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European Journal of Heart Failure 2005 7(7):1171-1176; doi:10.1016/j.ejheart.2005.03.011
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© 2005 European Society of Cardiology

Reversible ventricular dysfunction takotsubo cardiomyopathy

Yoshihiro J. Akashia,b,*, Haruki Mushab, Keisuke Kidab, Kae Itohb, Koji Inoueb, Kensuke Kawasakib, Nobuyuki Hashimotob and Fumihiko Miyakea

a Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine 2-16-1 Sugao Miyamae-district, Kawasaki-city, Kanagawa-prefecture 216-8511, Japan
b St. Marianna University Yokohama-city Seibu Hospital 1197-1 Yasashi-cho, Asahi-district Yokohama-city, Kanagawa-prefecture 241-0811, Japan

* Corresponding author. Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao Miyamae-district, Kawasaki-city, Kanagawa-prefecture 216-8511, Japan. Tel.: +81 44 977 8111; fax: +81 44 976 7093. E-mail address: Johnny{at}marianna-u.ac.jp


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Recently, many cardiologists have recognized the existence of a rapidly reversible form of heart failure of unknown origin characterized by a takotsubo-shaped, dyskinetic left ventricle on left ventriculography.

Aim: To determine the detailed clinical features of takotsubo cardiomyopathy.

Methods: Thirteen elderly patients (11 women and 2 men with a mean age of 75.3 years) who had normal coronary arteries and takotsubo-like left ventricular dysfunction were prospectively enrolled in this study.

Results: Cardiac enzymes did not increase significantly, but the mean plasma norepinephrine level was very high on admission (0.98 µg/l). Coronary angiography revealed normal coronary arteries in all patients, but left ventriculography showed apical akinesis combined with basal hyperkinesis, i.e., a takotsubo (Japanese octopus fishing pot)-shaped ventricle. Left ventricular wall motion normalized within a mean of 16.9 hospital days in 12 patients, but 1 patient died of acute renal failure on hospital day 7. Cardiac events did not recur during a follow-up period of 0.5 to 5 years.

Conclusion: Takotsubo cardiomyopathy seems to be a new type of acute heart failure, which generally has a good prognosis and does not recur. Myocardial damage by catecholamine overload, adrenoceptor hypersensitivity, and changes of catecholamine dynamics due to stress may cause this condition.

Key Words: Takotsubo • Reversible ventricular dysfunction • Cardiomyopathy • Catecholamine • Stunned myocardium • Heart failure

Received April 3, 2004; Revised April 25, 2004; Accepted March 11, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
In recent years, patients have been reported who have a clinical presentation that resembles acute myocardial infarction, but have normal coronary arteries and a takotsubo-shaped (Japanese for an octopus fishing pot) left ventricle with systolic dysfunction that characteristically resolves within a few weeks [1–21]. We investigated 13 patients with "takotsubo cardiomyopathy" admitted to our institution over the last 5 years to try to gain insights into its aetiology and associated clinical features.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Subjects
From January 1998 to December 2002, 653 patients were admitted to St. Marianna University Heart Center (Kawasaki, Japan) with the sudden onset of heart failure and acute development of Q waves and ST-T changes on the electrocardiogram (ECG) suggesting myocardial infarction. Myocardial infarction was confirmed in 637 patients, 13 (1.9%) were diagnosed as takotsubo cardiomyopathy and 3 patients had fulminant acute myocarditis. The diagnosis of takotsubo cardiomyopathy was based on the following findings:

(1) sudden onset of heart failure
(2) symptoms and ECG changes suggestive of acute myocardial infarction,
(3) a takotsubo-shaped dyskinetic left ventricle on echocardiography and left ventriculography,
(4) absence of coronary artery disease on angiography within 1 h of admission
(5) complete normalization of LV dysfunction within a few weeks in most cases.

Patients had haemodynamic monitoring by a thermodilution catheter after the initial coronary angiogram. Coronary angiography with acetylcholine provocation (30 s infusion of 50–100 µg) was repeated after LV dysfunction had resolved on echocardiography (within 1 month of hospitalization).

2.2. Statistical analysis
Data are expressed as the mean±S.D. Variables before and after the normalization of LV wall motion were compared using Student's paired t-test. Analysis of variance was used to investigate the relationship between the blood level of norepinephrine on admission and indices of cardiac function. A p value of less than 0.05 was considered significant.

2.3. Protocol and ethics
This study protocol was approved by the Committee on Human Investigation of St. Marianna University School of Medicine. The nature and purpose of the study and the risks involved were explained to the patients, and written informed consent to participation was obtained from all subjects prior to their enrollment, which was done prospectively at the time of diagnosing takotsubo cardiomyopathy.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The clinical features of the subjects are shown in Table 1. There were 11 women and 2 men (mean age±S.D.: 73.5±9.3 years). In 10 patients, there was a potential triggering event, including pacemaker implantation about 1 month previously in patient 1, pneumothorax about 3 h before the onset in patient 4, and a flu-like illness from 2 days previously in patient 6. Although most patients were under physical and/or mental stress around the time when cardiomyopathy occurred, there were no obvious events that could have triggered the onset in three cases. Patient 2 required mechanical ventilation for 2 days. Patients 3 and 9 required intra-aortic balloon pumping for 3 days each, and patients 9 (who developed sepsis after a small intestinal perforation) and 11 (who died on day 7 with acute renal failure and rhabdomyolysis after bilateral femoral artery embolism) required haemodialysis for 7–10 days. Case 8 developed ventricular fibrillation and received implantation of a cardioverter defibrillator (ICD) on hospital day 2. Among the 12 survivors, there were no further cardiac events during an observation period of 6 months to 5 years (Fig. 1).


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  		Table 1 Clinical characteristics, family history, past history, symptoms and electrocardiographic findings on admission

 


Figure 1
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  		Fig. 1 Progression of ECG changes in Case 3. The initial electrocardiogram obtained on admission showed ST elevation in leads II, III, aVf, V4 to V6. Twelve hours after admission, there was ST elevation in leads II, III and aVf, which remained for 2 weeks. Giant negative T waves in leads V4 to V6 improved within a month.

 
The laboratory data are shown in Table 2. We obtained the initial blood sample an average of 18.0±23.3 h after the onset of symptoms and enzymes reached maximal levels 35.2 h after the onset of symptoms. The plasma norepinephrine concentration was increased in 5 patients to 0.98±0.84 µg/l (normal: 0.24–0.57 µg/l). Paired serum samples gave negative results for viral infection in all cases and laboratory findings normalized within 1 week in most of the patients. Haemodynamic variables are shown in Table 3. The mean LVEF, pulmonary capillary wedge pressure, cardiac output, and cardiac index were 42.0±10.3%, 9.1±4.3 mm Hg, 2.6±0.6 l/min, and 1.9±0.3 l/min/m2, respectively. In the survivors, complete normalization of LV function was confirmed by 16.9±6.8 hospital days (LVEF improved to 65.8±8.0%, p<0.0001 vs. the initial value) (Fig. 2). Acetylcholine provocation after resolution did not induce coronary artery spasm.


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  		Table 2 Laboratory data on admission and peak cardiac enzymes

 


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  		Table 3 Initial cardiac catheterization data, haemodynamic support, and clinical course

 


Figure 2
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  		Fig. 2 Representative left ventriculography findings in Case 7. (a) There is apical akinesis and basal hyperkinesis on the 1st hospital day. (b) On the 12th hospital day, the pattern of contraction is normal.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Myocardial stunning due to impaired coronary blood flow may lead to reversible LV dysfunction [1,5,6], but myocardial perfusion scintigraphy shows few abnormal findings in patients with takotsubo cardiomyopathy [18,20] and no coronary spasm was observed with acetylcholine provocation testing. Another possible mechanism is inflammatory myocardial disease and myocardial infiltration by small mononuclear cells has been observed in some patients [13,14], which is not detected in ischemic stunning [22].

In most of our cases, cardiac enzymes were slightly increased on admission and increased further, but peak values were low compared to the severity of cardiac dysfunction. This syndrome appears predominantly to affect older women, which may reflect their relatively small left ventricular outflow tract leading to a degree of obstruction. Left ventricular filling pressures were increased and systemic blood pressure was low. These factors, combined with increased oxygen demand and reduced coronary perfusion pressure gradient, may lead to regional myocardial stunning.

ST segment deviation associated with histological evidence of myocardial damage in the absence of coronary artery disease has been reported in patients with fatal subarachnoid hemorrhage [23] and attributed to high plasma norepinephrine levels [14] [24–28]. An increase in plasma norepinephrine concentration was observed on admission in about half of our subjects and could have been due to the development of heart failure but the very high serum catecholamine levels observed in some of patients and regional differences in cardiac sympathetic activation could have contributed directly to the clinical picture [10,13,14,20,29]. However, others have reported plasma norepinephrine concentrations close to normal in patients with takotsubo cardiomyopathy [11].

In Japan, after the Hanshin–Awaji earthquake, Yamabe et al. [30] observed an increase in the incidence of patients with deep negative T waves. In a rat model, activation of cardiac adrenoceptors by psychological stress causes similar ECG changes [24,31,32]. The sympathoadrenal system plays a key role in the cardiovascular response to stress [33,34] and extreme psychological stress leads to cardiovascular adaptation [35–37]. Takotsubo cardiomyopathy is associated with small cell infiltration, contraction band necrosis, and mild fibrosis of the myocardium [14–16] that could be stress-related. Stress might be the trigger for takotsubo cardiomyopathy. MIBG scans in this population would be of interest to investigate regional myocardial sympathetic activation.

Takotsubo cardiomyopathy is a rare cause of acute heart failure in Japan and possibly other countries. The prognosis is good among patients who survive the initial onset and recurrent episodes have not been reported. Catecholamine overload, adrenoceptor hypersensitivity, or abnormal catecholamine dynamics due to stress may be the primary cause of this condition.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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