Factors Suggestive of Cardiac Complications in Takotsubo Cardiomyopathy: Multicenter Study

Background: Takotsubo cardiomyopathy (TM) is characterized by acute and transient myocardial segmental wall motion abnormality especially at the apical area with chest pain mimicking acute myocardial infarction. TM is generally accepted to show good prognosis, however, we experience some cases with severe cardiac complications including acute heart failure (AHF), cardiac rupture and ventricular arrhythmias. We characterized TM patients developing these complications. Methods and results: Eighty three patients were studied. Patients with AHF, cardiac rupture, ventricular arrhythmias and death due to cardiac complications (CC group, n = 29) were compared with other patients without cardiac complications (NC group, n = 54). There was no difference between the two groups in age, sex, and coronary risk factors. Common primary symptom in the CC group was dyspnea but was chest pain in NC group. A preceding emotional stress was a common trigger for CC group. Left ventriculography showed significantly decreased ejection fraction in the CC group (39.7 ± 10.2% vs. 53.9 ± 14.1%, p = 0.002). Similarly, more than two segments of impaired left ventricular wall motion was a significant predictor of severe cardiac complications. Conclusions: Clinical onset with dyspnea and extended area of left ventricular ballooning are signs predicting cardiac complications in TM. Received Date: March 29, 2016 Accepted Date: May 02, 2016 Published Date: May 12, 2016 Citation: Isobe, M., et al. Factors Suggestive of Cardiac Complications in Takotsubo Cardiomyopathy: Multicenter Study. (2016) J Heart Cardiol 2(1): 16. Open Access Review Article

However, the pathogenesis of TM remains to be elucidated. While the prognosis of TM is generally good, some patients develop severe cardiac complications such as cardiac failure, arrhythmia, and cardiac rupture [5][6][7] . TM is a syndrome that has a wide variety of pathologic features, and there is no consensus as to the definition of TM. It varies among researchers. The Mayo Clinic Criteria [8] are the most widely used diagnostic criteria, and have been employed in many studies addressing issues such as clinical characteristics, clinical course, and exacerbating factors in TM patients. In Japan, the Research Committee of Idiopathic Cardiomyopathy funded by the Japanese Ministry of Health, Labour and Welfare proposed diagnostic criteria for TM in 2004 [9] , quite different from those of the Mayo Clinic. The Japanese criteria use a different definition regarding the region of wall motion abnormality and exclude cerebrovascular disorders. To date, only a small number of studies have been conducted in patients with TM based on the Japanese diagnostic criteria. In the present study, we examined clinical characteristics and ECG changes in patients with TM based on the Japanese diagnostic criteria [9] and attempted to identify factors predicting severe cardiac complications.

Methods
We retrospectively reviewed the clinical characteristics of patients who had been diagnosed with TM at Tokyo Medical and Dental University Hospital and 7 affiliated hospitals during the period between 2001 and November 2010 in order to identify factors associated with severe cardiac complications. The diagnosis was made according to the guidelines for the diagnosis of this form of cardiomyopathy proposed by the aforementioned Research Committee of Idiopathic Cardiomyopathy [9] . In principle, patients who had undergone coronary artery angiography were included. Those with ischemic heart disease were excluded. According to the guidelines, TM is defined as a disease exhibiting an acute left ventricular apical ballooning of unknown cause, in which the left ventricle takes on the shape of a jar used for catching octopus, known in Japanese as "Takotsubo".
We also excluded patients with significant organic stenosis or spasm of the coronary arteries, cerebrovascular disorders, pheochromocytoma, and viral or idiopathic myocarditis. The data used for making the diagnosis included clinical symptoms, triggers, age, gender, ECG results, blood test results, and cardiac nuclear images.
We examined the associations between severe cardiac complications or death and clinical factors including patient backgrounds, initial symptoms, ECG results, and other test results. This study was approved by the institutional ethical review board at Tokyo Medical and Dental University, and according to the Ethical Guidelines for Epidemiological Research (Ministry of Education, Culture, Sports, Science and Technology/Ministry of Health, Labour and Welfare), we published all relevant details of this study instead of obtaining informed consent.
Information on symptoms and triggers was obtained by interviewing patients and their families. Baseline clinical characteristics were regarded as present when they were recorded in the hospital charts.
Wall motion analysis with left ventriculography (LVG) was performed using the right anterior oblique projection in which the left ventricle was divided into five segments (#1 anterobasal, #2 anterolateral, #3 apical, #4 diaphragmatic, and #5 posterobasal), and the motion of each segment was evaluated in six categories (normal, mild hypokinesis, moderate hypokinesis, severe hypokinesis, akinesis, and dyskinesis) by the physician who performed the test.
Descriptive statistics for clinical characteristics are presented as mean ± SD for continuous data and as counts and percentages for categorical data. Univariate analyses were performed using the chi-square test or Student's t test. The variables that were significant on univariate analysis were entered into a multivariate logistic regression model. All analyses were conducted by a physician (Tomoko Manno) with use of JMP ® 12 software (SAS Institute Inc., Cary, NC). All reported p values are 2-sided. Values are expressed as mean ± SD.
The patients were divided into the cardiac complication group (CC group) and the no-cardiac complication group (NC group). The CC group consisted of 29 patients who developed severe cardiac complications or died during hospitalization, while the NC group consisted of 54 patients. As shown in Table 1, the complications in the CC group were cardiac failure (including cardiogenic shock in 8) in 22 patients (26.5%), cardiac arrest in 2 (2.4%), ventricular arrhythmia in 4 (4.8%), and cardiac rupture in 1(1.2%). Of the CC group, 7 patients required mechanical assistance, including percutaneous cardiopulmonary support for 1, intra-aortic balloon pumping for Cardiac Complications in Takotsubo Cardiomyopathy 5, and electric cardioversion for 1. The patient backgrounds are presented in Table 2. The mean age was 71.9 ± 11.0 years. Most patients were women (n = 68, [81.9%]). The initial symptoms were classified into chest pain, dyspnea, consciousness disturbance, and others. Among these, chest pain was most frequent, being experienced by 45 patients (54.2%). Nine patients (10.8%) had no symptoms. Triggers were basically classified into physical stress, emotional stress, and uncertain. The physical stress was further classified into infection, post-surgery, hemodialysis, under treatment for another disease, exertion, and alcohol consumption. The proportions of patients with emotional stress and physical stress were nearly equal. Comparisons of patient backgrounds between the CC and NC groups revealed no significant difference in mean age (71.9 ± 12.7 vs. 71.8 ± 10.1 years; p = 0.99), gender distribution (although there were more women than men in both groups), or coronary risk factors including hypertension, hyperlipidemia, diabetes mellitus, and smoking.
ECG was analyzed in 49 patients who had undergone ECG monitoring for one week after the onset (18 for the CC group, and 31 for the NC group). Comparison of ECG between the two groups showed no significant difference in the deepest T-wave inversion (-1.31 ± 0.77 mV vs. -0.97 ± 0.51 mV; p = 0.377) or the maximum QTc interval (0.61 ± 0.10 msec vs. 0.56 ± 0.06 msec; p = 0.07), although the QTc interval tended to be longer in the CC than in the NC group. (Figure 1)

Discussion
Many recent studies on TM have used the Mayo Clinic Criteria proposed in 2004 (modified in 2008) to make the diagnosis. The Mayo Clinic Criteria are: (1)Transient hypokinesis, akinesis, or dyskinesis of the left ventricular mid-segments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often, but not always, present; (2) Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (3)New ECG abnormalities (ST-segment elevation and/or T-wave inversion) and/or modest elevation of cardiac troponin; (4) Absence of pheochromocytoma or myocarditis [8] . In the present study, we used the guidelines for TM diagnosis proposed by the Research Committee of Idiopathic Cardiomyopathy funded by the Japanese Ministry of Health, Labour and Welfare in 2004 [9] . The major differences between these two sets of diagnostic criteria are as follows. In the Mayo Clinic Criteria [8] , wall motion abnormality is essential but apical involvement is not a requirement. On the other hand, in the Japanese criteria [9] , an apical balloon-like dilation is an essential component of TM while cerebrovascular disorders are excluded.
Templin, C. et al. reported that TM can be classified into four different types according to the region affected by wall motion abnormality: apical type, mid-ventricular type, basal type, and focal type [10] . It is also known that abnormal ventricular contraction patterns can occur in a wide variety of regions in cerebrovascular disorders [11] . In the present study, we excluded patients with cerebrovascular disorders and examined those with apical type, which is the most typical form of TM. We believe that this patient selection might have allowed us to gain a better understanding of the pathology of TM.
It is true that vasospasm of coronary arteries could be associated with the pathogenesis of TM [3,7,17,18,20,21] , but details are still obscure. In the Japanese criteria [9] , patients with cardiac vasospasm should be excluded at the discretion of clinicians, but provocation test was not essential examination. In our study, 7 patients (8.4%) received provocation test of cardiac vasospasm and all of them showed negative results. Tsuchihashi, K. et al. suggested that cardiac vasospasm of TM patients is not necessarily excluded, because assessment of microvascular function is not easy in each patient [3] . Therefore, we did not investigate the presence of cardiac vasospasm in all patients thoroughly in this investigation. Further clinical studies are necessary to elucidate the influence of vasospasm on the clinical severity of TM.
Female patients accounted for approximately 80% of total cases in this study, an observation consistent with those of previous reports. The rates of cardiac complications did not differ significantly between the genders in this study. However, further investigation on this topic may be needed because Murakami and colleagues reported male gender to be an independent predictor of in-hospital composite cardiac events [12][13][14] .
As to the initial symptoms, chest pain was most common, as in previous studies. Among those with severe cardiac complications, dyspnea was most frequent. The results regarding the triggers of TM were consistent with those of many studies showing that physical stress and emotional stress each accounted for 30 -40% [15][16][17][18] , although there is a report indicating that physical stress accounts for 80% of all cases [19] . The present study revealed severe cardiac complications to be less frequent in univariate analysis in patients who experienced emotional stress at the onset.
Currently, blood test data are insufficient, but there are studies showing elevated WBC to be an independent predictor of cardiac events, and a brain natriuretic peptide level ≥ 238 pg/ml to be an independent predictor of delayed recovery [12,20,21] . We found herein that the patients with severe cardiac complications had elevated WBC, CRP, and CK values, suggesting that their myocardial injuries were quite extensive.
LVG showed an association between low ejection fraction and serious complications in this study, an observation consistent with those of previous studies [12,14,15] . This study also showed that the risk of serious cardiac complications increased as the region of wall motion abnormality became more extensive. With regard to ECG findings, there is a study showing greater mortality when the QTc interval was 400 -550 msec [22] . The present results indicate that patients with severe cardiac complications had a prolonged QTc interval, although the difference did not reach statistical significance.

Limitations
The present study has several limitations. There were many patients who did not undergo coronary angiography in the acute stage of the disease due to background factors such as advanced age. The number of subjects was limited because patients with concomitant ischemic heart disease confirmed by coronary angiography were excluded. This was a retrospective multicenter study, such that blood test results, ECG data, ECG monitoring, magnetic resonance imaging, radioisotope imaging, and ventricular pressure gradient measurement (for those undergoing coronary angiography) were not available in all patients.

Conclusion
We studied factors predicting severe cardiac complications in patients who had been diagnosed as TM using the diagnostic criteria proposed by the Research Committee of Idiopathic Cardiomyopathy funded by the Japanese Ministry of Health, Labour and Welfare. Comparison of clinical characteristics between those with and without severe cardiac complications (including death) showed association with dyspnea as the initial symptom, an extensive wall motion abnormality region, inflammatory reaction, and elevated cardiac enzymes. Clinicians should be aware that patients with these clinical characteristics have a high risk of developing severe cardiac complications and manage these patients meticulously.