International Journal of Cardiology 177 (2014) 11081110

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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 ndings, 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 proles.

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
signicant.
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 signicantly younger and presented with
signicantly worse consciousness level (Table 1). There were no significant intergroup differences in the physiological variables (Table 1). The
plasma epinephrine levels (pg/mL) were signicantly lower in TCM
group (96 72 vs. 392 331, p = 0.007) (Fig. 1A). Similarly, the plasma norepinephrine levels (pg/mL) were signicantly lower in TCM
group (1015 1038 vs. 2028 1216, p = 0.01) (Fig. 1B). The plasma

J. Inamasu et al. / International Journal of Cardiology 177 (2014) 11081110

Table 1
Comparison of demographic/physiological variables and blood levels of cardiac biomarkers between Takotsubo cardiomyopathy and neurogenic stunned myocardium
patients.

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

71.7 7.6
8:11
Chest pain 8
Dyspnea 7
Dizziness 4
N/A
14.7 0.7
8 (42%)
10 (53%)
6 (32%)
8 (42%)
2 (11%)
149 32
83 19
103 31
4/19 (21%)
2.92 4.61
460.2 575.1
33.8 46.1

57.5 13.7
6:6
Headache 5
Altered mental status 7

b0.01*
0.95
N/A

ACoA 4, ICA 2, MCA 2, VA 4

8.2 2.7
0
6 (50%)
2 (%)
2 (17%)
0
166 58
91 35
93 32
6/12 (50%)
1.75 3.22
252.4 305.1
25.8 18.0

N/A
b0.001**
0.03***
0.82
0.67
0.25
0.51
0.31
0.37
0.39
0.20
0.40
0.30
0.59

ACoA: anterior communicating artery; BNP: B-type natriuretic peptide; BP: blood pressure; CK-MB: creatine kinase MB isozyme; GCS: Glasgow Coma Scale; ICA: internal carotid
artery; MCA: middle cerebral artery; NA: not applicable; NSM: neurogenic stunned myocardium; TCM: Takotsubo cardiomyopathy; VA: vertebral artery.
*, **, ***: statistically signicant.

epinephrine and norepinephrine levels were both positively correlated

in TCM (R = 0.70, p = 0.0007) and in NSM group (R = 0.64, p = 0.03)
(Fig. 1C, D). There were no signicant intergroup differences in the
other biomarker levels (Table 1).
The E/E ratio was signicantly higher in TCM group (17.7 7.5 vs.
12.2 4.6, p = 0.04) (Table 2). There were no signicant differences

1109

Table 2
Comparison of echocardiographic and electrocardiographic parameters between
Takotsubo cardiomyopathy and neurogenic stunned myocardium patients.

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

42.6 9.2
45.9 7.7
34.2 8.4
126.1 37.7
78.2 26.7
86.2 29.3
1.02 0.60
4.89 1.91
17.7 7.5
173.6 47.5
1.67 0.31
12/19 (63%)
13/19 (68%)
479 4

44.2 9.1
45.0 7.9
37.0 8.1
108.5 46.3
59.8 20.6
73.5 22.0
0.88 0.39
5.30 1.95
12.2 4.6
172.7 40.2
1.71 0.34
6/12 (50%)
3/12 (25%)
468 4

0.65
0.74
0.30
0.33
0.07
0.26
0.53
0.58
0.04*
0.96
0.67
0.73
0.03**
0.50

DcT: deceleration time; LVEF: left ventricular ejection fraction; LVIDd: left ventricular internal dimension, diastole; LVIDs: left ventricular internal dimension, systole; LVMI: left
ventricular mass index; NSM: neurogenic stunned myocardium; RWMSI: Regional Wall
Motion Score Index; TCM: Takotsubo cardiomyopathy.
*, **: statistically signicant.

in the other TTE parameters. Comparison of the 16 segment model

showed no signicant differences in the frequency of regional WMA
(Fig. 2). The frequency of T-wave inversion was signicantly higher in
TCM group (68% vs. 25%, p = 0.03) (Table 2). By contrast, there were
no signicant intergroup differences in the frequency of ST-segment elevation or mean QTc interval (Table 2).
This study revealed several differences between TCM and NSM. In
neurochemical perspective, substantial differences in the epinephrine/
norepinephrine correlation coefcient were observed (Fig. 1C, D). Plasma epinephrine levels increase markedly and to a greater extent than
norepinephrine levels in response to various stresses [6]. The greater

Fig. 1. The plasma epinephrine levels (pg/mL) were 96 72 for Takotsubo cardiomyopathy (TCM) and 392 331 for neurogenic stunned myocardium (NSM) group (A). The difference
was statistically signicant (p = 0.007*). The plasma norepinephrine levels (pg/mL) were 1015 1038 for TCM and 2028 1216 for NSM (B). The difference was statistically signicant
(p = 0.01**). Linear regression analysis revealing that the plasma epinephrine and norepinephrine levels were positively correlated in TCM group (R = 0.70, p = 0.0007) (C). The plasma
epinephrine and norepinephrine levels were also positively correlated in NSM group (R = 0.64, p = 0.03) (D).

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J. Inamasu et al. / International Journal of Cardiology 177 (2014) 11081110

was signicantly more likely to induce typical TCM-like cardiac dysfunction [8].
Most echocardiographic parameters were comparable except the E/
E ratio (Table 2). The higher E/E ratio in TCM group indicates the presence of more severe diastolic dysfunction [9]. That difference could be
explained by differences in demographics: TCM patients were signicantly older and more likely to have had prior cardiac events, and stiffened myocardium in that group might have resulted in worse diastolic
dysfunction and a higher E/E ratio. On the other hand, the degree of systolic dysfunction, the degree of myocardial injury, and spatial RWMA
distribution were similar between the two groups. The lower frequency
of T-wave inversion in NSM group without signicant 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].
There are several limitations to this study. First, timing of follow-up
examinations was not standardized and we were unable to perform a
chronological evaluation. Second, the number of patients was small:
given that both disorders have low incidences making it difcult to accumulating adequate samples, it is important to establish national/
international registries. Finally, because of the short half-life of epinephrine, the epinephrine/norepinephrine coefcient may vary substantially
with the timing of blood collection [7].
In conclusion, more prominent diastolic dysfunction and more frequent T-wave inversion in TCM group may have resulted from demographic differences. While plasma catecholamine levels were raised in
greater magnitudes in NSM group, it remains unclear whether that difference explains the echocardiographic/electrocardiographic differences. The authors certify that they comply with the principles of
Ethical Publishing in the International Journal of Cardiology.
Disclosure
The rst author (JI) received a research grant from the Japan Brain
Foundation.
References
Fig. 2. Comparison of the 16 segment model between Takotsubo cardiomyopathy (A) and
neurogenic stunned myocardium group (B) revealing that there were no signicant differences in the frequency of regional wall motion abnormality in any of the corresponding
segments.

increase of epinephrine relative to norepinephrine in NSM group may

be reasonable considering the greater physiological stress in SAH
patients. In the pathogenesis of TCM, epinephrine has been considered
to play a pivotal role: the difference in distribution of 1/2adrenoceptors between the apical and basal myocardium is attributed
to the greater contractile response to epinephrine in the apical myocardium with subsequent apical stunning [7]. By contrast, the etiological
role of epinephrine in NSM is less clear: studies on aneurysmal SAH
implicate norepinephrine, not epinephrine, as the main causative
agent [5]. The greater epinephrine/norepinephrine correlation coefcient in NSM group (Fig. 1D) may not signify that epinephrine is the primary cause of SAH-induced WMA. Rather, the current results may
simply indicate that differences in the catecholamine levels and
adrenoceptor subtype afnity may not be as decisive in the pathogenesis
of WMA: a recent experimental study demonstrated that norepinephrine

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