Exploratory Review of the Takotsubo Syndrome and the Possible Role of the Psychosocial Stress Response and Inflammaging

Abstract

Takotsubo syndrome (TTS) is a cardiomyopathy that clinically presents as a transient and reversible left ventricular wall motion abnormality (LVWMA). Recovery can occur spontaneously within hours or weeks. Studies have shown that it mainly affects older people. In particular, there is a higher prevalence in postmenopausal women. Physical and emotional stress factors are widely discussed and generally recognized triggers. In addition, the hypothalamic-pituitary-adrenal (HPA) axis and the associated glucocorticoid-dependent negative feedback play an important role in the resulting immune response. This review aims to highlight the unstudied aspects of the trigger factors of TTS. The focus is on emotional stress/chronic unpredictable mild stress (CUMS), which is influenced by estrogen concentration and noradrenaline, for example, and can lead to changes in the behavioral, hormonal, and autonomic systems. Age- and gender-specific aspects, as well as psychological effects, must also be considered. We hypothesize that this leads to a stronger corticosteroid response and altered feedback of the HPA axis. This may trigger proinflammatory markers and thus immunosuppression, inflammaging, and sympathetic overactivation, which contributes significantly to the development of TTS. The aim is to highlight the importance of CUMS and psychological triggers as risk factors and to make an exploratory proposal based on the new knowledge. Based on the imbalance between the sympathetic and parasympathetic nervous systems, transcutaneous vagus nerve stimulation (tVNS) is presented as a possible new therapeutic approach.

Keywords: Takotsubo syndrome; central autonomic nervous system; glucocorticoids; hypothalamic-pituitary-adrenal axis; inflammaging; psychosocial stress; psyshological stress; sympathetic nerve action.

Figure 1

The potential contribution of chronic stress and inflammaging to TTS susceptibility. A novel concept for TTS development, involving underlying chronic stress, glucocorticoid resistance, altered immune response culminating in inflammaging, and altered control CAN and βAR signaling. The integration of these effects might enhance susceptibility to TTS following an acute trigger. CUMS: chronic unpredictable mild stress, E2: estradiol, TEST: testosterone, GC/NE: glucocorticoid/norepinephrine, HPA: hypothalamic-pituitary-adrenal, GR: glucocorticoid-receptor, HRT: hormone replacement therapy, CAN: central autonomic nervous system, LHS: limbic-hypothalamic system, NTS: nucleus tractus solitarii, RVLM: rostral ventrolateral medulla, PBN: parabigeminal nucleus, and TTS: takotsubo syndrome. Arrow up = upregulated, Arrow down = downregulated.