International Journal of Cardiology 176 (2014) 574–576

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Letter to the Editor

Takotsubo cardiomyopathy and stroke☆ Michelle L. Young a, James Stoehr a, Maria I. Aguilar b, F. David Fortuin c a b c

College of Health Sciences, Midwestern University, Glendale, AZ, United States Department of Neurology, Mayo Clinic Hospital, Phoenix, AZ, United States Division of Cardiovascular Diseases, Mayo Clinic Hospital, Phoenix, AZ, United States

a r t i c l e

i n f o

Article history: Received 3 June 2014 Accepted 26 July 2014 Available online 13 August 2014 Keywords: Apical ballooning syndrome Cardiomyopathy Stress-induced cardiomyopathy Stroke Takotsubo cardiomyopathy

The incidence and type of stroke in the setting of takotsubo cardiomyopathy (TC) can vary, depending on the patient population being studied [1–5]. For this reason, we sought to investigate the occurrence of TC together with stroke at our institution (Mayo Clinic, Scottsdale, Arizona). To do this, we identified all patients with a diagnosis of TC per ICD-9 (International Classification of Diseases, Ninth Edition) (ICD-9 code 429.83; October 1, 2006, to October 31, 2011) (Table 1) or apical ballooning syndrome (ICD-9 code 419.89; January 1, 2006, to September 30, 2006) in a retrospective analysis of the electronic medical records. These criteria identified 122 unique cases of TC, of whom 110 were treated in our hospital (Tables 2 and 3). Twelve patients were excluded because their initial diagnosis and treatment were provided at another institution. TC and stroke occurred in 7 of the 110 cases (6.4%). The clinical findings for each patient with coexisting TC and stroke are summarized in Table 4. Four patients (3.6%) had an initial diagnosis of TC and a subsequent diagnosis of stroke. One of these 4 patients had a previous history (ie, not diagnosed during the index hospitalization) of stroke. One patient was previously prescribed anticoagulation for atrial fibrillation, and 1 patient was already on aspirin. Two patients (1.8%) had an initial diagnosis of stroke followed by TC. Neither patient was on antithrombotic therapy prior to admission, and both patients experienced intracerebral Abbreviations: ICD-9, International Classification of Diseases, Ninth Revision; TC, takotsubo cardiomyopathy. ☆ Statement of authorship: Ms Young and Drs Stoehr, Aguilar, and Fortuin all take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

hemorrhage. Stroke or transient ischemic attack and TC were diagnosed simultaneously in 1 patient (0.9%), who was on aspirin therapy prior to admission. In the medical literature, the incidence of stroke after TC diagnosis has ranged from 0% to 7.7% (Table 5) [6–11]. The methodology of a larger study from the National Inpatient Sample database does not allow a timeline for diagnosis of neurological diagnoses, requiring the authors to assume that acute comorbidities were present before the onset of TC [12]. In that paper, stroke is not listed as an acute complication of TC, but rather as a preexisting comorbidity, and we suspect that this is secondary to the methodological limitations noted in the previous sentence. In the current study, the relatively high incidence (3.6%) of stroke following TC diagnosis suggests that stroke is not an uncommon complication of TC. The cumulative incidence of stroke after TC for all the studies in Table 5 is 16 (2.9%) occurrences in 560 patients. The mechanism responsible for this association remains unclear, but cardioembolism is a potential factor. In the current study, of the 7 patients who presented with stroke and TC, 1 had a cardiac thrombus that formed in the left ventricular apex. However, among the entire study population, a ventricular thrombus was identified in only 2 patients (1.8%). This relatively infrequent finding of cardiac thrombus is juxtaposed with results from a previous report of 3 of 21 patients (14%) with cardiac thrombus formation in patients with a TC diagnosis [3]. The concern that cardiac thrombus formation can occur during episodes of TC has led previous authors to suggest anticoagulation therapy for all TC patients [3]. On the basis of our findings alone, the importance of anticoagulant therapy for treatment of TC cannot be discounted. However, additional treatment options should be entertained because there is no consensus on: 1) the exact relationship between stroke and TC, 2) features identifying patients with TC at high risk for stroke, and 3) the efficacy and risk of anticoagulant therapy in the setting of TC. Many subjects with TC also have risk factors for stroke, making the association between these entities more challenging. Notably, 2 of the 7 subjects with stroke in our study had a history of atrial fibrillation. The incidence of stroke preceding TC diagnosis from various studies is reported in Table 5 [2,8,9,11,12]. Neurological events preceding TC diagnosis are typically characterized as the physical stress causing TC. In the current study, stroke in both cases was intracerebral hemorrhage, and the stroke was rated as moderate to severe on the basis of the National Institutes of Health Stroke Scale. The cumulative incidence of stroke preceding TC in these studies is 897 occurrences in 26,149 subjects; however, this is possibly an overestimation because the largest study [12] has methodological limitations as noted above and possibly

M.L. Young et al. / International Journal of Cardiology 176 (2014) 574–576 Table 1 Characteristics of 110 patients with takotsubo cardiomyopathy.


Table 2 Index hospital course of 110 patients with takotsubo cardiomyopathy.


Value, no. (%)a


Age at time of TC diagnosis, mean ± SD, year Female sex, No. (%) BMI, mean ± SD Race White Black Asian Hispanic Risk factors Hypertension Diabetes mellitus Dyslipidemia Chronic kidney disease Coronary artery disease PVD (including cerebrovascular disease) Stroke Atrial fibrillation Tobacco use Lifelong nonsmoker Past smoker Current smoker Pack-year history, mean ± SD Home medications Anticoagulant Clopidogrel Aspirin Antiarrhythmic Diuretic Statin/lipid lowering ACE inhibitor/ARB Calcium channel blocker β-Blocker Other None

70.1 ± 11.8 92 (83.6) 24.5 ± 4.7

Presenting signs and symptoms ECG changes Seizure activity Headache Hemiparesis Altered mental status Dyspnea Heart failure Diaphoresis Radiation of pain Chest pain/discomfort Cardiac biomarkers (ng/mL) Peak troponin T Peak CK-MB Ejection fraction, mean±SD, % TC wall motion abnormality Apical Mid Basal Thrombus present Patients with stroke Death during index hospitalization Medications at discharge Anticoagulant Clopidogrel Aspirin β-Blocker Antiarrhythmic Diuretic Statin Calcium channel blocker ACE inhibitor/ARB Other

105 (95) 2 (2) 1 (1) 2 (2) 74 (67) 18 (16) 63 (57) 12 (11) 23 (21) 21 (19) 18 (16) 21 (19) 36 (33) 53 (48) 19 (17) 33.0 ± 22.3 12 (11) 3 (3) 29 (26) 9 (8) 30 (27) 34 (31) 27 (25) 18 (16) 29 (26) 32 (29) 13 (12)

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index (weight in kilograms divided by height in meters squared [kg/m2]); PVD, peripheral vascular disease; and TC, takotsubo cardiomyopathy. a Values are number (percentage) unless indicated otherwise.

includes patients who had a stroke after their diagnosis of TC. We were also unable to determine whether TC occurred before or after stroke in 1 of our patients (Table 5). Because TC may be asymptomatic, and stroke patients may be unable to notify hospital staff of new symptoms they experience due to their neurologic injury, it remains possible that TC after stroke may often go undetected and may be underreported as a complication of stroke. We conclude that in this retrospective study of hospitalized patients, stroke was noted in 7 of 110 patients (6.4%) with a diagnosis of TC. It was more common for TC to precede stroke than for stroke to precede TC. Additional studies are warranted to better elucidate 1) the mechanistic relationship between TC and stroke, and 2) optimal treatment of TC to reduce complications such as stroke. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] de Gregorio C, Grimaldi P, Lentini C. Left ventricular thrombus formation and cardioembolic complications in patients with Takotsubo-like syndrome: a systematic review. Int J Cardiol Dec 17 2008;131(1):18–24. [2] Yoshimura S, Toyoda K, Ohara T, et al. Takotsubo cardiomyopathy in acute ischemic stroke. Ann Neurol Nov 2008;64(5):547–54. [3] Mitsuma W, Kodama M, Ito M, et al. Thromboembolism in Takotsubo cardiomyopathy. Int J Cardiol Feb 18 2010;139(1):98–100. [4] Tobar R, Rotzak R, Rozenman Y. Apical thrombus associated with Takotsubo cardiomyopathy in a young woman. Echocardiography May 2009;26(5):575–80. [5] Lee W, Profitis K, Barlis P, Van Gaal WJ. Stroke and Takotsubo cardiomyopathy: is there more than just cause and effect? Int J Cardiol Apr 14 2011;148(2):e37–9.

Value, no. (%)a 28 (25) 5 (5) 2 (2) 5 (5) 16 (15) 51 (46) 3 (3) 10 (9) 21 (19) 58 (53) 0.37 ± 0.45 17.7 ± 32.3 36.8 ± 11.8 84 (76) 22 (20) 4 (4) 2 (2) 7 (6) 2 (2) 31 (28) 8 (7) 64 (58) 80 (73) 12 (11) 35 (32) 58 (53) 14 (13) 56 (51) 27 (25)

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CK-MB, creatine kinase MB; and ECG, electrocardiogram. a Values are number (percentage) unless indicated otherwise.

[6] de Gregorio C. Cardioembolic outcomes in stress-related cardiomyopathy complicated by ventricular thrombus: a systematic review of 26 clinical studies. Int J Cardiol May 14 2010;141(1):11–7. [7] Parodi G, Bellandi B, Del Pace S, et al. Tuscany registry of tako-tsubo cardiomyopathy. Natural history of tako-tsubo cardiomyopathy. Chest Apr 2011;139(4):887–92. [8] Samardhi H, Raffel OC, Savage M, et al. Takotsubo cardiomyopathy: an Australian single centre experience with medium term follow up. Intern Med J Jan 2012; 42(1):35–42. [9] Citro R, Rigo F, Previtali M, et al. Differences in clinical features and in-hospital outcomes of older adults with tako-tsubo cardiomyopathy. J Am Geriatr Soc Jan 2012;60(1):93–8. [10] Lee PH, Song JK, Sun BJ, et al. Outcomes of patients with stress-induced cardiomyopathy diagnosed by echocardiography in a tertiary referral hospital. J Am Soc Echocardiogr Jul 2010;23(7):766–71. [11] Lee VH, Connolly HM, Fulgham JR, Manno EM, Brown Jr RD, Wijdicks EF. Tako-tsubo cardiomyopathy in aneurysmal subarachnoid hemorrhage: an underappreciated ventricular dysfunction. J Neurosurg Aug 2006;105(2):264–70. [12] Brinjikji W, El-Sayed AM, Salka S. In-hospital mortality among patients with takotsubo cardiomyopathy: a study of the National Inpatient Sample 2008 to 2009. Am Heart J Aug 2012;164(2):215–21.

Table 3 Post-hospitalization course of 66 patients with takotsubo cardiomyopathy. Characteristic

Value, no. (%)a

Subsequent clinical events (n = 66) None noted Subsequent stroke Coronary artery disease Congestive heart failure Subsequent TC episodes Days until TC documented as resolved (n = 64) Follow-up EF by echocardiogram, % (n = 64)

49 (74) 0 12 (18) 6 (9) 4 (6) 33.5 ± 31.8 62.0 ± 6.7

Abbreviations: EF, ejection fraction; and TC, takotsubo cardiomyopathy. a Values are number (percentage) unless indicated otherwise.


M.L. Young et al. / International Journal of Cardiology 176 (2014) 574–576

Table 4 Characteristics of 7 patients with takotsubo cardiomyopathy and stroke. Characteristic

Takotsubo precedes stroke (n = 4)

Age, year Sex BMI Anticoagulant prior to admission Aspirin prior to admission Thrombus present Thrombus site Prior history of stroke History of atrial fibrillation Type of stroke NIHSS stroke severity TC trigger Presenting symptoms

68 F 25.47 No No No NA No Yes TIA Unknown Acute illness AMS

80 M 24.5 No No No NA No No Ischemic Unknown Unknown Dyspnea

85 F 20.2 Yes No No NA No Yes Ischemic Unknown Acute illness Chest pain

TC distribution Peak troponin T (ng/mL) Time between diagnoses

Apical 0.12 5 days

Apical 0.63 13 days

Apical 0.9 2 days

84 F 25.33 No Yes No NA Yes No Ischemic Minor Emotional stress Chest pain with radiation, ECG changes Apical 0.13 2 days

Stroke precedes takotsubo (n = 2)

Concurrent diagnoses (n = 1)

70 F 22.19 No No No NA No No ICH Moderate Acute illness Chest pain, AMS, hemiparesis, MI Apical 0.68 26 h

60 F 26.4 No No No NA No No ICH Moderate–severe Acute illness AMS, hemiparesis

41 M 25.25 No Yes Yes LV apex No No TIA Minor Acute illness AMS, hemiparesis

Mid 0.17 21 h

Apical 0.01 NA

Abbreviations: AMS, altered mental status; BMI, body mass index (weight in kilograms divided by height in meters squared [kg/m2]); ECG, electrocardiogram; F, female; ICH, intracerebral hemorrhage; LV, left ventricular; M, male; MI, myocardial infarction; NA, not applicable; NIHSS, National Institutes of Health Stroke Scale; TC, takotsubo cardiomyopathy; TC distribution, location of left ventricular wall motion abnormalities; and TIA, transient ischemic attack.

Table 5 Comparison of published reports of concomitant takotsubo cardiomyopathy and stroke. TC precedes stroke Author (year) de Gregorio et al. (2010) [6] Parodi et al. (2011) [7] Samardhi et al. (2012) [8] Citro et al. (2012) [9] Lee et al. (2010) [10] Present study

Total no. of cases 36 116 52 190 56 110

No. (%) with stroke 9 (25) –a 2 (3.8)b 1 (0.5)c – 4 (3.6)

Stroke precedes TC Author (year)

Total no. of cases

No. (%) with stroke

Lee et al. (2006) [11]d Yoshmira et al. (2008) [2]e Samardhi et al. (2012) [8] Lee et al. (2010) [10] Brinjikji et al. (2012) [12]

661 569 52 56 24,701 110

8 (1.2) 7 (1.2) 1 (1.9)c 1 (1.8) 655 (2.7)f,g 223 (0.9)d,g 2 (1.8)


1 (0.9)

Present study Concurrent diagnoses Present study

Abbreviation: TC, takotsubo cardiomyopathy. a Two patients died from stroke at least 6 months after TC, and recurrent TC was excluded in both cases. b Both cases were cases of transient ischemic attack; neither had left ventricular thrombus. c Details of stroke not provided. d Subarachnoid hemorrhage. e Acute ischemic stroke. f Stroke or transient ischemic attack. g Methodology could not classify whether the neurological event occurred before or after TC; we assume that it occurred before TC.

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