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Transient ST-segment elevation in lead aVR associated with tako-tsubo cardiomyopathy
International Journal of Cardiology 134 (2009) e97 – e100 www.elsevier.com/locate/ijcard
Letter to the Editor
Transient ST-segment elevation in lead aVR associated with tako-tsubo cardiomyopathy Pawel Rostoff a,⁎, Pawel Latacz a , Wieslawa Piwowarska a , Ewa Konduracka a , Agnieszka Bolech a , Krzysztof Zmudka b a
Department of Coronary Disease, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Pradnicka 80, 31-202 Krakow, Poland b Department of Hemodynamics and Angiocardiography, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland Received 29 November 2007; accepted 20 January 2008 Available online 18 April 2009
Abstract ST-segment elevation in lead aVR in patients with angina at rest can be related to transmural ischemia of the basal part of the interventricular septum, frequently due to left main or multivessel coronary disease. However, this electrocardiographic (ECG) sign may also occur in other clinical conditions manifesting by acute chest pain. We present a case of a 76-year-old Caucasian woman with transient ST-segment elevation in lead aVR associated with tako-tsubo cardiomyopathy. Our report seems to confirm the hypothesis about the role of reversible myocardial ischemia involving the basal part of the interventricular septum in the pathogenesis of tako-tsubo cardiomyopathy. In conclusion, ST-segment elevation in lead aVR in patients with a clinical presentation of acute coronary syndrome may be not related to coronary artery disease. Takotsubo cardiomyopathy should be considered among the causes of ST-segment elevation in lead aVR in patients with angina at rest. Further studies are needed to evaluate the occurrence and importance of this ECG sign in patients with tako-tsubo cardiomyopathy. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Electrocardiography; Lead aVR; Apical ballooning; Tako-tsubo cardiomyopathy
1. Introduction ST-segment elevation in lead aVR in patients with angina at rest can be related to transmural ischemia of the basal part of the interventricular septum, frequently due to left main (LMCA) and/or multivessel coronary disease [1,2]. However, this electrocardiographic (ECG) sign may also occur in other clinical conditions manifesting by acute chest pain [1,2]. 2. Case presentation A 76-year-old Caucasian woman with arterial hypertension and hypercholesterolemia, treated with adjuvant tamoxifen monotherapy, because of grade 2, infiltrating ⁎ Corresponding author. Tel./fax: +48 12 633 67 44. E-mail address: [email protected] (P. Rostoff). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.01.003
ductal carcinoma of the left breast, was admitted to the emergency department with severe angina at rest and exertional dyspnea (NYHA class III), triggered by acute emotional stress. On admission, her blood pressure was 160/90 mmHg, and pulse rate was 76 beats/min. Electrocardiography showed STsegment elevation in leads aVR and V1 (Fig. 1a). The corrected QT interval (QTc) was 400 ms. Serum levels of troponin I, creatine kinase and MB isoenzyme were: 3.23 ng/mL (normal b 0.1 ng/mL), 153 U/L (normal b 145 U/L), and 19 U/L (normal b 24 U/L), respectively. NT-proBNP was 2241 pg/mL (normal b 450 pg/mL). The ECG recorded 4 h later showed QS-waves in leads V5– V6, ST-segment elevation in V3–V6, and biphasic T-waves in V5–V6 (Fig. 1b). The QTc was 455 ms. Interestingly, previously observed ST-segment changes in leads aVR and V1 were absent (Fig. 1b).
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P. Rostoff et al. / International Journal of Cardiology 134 (2009) e97–e100
Fig. 1. Time course of electrocardiographic changes: 12-lead ECG on admission (a), after 4 h (b), on day 7 of hospitalization (c), and 4 weeks after hospital discharge (d).
Coronary angiography revealed no significant coronary stenoses (Fig. 2a,b). Left ventriculography, however, disclosed apical ballooning with concomitant compensatory basal
hyperkinesis (Fig. 2c,d). Transthoracic echocardiography (TTE) confirmed the presence of left ventricular dyssynergy with the ejection fraction (LVEF) 35%. In addition, the
Fig. 2. Coronary angiography revealed no significant stenosis in the left (a) and right (b) coronary arteries. Left ventriculography disclosed apical ballooning with basal hyperkinesis (c,d). Transthoracic echocardiography showed a sigmoid deformity of the interventricular septum (e,f).
P. Rostoff et al. / International Journal of Cardiology 134 (2009) e97–e100
interventricular mid-basal septum had a localized area of increased thickness (end-diastole 1.7 cm compared to 1.0 cm in the mid-apical septum) (Fig. 2e,f). No dynamic left ventricular outflow tract (LVOT) obstruction or intraventricular pressure gradients were detected. Cardiac enzymes returned to normal within 4 days. The 24-hour urinary excretion of catecholamines, metoxycatecholamines and vanillylmandelic acid was within reference ranges. Thallium-201 scintigraphy, performed on day 6 of hospitalization, revealed a defect confined to the apical region. The ECG recorded 7 days after hospital admission showed ST-segment elevation in II, aVF, V2–V6, and negative T-waves in I, II, aVF, V2–V6 (Fig. 1c). The QTc was prolonged to 500 ms. The patient's hospital course was uneventful and she was discharged after 11 days. TTE performed 4 weeks later disclosed normal left ventricular function with LVEF 60%. The ECG showed persistent ST-segment elevation in leads V2–V6, with no QTc prolongation (425 ms) (Fig. 1d). At 6-month follow-up, the patient was well with no further recurrence of cardiovascular symptoms. 3. Discussion To the best of our knowledge, this is the first report documenting transient ST-segment elevation in lead aVR associated with stress-induced tako-tsubo cardiomyopathy (TTC). This observation is consistent with previously published data indicating that ST-segment elevation in lead aVR can be a presenting ECG finding in TTC patients [3,4]. In the patient described here, the diagnosis of TTC was made according to the Mayo Clinic criteria [5]. Characteristic reversible left ventricular dyssynergy, in the absence of significant coronary lesions, yielded the final diagnosis of tako-tsubo cardiomyopathy. Mechanisms of ST-segment elevation in lead aVR in patients with resting angina are poorly understood. According to the most accepted theory, it is caused by transmural ischemia of the basal part of the interventricular septum [1,2]. Previous studies have shown that ST-segment elevation in aVR may be especially useful in predicting LMCA disease in patients with angina at rest [1,6]. Yamaji et al. demonstrated that ST-segment elevation in lead aVR, particularly greater than that in lead V1, is strongly suggestive for acute LMCA occlusion [1]. Analysis of data from three large clinical studies revealed that the sensitivity for lead aVR ST-segment elevation in the prediction of acute LMCA occlusion is 77.6% [2]. Interestingly, in patients with acute coronary syndromes the specificity of this ECG sign for acute LMCA occlusion is relatively high (82.6%), whereas it is much lower (65.4%) for hemodynamically significant (N 50%) stenosis of the LMCA [2,6]. Lead aVR ST-segment elevation may also be found in other clinical conditions, including acute proximal occlusion of the left anterior descending coronary artery, acute pul-
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monary embolism, preexcitation syndrome-related narrow complex tachycardia, and severe, prolonged arterial hypotension [1,2,7]. The etiopathogenesis of tako-tsubo cardiomyopathy remains unclear [3,8]. There is increasing evidence that TTC is a form of myocardial stunning related to sympathetic hyperactivity [8,9]. A number of possible underlying mechanisms have been suggested, including multivessel epicardial spasm, diffuse coronary microvascular dysfunction/spasm and direct catecholamine-mediated cardiomyocyte injury [3,8]. The reversible diffuse impairment of coronary microcirculation, which can lead to transient global myocardial ischemia, is currently widely accepted as the essential pathogenetic mechanism of TTC [8]. It is possible that transient myocardial ischemia involving the basal interventricular septum could lead to ST-segment elevation in lead aVR in the patient reported here. Most cases of TTC (85%) affect postmenopausal women aged 60–75 years [8]. Thus, many researchers suggest possible role of estrogen deficiency in the pathogenesis of TTC [8]. Estrogen deprivation (natural or iatrogenic) impairs endothelial function and microcirculation via decreased expression of endothelial nitric oxide synthase (eNOS) and the subsequent reduction in nitric oxide (NO) bioavailability [8,9]. In the presented postmenopausal woman, chronic treatment with tamoxifen, a selective estrogen-receptor modulator (SERM) with strong anti-estrogenic activity, might additionally disturb coronary microcirculation [10,11]. However, recently published clinical and animal studies showed that tamoxifen improves endothelial function mostly due to enhancing NO release and reduction of plasma lipid and homocysteine levels [10,11]. Merli et al. [12] demonstrated that the age-related sigmoid deformity of the interventricular septum may predispose to the development of TTC, particularly in the presence of dehydration/hypovolemia or intense catecholaminergic stimulation. In some TTC patients with the sigmoid septum, dynamic LVOT obstruction or intraventricular pressure gradients can occur and cause myocardial ischemia, especially in the subendocardium [12]. However, in our patient no LVOT obstruction or intraventricular pressure gradients were found. Furthermore, it seems unlikely, that subendocardial ischemia could lead to ST-segment elevation in lead aVR. Although knowledge of the underlying mechanisms of tako-tsubo cardiomyopathy and dynamic ECG changes observed in TTC patients is still limited, our report seems to confirm the hypothesis about the role of reversible myocardial ischemia in the pathogenesis of TTC. In conclusion, ST-segment elevation in lead aVR in patients with a clinical presentation of acute coronary syndrome may be not related to coronary artery disease. Tako-tsubo cardiomyopathy should be considered among the causes of ST-segment elevation in lead aVR in patients with angina at rest. Further studies are needed to evaluate the occurrence and importance of this ECG sign in patients with tako-tsubo cardiomyopathy.
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P. Rostoff et al. / International Journal of Cardiology 134 (2009) e97–e100
References [1] Yamaji H, Iwasaki K, Kusachi S, et al. Prediction of acute left main coronary artery obstruction by 12-lead electrocardiography. ST segment elevation in lead aVR with less ST segment elevation in lead V1. J Am Coll Cardiol 2001;38:1348–54. [2] Rostoff P, Piwowarska W, Gackowski A, et al. Electrocardiographic prediction of acute left main coronary artery occlusion. Am J Emerg Med 2007;25:852–5. [3] Donohue D, Ahsan C, Sanaei-Ardekani M, Movahed MR. Early diagnosis of stress-induced apical ballooning syndrome based on classic echocardiographic findings and correlation with cardiac catheterization. J Am Soc Echocardiogr 2005;18:1423. [4] Tsuchihashi K, Ueshima K, Uchida T, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. J Am Coll Cardiol 2001;38:11–8. [5] Chun SG, Kwok V, Pang DK, Lau TK. Transient left ventricular apical ballooning syndrome (takotsubo cardiomyopathy) as a complication of permanent pacemaker implantation. Int J Cardiol 2007;117:e27–30.
[6] Rostoff P, Piwowarska W, Konduracka E, et al. Value of lead aVR in the detection of significant left main coronary artery stenosis in acute coronary syndrome. Kardiol Pol 2005;62:128–35. [7] Williamson K, Mattu A, Plautz CU, Binder A, Brady WJ. Electrocardiographic applications of lead aVR. Am J Emerg Med 2006;24:864–74. [8] Cocco G, Chu D. Stress-induced cardiomyopathy: a review. Eur J Intern Med 2007;18:369–79. [9] Hertting K, Krause K, Härle T, Boczor S, Reimers J, Kuck KH. Transient left ventricular apical ballooning in a community hospital in Germany. Int J Cardiol 2006;112:282–8. [10] Leung HS, Yung LM, Leung FP, et al. Tamoxifen dilates porcine coronary arteries: roles for nitric oxide and ouabain-sensitive mechanisms. Br J Pharmacol 2006;149:703–11. [11] Stamatelopoulos KS, Lekakis JP, Poulakaki NA, et al. Tamoxifen improves endothelial function and reduces carotid intima-media thickness in postmenopausal women. Am Heart J 2004;147:1093–9. [12] Merli E, Sutcliffe S, Gori M, Sutherland GG. Tako-Tsubo cardiomyopathy: new insights into the possible underlying pathophysiology. Eur J Echocardiogr 2006;7:53–61.
Letter to the Editor
Transient ST-segment elevation in lead aVR associated with tako-tsubo cardiomyopathy Pawel Rostoff a,⁎, Pawel Latacz a , Wieslawa Piwowarska a , Ewa Konduracka a , Agnieszka Bolech a , Krzysztof Zmudka b a
Department of Coronary Disease, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Pradnicka 80, 31-202 Krakow, Poland b Department of Hemodynamics and Angiocardiography, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland Received 29 November 2007; accepted 20 January 2008 Available online 18 April 2009
Abstract ST-segment elevation in lead aVR in patients with angina at rest can be related to transmural ischemia of the basal part of the interventricular septum, frequently due to left main or multivessel coronary disease. However, this electrocardiographic (ECG) sign may also occur in other clinical conditions manifesting by acute chest pain. We present a case of a 76-year-old Caucasian woman with transient ST-segment elevation in lead aVR associated with tako-tsubo cardiomyopathy. Our report seems to confirm the hypothesis about the role of reversible myocardial ischemia involving the basal part of the interventricular septum in the pathogenesis of tako-tsubo cardiomyopathy. In conclusion, ST-segment elevation in lead aVR in patients with a clinical presentation of acute coronary syndrome may be not related to coronary artery disease. Takotsubo cardiomyopathy should be considered among the causes of ST-segment elevation in lead aVR in patients with angina at rest. Further studies are needed to evaluate the occurrence and importance of this ECG sign in patients with tako-tsubo cardiomyopathy. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Electrocardiography; Lead aVR; Apical ballooning; Tako-tsubo cardiomyopathy
1. Introduction ST-segment elevation in lead aVR in patients with angina at rest can be related to transmural ischemia of the basal part of the interventricular septum, frequently due to left main (LMCA) and/or multivessel coronary disease [1,2]. However, this electrocardiographic (ECG) sign may also occur in other clinical conditions manifesting by acute chest pain [1,2]. 2. Case presentation A 76-year-old Caucasian woman with arterial hypertension and hypercholesterolemia, treated with adjuvant tamoxifen monotherapy, because of grade 2, infiltrating ⁎ Corresponding author. Tel./fax: +48 12 633 67 44. E-mail address: [email protected] (P. Rostoff). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.01.003
ductal carcinoma of the left breast, was admitted to the emergency department with severe angina at rest and exertional dyspnea (NYHA class III), triggered by acute emotional stress. On admission, her blood pressure was 160/90 mmHg, and pulse rate was 76 beats/min. Electrocardiography showed STsegment elevation in leads aVR and V1 (Fig. 1a). The corrected QT interval (QTc) was 400 ms. Serum levels of troponin I, creatine kinase and MB isoenzyme were: 3.23 ng/mL (normal b 0.1 ng/mL), 153 U/L (normal b 145 U/L), and 19 U/L (normal b 24 U/L), respectively. NT-proBNP was 2241 pg/mL (normal b 450 pg/mL). The ECG recorded 4 h later showed QS-waves in leads V5– V6, ST-segment elevation in V3–V6, and biphasic T-waves in V5–V6 (Fig. 1b). The QTc was 455 ms. Interestingly, previously observed ST-segment changes in leads aVR and V1 were absent (Fig. 1b).
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P. Rostoff et al. / International Journal of Cardiology 134 (2009) e97–e100
Fig. 1. Time course of electrocardiographic changes: 12-lead ECG on admission (a), after 4 h (b), on day 7 of hospitalization (c), and 4 weeks after hospital discharge (d).
Coronary angiography revealed no significant coronary stenoses (Fig. 2a,b). Left ventriculography, however, disclosed apical ballooning with concomitant compensatory basal
hyperkinesis (Fig. 2c,d). Transthoracic echocardiography (TTE) confirmed the presence of left ventricular dyssynergy with the ejection fraction (LVEF) 35%. In addition, the
Fig. 2. Coronary angiography revealed no significant stenosis in the left (a) and right (b) coronary arteries. Left ventriculography disclosed apical ballooning with basal hyperkinesis (c,d). Transthoracic echocardiography showed a sigmoid deformity of the interventricular septum (e,f).
P. Rostoff et al. / International Journal of Cardiology 134 (2009) e97–e100
interventricular mid-basal septum had a localized area of increased thickness (end-diastole 1.7 cm compared to 1.0 cm in the mid-apical septum) (Fig. 2e,f). No dynamic left ventricular outflow tract (LVOT) obstruction or intraventricular pressure gradients were detected. Cardiac enzymes returned to normal within 4 days. The 24-hour urinary excretion of catecholamines, metoxycatecholamines and vanillylmandelic acid was within reference ranges. Thallium-201 scintigraphy, performed on day 6 of hospitalization, revealed a defect confined to the apical region. The ECG recorded 7 days after hospital admission showed ST-segment elevation in II, aVF, V2–V6, and negative T-waves in I, II, aVF, V2–V6 (Fig. 1c). The QTc was prolonged to 500 ms. The patient's hospital course was uneventful and she was discharged after 11 days. TTE performed 4 weeks later disclosed normal left ventricular function with LVEF 60%. The ECG showed persistent ST-segment elevation in leads V2–V6, with no QTc prolongation (425 ms) (Fig. 1d). At 6-month follow-up, the patient was well with no further recurrence of cardiovascular symptoms. 3. Discussion To the best of our knowledge, this is the first report documenting transient ST-segment elevation in lead aVR associated with stress-induced tako-tsubo cardiomyopathy (TTC). This observation is consistent with previously published data indicating that ST-segment elevation in lead aVR can be a presenting ECG finding in TTC patients [3,4]. In the patient described here, the diagnosis of TTC was made according to the Mayo Clinic criteria [5]. Characteristic reversible left ventricular dyssynergy, in the absence of significant coronary lesions, yielded the final diagnosis of tako-tsubo cardiomyopathy. Mechanisms of ST-segment elevation in lead aVR in patients with resting angina are poorly understood. According to the most accepted theory, it is caused by transmural ischemia of the basal part of the interventricular septum [1,2]. Previous studies have shown that ST-segment elevation in aVR may be especially useful in predicting LMCA disease in patients with angina at rest [1,6]. Yamaji et al. demonstrated that ST-segment elevation in lead aVR, particularly greater than that in lead V1, is strongly suggestive for acute LMCA occlusion [1]. Analysis of data from three large clinical studies revealed that the sensitivity for lead aVR ST-segment elevation in the prediction of acute LMCA occlusion is 77.6% [2]. Interestingly, in patients with acute coronary syndromes the specificity of this ECG sign for acute LMCA occlusion is relatively high (82.6%), whereas it is much lower (65.4%) for hemodynamically significant (N 50%) stenosis of the LMCA [2,6]. Lead aVR ST-segment elevation may also be found in other clinical conditions, including acute proximal occlusion of the left anterior descending coronary artery, acute pul-
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monary embolism, preexcitation syndrome-related narrow complex tachycardia, and severe, prolonged arterial hypotension [1,2,7]. The etiopathogenesis of tako-tsubo cardiomyopathy remains unclear [3,8]. There is increasing evidence that TTC is a form of myocardial stunning related to sympathetic hyperactivity [8,9]. A number of possible underlying mechanisms have been suggested, including multivessel epicardial spasm, diffuse coronary microvascular dysfunction/spasm and direct catecholamine-mediated cardiomyocyte injury [3,8]. The reversible diffuse impairment of coronary microcirculation, which can lead to transient global myocardial ischemia, is currently widely accepted as the essential pathogenetic mechanism of TTC [8]. It is possible that transient myocardial ischemia involving the basal interventricular septum could lead to ST-segment elevation in lead aVR in the patient reported here. Most cases of TTC (85%) affect postmenopausal women aged 60–75 years [8]. Thus, many researchers suggest possible role of estrogen deficiency in the pathogenesis of TTC [8]. Estrogen deprivation (natural or iatrogenic) impairs endothelial function and microcirculation via decreased expression of endothelial nitric oxide synthase (eNOS) and the subsequent reduction in nitric oxide (NO) bioavailability [8,9]. In the presented postmenopausal woman, chronic treatment with tamoxifen, a selective estrogen-receptor modulator (SERM) with strong anti-estrogenic activity, might additionally disturb coronary microcirculation [10,11]. However, recently published clinical and animal studies showed that tamoxifen improves endothelial function mostly due to enhancing NO release and reduction of plasma lipid and homocysteine levels [10,11]. Merli et al. [12] demonstrated that the age-related sigmoid deformity of the interventricular septum may predispose to the development of TTC, particularly in the presence of dehydration/hypovolemia or intense catecholaminergic stimulation. In some TTC patients with the sigmoid septum, dynamic LVOT obstruction or intraventricular pressure gradients can occur and cause myocardial ischemia, especially in the subendocardium [12]. However, in our patient no LVOT obstruction or intraventricular pressure gradients were found. Furthermore, it seems unlikely, that subendocardial ischemia could lead to ST-segment elevation in lead aVR. Although knowledge of the underlying mechanisms of tako-tsubo cardiomyopathy and dynamic ECG changes observed in TTC patients is still limited, our report seems to confirm the hypothesis about the role of reversible myocardial ischemia in the pathogenesis of TTC. In conclusion, ST-segment elevation in lead aVR in patients with a clinical presentation of acute coronary syndrome may be not related to coronary artery disease. Tako-tsubo cardiomyopathy should be considered among the causes of ST-segment elevation in lead aVR in patients with angina at rest. Further studies are needed to evaluate the occurrence and importance of this ECG sign in patients with tako-tsubo cardiomyopathy.
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P. Rostoff et al. / International Journal of Cardiology 134 (2009) e97–e100
References [1] Yamaji H, Iwasaki K, Kusachi S, et al. Prediction of acute left main coronary artery obstruction by 12-lead electrocardiography. ST segment elevation in lead aVR with less ST segment elevation in lead V1. J Am Coll Cardiol 2001;38:1348–54. [2] Rostoff P, Piwowarska W, Gackowski A, et al. Electrocardiographic prediction of acute left main coronary artery occlusion. Am J Emerg Med 2007;25:852–5. [3] Donohue D, Ahsan C, Sanaei-Ardekani M, Movahed MR. Early diagnosis of stress-induced apical ballooning syndrome based on classic echocardiographic findings and correlation with cardiac catheterization. J Am Soc Echocardiogr 2005;18:1423. [4] Tsuchihashi K, Ueshima K, Uchida T, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. J Am Coll Cardiol 2001;38:11–8. [5] Chun SG, Kwok V, Pang DK, Lau TK. Transient left ventricular apical ballooning syndrome (takotsubo cardiomyopathy) as a complication of permanent pacemaker implantation. Int J Cardiol 2007;117:e27–30.
[6] Rostoff P, Piwowarska W, Konduracka E, et al. Value of lead aVR in the detection of significant left main coronary artery stenosis in acute coronary syndrome. Kardiol Pol 2005;62:128–35. [7] Williamson K, Mattu A, Plautz CU, Binder A, Brady WJ. Electrocardiographic applications of lead aVR. Am J Emerg Med 2006;24:864–74. [8] Cocco G, Chu D. Stress-induced cardiomyopathy: a review. Eur J Intern Med 2007;18:369–79. [9] Hertting K, Krause K, Härle T, Boczor S, Reimers J, Kuck KH. Transient left ventricular apical ballooning in a community hospital in Germany. Int J Cardiol 2006;112:282–8. [10] Leung HS, Yung LM, Leung FP, et al. Tamoxifen dilates porcine coronary arteries: roles for nitric oxide and ouabain-sensitive mechanisms. Br J Pharmacol 2006;149:703–11. [11] Stamatelopoulos KS, Lekakis JP, Poulakaki NA, et al. Tamoxifen improves endothelial function and reduces carotid intima-media thickness in postmenopausal women. Am Heart J 2004;147:1093–9. [12] Merli E, Sutcliffe S, Gori M, Sutherland GG. Tako-Tsubo cardiomyopathy: new insights into the possible underlying pathophysiology. Eur J Echocardiogr 2006;7:53–61.