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Home , Long QT syndrome, Torsades de pointes

CASE REPORTS Circ J 2006; 70: 1220–1222

Association of Takotsubo and Long QT Syndrome

Osamu Sasaki, MD; Toshihiko Nishioka, MD; Takashi Akima, MD*; Hirotsugu Tabata, MD**; Yasuhiro Okamoto, MD**; Masahiko Akanuma, MD**; Akimi Uehata, MD**; Bonpei Takase, MD*; Shuichi Katsushika, MD**; Kazushige Isojima, MD**; Shingo Ohtomi, MD†; Nobuo Yoshimoto, MD

A young woman presented with takotsubo cardiomyopathy after a syncopal attack caused by . Two-dimensional echocardiography on admission showed left ventricular apical akinesis (ballooning) and basal hyperkinesis, compatible with takotsubo cardiomyopathy. This gradually normalized in 2 months. ECG on admis- sion showed remarkable QT prolongation, U waves, and negative T waves, which also gradually normalized. Coronary angiography revealed no organic stenosis; however, acetylcholine provocation test caused the QT in- terval to again become prolonged. During treadmill exercise stress testing, the QT interval shortened as rate increased. Therefore, without genetic analysis, this patient was considered to have sporadic long QT syndrome in which takotsubo cardiomyopathy developed after the syncopal attack caused by torsades de pointes. (Circ J 2006; 70: 1220–1222) Key Words: Long QT syndrome; Takotsubo cardiomyopathy; Torsades de pointes

recently diagnosed cardiac syndrome, “takotsubo third heart sound and a grade 2/6 systolic murmur were cardiomyopathy” or “transient left ventricular (LV) audible at the apex. A apical ballooning”, is characterized by symptoms With the exception of mild liver dysfunction and hypo- and electrocardiographic changes mimicking acute myocar- kalemia (K+ =2.8 mmol/L), laboratory findings including dial infarction, but with minimal coronary atherosclerotic cardiac enzymes were within normal limits. Chest X-ray lesions. In the acute phase, LV contraction is hyperkinetic showed mild (cardiothoracic ratio=56%), and around the cardiac base and severely hypokinetic or akinetic ECG showed remarkable QT prolongation (QTc=730ms) throughout a broad area of the apex and mid-ventricle. It is and U waves. Negative T waves were observed in leads II, reported that many patients with this syndrome are elderly aVL and V2–6 (Fig2A). Transthoracic 2-dimensional echo- women and that the LV dysfunction rapidly normalizes.1,2 cardiography (2-DE) revealed the LV dysfunction with hyperkinesis of the basal wall and akinesis of the mid wall and the apex; these findings were compatible with takotsubo Case Report cardiomyopathy (Fig 3). Dilatation of the aortic root as A 22-year-old woman was transported by ambulance to seen in was not demonstrated on 2-DE. the emergency department, complaining of chest pain, There was no family history of sudden death, and the patient vomiting, and , which had developed while she was was not taking any drugs that could induce QT prolonga- in bed at night. On arrival at the emergency room, ECG tion or any dietary weight-loss supplement. monitoring showed multifocal premature ventricular con- The patient was treated with intravenous lidocaine for tractions (PVC). About 5 min later, torsades de pointes prevention of PVC and TdP, and intravenous dopamine for (TdP) developed and she lost consciousness. Electrical de- blood pressure maintenance. As the heart rate was 40– fibrillation was performed and the cardiac rhythm reverted 50beats/min with sinus ,β-blockers were with- to normal (Fig1). held and the intravenous lidocaine was replaced with oral On physical examination, her height was 170cm and she mexilletine (300mg/day). After administration of mexil- weighed 46kg. Consciousness was clear, pulse rate was 40– letine, 24-h Holter monitoring showed only 6 PVC. How- 50beats/min and systolic blood pressure was 60mmHg. A ever, 12-lead ECG still showed QT prolongation despite rapid normalization of the serum K+ level and mexilletine (Received March 7, 2006; revised manuscript received May 26, 2006; administration, and this took about 2 months to normalize accepted June 7, 2006) (Fig2). She continued to show of about Division of , Saitama Medical Center, Saitama Medical 45–50 beats/min throughout her hospital admission. LV University, Kawagoe, *First Department of Internal Medicine, Na- wall motion gradually recovered, and after 2 weeks only tional Defense Medical College, Tokorozawa, **First Department of mild hypokinesis of the apex was observed on 2-DE (Fig3). Internal Medicine, Self-Defense Forces Central Hospital and †Divi- At this point, no LV dilatation was observed and LV wall sion of Cardiology, Mishuku Hospital, Tokyo, Japan Mailing address: Toshihiko Nishioka, MD, Division of Cardiology, thickness was approximately 9mm. Coronary angiography Saitama Medical Center, Saitama Medical University, 1981 Tsujido- revealed no significant stenosis and coronary spasm was machi, Kamoda, Kawagoe 350-8550, Japan. E-mail: nishioka@ not induced by acetylcholine (Ach) provocation test. How- saitama-med.ac.jp ever, after 50mg of intracoronary Ach, the ECG showed

Circulation Journal Vol.70, September 2006 Takotsubo Cardiomyopathy and Long QT Syndrome 1221

Fig1. ECG monitoring showing torsades de pointes on admission. Electrical defibrillation was performed and car- diac rhythm reverted to normal sinus rhythm.

Fig2. Time course of ECG changes. The ECG on admission showed remarkable QT prolongation, U waves and nega- tive T waves, which gradually normalized. After intracoronary Ach infusion, the ECG showed remarkable QT prolonga- tion and U waves. ECG was almost normal after 2 months; however, 2 years later, the ECG again showed QT prolonga- tion. Ach, acetylcholine provocation test.

Fig 3. Two-dimensional echocardio- graphic findings on admission and 2 weeks later. On admission the left ven- tricular mid wall and apex showed bal- looning akinesis and the basal wall was hyperkinetic. (A) End-diastole, (B) end- systole. Two weeks later, these findings had disappeared and the left ventricular contraction was nearly normal. (C) End-diastole, (D) end-systole.

Circulation Journal Vol.70, September 2006 1222 SASAKI O et al. remarkable QT prolongation and U waves, similar to the after normalization of the serum K+ level, QT interval was ECG findings on admission (Fig2C). Left ventriculography prolonged again by Ach infusion and after mexilletine showed that wall motion was almost normal. Based on cessation10–12 2 years later. Therefore, without genetic these findings, this case was considered to represent tako- analysis, this patient is considered to have sporadic long QT tsubo cardiomyopathy, despite the fact that the patient was syndrome. Moreover, symptoms developed at rest, brady- a young woman. 201Tl myocardial scintigraphy on the 21st cardia of 40–50 beats/min was evident, the QT interval day showed almost normal perfusion; however, absence of shortened during exercise testing, and long QT syndrome is metaiodobenzylguanidine accumulation was seen in a considered to be linked to (LQT3).12 broad area with the exception of the LV lateral wall. This The precise mechanism of the association between tako- normalized after 2 months. Treadmill exercise stress testing tsubo cardiomyopathy and long QT syndrome is unclear. showed no significant ECG change and QT interval short- However, emotional and physical stress, such as fear of ened as heart rate increased. death and the for TdP in a patient with long She was treated with mexilletine on an outpatient basis QT syndrome patient may cause takotsubo cardiomyo- and ECG showed that the QT interval had almost normal- pathy. Further study is required to elucidate the character- ized; however, she failed to attend for follow-up after 13 istics of this specific syndrome. months. Eleven months after this, she was transported to hospital by ambulance for continuing chest discomfort, References , and abdominal pain. The ECG again showed 1. Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. Myocardial stun- QT prolongation (QTc =690 ms) and U waves (Fig 2E); ning due to simultaneous multivessel coronary spasms: A review of however, transthoracic 2-DE revealed only mild diffuse 5 cases. J Cardiol 1991; 21: 203–214. hypokinesis of the left ventricle without takotsubo-type 2. Pavin D, Breton HL, Daubert C. Human stress cardiomyopathy apical ballooning. Mexilletine was again prescribed and mimicking acute myocardial syndrome. Heart 1997; 78: 509–511. 3. Wittstein IS, Thiemann DR, Lima JAC, Baughman KL, Schulman QT interval subsequently recovered to nearly normal. We SP, Gerstenblith G, et al. Neurohumoral features of myocardial stun- recommended genetic analysis on each admission, but the ning due to sudden emotional stress. N Engl J Med 2005; 352: 539– patient did not give informed consent. 548. 4. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright RS, et al. Transient left ventricular apical ballooning: A syndrome that Discussion mimics ST-segment elevation [Systemic Review]. Ann Intern Med 2004; 141: 858–865. In 1991, this specific syndrome, characterized by tran- 5. Tsuchihashi K, Ueshima K, Uchida T, Oh-mura N, Kimura K, Owa sient LV contraction abnormality, was termed “takotsubo M, et al. Transient left ventricular apical ballooning without coronary cardiomyopathy” by Dote et al.1 It is also referred to as artery stenosis: A novel heart syndrome mimicking acute myocardial infarction. J Am Coll Cardiol 2001; 38: 11–18. “transient LV apical ballooning” or “stress cardiomyopa- 6. Kurisu S, Inoue I, Kawagoe T, Ishihara M, Shimatani Y, Nakamura thy”.1,2 The suggested etiology includes multiple coronary S, et al. Time course of electrocardiographic changes in patients with spasm, myocardial toxicity from catecholamines, or neu- Tako-Tsubo syndrome: Comparison with acute myocardial infarction rogenic stunning of the myocardium after emotional or with minimal enzymatic release. Circ J 2004; 68: 77–81. 7. Aizawa Y, Washizuka T, Igarashi Y, Kitakaze H, Chinushi M, Abe physical stress; however, the precise mechanism remains A, et al. Acetylcholine-induced prolongation of the QT interval in unknown.1,3,4 idiopathic long QT syndrome. Am J Cardiol 1996; 77: 879–882. Patients with this syndrome generally show T-wave in- 8. Aizawa Y, Matsubara T, Higuchi K, Washizuka T, Tamura Y, version and QT prolongation on ECG during the early Uchiyama H, et al. Intracoronary acetylcholine-induced prolongation 5,6 of the QT Interval and torsade des pointes in long QT interval phase, and these ECG changes typically normalize within syndrome. Jpn Heart J 1994; 35: 683–688. several weeks. In the present case, the QT interval was pro- 9. Furushima H, Niwano S, Chinushi M, Yamaura M, Taneda K, longed at presentation, gradually normalized, then became Washizuka T, et al. Effect of atropine on QT prolongation and prolonged again during the Ach provocation test and after torsade de pointes induced by intracoronary acetylcholine in the long QT syndrome. Am J Cardiol 1999; 83: 714–718. stopping mexilletine 2 years later. On this last occasion, 10. Shimizu W, Antzelevitch C. Cellular basis for the ECG features of takotsubo-type LV dysfunction was not observed. Although the LQT1 form of the long-QT syndrome: Effects of beta-adrenergic takotsubo cardiomyopathy might have caused gradual agonists and antagonists and blockers on transmural rather than rapid normalization of prolonged QT interval dispersion of and torsade de pointes. Circulation after mexilletine administration, it was not considered the 1998; 98: 2314–2322. 11. Shimizu W, Antzelevitch C. Sodium channel block with mexilletine sole cause of the QT prolongation observed in this case. is effective in reducing dispersion of repolarization and preventing Aizawa et al reported that intracoronary Ach infusion torsade de pointes in LQT2 and LQT3 models of the long-QT syn- induced prolongation of the QT interval and TdP in long drome. Circulation 1997; 96: 2038–2047. QT syndrome,7,8 and that this phenomenon was prevented 12. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu F, Towbin 9 JA, et al. Long QT syndrome patients with of the SCN5A by atropine administration. In the present case, apparent and HERG genes have differential responses to Na+ channel block- QT prolongation (QTc >700ms) and TdP were observed ade and to increases in heart rate: Implications for gene-specific in the absence of positive family history or therapy. Circulation 1995; 92: 3381–3386. known to affect QT interval, QT prolongation remained

Circulation Journal Vol.70, September 2006