International Journal of Cardiology 174 (2014) e21–e23
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Takotsubo cardiomyopathy in the setting of necrotizing myopathy Elvira Bangert a, Marina Afanasyeva b, Boleslaw Lach c, Sebastien X. Joncas d,e, Sachin Chopra f, Amin Mulji f, Philip Joseph f,⁎ a
McMaster University, Department of Medicine, Hamilton, Ontario, Canada University of Ottawa, Department of Epidemiology and Community Medicine, Faculty of Medicine, Ottawa, Ontario, Canada McMaster University, Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada d Stephenson Cardiovascular Magnetic Resonance Centre, University of Calgary, Alberta, Canada e Université de Sherbrooke, Department of Cardiology, Quebec, Canada f McMaster University, Department of Medicine, Division of Cardiology, Hamilton, Ontario, Canada b c
a r t i c l e
i n f o
Article history: Received 3 March 2014 Accepted 9 March 2014 Available online 17 March 2014 Keywords: Takotsubo cardiomyopathy Stress-induced cardiomyopathy Apical ballooning syndrome Heart failure Necrotizing myopathy Myopathy
Approximately 2–3% of patients presenting with acute coronary syndrome (ACS) have takotsubo cardiomyopathy (TC). Distinguishing TC from myocardial infarction or other cardiac pathologies is important since TC generally has favorable prognosis and may require a different short- and long-term management. TC has been called ‘broken heart syndrome’ and ‘stress-induced cardiomyopathy’ because it typically follows severe emotional or physical stress, acute medical illness or an administration of certain pharmacologic agents [1]. We present a case of TC in the setting of necrotizing myopathy (NM). A 61-year-old female presented to our emergency department with retrosternal chest pain, which lasted 30 min and was associated with shortness of breath, lightheadedness, as well as diaphoresis. She had a 1-day history of proximal muscle weakness and fever of 38 °C. She denied any recent stressful events. Her medical history included bipolar disorder, chronic obstructive pulmonary disease, a 45-pack-year history of smoking, degenerative disc disease, psoriasis, and peptic ulcer disease. In 2010, the patient had a transient episode of muscle weakness and elevated creatine kinase (CK), which coincided with her hospitalization for left upper lobe lung abscess. Her home medications included valproic acid, zopiclone, clonazepam, and pantoprazole. ⁎ Corresponding author at: C3-110 DBCVSRI, Hamilton General Hospital, 237 Barton St. E., Hamilton, Ontario L8L 2X2, Canada. Tel.: +1 905 521 2100x40327; fax: +1 905 527 0271. E-mail address: [email protected] (P. Joseph).
http://dx.doi.org/10.1016/j.ijcard.2014.03.045 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Electrocardiography (ECG) revealed sinus rhythm, incomplete right bundle branch block, anterolateral Q waves, and 1-mm ST segment elevation in leads V2 to V5. Serum troponin I and CK levels were elevated (11.60 μg/L and 732 U/L respectively). Her oxygen saturation was 85% on room air and lung auscultation revealed bilateral crackles. Chest radiography showed no signs of pneumonia and a normal cardiac silhouette. Her blood work results were significant for elevated leukocytes (18.8 × 109/L), elevated neutrophils (9.9 × 109/L), and increased erythrocyte sedimentation rate (17 mm/h). An ACS was suspected and she received aspirin, clopidogrel, intravenous heparin, and a statin. Selective coronary angiography showed no flow-limiting coronary artery disease, with the greatest stenosis in the proximal left anterior descending artery of 30%. Left ventriculography revealed anterolateral, apical, and inferoapical akinesis with hyperdynamic function of the basal region (Supplementary video 1). Echocardiography showed the same pattern of wall motion abnormalities, left-ventricular ejection fraction (LVEF) of 30–35%, and no significant valve disease. On the second day of her hospital stay, the patient developed another episode of chest pain and ECG showed diffuse ST elevation extending beyond a geographic territory of a single coronary artery (Fig. 1A). Her CK level rose to 31,241 U/L but troponin I decreased to 10.54 μg/L. Her statin was subsequently discontinued. Serum levels of C-reactive protein and rheumatoid factor were elevated (45.7 mg/L and 50.1 IU/mL respectively). Antineutrophil cytoplasmic (both cANCA and pANCA) and antinuclear antibodies were negative. Cardiac magnetic resonance imaging (CMR) demonstrated leftventricular (LV) akinesis of mid and apical segments, hyperkinesis of the basal segment, and LVEF of 28% (Fig. 1B and C; Supplementary video 2). Turbo inversion recovery magnitude (TIRM) edema-sensitive sequence showed high signal within LV myocardium, more confluent towards the apex (Fig. 1D). Delayed gadolinium enhancement images showed no areas of high signal, arguing against regional necrosis or fibrosis typically seen in the context of myocarditis or myocardial infarct (Fig. 1E). To investigate the reason for proximal muscle weakness, electromyography (EMG) and muscle biopsy were performed. EMG revealed a myopathic process involving both quadriceps muscles, with evidence of fibrillations, high-frequency discharges, and “myopathic” potentials. Quadriceps muscle biopsy showed fiber necrosis and macrophage
e22
E. Bangert et al. / International Journal of Cardiology 174 (2014) e21–e23
Fig. 1. A. Electrocardiogram performed on the 2nd day of hospital stay showing diffuse ST-segment elevation. B. Cardiac magnetic resonance imaging long axis 4-chamber view in diastole. C. Cardiac magnetic resonance imaging long axis 4-chamber view in systole demonstrating apical ballooning of the left ventricle. D. Regional increase of signal intensity in the apical segments on turbo inversion recovery magnitude imaging compatible with myocardial edema. E. Inversion recovery late gadolinium enhancement imaging. The absence of late gadolinium enhancement is characteristic of takotsubo cardiomyopathy.
Fig. 2. Microscopic examination of quadriceps muscle biopsy specimens. Macrophage infiltration of necrotic muscle fibers is illustrated by (A) hematoxylin & eosin staining and (B) a strong reaction in non-specific esterase preparation.
E. Bangert et al. / International Journal of Cardiology 174 (2014) e21–e23
invasion as well as early fiber regeneration, consistent with necrotizing myopathy (NM) (Fig. 2). The patient was treated with metoprolol, ramipril, and furosemide. For NM, she received prednisone and azathioprine. Over the next few days her muscle weakness significantly improved and serum CK level normalized. One month post-discharge, echocardiography showed resolution of the wall motion abnormalities and an improvement in LVEF to 63%. TC typically affects postmenopausal women. Our patient's presentation of new-onset chest pain and dyspnea, modest elevation in cardiac troponin, ECG findings of diffuse ST-elevation associated with new right bundle-branch block and Q waves, as well as minimal coronary artery disease on coronary angiography was also typical for TC [2]. Consistent with the 2008 Mayo Clinic criteria for TC diagnosis [3], there was midsegmental to apical LV hypokinesis on echocardiography, angiography, and CMR. Regional wall motion abnormalities extended beyond a single epicardial vascular distribution. CMR has been emerging as a gold standard for noninvasive characterization of myocardial edema, inflammation, and fibrosis/necrosis in patients presenting with chest pain, raised troponins, and unobstructed coronary arteries [4]. In this case, CMR is useful in distinguishing TC from myocarditis, which may also present with clinical and ECG features of ACS in the setting of unobstructed coronary arteries and LV apical ballooning [4,5]. Our patient's CMR findings of a regional apical elevated signal on edema-sensitive pulse sequence imaging, combined with the absence of late gadolinium enhancement (LGE), argue against myocarditis or myocardial infarction, and represent a typical pattern for TC [5, 6]. Eitel et al. [6] showed no increased signal on LGE imaging in all their cases of TC when using a 5-standard deviation cut-off for signal intensity. However, myocardial edema was detected on edema-sensitive pulse sequence images in 81% of TC cases. The reversibility of both clinical symptoms and LV systolic dysfunction is also characteristic of TC [1]. Usually, clinical recovery occurs within 1 to 4 weeks. However, the normalization of cardiac function and clinical symptoms may be delayed for 2.5–12 months in 5% of patients [7]. In this patient, LVEF improved from 35% to 63% at 1 month post-discharge. The unusual presentation in this case was the fact that TC occurred in the setting of NM, a subtype of idiopathic inflammatory myopathy, histologically distinguished by the presence of both necrotic and regenerative fibers in the absence of an inflammatory infiltrate [8,9]. NM has been reported in association with statin treatment. Although our patient had received a statin, it was discontinued after 4 days when her CK level started to rise. Moreover, the onset of muscle weakness was prior to the initiation of the statin, making statin treatment a highly unlikely cause of her NM. The combination of proximal muscle weakness, elevated
e23
muscle enzymes, characteristic EMG and pathological changes, as well as the patient's response to immunosuppressive treatment is strongly suggestive of the diagnosis of an acute immune-mediated NM [8,9]. Given the temporal association and the absence of other known causes, we suggest that in our patient NM was the main trigger of TC. This case illustrates the importance of considering TC as a part of a differential diagnosis when patients present with a clinical picture of acute myocardial infarction. It also illustrates the utility of CMR in differentiating TC from myocarditis or acute myocardial infarction. Finally, to our knowledge this is the first report of TC occurring in the setting of NM [10]. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2014.03.045. Acknowledgment All authors of this manuscript would like to acknowledge the contribution of Dr. David Landry for his help with reviewing CMR imaging, Dr. Alfred Cividino for helpful discussions of the case, Dr. Elena Fernandez Pena for critical reading of the manuscript, and Dr. Omid Salehian for his help with the supplementary material. We certify that we comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] Sharkey S, Windenburg D, Lesser J, et al. Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. JACC 2010;55(4). [2] Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med Feb 2005;352(6):539–48. [3] Prasad A, Lerman A, Rihal C, et al. Apical ballooning syndrome (tako-tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J Mar 2008;155(3):408–17. [4] Lockie T, Nagel E, Redwood S, et al. Use of cardiovascular magnetic resonance imaging in acute coronary syndromes. Circulation 2009;119:1671–81. [5] Friedrich M, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol 2009;53:1475–87. [6] Eitel I, Von Knobelsdorff-Brenkenhoff F, Bernhardt P, et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA Jul 2011;306(3):277–86. [7] Elesber AA, Prasad A, Lennon RJ, et al. Four-year recurrence rate and prognosis of the apical ballooning syndrome. J Am Coll Cardiol 2007;50:448e52. [8] Lazarou IN, Guerne PA. Classification, diagnosis, and management of idiopathic inflammatory myopathies. J Rheumatol 2013;40(5):550–64. [9] Ernste FC, Reed AM. Idiopathic inflammatory myopathies: current trends in pathogenesis, clinical features, and up-to-date treatment recommendations. Mayo Clin Proc 2013;88(1):83–105. [10] Porto I, Della Bona R, Leo A, et al. Stress cardiomyopathy (tako-tsubo) triggered by nervous system diseases: a systematic review of the reported cases. Int J Cardiol Sep 10 2013;167(6):2441–8.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Takotsubo cardiomyopathy in the setting of necrotizing myopathy Elvira Bangert a, Marina Afanasyeva b, Boleslaw Lach c, Sebastien X. Joncas d,e, Sachin Chopra f, Amin Mulji f, Philip Joseph f,⁎ a
McMaster University, Department of Medicine, Hamilton, Ontario, Canada University of Ottawa, Department of Epidemiology and Community Medicine, Faculty of Medicine, Ottawa, Ontario, Canada McMaster University, Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada d Stephenson Cardiovascular Magnetic Resonance Centre, University of Calgary, Alberta, Canada e Université de Sherbrooke, Department of Cardiology, Quebec, Canada f McMaster University, Department of Medicine, Division of Cardiology, Hamilton, Ontario, Canada b c
a r t i c l e
i n f o
Article history: Received 3 March 2014 Accepted 9 March 2014 Available online 17 March 2014 Keywords: Takotsubo cardiomyopathy Stress-induced cardiomyopathy Apical ballooning syndrome Heart failure Necrotizing myopathy Myopathy
Approximately 2–3% of patients presenting with acute coronary syndrome (ACS) have takotsubo cardiomyopathy (TC). Distinguishing TC from myocardial infarction or other cardiac pathologies is important since TC generally has favorable prognosis and may require a different short- and long-term management. TC has been called ‘broken heart syndrome’ and ‘stress-induced cardiomyopathy’ because it typically follows severe emotional or physical stress, acute medical illness or an administration of certain pharmacologic agents [1]. We present a case of TC in the setting of necrotizing myopathy (NM). A 61-year-old female presented to our emergency department with retrosternal chest pain, which lasted 30 min and was associated with shortness of breath, lightheadedness, as well as diaphoresis. She had a 1-day history of proximal muscle weakness and fever of 38 °C. She denied any recent stressful events. Her medical history included bipolar disorder, chronic obstructive pulmonary disease, a 45-pack-year history of smoking, degenerative disc disease, psoriasis, and peptic ulcer disease. In 2010, the patient had a transient episode of muscle weakness and elevated creatine kinase (CK), which coincided with her hospitalization for left upper lobe lung abscess. Her home medications included valproic acid, zopiclone, clonazepam, and pantoprazole. ⁎ Corresponding author at: C3-110 DBCVSRI, Hamilton General Hospital, 237 Barton St. E., Hamilton, Ontario L8L 2X2, Canada. Tel.: +1 905 521 2100x40327; fax: +1 905 527 0271. E-mail address: [email protected] (P. Joseph).
http://dx.doi.org/10.1016/j.ijcard.2014.03.045 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Electrocardiography (ECG) revealed sinus rhythm, incomplete right bundle branch block, anterolateral Q waves, and 1-mm ST segment elevation in leads V2 to V5. Serum troponin I and CK levels were elevated (11.60 μg/L and 732 U/L respectively). Her oxygen saturation was 85% on room air and lung auscultation revealed bilateral crackles. Chest radiography showed no signs of pneumonia and a normal cardiac silhouette. Her blood work results were significant for elevated leukocytes (18.8 × 109/L), elevated neutrophils (9.9 × 109/L), and increased erythrocyte sedimentation rate (17 mm/h). An ACS was suspected and she received aspirin, clopidogrel, intravenous heparin, and a statin. Selective coronary angiography showed no flow-limiting coronary artery disease, with the greatest stenosis in the proximal left anterior descending artery of 30%. Left ventriculography revealed anterolateral, apical, and inferoapical akinesis with hyperdynamic function of the basal region (Supplementary video 1). Echocardiography showed the same pattern of wall motion abnormalities, left-ventricular ejection fraction (LVEF) of 30–35%, and no significant valve disease. On the second day of her hospital stay, the patient developed another episode of chest pain and ECG showed diffuse ST elevation extending beyond a geographic territory of a single coronary artery (Fig. 1A). Her CK level rose to 31,241 U/L but troponin I decreased to 10.54 μg/L. Her statin was subsequently discontinued. Serum levels of C-reactive protein and rheumatoid factor were elevated (45.7 mg/L and 50.1 IU/mL respectively). Antineutrophil cytoplasmic (both cANCA and pANCA) and antinuclear antibodies were negative. Cardiac magnetic resonance imaging (CMR) demonstrated leftventricular (LV) akinesis of mid and apical segments, hyperkinesis of the basal segment, and LVEF of 28% (Fig. 1B and C; Supplementary video 2). Turbo inversion recovery magnitude (TIRM) edema-sensitive sequence showed high signal within LV myocardium, more confluent towards the apex (Fig. 1D). Delayed gadolinium enhancement images showed no areas of high signal, arguing against regional necrosis or fibrosis typically seen in the context of myocarditis or myocardial infarct (Fig. 1E). To investigate the reason for proximal muscle weakness, electromyography (EMG) and muscle biopsy were performed. EMG revealed a myopathic process involving both quadriceps muscles, with evidence of fibrillations, high-frequency discharges, and “myopathic” potentials. Quadriceps muscle biopsy showed fiber necrosis and macrophage
e22
E. Bangert et al. / International Journal of Cardiology 174 (2014) e21–e23
Fig. 1. A. Electrocardiogram performed on the 2nd day of hospital stay showing diffuse ST-segment elevation. B. Cardiac magnetic resonance imaging long axis 4-chamber view in diastole. C. Cardiac magnetic resonance imaging long axis 4-chamber view in systole demonstrating apical ballooning of the left ventricle. D. Regional increase of signal intensity in the apical segments on turbo inversion recovery magnitude imaging compatible with myocardial edema. E. Inversion recovery late gadolinium enhancement imaging. The absence of late gadolinium enhancement is characteristic of takotsubo cardiomyopathy.
Fig. 2. Microscopic examination of quadriceps muscle biopsy specimens. Macrophage infiltration of necrotic muscle fibers is illustrated by (A) hematoxylin & eosin staining and (B) a strong reaction in non-specific esterase preparation.
E. Bangert et al. / International Journal of Cardiology 174 (2014) e21–e23
invasion as well as early fiber regeneration, consistent with necrotizing myopathy (NM) (Fig. 2). The patient was treated with metoprolol, ramipril, and furosemide. For NM, she received prednisone and azathioprine. Over the next few days her muscle weakness significantly improved and serum CK level normalized. One month post-discharge, echocardiography showed resolution of the wall motion abnormalities and an improvement in LVEF to 63%. TC typically affects postmenopausal women. Our patient's presentation of new-onset chest pain and dyspnea, modest elevation in cardiac troponin, ECG findings of diffuse ST-elevation associated with new right bundle-branch block and Q waves, as well as minimal coronary artery disease on coronary angiography was also typical for TC [2]. Consistent with the 2008 Mayo Clinic criteria for TC diagnosis [3], there was midsegmental to apical LV hypokinesis on echocardiography, angiography, and CMR. Regional wall motion abnormalities extended beyond a single epicardial vascular distribution. CMR has been emerging as a gold standard for noninvasive characterization of myocardial edema, inflammation, and fibrosis/necrosis in patients presenting with chest pain, raised troponins, and unobstructed coronary arteries [4]. In this case, CMR is useful in distinguishing TC from myocarditis, which may also present with clinical and ECG features of ACS in the setting of unobstructed coronary arteries and LV apical ballooning [4,5]. Our patient's CMR findings of a regional apical elevated signal on edema-sensitive pulse sequence imaging, combined with the absence of late gadolinium enhancement (LGE), argue against myocarditis or myocardial infarction, and represent a typical pattern for TC [5, 6]. Eitel et al. [6] showed no increased signal on LGE imaging in all their cases of TC when using a 5-standard deviation cut-off for signal intensity. However, myocardial edema was detected on edema-sensitive pulse sequence images in 81% of TC cases. The reversibility of both clinical symptoms and LV systolic dysfunction is also characteristic of TC [1]. Usually, clinical recovery occurs within 1 to 4 weeks. However, the normalization of cardiac function and clinical symptoms may be delayed for 2.5–12 months in 5% of patients [7]. In this patient, LVEF improved from 35% to 63% at 1 month post-discharge. The unusual presentation in this case was the fact that TC occurred in the setting of NM, a subtype of idiopathic inflammatory myopathy, histologically distinguished by the presence of both necrotic and regenerative fibers in the absence of an inflammatory infiltrate [8,9]. NM has been reported in association with statin treatment. Although our patient had received a statin, it was discontinued after 4 days when her CK level started to rise. Moreover, the onset of muscle weakness was prior to the initiation of the statin, making statin treatment a highly unlikely cause of her NM. The combination of proximal muscle weakness, elevated
e23
muscle enzymes, characteristic EMG and pathological changes, as well as the patient's response to immunosuppressive treatment is strongly suggestive of the diagnosis of an acute immune-mediated NM [8,9]. Given the temporal association and the absence of other known causes, we suggest that in our patient NM was the main trigger of TC. This case illustrates the importance of considering TC as a part of a differential diagnosis when patients present with a clinical picture of acute myocardial infarction. It also illustrates the utility of CMR in differentiating TC from myocarditis or acute myocardial infarction. Finally, to our knowledge this is the first report of TC occurring in the setting of NM [10]. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2014.03.045. Acknowledgment All authors of this manuscript would like to acknowledge the contribution of Dr. David Landry for his help with reviewing CMR imaging, Dr. Alfred Cividino for helpful discussions of the case, Dr. Elena Fernandez Pena for critical reading of the manuscript, and Dr. Omid Salehian for his help with the supplementary material. We certify that we comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] Sharkey S, Windenburg D, Lesser J, et al. Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. JACC 2010;55(4). [2] Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med Feb 2005;352(6):539–48. [3] Prasad A, Lerman A, Rihal C, et al. Apical ballooning syndrome (tako-tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J Mar 2008;155(3):408–17. [4] Lockie T, Nagel E, Redwood S, et al. Use of cardiovascular magnetic resonance imaging in acute coronary syndromes. Circulation 2009;119:1671–81. [5] Friedrich M, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol 2009;53:1475–87. [6] Eitel I, Von Knobelsdorff-Brenkenhoff F, Bernhardt P, et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA Jul 2011;306(3):277–86. [7] Elesber AA, Prasad A, Lennon RJ, et al. Four-year recurrence rate and prognosis of the apical ballooning syndrome. J Am Coll Cardiol 2007;50:448e52. [8] Lazarou IN, Guerne PA. Classification, diagnosis, and management of idiopathic inflammatory myopathies. J Rheumatol 2013;40(5):550–64. [9] Ernste FC, Reed AM. Idiopathic inflammatory myopathies: current trends in pathogenesis, clinical features, and up-to-date treatment recommendations. Mayo Clin Proc 2013;88(1):83–105. [10] Porto I, Della Bona R, Leo A, et al. Stress cardiomyopathy (tako-tsubo) triggered by nervous system diseases: a systematic review of the reported cases. Int J Cardiol Sep 10 2013;167(6):2441–8.
