- Email: [email protected]
Read My Lips
JACC: CLINICAL ELECTROPHYSIOLOGY
VOL.
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
-, NO. -, 2017
ISSN 2405-500X/$36.00 http://dx.doi.org/10.1016/j.jacep.2017.05.016
EDITORIAL COMMENT
Read My Lips A Positive Ajmaline Test Does Not Always Mean You Have Brugada Syndrome* Sami Viskin, MD, Raphael Rosso, MD
I
t would be unthinkable, at least to most electro-
from 50% to 74% (3). We have struggled to under-
physiologists, to recommend implantable cardi-
stand how we ended up with such a “double stan-
overter defibrillator (ICD) implantation to a
dard” (4). Undeniably, the fact that the ajmaline test
patient with ventricular fibrillation (VF) that was
is perceived as z100% specific for diagnosing Bru-
clearly due to sotalol-induced QT prolongation with
gada syndrome (5) led to the collective belief that all
torsade de pointes. Instead, once the QT interval
patients with a positive ajmaline test have Brugada
normalizes after discontinuing the culprit drug (and
syndrome. By the present guidelines, a positive ajma-
assuming the family history is negative), we would
line confers an unequivocal diagnosis of Brugada syn-
diagnose acquired long QT syndrome and would limit
drome (2), whereas a more recent consensus report
our treatment recommendations to strict avoidance
grants a diagnosis of probable Brugada syndrome to
of QT-prolonging medications in the future. At the
asymptomatic patients when a positive ajmaline test
same time, 1 in 5 patients undergoing ICD implanta-
is the only positive criteria (6).
tion for Brugada syndrome in Europe are asymptom-
We recently argued that the specificity of the
atic and had “their Brugada syndrome” diagnosed
ajmaline test is overrated (7). It is therefore rewarding
by virtue of a positive ajmaline test (1). Clearly, we
that, in this issue of JACC: Clinical Electrophysiology,
continue to diagnose asymptomatic young male sub-
Tadros et al. (8) confirm that the specificity of the
jects as “Brugada syndrome” (essentially implying a
ajmaline test is not as perfect as was originally pro-
diagnosis of congenital Brugada syndrome), when
posed (5), not even when the patient population
they develop a type 1 Brugada electrocardiogram
studied has a high pre-test probability for a congen-
(ECG) in response to an ajmaline test (2). (“Ajmaline
ital arrhythmic disorder.
test” is used throughout to describe the use of intra-
In the present study, Tadros et al. (8) reviewed the
venous sodium channel blockers to unravel a type 1
results of 637 ajmaline tests performed on 54 pro-
Brugada ECG and diagnose Brugada syndrome, with
bands with unexplained cardiac arrest and on 583
the understanding that flecainide, pilsicainide, and
family members. Unexplained cardiac arrest was
procainamide are used in different countries for the
defined as that occurring in the absence of coronary
same purpose.) In fact, among patients diagnosed
artery disease, cardiomyopathy, or obvious channel-
with Brugada syndrome in the absence of symptoms,
opathy. In total, 14% of all ajmaline tests performed
the percentage of patients with an ajmaline-based
were positive, including 20% of the tests of cardiac
diagnosis increased significantly over the last decade
arrest survivors. Importantly, a confounding ajmaline test, representing a positive ajmaline test in individuals who, to the best judgment of the investigators, do not have Brugada syndrome, were
*Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology. From the Department of Cardiology, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Both
found in 8% of families undergoing this test (8). Considering the renowned expertise of the investigators, it is fair to say that these “confounding ajmaline tests” simply represent false-positive test
authors have reported that they have no relationships relevant to the
results. The inevitable conclusion is that, in 8% of
contents of this paper to disclose.
families tested for Brugada syndrome, a positive
2
Viskin and Rosso
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2017 - 2017:-–-
Positive Ajmaline Test Does Not Always Mean Brugada Syndrome
ajmaline test would lead to a wrong diagnosis in some
by EP studies when the ajmaline test is positive, for
individuals.
the purpose of risk stratification (11). However, this
Limitations of this study must be emphasized. On
study entered patients reported by the investigators
the one hand, the investigators may have over-
since their first description of this disease in 1992 (12)
estimated the false-positive rate of the ajmaline test.
and therefore includes more patients with malignant
To avoid inconclusive tests, they used doses larger
expression (13). Patients with Brugada syndrome
than the usual (1 mg/kg) dosage whenever coved-
diagnosed during the last decade have a more benign
type ST-segment elevation of less than 2 mm was
phenotype, translating into lower long-term risk (3).
observed near the end of the standard-dose infusion
This fact inevitably weakens the positive predictive
(8). In fact, 50% of all positive ajmaline tests and all
value of all prognostic tests, making EP studies no
the false-positive tests were achieved with these
longer predictive of spontaneous VF among patients
slightly “excessive” (mean 1.18 mg/kg) doses (8). This
recognized nowadays (3). Moreover, in the largest
does not necessarily mean that all these tests would
pooled analysis of Brugada syndrome (14), the risk of
have been negative had the investigators stopped
spontaneous VF among 696 asymptomatic patients
injecting ajmaline at 1 mg/kg. This is because, during
was only 0.3% per year when their type 1 Brugada
positive tests, the ST-segment tends to rise further
ECG was only observed in response to a drug chal-
during the first minute after the drug infusion is
lenge. In fact, the long-term risk of patients with
terminated. Besides, there is nothing “sacred” about
asymptomatic drug-induced Brugada was not higher,
the 1 mg/kg dose, which was adopted from older
in any significant way, if they had inducible VF dur-
studies using ajmaline to challenge atrioventricular
ing EP studies (14).
conduction in elderly patients with bundle branch block (9).
Because of their lower risk, asymptomatic patients are often left untreated, at least in some high-volume
On the other hand, the investigators likely under-
centers, when their diagnosis is based on a positive
estimated the false-positive rate of the ajmaline test
ajmaline test. Yet, for some of these asymptomatic
because they did not systematically test with ajma-
low-risk patients, having a positive diagnosis of Bru-
line all the cardiac arrest survivors and their relatives.
gada syndrome not followed by specific therapy may
Instead, they performed the ajmaline test only on
trigger an incapacitating fear of imminent sudden
those in whom a diagnosis remained elusive after
death. With this in mind, during a recent consensus
extensive work-up. From the clinical and ethical
conference (6), we called for limiting the ajmaline test
points of view, this is the correct use of the test;
to those who are well-informed of the advantages
however, by excluding patient categories with a low
and disadvantages conferred by the information
prevalence of Brugada syndrome, the investigators
provided by the test results.
voided the use of ajmaline in those where a positive
To conclude, a note of caution: In a recent study
test would most likely represent a false-positive
simulating screening for Brugada syndrome, as many
result (10).
as 45% of healthy control subjects had “minor im-
The ajmaline test is important and is here to stay.
perfections in the right precordial leads” that could
Thus, we need to understand the meaning of its re-
be interpreted as type 2/3 Brugada ECG (15). We are
sults. It is therefore timely that Sierra et al. (11)
forced to wonder how often asymptomatic in-
updated their long-term observations on Brugada
dividuals enter a path to “rule out Brugada syn-
syndrome, reporting now on 421 patients. Interest-
drome” for the wrong reasons, have a false positive
ingly, 62% of their cardiac-arrest survivors diagnosed
ajmaline test followed by a positive EP study, and,
as having Brugada syndrome and 85% of all their
faced with the alternative of facing sudden death,
asymptomatic patients, had their diagnoses based on
end
a positive ajmaline test (11). The risk of spontaneous
Considering the imperfections of the ajmaline test (7),
VF during 5 years of follow-up, among initially
the study by Tadros et al. (8) has a clear message: A
asymptomatic patients with an ajmaline-based diag-
positive ajmaline test does not always mean you have
nosis of Brugada syndrome, was 50% lower than for
Brugada syndrome.
up
with
an
unjustified
ICD
implantation.
those with spontaneous type 1 Brugada ECG. Yet, their long-term risk was 7-fold higher when they also
ADDRESS
had inducible VF during electrophysiologic (EP)
Viskin, Department of Cardiology, Tel Aviv Medical
FOR
CORRESPONDENCE:
studies (11). These results led Brugada to conclude
Center, Weizman 6, Tel Aviv 64239, Israel. E-mail:
that there is still room for the ajmaline test, followed
[email protected].
Dr.
Sami
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2017
- 2017:-–-
Viskin and Rosso Positive Ajmaline Test Does Not Always Mean Brugada Syndrome
REFERENCES 1. Sacher F, Probst V, Maury P, et al. Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study-part 2. Circulation 2013;128: 1739–47. 2. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/ APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;10:1932–63. 3. Casado-Arroyo R, Berne P, Rao JY, et al. Longterm trends in newly diagnosed Brugada syndrome: implications for risk stratification. J Am Coll Cardiol 2016;68:614–23. 4. Havakuk O, Viskin S. A tale of 2 diseases: the history of long-QT syndrome and Brugada syndrome. J Am Coll Cardiol 2016;67:100–8. 5. Brugada R, Brugada J, Antzelevitch C, et al. Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation 2000; 101:510–5.
6. Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Heart Rhythm 2016;13:e295–324. 7. Viskin S, Rosso R, Friedensohn L, Havakuk O, Wilde AA. Everybody has Brugada syndrome until proven otherwise? Heart Rhythm 2015;12:1595–8. 8. Tadros R, Nannenberg EA, Lieve KV, et al. Yield and pitfalls of ajmaline testing in the evaluation of unexplained cardiac arrest and sudden unexplained sudden death: single-center experience with 482 families. J Am Coll Cardiol EP 2017;3: XXX–XX. 9. Chiale PA, Przybylski J, Laino RA, et al. Usefulness of the ajmaline test in patients with latent bundle branch block. Am J Cardiol 1982;49:21–6. 10. Jackson BR. The dangers of false-positive and false-negative test results: false-positive results as a function of pretest probability. Clin Lab Med 2008;28:305–19.vii. 11. Sierra J, Ciconte G, Conte G, et al. Long term prognosis of drug-induced Brugada syndrome. Heart Rhythm 2017. In press.
12. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992;20:1391–6. 13. Viskin S, Rogowski O. Asymptomatic Brugada syndrome: a cardiac ticking time-bomb? Europace 2007;9:707–10. 14. Sroubek J, Probst V, Mazzanti A, et al. Programmed ventricular stimulation for risk stratification in the Brugada syndrome: a pooled analysis. Circulation 2016;133:622–30. 15. Konigstein M, Rosso R, Topaz G, et al. Druginduced Brugada syndrome: clinical characteristics and risk factors. Heart Rhythm 2016;13: 1083–7.
KEY WORDS Brugada syndrome, sodium channel blocker, sudden cardiac death, unexplained cardiac arrest Brugada syndrome, sodium channel blocker, sudden cardiac death, unexplained cardiac arrest
3
VOL.
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
-, NO. -, 2017
ISSN 2405-500X/$36.00 http://dx.doi.org/10.1016/j.jacep.2017.05.016
EDITORIAL COMMENT
Read My Lips A Positive Ajmaline Test Does Not Always Mean You Have Brugada Syndrome* Sami Viskin, MD, Raphael Rosso, MD
I
t would be unthinkable, at least to most electro-
from 50% to 74% (3). We have struggled to under-
physiologists, to recommend implantable cardi-
stand how we ended up with such a “double stan-
overter defibrillator (ICD) implantation to a
dard” (4). Undeniably, the fact that the ajmaline test
patient with ventricular fibrillation (VF) that was
is perceived as z100% specific for diagnosing Bru-
clearly due to sotalol-induced QT prolongation with
gada syndrome (5) led to the collective belief that all
torsade de pointes. Instead, once the QT interval
patients with a positive ajmaline test have Brugada
normalizes after discontinuing the culprit drug (and
syndrome. By the present guidelines, a positive ajma-
assuming the family history is negative), we would
line confers an unequivocal diagnosis of Brugada syn-
diagnose acquired long QT syndrome and would limit
drome (2), whereas a more recent consensus report
our treatment recommendations to strict avoidance
grants a diagnosis of probable Brugada syndrome to
of QT-prolonging medications in the future. At the
asymptomatic patients when a positive ajmaline test
same time, 1 in 5 patients undergoing ICD implanta-
is the only positive criteria (6).
tion for Brugada syndrome in Europe are asymptom-
We recently argued that the specificity of the
atic and had “their Brugada syndrome” diagnosed
ajmaline test is overrated (7). It is therefore rewarding
by virtue of a positive ajmaline test (1). Clearly, we
that, in this issue of JACC: Clinical Electrophysiology,
continue to diagnose asymptomatic young male sub-
Tadros et al. (8) confirm that the specificity of the
jects as “Brugada syndrome” (essentially implying a
ajmaline test is not as perfect as was originally pro-
diagnosis of congenital Brugada syndrome), when
posed (5), not even when the patient population
they develop a type 1 Brugada electrocardiogram
studied has a high pre-test probability for a congen-
(ECG) in response to an ajmaline test (2). (“Ajmaline
ital arrhythmic disorder.
test” is used throughout to describe the use of intra-
In the present study, Tadros et al. (8) reviewed the
venous sodium channel blockers to unravel a type 1
results of 637 ajmaline tests performed on 54 pro-
Brugada ECG and diagnose Brugada syndrome, with
bands with unexplained cardiac arrest and on 583
the understanding that flecainide, pilsicainide, and
family members. Unexplained cardiac arrest was
procainamide are used in different countries for the
defined as that occurring in the absence of coronary
same purpose.) In fact, among patients diagnosed
artery disease, cardiomyopathy, or obvious channel-
with Brugada syndrome in the absence of symptoms,
opathy. In total, 14% of all ajmaline tests performed
the percentage of patients with an ajmaline-based
were positive, including 20% of the tests of cardiac
diagnosis increased significantly over the last decade
arrest survivors. Importantly, a confounding ajmaline test, representing a positive ajmaline test in individuals who, to the best judgment of the investigators, do not have Brugada syndrome, were
*Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology. From the Department of Cardiology, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Both
found in 8% of families undergoing this test (8). Considering the renowned expertise of the investigators, it is fair to say that these “confounding ajmaline tests” simply represent false-positive test
authors have reported that they have no relationships relevant to the
results. The inevitable conclusion is that, in 8% of
contents of this paper to disclose.
families tested for Brugada syndrome, a positive
2
Viskin and Rosso
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2017 - 2017:-–-
Positive Ajmaline Test Does Not Always Mean Brugada Syndrome
ajmaline test would lead to a wrong diagnosis in some
by EP studies when the ajmaline test is positive, for
individuals.
the purpose of risk stratification (11). However, this
Limitations of this study must be emphasized. On
study entered patients reported by the investigators
the one hand, the investigators may have over-
since their first description of this disease in 1992 (12)
estimated the false-positive rate of the ajmaline test.
and therefore includes more patients with malignant
To avoid inconclusive tests, they used doses larger
expression (13). Patients with Brugada syndrome
than the usual (1 mg/kg) dosage whenever coved-
diagnosed during the last decade have a more benign
type ST-segment elevation of less than 2 mm was
phenotype, translating into lower long-term risk (3).
observed near the end of the standard-dose infusion
This fact inevitably weakens the positive predictive
(8). In fact, 50% of all positive ajmaline tests and all
value of all prognostic tests, making EP studies no
the false-positive tests were achieved with these
longer predictive of spontaneous VF among patients
slightly “excessive” (mean 1.18 mg/kg) doses (8). This
recognized nowadays (3). Moreover, in the largest
does not necessarily mean that all these tests would
pooled analysis of Brugada syndrome (14), the risk of
have been negative had the investigators stopped
spontaneous VF among 696 asymptomatic patients
injecting ajmaline at 1 mg/kg. This is because, during
was only 0.3% per year when their type 1 Brugada
positive tests, the ST-segment tends to rise further
ECG was only observed in response to a drug chal-
during the first minute after the drug infusion is
lenge. In fact, the long-term risk of patients with
terminated. Besides, there is nothing “sacred” about
asymptomatic drug-induced Brugada was not higher,
the 1 mg/kg dose, which was adopted from older
in any significant way, if they had inducible VF dur-
studies using ajmaline to challenge atrioventricular
ing EP studies (14).
conduction in elderly patients with bundle branch block (9).
Because of their lower risk, asymptomatic patients are often left untreated, at least in some high-volume
On the other hand, the investigators likely under-
centers, when their diagnosis is based on a positive
estimated the false-positive rate of the ajmaline test
ajmaline test. Yet, for some of these asymptomatic
because they did not systematically test with ajma-
low-risk patients, having a positive diagnosis of Bru-
line all the cardiac arrest survivors and their relatives.
gada syndrome not followed by specific therapy may
Instead, they performed the ajmaline test only on
trigger an incapacitating fear of imminent sudden
those in whom a diagnosis remained elusive after
death. With this in mind, during a recent consensus
extensive work-up. From the clinical and ethical
conference (6), we called for limiting the ajmaline test
points of view, this is the correct use of the test;
to those who are well-informed of the advantages
however, by excluding patient categories with a low
and disadvantages conferred by the information
prevalence of Brugada syndrome, the investigators
provided by the test results.
voided the use of ajmaline in those where a positive
To conclude, a note of caution: In a recent study
test would most likely represent a false-positive
simulating screening for Brugada syndrome, as many
result (10).
as 45% of healthy control subjects had “minor im-
The ajmaline test is important and is here to stay.
perfections in the right precordial leads” that could
Thus, we need to understand the meaning of its re-
be interpreted as type 2/3 Brugada ECG (15). We are
sults. It is therefore timely that Sierra et al. (11)
forced to wonder how often asymptomatic in-
updated their long-term observations on Brugada
dividuals enter a path to “rule out Brugada syn-
syndrome, reporting now on 421 patients. Interest-
drome” for the wrong reasons, have a false positive
ingly, 62% of their cardiac-arrest survivors diagnosed
ajmaline test followed by a positive EP study, and,
as having Brugada syndrome and 85% of all their
faced with the alternative of facing sudden death,
asymptomatic patients, had their diagnoses based on
end
a positive ajmaline test (11). The risk of spontaneous
Considering the imperfections of the ajmaline test (7),
VF during 5 years of follow-up, among initially
the study by Tadros et al. (8) has a clear message: A
asymptomatic patients with an ajmaline-based diag-
positive ajmaline test does not always mean you have
nosis of Brugada syndrome, was 50% lower than for
Brugada syndrome.
up
with
an
unjustified
ICD
implantation.
those with spontaneous type 1 Brugada ECG. Yet, their long-term risk was 7-fold higher when they also
ADDRESS
had inducible VF during electrophysiologic (EP)
Viskin, Department of Cardiology, Tel Aviv Medical
FOR
CORRESPONDENCE:
studies (11). These results led Brugada to conclude
Center, Weizman 6, Tel Aviv 64239, Israel. E-mail:
that there is still room for the ajmaline test, followed
[email protected].
Dr.
Sami
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2017
- 2017:-–-
Viskin and Rosso Positive Ajmaline Test Does Not Always Mean Brugada Syndrome
REFERENCES 1. Sacher F, Probst V, Maury P, et al. Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study-part 2. Circulation 2013;128: 1739–47. 2. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/ APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;10:1932–63. 3. Casado-Arroyo R, Berne P, Rao JY, et al. Longterm trends in newly diagnosed Brugada syndrome: implications for risk stratification. J Am Coll Cardiol 2016;68:614–23. 4. Havakuk O, Viskin S. A tale of 2 diseases: the history of long-QT syndrome and Brugada syndrome. J Am Coll Cardiol 2016;67:100–8. 5. Brugada R, Brugada J, Antzelevitch C, et al. Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation 2000; 101:510–5.
6. Antzelevitch C, Yan GX, Ackerman MJ, et al. J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Heart Rhythm 2016;13:e295–324. 7. Viskin S, Rosso R, Friedensohn L, Havakuk O, Wilde AA. Everybody has Brugada syndrome until proven otherwise? Heart Rhythm 2015;12:1595–8. 8. Tadros R, Nannenberg EA, Lieve KV, et al. Yield and pitfalls of ajmaline testing in the evaluation of unexplained cardiac arrest and sudden unexplained sudden death: single-center experience with 482 families. J Am Coll Cardiol EP 2017;3: XXX–XX. 9. Chiale PA, Przybylski J, Laino RA, et al. Usefulness of the ajmaline test in patients with latent bundle branch block. Am J Cardiol 1982;49:21–6. 10. Jackson BR. The dangers of false-positive and false-negative test results: false-positive results as a function of pretest probability. Clin Lab Med 2008;28:305–19.vii. 11. Sierra J, Ciconte G, Conte G, et al. Long term prognosis of drug-induced Brugada syndrome. Heart Rhythm 2017. In press.
12. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992;20:1391–6. 13. Viskin S, Rogowski O. Asymptomatic Brugada syndrome: a cardiac ticking time-bomb? Europace 2007;9:707–10. 14. Sroubek J, Probst V, Mazzanti A, et al. Programmed ventricular stimulation for risk stratification in the Brugada syndrome: a pooled analysis. Circulation 2016;133:622–30. 15. Konigstein M, Rosso R, Topaz G, et al. Druginduced Brugada syndrome: clinical characteristics and risk factors. Heart Rhythm 2016;13: 1083–7.
KEY WORDS Brugada syndrome, sodium channel blocker, sudden cardiac death, unexplained cardiac arrest Brugada syndrome, sodium channel blocker, sudden cardiac death, unexplained cardiac arrest
3