Download Takotsubo cardiomyopathy and the long-QT syndrome

EDITORIAL
Europace (2009) 11, 697–700
doi:10.1093/europace/eup081
Takotsubo cardiomyopathy and the long-QT
syndrome: an insult to repolarization reserve
Elijah R. Behr 1* and Saagar Mahida2
1
Cardiac and Vascular Division, St George’s University of London, London SW17 0RE, UK; and 2Leeds General Infirmary, Leeds, UK
Received 9 March 2009; accepted after revision 10 March 2009; online publish-ahead-of-print 6 April 2009
This editorial refers to ‘A fatal combination in an old
lady: Tako-Tsubo cardiomyopathy, long QT syndrome,
and cardiac hypertrophy’ by H. Wedekind et al., on
page 820
Torsades de pointes and QTc
prolongation as a predictor of risk
More recent case reports have emerged that document TdP in
patients with TCM. Table 1 describes the 11 reported cases currently published in the English language. The mean age of these
individuals at presentation was 63 years (range 22 –87), and the
majority were female [9/11 (82%)]. This is similar to the several
series described in Bybee et al.’s review whose mean age ranged
from 62 to 75 years and whose female proportion ranged from
82 to 100%.1 In TdP cases, in whom the data were available, the
mean QTc at presentation was 595ms, the mean maximal QTc
recorded was 706ms, and the mean post-TCM QTc was 481ms
(Table 2). Comparing paired data where available (paired Student’s
t-test), the maximal QTc was significantly greater than the presenting QTc (P ¼ 0.0075) and the post-TCM QTc (P ¼ 0.0003), in
keeping with Koji’s findings of variation of QT interval between
acute, subacute, and chronic phases.7 None of these individuals
were on QT prolonging drugs as far as can be ascertained. Comparison to the series where TdP was not identified (Table 2)
suggests that the QT prolongation described in the TdP cases is
greater. Desmet et al.’s6 series reports individuals’ acute phase
QTc intervals and allows a direct comparison to be made
(Table 2). The presenting and maximal QTc intervals in the TdP
cases are significantly longer suggesting this as an association
The opinions expressed in this article are not necessarily those of the Editors of Europace or of the European Society of Cardiology.
* Corresponding author. Tel: þ44 2087255939, Fax: þ44 2087253328, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: [email protected].
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Takotsubo cardiomyopathy (TCM) is a transient syndrome with
acute, subacute, and chronic phases, and is commonly induced
by emotional or physical stress. It is characterized by chest pain,
electrocardiogram (ECG) changes, and minimal myocardial enzymatic release mimicking acute myocardial infarction in patients
with unobstructed coronary arteries on angiography. Assessment
of left ventricular function in patients with TCM reveals apical ballooning and hypokinesia with the preservation of basal contraction.
Electrocardiogram changes include ST-segment elevation, the evolution of marked anterior T-wave inversion, and prolongation of the
QT interval. These features all appear to resolve with time.1
Wedekind et al. 2 report a case of clinically silent pre-existing
long-QT syndrome (LQTS) exacerbated by TCM and resulting in
life-threatening arrhythmias. This mirrors our own description
last year of a similar case3 and prompts an evaluation of the true
significance of QT prolongation in this context.
The association between TCM and QT prolongation has been
well documented (Table 2). Seth et al. 4 reported 12 cases of
TCM with an average QTc interval of 478ms. Similarly, Abe
et al. 5 described 17 patients, most of whom had a prolonged
QTc interval in the acute and subacute phases of the condition.
The QT interval normalized in all cases between 97 and 191
days from the onset of symptoms. As part of a report on 13
patients by Desmet et al.,6 each patient’s ECG during the acute
phase was described with QTc intervals ranging from 310 to
674ms. Koji et al. specifically evaluated the QT interval in 10 consecutive cases of TCM although individual patients’ measurements
were not detailed. They demonstrated mean maximal QTc intervals in the acute (475 + 46ms), subacute (555 + 46ms), and
chronic phases (444 + 41ms) of the condition.7 The subacute
phase QTc was significantly prolonged compared with acute and
chronic phases. It was, therefore, proposed that this temporary
QT prolongation reflects the transient myocardial insult of TCM.7
Despite these consistent findings, ventricular arrhythmias in
patients with TCM are relatively uncommon. In a review of
seven case series containing a total of 180 cases, Bybee et al. 1
reported a 1–1.5% incidence of ventricular arrhythmias. In a
more recent series of 14 patients, Bonello et al. 8 reported two
cases of malignant ventricular arrhythmias (one patient with ventricular tachycardia and the other with ventricular fibrillation).
A number of individual case reports have also documented the
incidence of ventricular tachycardia and ventricular fibrillation in
patients with TCM. None of these described, however, the presence of torsades de pointes (TdP).
698
Table 1 Case reports of Takotsubo cardiomyopathy and torsades de pointes
Reference
Age M/F
PMH
FH
SD
FH
LQTS
Prior
syncope
QT prolonging
medications
Presenting QTc Max QTc
(ms)
(ms)
Post-QTc (ms)
(after X days)
Outcome
Genetic
testing
.............................................................................................................................................................................................................................................
Wedekind
et al. 2
81
F
Prior QTc prolongation
(520 ms), pacemaker,
and hypertension
Yes
Yes
No
No
690
690
NS
ICD implanted
No
Mahida et al. 3
55
F
Diabetes and
hyperlipidaemia
No
No
Yes
No
510
735
490 (56)
Discharged
ICD declined
Yes
b-Blocker
Discharged
Kurisu et al. 9
87
F
None
No
No
Yes
NS
640a
880
440 (6)
Kurisu et al. 9
78
M
NS
No
No
No
NS
640a
920
600 (7)
Ghosh et al. 10
59
F
No
No
No
NS
NS
669
Normal (NS)
Discharged
Discharged
No
Furushima
et al. 11
61
F
Anxiety, hypertension,
and alcohol excess
NS
No
No
No
NS
740
740
470 (168)
ICD implanted
No
Pacemaker
implanted
No
Discharged
Pacemaker
implanted
No
b-Blocker
Discharged
Sasaki et al. 12
22
F
NS
No
No
No
No
730
730
520 (22)
Mexilitine
Discharged
No
Denney
et al. 13
32
M
Obesity, migraine, asthma, Yes
and rhinitis
No
No
Nob
416
467
406 (4)
b-Blocker
No
F
None
No
No
No
630c
727
440 (NS)
ICD implanted
No
No
Discharged
Mofrad et al. 14 70
No
Nault et al. 15
76
M
None
No
No
No
No
630
786
Normal (2)
Discharged
Discharged
Finstere
et al. 16
75
F
Mitochondrial disorder
No
No
No
NS
326d
425d
NS
b-Blocker
No
Death prior to
discharge
Editorial
NS, not specified; PMH, previous medical history; FH, family history; TCM, Takotsubo cardiomyopathy; LQTS, long-QT syndrome; SD, sudden death.
a
In the presence of high-degree AV Block.
b
Patient receiving pseudoephedrine.
c
In the presence of hypokalaemia.
d
Calculated from ECGs presented in the report.
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699
Editorial
Table 2 Comparison of QTc intervals in non-torsades de pointes series and the series of torsades de pointes reports
Reference
Number of cases
Mean reported QTc (ms)
(95% Confidence interval)
Median reported QTc (ms)
Range (ms)
...............................................................................................................................................................................
Seth et al. 4
12
478 (+96)
NS
NS
Abe et al. 5
17
NS
500
436– 581
Desmet et al. 6
Koji et al. 7
13
10
450*,†
555 (+46)
436
NS
310– 674
NS
TdP reports presenting QTc (Table 1)
10
595*
635
326– 740
TdP reports maximal QTc (Table 1)
11
706†
730
425– 920
TdP, torsades de pointes; NS, not specified.
*P ¼ 0.01 (two-tailed Student’s t-test).
†
P ¼ 0.00014 (two-tailed Student’s t-test).
with, if not, a potential predictor for the development of TdP.
Indeed if a cut-off of acute phase QTc .500ms is utilized then
9 of 11 TdP cases would have been predicted to be at risk (sensitivity 82%) and 11 of 13 non-TdP cases from Desmet’s series
would have been predicted not to be at risk (specificity 85%).
The presence of significant QT prolongation at other times than
during the TCM episode in at least 4 of 11 TdP cases (36%) also
suggests that there is an underlying predisposition towards repolarization abnormality: a reduced repolarization reserve.17 This
term was first coined to describe the impact of QT prolonging
drugs on predisposed individuals who then developed TdP. It is,
therefore, reasonable to regard TCM as a similar transient acquired
insult upon myocardial repolarization that may relate to an acute
disturbance of cardiac autonomic function18 and precipitates TdP
in more vulnerable individuals. In common with drug-induced
LQTS, these individuals may carry clinically silent or unexpressed
mutations implicated in the congenital LQTS or may harbour multiple common population variants that impair the repolarization
reserve in more subtle ways.17 They may also have other predisposing abnormalities such as structural cardiac disease, metabolic
disease, or bradycardia.17 There has been little genetic study in
TCM at present, but systematic genetic research of TdP cases
compared with non-TdP TCM is required to determine whether
this phenomenon is driven by genotype and if so whether rare
mutations or common variants are more important. This leaves
open the future possibility of genetic testing assisting in determining the risk of TdP during acquired insults such as TCM.
Management
In the acute and subacute phases, it therefore appears reasonable
to monitor the QT interval closely in individuals with possible
TCM and if the QTc prolongs, particularly if it is .500ms,
measures should be taken to monitor cardiac rhythm closely and
prevent or treat TdP appropriately. As two of the cases were
associated with bradycardia due to heart block, a known
Conclusion
These reports suggest that severe prolongation of the QT interval
in TCM may be a marker for the risk of sudden death and should
be monitored for in all suspicious cases. This may reflect an underlying abnormality of repolarization that may be genetic in basis and
carry a risk of sudden death. Further research is required to study
this hypothesis.
Conflict of interest: none declared.
References
1. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright S et al. Systematic
review: transient left ventricular apical ballooning: a syndrome that mimics
ST-segment elevation acute myocardial infarction. Ann Intern Med 2004;141:
858 –65.
2. Wedekind H, Müller JG, Ribbing M, Skurzewski P, Bozzetti C, Meyer-Krahmer HJ
et al. A fatal combination in an old lady: Tako-Tsubo cardiomyopathy, long QT
syndrome, and cardiac hypertrophy. Europace 2009;11:820 –2.
3. Mahida S, Dalageorgou C, Behr E. Long QT syndrome and Torsades de Pointes in
a patient with Takotsubo cardiomyopathy: an unusual case. Europace 2009;11:
376 –8.
4. Seth PS, Aurigemma GP, Krasnow JM, Tighe DA, Untereker WJ, Mayer TE. A syndrome of transient left ventricular apical wall motion abnormality in the absence
of coronary disease: a perspective from the United States. Cardiology 2003;100:
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5. Abe Y, Kondo M, Matsuoka R, Araki M, Dohyama K, Tanio H. Assessment of clinical features in transient left ventricular apical ballooning. J Am Coll Cardiol 2003;41:
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6. Desmet WJ, Adriaenssens BF, Dens JA. Apical ballooning of the left ventricle: first
series in white patients. Heart 2003;89:1027 –31.
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Takotsubo cardiomyopathy:
another form of acquired
long-QT syndrome
precipitant of the acquired LQTS,17 temporary transvenous
pacing should be considered as a therapeutic option.9
These cases also provide a useful indication to long-term management of these uncommon presentations of TCM. Given its
transient nature and the female predominance, unless there are
additional features suggestive of high risk LQTS (for example, a
post-TCM QTc . 500ms, previous syncope, or previous cardiac
arrest) then it is reasonable to advise treatment with a b-blocker
alone. Otherwise an ICD may offer more appropriate long-term
management. In the two cases of TdP and TCM that were complicated by high-degree AV block, the patients in question appeared
to do well with permanent pacing alone after some improvement
in their QT interval.
700
7. Koji M, Setsuya O, Eitaro F, Fumiya U, Atsunotu K, Toshikazu S et al. Evaluation of the
arrhythmogenecity of stress induced ‘Takotsubo cardiomyopathy’ from the time
course of the 12-lead surface electrocardiogram. Am J Cardiol 2003;92:230 –3.
8. Bonello L, Com O, Ait-Moktar O, Théron A, Moro PJ, Salem A et al. Ventricular
arrhythmias during Tako-tsubo syndrome. Int J Cardiol 2008;128:e50– 3.
9. Kurisu S, Inoue I, Kawagoe T, Ishihara M, Shimatani Y, Nakama Y et al. Torsade de
pointes associated with bradycardia and takotsubo cardiomyopathy. Can J Cardiol
2008;24:640 –2.
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Cardiol 2008; Epub ahead of print 8 July 2008.
11. Furushima H, Chinushi M, Sanada A, Aizawa Y. Ventricular repolarization gradients in a patient with takotsubo cardiomyopathy. Europace 2008;10:1112 –5
[Epub 19 June 2008].
12. Sasaki O, Nishioka T, Akima T, Tabata H, Okamoto Y, Akanuma M et al. Association of takotsubo cardiomyopathy and long QT syndrome. Circ J 2006;70:
1220 –2.
Editorial
13. Denney SD, Lakkireddy DR, Khan IA. Long QT syndrome and torsade de pointes
in transient left ventricular apical ballooning syndrome. Int J Cardiol 2005;100:
499 –501.
14. Mofrad PS, Rashid H, Tracy CM. New-onset QT prolongation and torsades de
pointes accompanied by left ventricular dysfunction secondary to acute pancreatitis. Pacing Clin Electrophysiol 2003;26:1765 –8.
15. Nault MA, Baranchuk A, Simpson CS, Redfearn DP. Takotsubo cardiomyopathy:
a novel ‘proarrhythmic’ disease. Anadolu Kardiyol Derg 2007;7 (Suppl 1):
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16. Finstere J, St Stöllberger C, Sehnal E, Valentin A, Huber J, Schmiedel J. Apical ballooning (Takotsubo syndrome) in mitochondrial disorder during mechanical ventilation. J Cardiovasc Med (Hagerstown) 2007;8:859 –63.
17. Roden DM. Long QT syndrome: reduced repolarization reserve and the genetic
link. J Intern Med 2006;259:59 –69.
18. Akashi YJ, Barbaro G, Sakurai T, Nakazawa K, Miyake F. Cardiac autonomic imbalance in patients with reversible ventricular dysfunction takotsubo cardiomyopathy. QJM 2007;100:335 – 43.
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