Fig 2: A proposed mechanism of takotsubo syndrome (TTS). (a) ß-adrenoceptors (ARs) signaling including G protein-coupled receptor kinase 2 (GRK2) and ß-arrestin2 under physiological catecholamine concentrations in cardiomyocyte, which mirrors the state in the normal control group. (b) ß-ARs signaling under supraphysiological catecholamine concentrations in cardiomyocyte. GRK2 and ß-arrestin2 are overexpressed and subsequently phosphorylation of cyclic-AMP response element binding protein (CREB) is decreased by the inactivation of protein kinase A (PKA) signaling. The reactive oxygen species (ROS) is also produced. GRK2 and ß-arrestin2 translocate to the cell membrane, where they are thought to trigger receptor internalization, G-protein uncoupling in ß1- and ß2-ARs, and Ga protein switching from stimulatory Gas to inhibitory Gai in ß2-AR. These protective reactions of ß-ARs against catecholamine excess and ROS production are associated with some of the mechanisms of developing left ventricular hypokinesis in the TTS heart. AC: adenylyl cyclase, cAMP: cyclic adenosine monophosphate, ATP: adenosine triphosphate.

Fig 3: Localization of G protein-coupled receptor kinase 2 (GRK2), ß-arrestin2, and 8-hydroxy-2'deoxyguanosine (8-OHdG) in two patients with takotsubo syndrome who underwent endomyocardial biopsy in both the acute and recovery phases. Micrographs showing immunofluorescence stainings of GRK2 and ß-arrestin2, and immunohistochemical staining of 8-OHdG in the acute and recovery phases. Arrowheads (yellow) indicate positive signals for GRK2 and ß-arrestin2 on the cell membrane, and Arrowheads (red) indicate 8-OHdG-positive nuclei.