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Tako-Tsubo cardiomyopathy (TTC) is characterized by rapid regeneration of contractile dysfunction. From recent studies it is known that excessive catecholamine levels due to emotional or physical stress might play a central role. After sympathetic activation, the PIK3/AKT pathway is a key regulator of many cellular responses, including cytoprotective effects. Thus, the purpose of this study was to investigate whether the PIK3/AKT pathway plays a pivotal role in TTC.A total of 16 consecutive patients diagnosed with TTC were studied. Left ventricular biopsies were taken during the acute phase and after functional recovery. Specimens were examined by quantitative RT–PCR and western blotting. Representative genes of the PI3K/AKT pathway (PIK3-R1, PTEN, GSK3β, mTOR, PP2A, eIF4E) were compared with left ventricular controls from non-transplanted healthy hearts. PI3K expression was increased during the acute phase and after functional recovery. AKT protein levels were unaltered, but phosphorylation significantly increased during the acute phase. Both PTEN (PI3K antagonist) and PP2 (unspecific phosphatase) were down-regulated. Phosphorylation of the PI3K/AKT downstream target mTOR was increased, while expression of both GSK3 isoforms was decreased. The Bax/Bcl2 ratio was increased in the acute and recovery phases.PI3K/AKT signalling is activated in TTC. This activated cell survival cascade might protect cardiomyocytes from cell death and also contribute to rapid regeneration in TTC.