Alteration of β-Adrenoceptor Signaling in Left Ventricle of Acute Phase Takotsubo Syndrome: a Human Study

Abstract

Accumulating evidence indicates alteration of the β-adrenoceptor (AR), such as desensitization and subtype switching of its coupling G protein, plays a role in the protection against catecholamine toxicity in heart failure. However, in human takotsubo syndrome (TTS), which is associated with a surge of circulating catecholamine in the acute phase, there is no histologic evidence of β-AR alteration. The purpose of this study was to investigate the involvement of alteration of β-AR signaling in the mechanism of TTS development. Left ventricular (LV) biopsied samples from 26 patients with TTS, 19 with normal LV function, and 26 with dilated cardiomyopathy (DCM) were studied. G protein-coupled receptor kinase 2 (GRK2) and β-arrestin2, which initiate the alteration of β-AR signaling, were more abundantly expressed in the myocardium in acute-phase TTS than in those of DCM and normal control as indicated by immunohistochemistry. The percentage of cardiomyocytes that showed positive membrane staining for GRK2 and β-arrestin2 was also significantly higher in acute-phase TTS. Sequential biopsies in the recovery-phase for two patients with TTS revealed that membrane expression of GRK2 and β-arrestin2 faded over time. This study provided the first histologic evidence of the involvement of alteration of β-ARs in the development of TTS.

Relationship between Heart Disease and Liver Disease: A Two-Way Street

“…The exposure of myocardium to large concentrations of circulating catecholamines during LT makes the heart susceptible to adverse events including multivessel epicardial vasospasm [71]. In addition, the altered adrenergic and Gs protein signaling pathways that are commonly found in heart tissue of cirrhotic patients have been suggested to contribute in TTC physiology [72].…”

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“…Location and the extent of wall motion abnormalities in TTS may be explained by the distribution of the β2-AR [ 18 ]. More recently, we demonstrated in vivo evidence of β-AR alteration [ 19 ]. Left ventricular biopsy samples from patients with TTS demonstrated more abundantly expressed G protein coupled receptor kinase 2 (GRK2) and β-arrestin2, both of which are known to desensitize β-AR, than in samples from dilated cardiomyopathy.…”

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“…Specifically, L41Q polymorphism of GRK5, one of the two isoforms predominant in the heart, makes patients susceptible to TTS . An interesting study showed that GRK2 and β‐arrestin 2 expression in the myocardium was higher in TTS than in dilated cardiomyopathy or controls in the acute phase, supporting the concept that β‐adrenergic receptors on the cell membrane are modified by GRK2 and β‐arrestin 2, confirming their role in the development of LV dysfunction in TTS …”