# Cardiac Nuclear Imaging Findings in Atypical Variants of Takotsubo Cardiomyopathy
## 4 Discussion and Limitations  
Different studies have shown a decreased tracer uptake at myocardial perfusion imaging during the acute phase of TTC, and its gradual improvement in the subacute and chronic phases [86; 87]. However, most literature data show normal myocardial perfusion during the subacute phase of TTC in hypo-contractile ventricular segments reflecting preserved coronary blood flow and blood flow reserve [88; 89; 90]. The association between normal perfusion and reduced metabolism is commonly known as inverse flow-metabolism mismatch and it is considered the metabolic state of stunned myocardium [91]. According to these findings, stunned myocardium mediated by catecholamine oversecretion seems to play a crucial role in TTC, with transient coronary microvascular dysfunction representing a potentially associated phenomenon secondary to acute catecholamine release, rather than the primary causative mechanism of the disease. Cardiac autonomic innervation is a complex system. To preserve homeostasis, the stress-activated post-ganglionic sympathetic nerve releases norepinephrine into the synaptic cleft, producing a wide range of cardiac effects on the heart rate, blood pressure, and contractility through the interaction with a post-synaptic adrenergic receptor (AR). However, during the acute phase of TTC, high circulating levels of epinephrine and norepinephrine may cause catecholamine toxicity in myocardial cells. Animal studies have suggested that acute catecholamine overload may lead to a stunning of the myocardium [92] and have a negative intoropic action with apical ballooning in rats [93], due to a shift to an inhibitory signal mediated by 82 AR, particularly abundant in the apical region [94]. In addition to the highest density of -AR, the mammalian left ventricular apex shows the lowest density of sympathetic innervation, a combination making it particularly sensitive and vulnerable to exaggerated sympathetic stimulation than the mid and basal segments [95; 96]. The description of the variant forms of TTC sparing the apex might be explained by the interindividual differences in the distribution of sympathetic receptors in the left ventricle, as speculated by [PERSON] et al. [70], as well as by [PERSON] and coworkers in the case series published in 2008 and a year later in a retrospective study [71; 72]. However, as a case of both typical and atypical TTC occurring in the same patient at different periods was reported [97], probably, the pathogenesis of TTC variants cannot be explained only by the individual distribution of AR in the myocardium [81]. The reason atypical variants occur and whether they resemble basic pathophysiology with TTC simply affecting different left ventricular regions still remains a matter of speculation. In this background, cardiac nuclear imaging may improve the current knowledge of the atypical manifestations of this fascinating and still mysterious disease. Given the hypothesis of enhanced catecholamine release secondary to exaggerated sympathetic stimulation as the central causative mechanism of TTC, 123I-mIBG scintigraphy seems to be the most specific diagnostic imaging tool [98; 99]. 123I-mIBG, a structural analog of norepinephrine reflecting sympathetic neuron integrity and function, represents an extremely useful imaging tool for detecting abnormalities in the myocardial adrenergic