
tachycardia. This emphasizes the clinical relevance of calculating QTc at this time points as well.
Mechanism of adenosine-mediated QT changes
The dependence of QT duration on heart rate is steeper in
patients with LQTS than in controls.6 Thus, maladjustment
of the QT interval to the heart rate oscillations induced by
adenosine probably caused the striking QT changes in our
LQT patients. However, the fact that the maximal effects
on QT morphology did not occur at the time of maximal
tachycardia, but shortly thereafter, suggests that rateindependent mechanisms also affected QT morphology.
Adenosine has no direct effect on the ventricular actionpotential duration24 and the changes in T-wave morphology
induced by adenosine in this study are comparable to those
reported with epinephrine.25 Because tachycardia, hypertension, and increased sympathetic nerve traffic follow the
bradycardia response to adenosine only in awake patients
(anaesthetized patients develop only bradycardia),26 it is
likely that a reflex sympathetic surge, secondary to the
chest pain and dyspnoea caused by adenosine, is responsible
for the QT changes observed during the tachycardia phase of
our adenosine challenge. Accordingly, adenosine could be
better than epinephrine23 in simulating ‘physiologic
stress’, the common trigger of arrhythmias in the LQTS.
Limitations
Experimental27 and clinical28 data suggest that LQTS
patients with different genotypes respond differently to
heart rate changes. Accordingly, patients with LQT3 would
be expected to develop more QT changes during the bradycardia phase of the adenosine test, whereas LQT1 patients
would be expected to show QT prolongation specifically
during tachycardia. The small number of genotyped patients
in our series precludes reaching any conclusions regarding
this important point, and the relatively high proportion of
patients with LQT2 in our series may have biased our
results towards ‘more T-wave changes’. In addition, the
study group consisted only of patients with high pre-test
probability of LQTS. On one hand, this may have limited
the diagnostic ‘added value’ of our test. On the other
hand, the adenosine test may not necessarily perform as
well in patients with less obvious LQTS or in patients with
abnormal repolarization due to other causes (like left ventricular hypertrophy). Finally, because of the small number
Adenosine test for diagnosing LQTS
of controls studied, the ‘normal’ response of the QT interval
to adenosine has to be defined further.
Clinical implications
By performing rigorously controlled testing, two
groups21,22,25,29 have established the epinephrine challenge
test as the most useful test for diagnosing LQTS in borderline
cases.23 By provoking ‘reflex tachycardia’, adenosine may
be a better simulator of ‘physiologic stress’, the common
trigger of arrhythmias in the LQTS, than exogenous epinephrine infusion. In addition, the adenosine challenge test provides additional diagnostic information during the
bradycardia phase, which is absent during the epinephrine
challenge. However, it is impossible to conclude which of
these tests will provide the highest diagnostic value
before comparison of our adenosine challenge test with
the epinephrine protocols21,22 is performed in the same
patients. The adenosine challenge test (like any challenge
test performed in patients with suspected LQTS) should
be performed only by personnel experienced and equipped
for treating ventricular arrhythmias. We did not encounter
serious side effects while using adenosine for diagnostic purposes in this and other studies.14,15 Nevertheless, it is worth
remembering that cases of torsade de pointes during clinical
use of adenosine have been described.30,31
Conflict of interest: none declared.
References
1. Viskin S. The long QT syndromes and torsade de pointes. Lancet
1999;354:1625–1633.
2. Moss AJ. Long QT syndrome. JAMA 2003;289:2041–2044.
3. Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long QT syndrome.
N Engl J Med 1992;327:846–852.
4. Allan WC, Timothy K, Vincent GM, Palomaki GE, Neveux LM, Haddow JE.
Long QT syndrome in children: the value of rate corrected QT interval and
DNA analysis as screening tests in the general population. J Med Screen
2001;8:173–177.
5. Vincent GM. Role of DNA testing for diagnosis, management and genetic
screening in long QT syndrome, hypertrophic cardiomyopathy and Marfan
syndrome. J Cardiovasc Electrophysiol 2001;86:12–14.
6. Merri M, Moss AJ, Benhorin J, Locati EH, Alberti M, Badilini F. Relation
between ventricular repolarization duration and cardiac cycle length
during 24-hour Holter recordings. Findings in normal patients and
patients with long QT syndrome. Circulation 1992;85:1816–1821.
7. Cruz Filho FE, Maia IG, Fagundes ML, Barbosa RC, Alves PA, Sa RM,
Boghossian SH, Ribeiro JC. Electrical behavior of T-wave polarity alternans in patients with congenital long QT syndrome. J Am Coll Cardiol
2000;36:167–173.
8. Chinushi M, Restivo M, Caref EB, El-Sherif N. Electrophysiological basis of
arrhythmogenicity of QT/T alternans in the long QT syndrome: tridimensional analysis of the kinetics of cardiac repolarization. Circ Res
1998;83:614–628.
9. Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The
long QT syndromes: a critical review, new clinical observations and a
unifying hypothesis. Prog Cardiovasc Dis 1988;31:115–172.
10. Viskin S, Zelster D, Antzelevitch C. When u say ‘U Waves’, what do u
mean? Pacing Clin Electrophysiol 2004;27:145–147.
11. Viskin S, Alla SR, Barron HV, Heller K, Saxon L, Kitzis I, Van Hare GF,
Wong MJ, Lesh MD, Scheinman MM. Mode of onset of torsade de pointes
in congenital long QT syndrome. J Am Coll Cardiol 1996;28:1262–1268.
475
12. Viskin S, Fish R, Zeltser D, Heller K, Brosh D, Laniado S, Barron HV.
Arrhythmias in the congenital long QT syndrome: how often is torsade
de pointes pause-dependent? Heart 2000;83:661–666.
13. Belhassen B, Viskin S. What is the drug of choice for the acute
termination of paroxysmal supraventricular tachycardia: verapamil,
adenosine triphosphate, or adenosine? Pacing Clin Electrophysiol
1993;16:1735–1741.
14. Belhassen B, Fish R, Glikson M, Glick A, Eldar M, Laniado S, Viskin S.
Noninvasive diagnosis of dual AV node physiology in patients with
AV nodal reentrant tachycardia by administration of adenosine-50 triphosphate during sinus rhythm. Circulation 1998;98:47–53.
15. Viskin S, Fish R, Glick A, Glikson M, Eldar M, Belhassen B. The adenosine
triphosphate test: a bedside diagnostic tool for identifying the mechanism of supraventricular tachycardia in patients with palpitations. J Am
Coll Cardiol 2001;38:173–177.
16. Lerman BB, Belardinelli L. Cardiac electrophysiology of adenosine: basic
and clinical concepts. Circualtion 1991;83:1499–1509.
17. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for
the long QT syndrome. An update. Circulation 1993;88:782–784.
18. Vincent GM. How to make the diagnosis of Long QT syndrome in patients
with reduced penetrance of the prolonged QT phenotype when DNA
testing is not available or is negative. First International Symposium
on Long QT Syndrome. http://www.lqts-symposium.org/topics/
ing_vincent.pdf (2004).
19. Takenaka K, Ai T, Shimizu W, Kobori A, Ninomiya T, Otani H, Kubota T,
Takaki H, Kamakura S, Horie M. Exercise stress test amplifies genotypephenotype correlation in the LQT1 and LQT2 forms of the long-QT
syndrome. Circulation 2003;107:838–844.
20. Dillenburg RF, Hamilton RM. Is exercise testing useful in identifying congenital long QT syndrome? Am J Cardiol 2002;89:233–236.
21. Shimizu W, Noda T, Takaki H, Kurita T, Nagaya N, Satomi K, Suyama K,
Aihara N, Kamakura S, Sunagawa K, Echigo S, Nakamura K, Ohe T,
Towbin JA, Napolitano C, Priori SG. Epinephrine unmasks latent mutation
carriers with LQT1 form of congenital long-QT syndrome. J Am Coll
Cardiol 2003;41:633–642.
22. Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen WK, Porter CB.
Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc
2002;77:413–421.
23. Viskin S. Drug challenge with epinephrine or isoproterenol for diagnosing
a long QT syndrome: Should we try this at home? J Cardiovasc
Electrophysiol 2005;16:285–287.
24. Belardinelli L, Isenberg G. Actions of adenosine and isoproterenol on
isolated mammalian ventricular myocytes. Circ Res 1983;53:287–297.
25. Khositseth A, Hejlik JB, Shen WK, Ackerman MJ. Epinephrine-induced
T-wave notching in congenital long QT syndrome. Heart Rhythm
2005;2:141–146.
26. Biaggioni I, Killian TJ, Mosqueda-Garcia R, Robertson RM, Robertson D.
Adenosine increases sympathetic nerve traffic in humans. Circulation
1991;83:1668–1675.
27. Shimizu W, Antzelevitch C. Cellular basis for the ECG features of
the LQT1 form of the long QT syndrome. Effects of beta-adrenergic
agonists and antagonists and sodium channels blockers on transmural
dispersion of repolarization and torsade de pointes. Circulation 1998;
98:2314–2322.
28. Nemec J, Buncova M, Bulkova V, Hejlik J, Winter B, Shen WK, Ackerman MJ.
Heart rate dependence of the QT interval duration: differences among
congenital long QT syndrome subtypes. J Cardiovasc Electrophysiol
2004;15:550–556.
29. Shimizu W, Noda T, Takaki H, Nagaya N, Satomi K, Kurita T, Suyama K,
Aihara N, Sunagawa K, Echigo S, Miyamoto Y, Yoshimasa Y, Nakamura K,
Ohe T, Towbin JA, Priori SG, Kamakura S. Diagnostic value of epinephrine
test for genotyping LQT1, LQT2, and LQT3 forms of congential long QT
syndrome. Heart Rhythm 2004;3:273–286.
30. Wesley RC, Turnquest P. Torsade de pointes after intravenous adenosine
in the presence of prolonged QT syndrome. Am Heart J
1992;123:794–796.
31. Harrington GR, Froelich EG. Adenosine-indued torsade de pointes. Chest
1993;103:1299–1301.
32. Viskin S, Fish R, Roth A, Copperman Y. Prevention of torsade de pointes
in the congenital long QT syndrome: use of a pause-prevention pacing
algorithm. Heart 1998;79:417–419.