International Journal of Cardiology 177 (2014) 1108–1110

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International Journal of Cardiology
journal homepage: www.elsevier.com/locate/ijcard

Letter to the Editor

Are there differences between Takotsubo cardiomyopathy and
neurogenic stunned myocardium? A prospective observational study
Joji Inamasu a,⁎,1, Eiichi Watanabe b,2, Kentaro Okuda b,3, Tadashi Kumai a,4, Keiko Sugimoto c,5,
Yukio Ozaki b,6, Yuichi Hirose a,7
a
b
c

Department of Neurosurgery, Fujita Health University School of Medicine, Toyoake, Japan
Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan
Department of Laboratory Medicine, Fujita Health University School of Medical Technology, Toyoake, Japan

a r t i c l e

i n f o

Article history:
Received 11 August 2014
Accepted 14 August 2014
Available online 23 August 2014
Keywords:
Catecholamine
Echocardiography
Electrocardiogram
Neurogenic stunned myocardium
Takotsubo cardiomyopathy

Many similarities have been noted between Takotsubo cardiomyopathy (TCM) and neurogenic stunned myocardium (NSM): both exhibit
characteristic echocardiographic/electrocardiographic findings, and
sympathetic over-activity is implicated as a common etiological mechanism [1,2]. In this single-center, prospective observational study, we
aimed to clarify the potential differences between TCM and NSM by

⁎ Corresponding author at: Department of Neurosurgery, Fujita Health University
School of Medicine, 1-98 Kutsukake, Toyoake 470-1192, Japan. Tel.: +81 562 93 9153;
fax: +81 562 93 3118.
E-mail address: inamasu@fujita-hu.ac.jp (J. Inamasu).
1
Joji Inamasu, MD, PhD, FACS takes responsibility for all aspects of the reliability and
freedom from bias of the data presented and their discussed interpretation.
2
Eiichi Watanabe, MD, PhD takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
3
Kentaro Okuda, MD, PhD takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
4
Tadashi Kumai, MD takes responsibility for all aspects of the reliability and freedom
from bias of the data presented and their discussed interpretation.
5
Keiko Sugimoto, PhD takes responsibility for all aspects of the reliability and freedom
from bias of the data presented and their discussed interpretation.
6
Yukio Ozaki, MD, PhD, FESC takes responsibility for all aspects of the reliability and
freedom from bias of the data presented and their discussed interpretation.
7
Yuichi Hirose, MD, PhD takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

http://dx.doi.org/10.1016/j.ijcard.2014.08.084
0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

comparing their neurochemical, echocardiographic, and electrocardiographic profiles.
After approval by our institutional internal review board, we prospectively assessed the following parameters in aneurysmal subarachnoid hemorrhage (SAH) patients who presented within 24 h of onset:
blood levels of catecholamines (epinephrine/norepinephrine) and
other cardiac biomarkers (troponin I, B-type natriuretic peptide, and
creatine kinase isoenzyme), transthoracic echocardiography (TTE),
and ECG. Similarly, TCM patients underwent routine measurement of
plasma catecholamines and other cardiac biomarkers within 24 h of
onset. The diagnosis of TCM/NSM was based on the Proposed Mayo
Clinic Criteria [3]. Standard Doppler assessment of diastolic function
was performed according to the American Society of Echocardiography
guidelines [4]. Early diastolic (E) wave velocities and atrial (A) wave velocities, and the E wave deceleration time were measured using pulse
wave Doppler recording. Septal and lateral mitral annular early diastolic
velocities (E′) were measured from an apical 4-chamber view using offline color tissue Doppler images, and the E/ E′ ratio was calculated [4].
For the evaluation of ventricular wall motion abnormality (WMA), the
American Society of Echocardiography's 16 segment model and Regional Wall Motion Score Index (RWMSI) were used [4,5]. The frequencies of
WMA were illustrated by the 16 segment model, and those in corresponding segments were compared between the two groups. Moreover,
the frequencies of ST-segment elevation, T-wave inversion, and mean
QTc interval were compared. The Fisher's exact test and Student t-test
were used to compare categorical and continuous variables. Linear regression analysis was performed to evaluate the correlation between
plasma epinephrine and norepinephrine levels. JMP software (SAS Institute, Cary, NC) was used for statistical analyses. Numerical data are
expressed as mean ± SD, and p b 0.05 was considered statistically
significant.
Between January 2012 and December 2013, 19 patients were diagnosed with TCM and 12 patients with aneurysmal SAH were diagnosed
with NSM. NSM group was significantly younger and presented with
significantly worse consciousness level (Table 1). There were no significant intergroup differences in the physiological variables (Table 1). The
plasma epinephrine levels (pg/mL) were significantly lower in TCM
group (96 ± 72 vs. 392 ± 331, p = 0.007) (Fig. 1A). Similarly, the plasma norepinephrine levels (pg/mL) were significantly lower in TCM
group (1015 ± 1038 vs. 2028 ± 1216, p = 0.01) (Fig. 1B). The plasma

59 ACoA: anterior communicating artery.1 108.74 0.01**).4 126.1 45. The plasma epinephrine levels (pg/mL) were 96 ± 72 for Takotsubo cardiomyopathy (TCM) and 392 ± 331 for neurogenic stunned myocardium (NSM) group (A).3 1.75 ± 3.5 ± 46.3 59.71 ± 0.7 ± 40. NSM: neurogenic stunned myocardium.5 1.1 ± 37.03) (Fig.04) (Table 2).1 33.88 ± 0. p = 0.8 ± 46. LVIDd: left ventricular internal dimension.6 ± 47.2 ± 26. Inamasu et al. NSM: neurogenic stunned myocardium. VA: vertebral artery.5 ± 22. 1C.61 460.7 ± 7.34 6/12 (50%) 3/12 (25%) 468 ± 4 0. D).7 6:6 Headache 5 Altered mental status 7 b0.31 0.07 0.5 vs. The plasma epinephrine and norepinephrine levels were also positively correlated in NSM group (R = 0.J.30 ± 1. Comparison of the 16 segment model showed no significant differences in the frequency of regional WMA (Fig. 25%.95 12.0007) and in NSM group (R = 0. BNP: B-type natriuretic peptide.03) (Table 2).25 0.50 DcT: deceleration time.7 0 6 (50%) 2 (%) 2 (17%) 0 166 ± 58 91 ± 35 93 ± 32 6/12 (50%) 1.37 0. LVEF: left ventricular ejection fraction.7 78. p = 0. GCS: Glasgow Coma Scale.01* 0. ICA: internal carotid artery.2 ± 8.31 12/19 (63%) 13/19 (68%) 479 ± 4 44. p = 0.65 0.2 ± 29.04* 0.53 0.2 ± 4. NA: not applicable.39 5.0 0.7 ± 7. LVMI: left ventricular mass index.2 ± 9. The E/E′ ratio was significantly higher in TCM group (17. ICA 2.64. BP: blood pressure.2 ± 4. TCM: Takotsubo cardiomyopathy.6 ± 9. Plasma epinephrine levels increase markedly and to a greater extent than norepinephrine levels in response to various stresses [6]. The difference was statistically significant (p = 0. The greater Fig.73 0. Linear regression analysis revealing that the plasma epinephrine and norepinephrine levels were positively correlated in TCM group (R = 0.67 ± 0. *. substantial differences in the epinephrine/ norepinephrine correlation coefficient were observed (Fig. *. In neurochemical perspective. p = 0.1 25. . The difference was statistically significant (p = 0. There were no significant differences 1109 Table 2 Comparison of echocardiographic and electrocardiographic parameters between Takotsubo cardiomyopathy and neurogenic stunned myocardium patients. **.007*).2 1.40 0. / International Journal of Cardiology 177 (2014) 1108–1110 Table 1 Comparison of demographic/physiological variables and blood levels of cardiac biomarkers between Takotsubo cardiomyopathy and neurogenic stunned myocardium patients.5 ± 13. 12.0 N/A b0.64.6 73.82 0.6 8:11 Chest pain 8 Dyspnea 7 Dizziness 4 N/A 14. TCM: Takotsubo cardiomyopathy. epinephrine and norepinephrine levels were both positively correlated in TCM (R = 0. Age (y) Male:Female Presenting symptoms Aneurysm locations Admission GCS scores Prior cardiac events Hypertension Hyperlipidemia Diabetes mellitus Psychiatric history Systolic BP (mm Hg) Diastolic BP (mm Hg) Heart rate (bpm) Pulmonary edema Troponin I (ng/mL) BNP (pg/mL) CK-MB (ng/mL) TCM (n = 19) NSM (n = 12) p-Value 71.0 ± 8. The plasma norepinephrine levels (pg/mL) were 1015 ± 1038 for TCM and 2028 ± 1216 for NSM (B).02 ± 0.8 ± 20. p = 0.20 0.96 0.30 0.67 0. 2).9 37.6 172.001** 0.26 0. ***: statistically significant.2 ± 575.67 0. RWMSI: Regional Wall Motion Score Index.91 17.92 ± 4. diastole.7 ± 0.7 34.39 0.9 ± 7.22 252. **: statistically significant. p = 0. This study revealed several differences between TCM and NSM. systole.51 0. LVEF (%) LVIDd (mm) LVIDs (mm) LVMI (g/m2) E (m/s) A (m/s) E/A E′ (m/s) E/E′ DcT (ms) RWMSI ST-segment elevation T-wave inversion QTc (ms) TCM (n = 19) NSM (n = 12) p-Value 42.70. MCA 2.95 N/A ACoA 4.2 45.03*** 0.4 ± 305.8 ± 18.7 86.33 0. CK-MB: creatine kinase MB isozyme. The frequency of T-wave inversion was significantly higher in TCM group (68% vs. MCA: middle cerebral artery. 1C.03** 0.7 8 (42%) 10 (53%) 6 (32%) 8 (42%) 2 (11%) 149 ± 32 83 ± 19 103 ± 31 4/19 (21%) 2. 1.03) (D).58 0.30 0.70.0007) (C).89 ± 1.0 ± 7. D).60 4.1 57. VA 4 8. There were no significant intergroup differences in the other biomarker levels (Table 1).2 ± 2.7 ± 7. in the other TTE parameters. By contrast.5 173. there were no significant intergroup differences in the frequency of ST-segment elevation or mean QTc interval (Table 2). LVIDs: left ventricular internal dimension.6.

129:1659–67.142:120–5. Lerman A. Ali A.305:800–11.102:1545–50. The lower frequency of T-wave inversion in NSM group without significant difference in STsegment elevation may be explained by the general propensity for SAH patients to present earlier after onset: conversion from ST-segment elevation to T-wave inversion might have not occurred in most NSM patients by the time of their arrival [10].1110 J. epinephrine has been considered to play a pivotal role: the difference in distribution of β1/β2adrenoceptors between the apical and basal myocardium is attributed to the greater contractile response to epinephrine in the apical myocardium with subsequent apical stunning [7]. Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: A systematic review. Am Heart J 2008.155: 408–17. and spatial RWMA distribution were similar between the two groups. Inamasu J. Different catecholamines induce different patterns of takotsubo-like cardiac dysfunction in an apparently afterload dependent manner. References Fig. 1D) may not signify that epinephrine is the primary cause of SAH-induced WMA. [6] Goldstein DS. and stiffened myocardium in that group might have resulted in worse diastolic dysfunction and a higher E/E′ ratio. Eisenhofer G. Suffoletto MS. 2. On the other hand. First. Harding SE. The role of norepinephrine and estradiol in the pathogenesis of cardiac wall motion abnormality associated with subarachnoid hemorrhage. Prasad S. not epinephrine.168:4593–5. and pulmonary congestion in patients with subarachnoid hemorrhage. There are several limitations to this study. The authors certify that they comply with the principles of Ethical Publishing in the International Journal of Cardiology. Kopin IJ. Am J Cardiol 2008. the current results may simply indicate that differences in the catecholamine levels and adrenoceptor subtype affinity may not be as decisive in the pathogenesis of WMA: a recent experimental study demonstrated that norepinephrine [1] Pilgrim TM. et al.43:1897–903. Shao Y. Plausible mechanisms of the rapid conversion of ST-segment elevation to T-wave inversion in Takotsubo syndrome. That difference could be explained by differences in demographics: TCM patients were significantly older and more likely to have had prior cardiac events. increase of epinephrine relative to norepinephrine in NSM group may be reasonable considering the greater physiological stress in SAH patients. Hannam S. Circulation 2014. Int J Cardiol 2008. Int J Cardiol 2014. / International Journal of Cardiology 177 (2014) 1108–1110 was significantly more likely to induce typical TCM-like cardiac dysfunction [8]. the number of patients was small: given that both disorders have low incidences making it difficult to accumulating adequate samples. [3] Prasad A. the epinephrine/norepinephrine coefficient may vary substantially with the timing of blood collection [7]. more prominent diastolic dysfunction and more frequent T-wave inversion in TCM group may have resulted from demographic differences.5:22–9. Stroke 2012. [10] Madias JE. Finally. [8] Redfors B. O'Connor MJ. [5] Sugimoto K. et al. Systolic and diastolic mechanics in stress cardiomyopathy. In conclusion. Stress (Takotsubo) cardiomyopathy: a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. In the pathogenesis of TCM. The greater epinephrine/norepinephrine correlation coefficient in NSM group (Fig. Poole-Wilson PA. . Rather. et al. Wyss TR. Rees PS. Sources and significance of plasma levels of catechols and their metabolites in humans. timing of follow-up examinations was not standardized and we were unable to perform a chronological evaluation. J Pharmacol Exp Ther 2003. Disclosure The first author (JI) received a research grant from the Japan Brain Foundation. cardiac dysfunction. Second. the etiological role of epinephrine in NSM is less clear: studies on aneurysmal SAH implicate norepinephrine. Int J Cardiol 2010. Rihal CS. Mikhailidis DP. Takotsubo cardiomyopathy: the current state of knowledge. Hirose Y.174:330–6. it remains unclear whether that difference explains the echocardiographic/electrocardiographic differences. Comparison of the 16 segment model between Takotsubo cardiomyopathy (A) and neurogenic stunned myocardium group (B) revealing that there were no significant differences in the frequency of regional wall motion abnormality in any of the corresponding segments. Omerovic E. [2] Bielecka-Dabrowa A. the degree of myocardial injury. it is important to establish national/ international registries. Inamasu et al. Nat Clin Pract Cardiovasc Med 2008. Most echocardiographic parameters were comparable except the E/ E′ ratio (Table 2). et al. [7] Lyon AR. Gan LM. Int J Cardiol 2013. Crago EA. because of the short half-life of epinephrine. the degree of systolic dysfunction. [4] Tanabe M. While plasma catecholamine levels were raised in greater magnitudes in NSM group. By contrast. Lundgren J.124:283–92. Baicu CF. as the main causative agent [5]. [9] Medeiros K. The higher E/E′ ratio in TCM group indicates the presence of more severe diastolic dysfunction [9]. Relation of elevation in cardiac troponin I to clinical severity.