To the best of our knowledge, this is the first case-control study to report Takotsubo syndrome after cardiac surgery. We also identified that of the patients who developed Takotsubo syndrome, 69.2% had undergone mitral valve surgery. We identified atrio-ventricular valve surgery, and the immediate postoperative use of epinephrine or dobutamine as specific risk factors for Takotsubo syndrome following cardiac surgery. Our findings are consistent with those previously reported. In the literature, 14 cases of Takotsubo syndrome after cardiac surgery have been reported, with the majority of these cases (n = 10, 71.4%) occurred after mitral valve surgery (2, 7, 11–22). Like all other surgeries, cardiac surgery can cause emotional and/or physiological stress which may trigger Takotsubo syndrome. In addition, cardiopulmonary bypass needed during cardiac surgery induces a systemic inflammatory response which may also cause coronary microvascular dysfunction and excessive catecholamine release (7). Direct manipulation and incision of the heart also increases its vulnerability to catecholamine-induced cardiac toxicity (21). We note, however, that the reason why Takotsubo syndrome occurs more frequently after mitral valve surgery than other cardiac surgery is unknown.
Several differential diagnoses for Takotsubo syndrome have previously been presented. Of these, papillo-annular discontinuity after mitral valve replacement, which leads to a spherical LV and, thus, decreases LV systolic function, should be differentiated from ‘transient’ Takotsubo syndrome (12, 23). Other causes of myocardial stunning after cardiac surgery, such as suboptimal myocardial protection or coronary air embolism, should also be considered as differential diagnoses of Takotsubo syndrome. These differential diagnoses should be identified intra-operatively, using transesophageal echocardiography, based on the characteristic echocardiographic finding of Takotsubo syndrome, namely apical ballooning that extends beyond a single coronary territory (15).
In 2008, Takotsubo syndrome, induced by pharmacological stress (epinephrine infusion), was first described by Wong et al. (11). In the following year, Abraham at al. reported that exogenous catecholamines and beta-receptor agonists (epinephrine, dobutamine), like endogenous catecholamines, could induce Takotsubo syndrome (24). Previous findings that excessive release of catecholamine may cause Takotsubo syndrome (3, 4) are convincing and are consistent with our own results that immediate postoperative use of epinephrine and dobutamine as risk factors for Takotsubo syndrome following cardiac surgery. Previous reports on the occurrence of Takotsubo syndrome after cardiac surgery indicated that, in most cases, the syndrome developed several minutes to several days after the release of cross-clamping (2, 7, 11, 12, 14–22). Of note, Ohata et al. did report on a case of Takotsubo syndrome that developed 1-month after aortic valve replacement in a 70-year-old female (13). In our study, intra-operative transesophageal echocardiography was performed in all cases, with TTE routinely performed at least 4 days after surgery. We do note that in the case of unstable vital signs, or if the patient complained of chest discomfort, TTE was immediately performed. The median interval between the cardiac surgery and the diagnosis of Takotsubo syndrome in our study cohort was 4.0 (Interquartile range, 3.0–5.0) days. Therefore, our imaging protocol would have been appropriate to detect Takotsubo syndrome in most cases.
Takotsubo syndrome has been known to occur mostly in elderly women (25). Ueyama et al. reported that, in rats, the use of estradiol might be protective against LV dysfunction induced by emotional stress (26). In the present study, there were more female patients in Takotsubo group (75.0%) than in control group (59.6%), although this difference was not significant (P = 0.08). However, female sex was identified as a risk factor for Takotsubo syndrome after cardiac surgery on univariable analysis, but was not retained as an independent risk factor on multivariable analysis.
Characteristically, Takotsubo syndrome is a transient heart failure syndrome (27), with a mortality rate of 3.2% having been reported in a previous case-summary study (25). The mortality rate of Takotsubo syndrome after cardiac surgery in our study cohort was 3.8% and, thus, was comparable to previously published data. Of note, the mortality rate in the Takotsubo group (3.8%) was similar to that in the control group (7.7%; P = 0.58). Madias reported a low prevalence of diabetes mellitus among patients with Takotsubo syndrome (28). Based on this finding, Madias suggested that diabetic autonomic neuropathy and decreased catecholamine release might have protective effect against Takotsubo syndrome. Madias did report that the prevalence of hypertension in patients with Takotsubo syndrome was comparable to that in the general population. In contrast, in our study, the prevalence of hypertension was lower in the Takotsubo syndrome than control group, while the prevalence of diabetes mellitus was similar between the two groups. In our multivariable analysis, hypertension was identified as having a protective factor against Takotsubo syndrome after cardiac surgery. It is possible that anti-hypertensive medications, such as beta-receptor antagonists, taken before cardiac surgery may lower the risk of Takotsubo syndrome following cardiac surgery. However, data about anti-hypertensive medications prescribed to the patients in our study cohort by their primary-care physician could not be accurately identified and, thus, analysis of the plausible protective role of anti-hypertensive medications was not possible.