**6. Pathophysiology**

There have been several hypotheses postulated in contemporary literature, insinuating the complex pathophysiological evolution of the Takotsubo syndrome from either possible coronary microvascular dysfunction, coronary artery spasm, catecholamine-induced myocardial stunning, acute left ventricular outflow obstruction, acute increased ventricular afterload, myocardial microinfarction or abnormalities in cardiac fatty acid metabolism [10]. The potential for excessive hypothalamic-pituitary-adrenal axis (HPA) gain and epinephrine release in the event of a stressful trigger, and the corresponding response of the cardiovascular system and the sympathetic nervous system to the following surge in levels of catecholamines is the driving theory currently attributed to the pathophysiological evolution of TTS [10, 18].

The consistent presence of microvascular dysfunction in TTS patients has been effectively elucidated in the studies by Uchida et al. (report of extensive endothelial cell apoptosis on myocardial biopsy) and Afonso et al. (demonstrated circulatory disturbance on myocardial contrast echocardiography). A detailed study describing coronary microvascular dysfunction in patients diagnosed with the Takotsubo syndrome suggested abnormalities consistent with endothelium-dependent vasodilation, excessive vasoconstriction and impairment of myocardial perfusion [19]. Additionally, myocardial biopsy of these patients showed regions with contraction band necrosis, inflammatory cell infiltration and localised fibrosis [20]. These changes have been attributed to direct catecholamine toxicity on cardiac muscle cells [21]. Kurisu et al. demonstrated using the TIMI frame count method, which impaired coronary blood flow corresponding to LV wall-motion abnormalities immediately after onset of TTS and improved on the resolution of the LV dysfunction, giving credence to the theory of coronary microvascular impairment.

In another study, 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 possible role of systemic inflammation mediated by catecholamine-induced proinflammatory cytokines like TNF-alpha and interleukin-6 has been used to explain the myocardial oedema observed in cardiac MRI [23].

Recent studies conducted by Wittstein et al. (proving catecholamine levels are two to three times greater in patients with TTS as compared to those with myocardial infarction) and Lyon et al. (proposing '*stimulus trafficking*' as the cause of decline of myocyte contractile function in TTS patients) give support to the theory that catecholamine-induced cardiotoxicity plays a significant role in the development of the Takotsubo syndrome [17]. It is currently hypothesised that the pathophysiology of TTS could be dictated by changes in beta-adrenergic receptor (AR) signalling [24–26]. A switch in intracellular signal trafficking from Gs protein to Gi protein (signalling through the β2AR) mediates a negative inotropic effect, greatest at the apical myocardium where the density of β-adrenoceptors is the highest. This mechanism of stimulus trafficking is triggered by excessively high levels of catecholamines and has been used to explain the acute apical cardio-depression in TTS [26].
