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European Journal of Heart Failure 2008 10(10):1015-1019; doi:10.1016/j.ejheart.2008.07.008
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© 2008 European Society of Cardiology

Long-term prognosis of the transient left ventricular dysfunction syndrome (Tako-Tsubo cardiomyopathy): Focus on malignancies

Christof Burgdorf*, Volkhard Kurowski, Hendrik Bonnemeier, Heribert Schunkert and Peter Walter Radke

Department of Internal Medicine II, University Hospital Schleswig-Holstein Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany

* Corresponding author. Tel.: +49 451 500 2421; fax: +49 451 500 2363. E-mail address: christof.burgdorf{at}uk-sh.de (C. Burgdorf).


   Abstract
Top
 Abstract
1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusions
 References
 
Background: The pathophysiology and long-term prognosis of the transient left ventricular dysfunction syndrome (LVDS, Tako-Tsubo cardiomyopathy) is largely unknown.

Aims: To investigate the prevalence of malignancies and long-term mortality in patients with LVDS.

Methods and results: Fifty patients with LVDS (47 females and 3 men, age 70±10 years) and 50 age- and gender-matched control patients with acute anterior myocardial infarction (MI) were evaluated. Nine patients (18%) with LVDS and 3 patients (6%) with MI had a previous history of malignancy at the time of the index event. On follow-up (2.9±1.6 years), 7 malignancies were newly diagnosed in the LVDS cohort whereas no new case of malignancy was found in the control group (p=0.01, odds ratio 16.95, 95% confidence interval [CI] 1.93–304.60). Overall mortality during follow-up did not differ significantly between both groups (hazard ratio 1.44 for death in LVDS patients, 95% CI 0.52–3.95, p=0.49); however, of those patients who died, cardiac deaths were more frequent in patients with MI (100% versus 11%in patients with LVDS, p<0.001).

Conclusions: Our data suggest an association of LVDS with malignancies, potentially as a result of paraneoplastic phenomena. Long-term prognosis of patients with LVDS is no better than in patients with acute MI.

Key Words: Left ventricular dysfunction syndrome • Tako-Tsubo cardiomyopathy • Malignancy • Prevalence • Mortality • Myocardial infarction

Received April 10, 2008; Revised June 3, 2008; Accepted July 17, 2008


   1. Background
Top
 Abstract
 1. Background
2. Aims
 3. Methods
 4. Results
 5. Conclusions
 References
 
The underlying pathophysiologic mechanisms and predispositions for the transient left ventricular dysfunction syndrome (LVDS, Tako-Tsubo cardiomyopathy), a recently described acquired cardiomyopathy, have thus far not been entirely understood. LVDS is characterized by acute but rapidly reversible left ventricular (LV) systolic dysfunction in the absence of atherosclerotic coronary artery disease [1-7]. Clinically, LVDS often mimics ST-segment elevation myocardial infarction (MI) or non-ST-segment elevation MI. Patients with LVDS seem to have a good prognosis in the absence of significant underlying comorbid conditions [7]. Only very recently, Elesber and co-workers have described the survival of a large cohort of 100 patients with LVDS [8]. While the cause of death during a mean follow-up of nearly 5 years was heterogeneous, the rate of cardiac death was identical to the rate of death from cancer in patients with LVDS in the latter study. Indeed, in our recently published prospective LVDS registry [9], we observed a high rate of concomitant malignancies in patients with LVDS.


   2. Aims
Top
 Abstract
 1. Background
 2. Aims
3. Methods
 4. Results
 5. Conclusions
 References
 
The purpose of the present case-control study was to investigate the prevalence of malignancies as well as overall mortality in patients with LVDS compared to control patients with acute MI.


   3. Methods
Top
 Abstract
 1. Background
 2. Aims
 3. Methods
4. Results
 5. Conclusions
 References
 
The investigation conforms to the principles outlined in the Declaration of Helsinki and the study protocol was approved by an institutional ethics committee. All patients gave informed consent.

3.1. Study patients
Between May 1998 and December 2007, 50 patients who fulfilled the modified Mayo Clinic criteria [10] for the clinical diagnosis of LVDS were identified from the Cardiac Catheterization Laboratory database of the University Hospital Schleswig-Holstein, Campus Lübeck (n=32476 patients). For any of the patients with LVDS, a control patient with either ST-segment elevation MI or non-ST-segment elevation MI who matched the respective LVDS patient for age, gender, type of anterior/anterolateral ST-segment changes (ST-segment elevation or ST-segment depression/T-wave inversion), and LV function was selected from the database. All other clinical and angiographic variables were blinded during the matching process.

3.2. Clinical assessment
At the time of the index event, complete medical history was assessed using a standardized patient questionnaire and all available medical records. Twelve-lead electrocardiograms and routine laboratory data including a quantitative troponin T test were obtained serially. ST-segment elevation was defined as a deviation of >1 mm in amplitude in more than 2 contiguous leads, deep T-wave inversion was defined as inversions of >3 mm in amplitude in at least 3 contiguous leads. Electrocardiographic changes that did not fulfill these criteria were grouped under non-specific ST/T-wave changes. Left ventriculography and multi-plane coronary angiography were performed in all patients by the femoral approach using standard techniques. Overall LV ejection fraction was calculated from planimetric evaluation of end-diastolic and end-systolic volume in the 30° right anterior oblique projection. Obstructive coronary heart disease was defined as >50% reduction in the lumen diameter of the major epicardial coronary artery. Two-dimensional transthoracic echocardiographic studies were performed in all patients in a standard fashion to assess LV systolic function and wall motion abnormalities. Estimation of the LV ejection fraction was done in the four-chamber view according to the method of Simpson [11].

3.3. Clinical follow-up
After hospital discharge, follow-up data from all patients were collected using standardized telephone interviews with patients and/or relatives. The cause of death was confirmed by review of all available clinical information at the time of death.

3.4. Statistical analysis
Continuous data are presented as mean±standard deviation unless otherwise stated; frequencies and percentages are used to describe discrete variables. Continuous data were analyzed using the Mann-Whitney nonparametric U test and categorical variables using the two-tailed Fisher's exact test. Comparison of survival rates was performed by means of a log-rank test. A p value of less than 0.05 was considered statistically significant.


   4. Results
Top
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
5. Conclusions
 References
 
4.1. Clinical characteristics
Clinical characteristics of the LVDS and MI cohort are summarized in Table 1. Significant differences at baseline were found with respect to the metabolic states, frequencies of chest pain at hospital admission, days of initial hospitalization, peak troponin T levels, follow-up LV ejection fractions, and discharge medications. Precipitating factors were emotional stress in 10 patients (20%) and physical stress in 8 patients (16%) with LVDS. In the MI cohort, precipitating emotional stress was not found; however, 4 patients (8%) with MI had acute physical stress immediately before the index event. Forty-four patients (88%) with LVDS had normal coronary arteries or slight luminal irregularities on coronary angiogram, the remaining 6 patients (12%) had a luminal narrowing of 50% in the mid left anterior descending artery or left circumflex artery. Ventriculography indicated typical apical wall motion abnormality in 32 patients (64%) and an atypical (midventricular) pattern in 18 patients (36%) with LVDS.


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  		Table 1 Patient clinical characteristics

 
4.2. Prevalence of malignancies
Nine patients (18%) with LVDS and 3 patients (6%) with MI had a previous history of malignancy at the time of the index event (Fig. 1). During the mean follow-up of 2.9±1.6 years (median 2.8 years, 25th and 75th interquartile 1.5 and 4.4 years), 7 malignancies were newly diagnosed in the LVDS cohort whereas no new case of malignancy was found in the MI cohort (p=0.01, odds ratio 16.95, 95% confidence interval [CI] 1.93-304.60). As depicted in Table 2, 8 distinct cancer entities were observed in patients with LVDS, only 1 cancer entity was found in patients with MI (Table 3). Cancer therapies comprised both surgery or chemotherapy alone or an individual combination of surgery, radiation, and chemotherapy (Tables 2 and 3). One male patient with LVDS had 2 different malignancies, 1 female patient with LVDS had breast cancer initially in the left breast and 5 years later in the right breast (Table 2). More interestingly, in the first year after the index hospitalization for LVDS, the highest number of newly diagnosed cancers was documented (Fig. 1). There was no difference of overall cancer prevalence between patients with typical apical wall motion abnormality (9/32 patients, 28%) and patients with an atypical (midventricular) pattern (5/18 patients, 28%). Furthermore, in the 9 patients with LVDS and previous history of malignancy, LV function at hospital admission (assessed by cardiac angiogram) was comparable in those patients with concomitant chemotherapy for cancer (n=4) and those patients without chemotherapy (n=5) (ejection fraction 46±8% versus 42±5%, p=0.64). None of the LVDS patients with previous history of cancer and concomitant chemotherapy had chemotherapy within the past 2 years before the index event.


Figure 01
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  		Fig. 1 Number of newly diagnosed cancers in temporal relation to the index event (i.e. hospitalisation for either transient left ventricular dysfunction syndrome [LVDS] or acute myocardial infarction [MI]). One male patient with LVDS had two different malignancies, 1 female patient with LVDS had breast cancer initially in the left breast and 5 years later in the right breast, thus the total number of diagnosed cancers increased to 16 in the upper panel.

 


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  		Table 2 Cancer entities, stages at first diagnosis, and cancer therapies of patients with transient left ventricular dysfunction syndrome

 


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  		Table 3 Cancer entities, stages at first diagnosis, and cancer therapies of patients with acute myocardial infarction

 
4.3. Mortality
Within the observational period, the overall mortality (i.e. in-hospital and out-patient) tended to be higher in the LVDS cohort. The hazard ratio for death in the LVDS group as compared with the MI group was 1.44 (95% CI 0.52-3.95). However, of those patients who died, cardiac deaths were more frequent in patients with MI (100% versus 11% in patients with LVDS, p<0.001). In detail, of the 50 patients with LVDS, 3 patients (6%) died during the initial hospitalization, all due to septic shock. Six additional patients (12%) died on follow-up due to heart failure (n=1), cerebral embolism (n=2), bronchial carcinoma (n=1), pneumonia (n=1), and old age (n=1). In the MI cohort, 5 patients (10%) died during the initial hospitalization due to cardiogenic shock, 1 patient died on follow-up after reinfarction.


   5. Conclusions
Top
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusions
References
 
Despite an increasing number of observational and functional studies, the pathophysiological basis of the LVDS is far from being understood. Clearly, a number of studies suggest an association between stress triggers and the distinct phenotype; however, most women do not develop a LVDS despite such triggers implying a "missing link" to better understand the disease pathophysiology. A very recent study has reported an identical cardiovascular and cancer-related mortality in a large cohort of LVDS patients, suggesting that malignancies may provide such pathophysiological link [8].

To exclude a potential (i.e. physician referral) bias, we compared LVDS patients with a well matched population with acute MI showing a significantly higher prevalence of malignancies in LVDS patients. In addition, we compared the prevalence of malignancies in our LVDS cohort with population-based data. Interestingly, in the EUROPREVAL study, a total prevalence of 11% for all cancers was found for the general population in Germany with an age higher than 65 years [12]. More recent data from the cancer registry of Saarland in Germany indicate an even lower total prevalence of 4.7% for women and 4.0% for men which is very well in line with our MI control group. Taken together, the high prevalence of cancer in patients with LVDS allows suggesting a possible relation of malignancies with this specific cardiomyopathy, potentially as a result of paraneoplastic phenomena.

The exact mechanisms of action, clearly, remain speculative. However, at least two hypotheses for the association of cancer and LVDS are conceivable. Firstly, the diagnosis "ancer" may alter the psychic threshold for stress stimuli. Thus, lower stimuli may generate inadequate increases in cardiac sympathetic nervous activity. Secondly, cancer itself may aggravate cardiac adrenoceptor sensitivity. Of note, about 20% of all human cancers are associated with chronic infection or chronic inflammatory states [13], and it is conceivable that excess levels of inflammatory mediators such as cytokines, free radicals, prostaglandins, catecholamines, or growth factors trigger such increase of adrenoceptor sensitivity. Indeed, marked elevation of plasma catecholamine levels was found in almost 75% of patients with LVDS [3]. Finally, it is not far to assume, that there might be even a combination of both hypotheses.

It is noteworthy that only 1 patient with LVDS in our study died from cancer during follow-up and that cardiac deaths were more frequent in patients with MI. These findings are in contrast to the study of Elesber et al. who found nearly identical rates of cardiovascular and non-cardiovascular deaths [8]. Unfortunately, in the latter study the total occurrence of malignant neoplasms was not stated; however, it appears likely that these patients had comparable rates or even higher rates of malignancy than our patients as only the cause of death was reported. Although there was no difference in long-term survival between the current cohort of LVDS patients and the cohort investigated by Elesber et al. [8], a non-expected finding of the present study was that the patients with LVDS and MI had comparable rates of overall survival which is probably the result of an equivalent number of cardiovascular deaths in the MI cohort and non-cardiovascular deaths in the LVDS cohort. This is in contrast to previous studies suggesting a clinically uneventful and benign course of patients with LVDS. Based on the paper by Elesber et al. and our data, patients with LVDS are characterized by the same prognosis as compared to patients with acute MI making this entity by far less benign than initially suggested.

It may be regarded as a limitation that the LVDS cohort only consists of patients with typical apical wall motion abnormality or an atypical (midventricular) pattern. Therefore, we would like to emphasise that the present findings cannot be necessarily extrapolated to patients with other forms of LVDS.

Taken together, our study is the first to investigate the occurrence of malignancies in patients with LVDS. The present results suggest that LVDS is associated with diverse malignancies in the sense of a yet not noticed paraneoplastic disease. The long-term prognosis of patients with LVDS is no better than patients with acute MI and, thus, LVDS should no longer be regarded as a benign disease.


   References
Top
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusions
 References
 

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