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As has been widely reported in the past, TTC usually is precipitated by an acute episode of emotional and or physiological stress.1–4 Recently, diverse clinical features of TTC have been observed, suggesting the possibility of ≥1 clinical phenotype, according to triggering stressors.5–8 However, a limited amount of literature currently exists on the similarities and differences of clinical features between patients with TTC according to preceding stressor patterns.9
To the best of our knowledge, this is one of the largest studies investigating the similarities and differences of clinical features, laboratory parameters, and electrocardiographic and echocardiographic findings between patients with TTC presenting with and those without stressors. In the present study, the E group had significantly higher prevalence of chest pain and palpitation, whereas the P group had significantly higher prevalence of cardiogenic shock; higher hs-CRP, CK-MB, and NT-proBNP levels; and higher LVEDP and LVESD, but lower LVEF. The E group had lesser prevalence of the apical ballooning pattern than other groups. The P group required more frequent hemodynamic support and had significantly longer ICU and in-hospital stays.
In contrast with the previously published data,5–8 our study showed that physical stress, rather than emotional stress, was the predominant triggering event for TTC. Tako-tsubo cardiomyopathy associated with sepsis and respiratory failure without obstructive coronary artery disease was already reported,6–8 and several hypotheses have been proposed, including catecholamine-mediated cardiotoxicity, spasm of the epicardial and/or microvascular coronary circulation, and endothelial-cell dysfunction.18–20 It was also surprising to know that TTC could occur during or after uneventful elective procedures or surgery performed under regional or general anesthesia.
A notable finding in our study was that 24 (18%) of 137 enrolled patients had a history of cancer at the index hospitalization for TTC. Our finding may support the results of recently published reports showing 23.6% of patients with TTC had cancer, which greatly exceeds the expected prevalence of cancer in age-matched populations in the United States (8.2%), Germany (11.2%), and all European countries combined (7.8%).21,22 Burgdorf et al suggested increased basal sympathetic tone in patients with cancer may be associated with susceptibility to TTC with additional stress, and that paraneoplastic mediators may directly alter cardiac adrenoreceptors.21,22 In the present study, most clinical features were similar among the subgroups. The overlapping clinical features in all these presentations may suggest that myocardial stunning resulting from emotional stress may share a common mechanism with that from physical stress or without triggering stressors, which has been described after subarachnoid hemorrhage and stroke and which is believed to be mediated by catecholamine.23
Our study showed that the E group had significantly higher prevalence of chest pain and palpitation than the other groups. Some studies reported that catecholamine-mediated myocardial injury has been observed postmortem in people who died under terrifying circumstances such as violent assault, suggesting that catecholamine may be an important link between emotional stress and cardiac injury.23 Therefore, we reasoned that these subjective symptoms predominant in the E group might reflect the emotionally stressful event triggering an excessive release of catecholamine, resulting in the presentation of these subjective symptoms; these patients appear to be more vulnerable to sympathetically mediated myocardial stunning.
Interestingly, in our study, the P group had a significantly higher prevalence of cardiogenic shock, but lower LVEF than the other groups. Also, the P group had significantly higher hs-CRP, peak CK-MB, NT-proBNP, and LVEDP levels than the other groups. These observations may suggest that patients with physical stressors have more cardiovascular impairment and that perhaps other factors such as significant underlying comorbidities contribute to myocardial stunning. The possible explanations may include myocardial stunning, inflammation, and microvascular spasm in physically stressed TTC patients.1,23,24 Therefore, we reasoned that patients with physical stressors had the greater extent of affected myocardium, and cardiac markers such as CK-MB may reflect this extent of affected myocardium. On the other hand, our patients with preceding emotional stressors had relatively preserved myocardial function with higher LVEF and lower LVEDP on initial presentation. These findings may suggest a transient catecholamine-induced myocardial stunning in this group.
A remarkable finding of our study was that the P and N groups had a higher prevalence of the typical ballooning pattern, whereas the E group had a higher prevalence of the inverted ballooning pattern. The hypothesis is that the extent of affected myocardium could be smaller and wall-motion abnormalities resolve more rapidly in the E group than in the P group. Classic TTC involves the apical and/or midventricular segments, whereas the apical segment is spared in inverted TTC.25,26 It has also been suggested that wall-motion abnormalities in inverted TTC resolve more rapidly than in TTC.27,28 It is therefore reasonable to suppose that differences of myocardial insults with triggering stressor patterns may effect different ballooning patterns between the 2 groups. Further research is required to study our hypothesis about these differences.
In contrast with a recently published study showing the emotional-stress group was younger than the idiopathic/physical-stress group,9 our data reported that the groups did not differ significantly in terms of age. The possible hypothesis for this discrepancy is that racial differences may affect emotional stressor and susceptibility to TTC with aging. Also, this discrepancy may be related to differences in activated sympathetic tones after a stressful event according to racial differences.
Notably, in our study, 51 (37%) of 137 enrolled patients needed treatment with inotropics during the index hospitalization. Moreover, the P group had a significantly higher prevalence of inotropic use and diuretic use, higher frequency of ICU stay, and had significantly longer durations of in-hospital and ICU stays than the E group. These findings are in contrast with results of the previous studies showing the use of inotropic agents, particularly in patients with cardiogenic shock, may increase the LV outflow tract pressure gradient and worsen cardiogenic shock in patients with TTC.4,29 It seems likely that cardiogenic shock due to heart failure is treated with standard therapies such as inotropes and intra-aortic balloon pump, although a cautious trial of intravenous fluids and β-blockers may help by reducing pressure gradients, thereby reducing the LV outflow obstruction in the absence of shock. Based on findings of aforementioned studies,18–20 in addition to the results of the present study, we reasoned that clinicians should monitor physically stressed TTC patients carefully for hemodynamic compromise. In our study, in-hospital and follow-up cardiac mortalities were 0% and 0% respectively, in TTC patients, irrespective of stressor patterns. These findings may emphasize that the prognosis of TTC itself may be excellent if a meticulous therapeutic strategy under careful monitoring is performed in these physically stressed patients, particularly in hemodynamic instability.
In the present study, the overall mortality (9%) was relatively higher than in previous studies.1–4 However, the overall mortality associated with TTC itself was 0%. It was comparable with results of published reports in other areas of the world.1–4 During the follow-up period of 5.7 years, most patients (50%) died of malignancy in our study. According to aforementioned reports, malignancies may be associated with TTC, potentially as a result of paraneoplastic phenomena.21,22 These findings may indicate that patients with TTC have an excellent prognosis in the absence of significant underlying comorbidities such as malignancy or stroke.
There are some limitations that should be considered in our study. First, this was a retrospective analysis. Second, the results of our study may be limited by the relatively small number of patients. However, this is one of the largest studies yet published to compare clinical characteristics, echocardiographic findings, and NT-proBNP levels between TTC subgroups in detail. Third, we did not perform systemic investigations, such as catecholamine measurements, magnetic resonance imaging, viral antibody titers, or pathology. Because TTC is a kind of exclusion diagnosis, some patients with other diseases, such as myocarditis, may be misdiagnosed in our study. However, diagnosis of TTC on the basis of clinical presentation and characteristic wall-motion abnormality is realistic and often used in many studies.