The Takotsubo Syndrome (TTS) is as an acute and usually reversible from of heart failure characterized by a transient dysfunction of the left ventricle [1, 2]. The TTS patient presents with clinical features such as acute chest pain and dyspnea, bearing some similarity to the patient presenting with an acute myocardial infarction or an acute coronary syndrome (ACS) [3]. An increase in cardiac troponin and creatine kinase levels as well as electrocardiogram (ECG) changes on admission suggesting ST-segment elevation in precordial leads adds to the confusion in early diagnosis. The absence of significant coronary stenosis on coronary angiography, which could correlate with this presentation, and the history of an emotional or physical trigger, leads to the potential diagnosis of TTS [3, 4]. This non-ischemic syndrome has also alternatively been labeled as a stress- or stress-induced cardiomyopathy, an apical ballooning syndrome, or ‘broken heart syndrome’ [4‐8].

The classical pattern of left ventricular (LV) morphology in TTS, present in almost 50–80% of all patients, is the apical variant, which is characterized by apical ballooning of the LV at end-systole. Other morphological presentations include those defined by a predominantly hypokinetic circumferential base (inverted Takotsubo variant), or a hypokinetic circumferential mid ventricle (mid LV variant), or demonstrating focal variations [9‐13].

The pathophysiology of TTS has been well-debated, however is still poorly described. The influence of an acute catecholaminergic surge contributing to some form of myocardial stunning has been hypothesized by several researchers [14]. Stressful triggers could potentially contribute to an increased hypothalamic-pituitary-adrenal axis (HPA) gain and catecholamine release. This resulting catecholamine surge possibly directs a pathological response from the cardiovascular as well the sympathetic nervous system and serves as the basis for the evolution of TTS [15, 16].

This interesting correlate, naturally, has far-reaching clinical implications. The therapeutic use of catecholamines has been routinely advocated in cases of circulatory compromise, however, its use in the setting of TTS could have potential drawbacks. Extrapolating this thought, our study attempts to explore the hither to poorly understood pathophysiological mechanisms involved in the TTS and determine if external catecholamines contribute to an adverse clinical outcome already compromised by the initial insult.

The principal foundation of this study was to determine the role and influence of catecholamine therapy in the treatment of the hemodynamically unstable TTS patient. At the outset, patients receiving catecholamine support showed higher degrees of circulatory and cardiac compromise, and the course of disease was often complicated by the occurrence of different TTS-associated complications. This group of patients also demonstrated poorer in-hospital outcomes and had higher long-term mortality rates as compared to the group of patients not receiving any catecholamine support therapy. It could therefore be inferred that circulatory support in the form of catecholamines entails a poorer outcome for the TTS patient. A pertinent question arises when debating the role of catecholamines exacerbating the mortality risk in such a clinical scenario solely on the basis of the pathophysiology of the syndrome. All patients, irrelevant of diagnosis, requiring catecholamine support constitute a clinically compromised group, however, do TTS patients in circulatory or cardiac shock suffer from additional drawbacks due to this line of management? Our results indicate that contemporary circulatory support drugs like catecholamines additionally exacerbates the risk of mortality in a TTS patient. This study is probably the first of many to follow, that has attempted to express this distinct correlation. Although, many studies have attributed some form of catecholamine toxicity leading to the pathophysiological evolution of TTS, we shall explore this line of discussion further, considering the potential impact on current treatment strategies.

A detailed research of recently published literature highlights the several hypotheses which have been postulated to explain the pathogenesis of TTS. These mechanisms essentially entail the possibility of coronary microvascular dysfunction, coronary artery spasm, catecholamine-induced myocardial stunning, acute LV outflow obstruction, acute increased ventricular afterload, myocardial microinfarction or abnormalities in cardiac fatty acid metabolism influencing the development of TTS [15].

A common link serving these several theories can be construed with the consistent demonstration of some form of microvascular dysfunction among all TTS patients. The research work conducted by Uchida et al. could successfully exhibit the presence of extensive endothelial apoptosis in myocardial biopsies [18] while Afonso et al. demonstrated circulatory disturbances in myocardial contrast echocardiography [19]. Abnormalities associated with endothelium dependent vasodilatation, excessive vasoconstriction and impairment of myocardial perfusion have been associated with coronary microvascular dysfunction seen in TTS patients [20]. The additional demonstration of regional contraction band necrosis, inflammatory cell inflammation and localised fibrosis, all attributed to direct catecholamine toxicity, further corroborates this theory [17, 21]. Interesting results interpreted from the research of Morel et al. suggested that an increase in C-reactive protein levels and white blood cell counts corresponded to increased levels of catecholamines in TTS patients [22]. The raised levels could in theory initiate a systemic inflammation mediated by cytokines like TNF-alpha and interleukin-6, explaining the observation of myocardial oedema in cardiac MRI [23]. In animal models of TTS, as prepared by Paur et al., the use of high bolus doses of catecholamines has simulated LV apical ballooning [24]. Additional studies by Wittstein et al., proving increased levels of circulating catecholamines in TTS patients as compared to those with myocardial infarction, as well as the theory of “stimulus trafficking” (involving a switch in intracellular signal trafficking from Gs protein to Gi protein) proposed by Lyon et al. have all given credence to the hypothesised pathogenic role of catecholamines in the development of TTS [24‐26].

Although, these above-mentioned studies effectively hint at a definitive pathophysiological role played by catecholamines in the evolution of the syndrome, they fall short of explaining the potential effects of exogenous catecholamines in exacerbating a case of existing TTS.

A detailed analysis of our published research in this respect revealed that in-hospital events as well as short- and long-term mortality rates among TTS patients diagnosed with a significantly reduced LVEF on admission were significantly higher [27, 28]. We also showed that rates of in-hospital events and short- as well as long-term mortality rates were significantly higher in TTS patients suffering from arrhythmias such as atrial fibrillation [29, 30]. Although, such clinical scenarios do place the TTS patient at the worse end of the spectrum, it does not effectively explain the additional deleterious effects observed when patients received exogenous catecholamines as a form of therapy. An extrapolation of our data suggests reduced LVEF and use of positive inotropic agents as independent predictors of adverse outcome. A plausible explanation for this observation is perhaps the reactivation of catecholamine receptors or their downstream molecular pathways in the acute phase of TTS, which exacerbates the effects of the syndrome.

Our study has significant clinical implications. The essential role of catecholamines in the treatment of circulatory compromise has been consistently validated in the past, however, its use in TTS patients is now certainly questionable. Considering the pathophysiology of the syndrome, it would be pertinent to avoid any sort of catecholamine therapy for such patients. The Heart Failure Association of the European Society of Cardiology has recommended the avoidance or withdrawal of exogenous catecholamines as they could probably prolong or exacerbate the acute phase of the syndrome by activation of catecholamine receptors or their downstream molecular pathways [31]. It is for this reason that experts have suggested the early use of left ventricular assist device (LVAD) or extracorporeal membrane oxygenation (ECMO) as a bridge to recovery in highly unstable patients. Although treatment with levosimendan in this scenario is controversial, the absence of mechanical support may necessitate its use in certain scenarios [15].

This study clearly highlights the pitfalls associated with catecholamine use in patients suffering from circulatory compromise. The observation that most patients did not noticeably profit from this line of management and consistently suffered from poorer clinical outcomes with higher long-term mortality rates cements further support to recently postulated hypotheses and current recommendations for clinical management.

This study equivocally suggests that TTS patients receiving catecholamine therapy show higher grades of circulatory and cardiac compromise, have poorer in-hospital outcomes and demonstrate higher long-term mortality rates in comparison to patients not receiving any form of catecholamine support. Although, these patients could in effect be suffering from a severe form of TTS, the interplay between the several mechanisms involved in the pathogenesis of this syndrome dictates the planning of therapeutic strategies precluding exogenous catecholamine use.