Subjects

From June 2003 to September 2008, all patients who underwent echocardiography during admission to the Asan Medical Center, a tertiary referral hospital in Seoul, South Korea, were assessed for their eligibility to enroll in this prospective study. Those who met the following inclusion criteria were enrolled: (1) development of typical takotsubo or inverted takotsubo on echocardiography ( Figure 1 , Videos 1-4 ; view video clips online); (2) no evidence of obstructive epicardial coronary artery disease, including no history of angina and a normal coronary angiogram or myocardial perfusion scan; for those patients who could not undergo invasive coronary angiography or myocardial perfusion scanning because of their condition, typical evolutionary electrocardiogram (ECG) changes, including prominent ST segment elevation and deep T-wave inversion with a marked discrepancy between the extent of wall motion abnormalities and cardiac biomarkers (peak troponin I level < 10 ng/mL), were used to indicate the absence of epicardial coronary artery obstruction; (3) the presence of a definite antecedent stressor, identified by the attending physicians; and (4) the absence of preexisting cardiomyopathy, head trauma, intracranial bleeding, pheochromocytoma, or catecholaminergic inotropic medication before echocardiography. Follow-up echocardiography was performed at least every week to assess LV function. Digitally stored echocardiographic images were reviewed again by experienced echocardiography specialists (JKS and JMS) to search for right ventricular dysfunction, LV thrombus, LV outflow tract obstruction, pericardial effusion, or inferior vena cava plethora (distended vena cava without inspiratory collapse). The severity of mitral regurgitation was assessed by using the ratio of distal jet area/left atrial area on color Doppler imaging, and grade ≥ 3 was defined as the ratio ≥ 35%.

Representative echocardiographic images of typical takotsubo (A-D) and inverted takotsubo cardiomyopathy (E, F) . In takotsubo cardiomyopathy, symmetric apical ballooning is characteristic in systole ( B, arrow ) compared with diastole (A) . In rare cases, hypercontractile basal contraction contributes to the development of systolic anterior motion of the mitral valve ( C, arrow ), which results in LV outflow tract obstruction and mitral regurgitation (D) . In inverted takotsubo type, hypercontractile motion of the apex ( F, arrow ) is characteristic. Ao, Aorta; LA, left atrium; LV, left ventricle.

Clinical Data

The laboratory findings, hospital management, and outcome were determined by careful analysis of the medical records of all patients. The magnitude of systemic illness was quantified by the Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system, which was calculated using the worst physiologic parameters during the first 24 hours after the event. Shock was defined as a systolic blood pressure less than 90 mm Hg despite the administration of ≥ 40 mL/kg of isotonic fluid in 1 hour. Follow-up data were collected by direct telephone interviews and a detailed review of all medical records. The cause and date of death were confirmed by information from the National Population Registry of the Korea National Statistical Office, together with a review of all available clinical records at the time of death.

Data Analysis

Numeric variables are summarized by using median and interquartile range (IQR). Between-group comparisons were performed by using the Mann–Whitney U test or Kruskal–Wallis test as appropriate. Nominal variables were compared by using the Fisher exact test. In univariate analysis, 7 parameters showed a marginal association with a fatal outcome ( P < .10), and these variables were tested in backward stepwise multivariable logistic regression analysis to identify independent predictors of in-hospital death. All P values were 2-sided, and a probability value of P < .05 was considered significant. All statistical analyses were performed with SPSS (version 12.0; SPSS Inc, Chicago, IL).

Triggering Events and Clinical Presentation

A total of 56 consecutive patients (median age of 64 years [IQR 52-74 years]) with typical takotsubo (n = 48) or inverted takotsubo (n = 8) on echocardiography were enrolled in this study. This cohort included 44 female patients (79%). Twenty-four patients (43%) underwent echocardiography in the emergency department, mainly because of chest pain or mild elevation of cardiac biomarkers. For the remaining 32 patients (57%), who underwent echocardiography during their hospital admission, echocardiography was requested because of the sudden development of dyspnea, ECG abnormalities, or pulmonary congestion documented by chest radiography. The triggering events were classified according to whether the stressors were emotional or physical ( Figure 2 ). The events involving physical stressors were further divided according to whether patients were admitted for a serious medical problem (acute medical illness group) or for prescheduled surgery or procedures (surgery/procedure group). Emotional stress was documented in 18% of patients (10/56), whereas acute medical illness and elective surgery/procedures were the precipitants in 52% of patients (29/56) and 30% of patients (17/56), respectively. Nine patients were taking a beta-receptor blocker (atenolol [n = 5], carvedilol [n = 3], and bisoprolol [n = 1]) to control blood pressure.

Precipitants of 56 patients with SIC.

Baseline Clinical Characteristics

The groups did not differ significantly in terms of age, gender ratio, and cardiovascular risk factors ( Table 1 ). Sudden development of chest pain was the most common clinical presentation in the emotional stress group (50%), but in the acute medical illness and surgery/procedure groups, the important clinical presentations were sudden dyspnea, ECG abnormality, hypotension, and oxygen desaturation. Shock developed only in the acute medical illness and surgery/procedure groups with a higher frequency of endotracheal intubation and significantly higher APACHE II scores compared with the emotional stress group.

Table 2 compares the baseline laboratory findings of all patients and the patients in the 3 groups. The median (and IQR) LV ejection fraction and peak troponin I level of all patients were 33% (26-39) and 3.5 ng/mL (0.8-7.0), respectively, and there were no differences between the groups. The 3 groups did not differ in the frequency of ECG abnormalities, such as ST segment elevation mimicking acute myocardial infarction and deep T-wave inversion. The most frequent ECG abnormality was QT prolongation (n = 50 [89%]). Although typical takotsubo was the predominant pattern, the frequency of inverted takotsubo was significantly lower in the acute medical illness group than in the emotional stress and surgery/procedure groups.

Table 2

Laboratory data

Variables	Total	Emotional (n = 10)	Surgery or procedure (n = 17)	Acute medical illness (n = 29)	P value
ECG abnormalities, n (%)
ST-segment elevation	16 (28.6)	4 (40.0)	4 (23.5)	8 (27.6)	.675
T wave inversion	45 (80.4)	8 (80.0)	13 (76.5)	24 (82.8)	.902
QTc prolongation	50 (89.3)	9 (90.0)	15 (88.2)	26 (89.7)	1.000
Atrial fibrillation	6 (10.7)	1 (10.0)	2 (11.8)	3 (10.3)	1.000
Atrial flutter	3 (5.4)	1 (10.0)	1 (5.9)	1 (3.4)	.751
Ventricular tachycardia	5 (8.9)	0	2 (11.8)	3 (10.3)	.693
Abnormality in chest x-ray, n (%)
Pulmonary edema	27 (48.2)	5 (50.0)	8 (47.1)	14 (48.3)	1.000
Pleural effusion	29 (51.8)	4 (40.0)	8 (47.1)	17 (58.6)	.556
Peak troponin I, ng/mL (median [IQR])	3.5 (0.8-7.0)	3.7 (0.6-11.5)	4.2 (2.8-8.3)	2.9 (0.4-6.7)	.213
Echocardiographic abnormalities, n (%)
Takotsubo	48 (85.7)	8 (80.0)	12 (70.6)	28 (96.6)	.026
Inverted takotsubo	8 (14.3)	2 (20.0)	5 (29.4)	1 (3.4)	.026
LV outflow tract obstruction	2 (3.6)	1 (10.0)	1 (5.9)	0	.228
Mitral regurgitation grade ≥ 3	3 (5.4)	1 (10.0)	0	2 (6.9)	.573
RV dysfunction	12 (21.4)	3 (30.0)	4 (23.5)	5 (17.2)	.528
Pericardial effusion	17 (30.4)	2 (20.0)	5 (29.4)	10 (34.5)	.801
LV thrombus	2 (3.6)	0	1 (5.9)	1 (3.4)	1.000
TR jet velocity, m/s (median [IQR])	2.7 (2.4-3.0)	2.7 (2.4-3.0)	2.7 (2.3-3.2)	2.7 (2.5-3.0)	.907
LV EF, % (median [IQR])	33 (26-39)	35 (24-39)	36 (28-43)	31 (27-37)	.412
Follow-up LV EF, % (median [IQR])	59 (55-63)	57 (52-61)	58 (55-61)	60 (54-63)	.536
Evaluation of obstructive CAD, n (%)
Coronary angiography	22 (39.3)	7 (70.0)	8 (47.1)	7 (24.1)	.029
Thallium 201 perfusion scan	15 (26.8)	2 (20.0)	2 (11.8)	11 (37.9)	.139

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