Peripheral physiologic responses to acute psychological stress in Takotsubo syndrome: A systematic review and meta-analysis

Takotsubo syndrome (TTS) can be triggered by emotional stress, particularly in postmenopausal women, the primary patient group. However, the psychobiological mechanisms remain elusive. This systematic review aimed to synthesize the literature on peripheral physiological responses to acute psychological stress in TTS patients compared to controls. A meta-analysis was performed when data allowed. The review followed PRISMA guidelines and was registered on PROSPERO (CRD42023393222). PubMed, Embase, APA PsycInfo, Cochrane CENTRAL, ClinicalTrials.gov, and WHO ICTRP were searched from inception to February 2023, with PubMed re-searched in May 2024. Eligible studies involved adult TTS patients, included a control group, used standardized acute psychological stress induction, and measured at least one peripheral physiological marker pre- and post-stress. Risk of bias was assessed with the BIOCROSS tool. Meta-analysis used the R package metafor. Of 5752 records screened, 13 studies (k = 13) comprising 176 TTS patients and 197 controls were included. In the meta-analysis, TTS patients had higher post-stress plasma norepinephrine levels [Hedges' g= 0.50, 95 % CI (0.17, 0.84), p = 0.003, k = 5] and a marginally significant increase in stress-induced norepinephrine [g= 0.28, 95 % CI (-0.05, 0.61), p = 0.09, k = 5] compared to controls without established cardiovascular disease. They showed a smaller left ventricular ejection fraction change [g= -0.44, 95 % CI (-0.87, −0.02), p = .043, k = 3]. The systematic review additionally supported endothelial/vasomotor dysfunction (k = 3), wall motion abnormalities (k = 2), and impaired myocardial perfusion (k = 2) in TTS patients. TTS patients may exhibit distinct physiological responses to psychological stress, particularly in catecholamine levels and cardiac function. Limited studies and unclear bias reduce evidence strength. • TTS patients show significantly higher post-stress plasma norepinephrine levels. • Acute stress leads to reduced left ventricular ejection fraction in TTS patients. • TTS patients exhibit stress-induced endothelial dysfunction and vasomotor issues. • Stress-induced myocardial perfusion abnormalities are more common in TTS patients. • Findings support SNS hyperreactivity as a key mechanism in TTS pathophysiology.