Stress-associated neurobiological activity associates with the risk for and timing of subsequent Takotsubo syndrome

Abstract

Aims Activity in the amygdala, a brain centre involved in the perception of and response to stressors, associates with: (i) heightened sympathetic nervous system and inflammatory output and (ii) risk of cardiovascular disease. We hypothesized that the amygdalar activity (AmygA) ratio is heightened among individuals who develop Takotsubo syndrome (TTS), a heart failure syndrome often triggered by acute stress. We tested the hypotheses that (i) heightened AmygA precedes development of TTS and (ii) those with the highest AmygA develop the syndrome earliest. Methods and results Individuals (N=104, median age 67.5 years, 72% female, 86% with malignancy) who underwent clinical 18 F-FDG-PET/CT imaging were retrospectively identified: 41 who subsequently developed TTS and 63 matched controls (median follow-up 2.5 years after imaging). AmygA was measured using validated methods. Individuals with (vs. without) subsequent TTS had higher baseline AmygA (P=0.038) after adjusting for TTS risk factors. Further, AmygA associated with the risk for subsequent TTS after adjustment for risk factors [standardized hazard ratio (95% confidence interval): 1.643 (1.189, 2.270), P=0.003]. Among the subset of individuals who developed TTS, those with the highest AmygA (>mean + 1 SD) developed TTS ∼2 years earlier after imaging vs. those with lower AmygA (P=0.028). Conclusion Higher AmygA associates with an increased risk for TTS among a retrospective population with a high rate of malignancy. This heightened neurobiological activity is present years before the onset of TTS and may impact the timing of the syndrome. Accordingly, heightened stress-associated neural activity may represent a therapeutic target to reduce stress-related diseases, including TTS.

Novel Imaging and Genetic Risk Markers in Takotsubo Syndrome

“…The amygdala activity using [18F] fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDGPET/CT) was measured retrospectively in 104 patients who underwent clinical 18F-FDG-PET/CT imaging, including 41 who subsequently developed TTS and 63 matched controls. Patients with subsequent TTS had higher baseline amygdala activity and, among the patients who developed TTS, those with higher amygdala activity developed TTS about 2 years earlier compared with those with lower level of amygdala activity (97).…”

“…These neuroimaging findings demonstrate structural and functional alterations of stress-related brain networks in patients with TTS even before the acute event, suggesting long-lasting psychological stress. Chronically heightened stress-associated neural activity may hypothetically induce an individual to react to subsequent stressors with a more vigorous neurophysiological response, thus increasing TTS risk (97). Consequently "heartbrain axis" could represent a potential target to reduce TTS risk.…”

Five recurrent episodes of Takotsubo syndrome provoked by various triggers over a period of 7 years: a case report

“… 11 Possibly, the mechanisms of effective combination therapy involve a reduction in sympathetic activity or the suppression of inflammatory reactions through interactions with the renin–angiotensin system. 12 However, a recent study demonstrated that combination therapy lacked efficacy for TTS recurrence. 1 Our case is worthwhile as the heterogeneous TTS recurrences occurred in the same individual.…”

Gender-Related Differences in Chest Pain Syndromes in the Frontiers in CV Medicine Special Issue: Sex & Gender in CV Medicine

“…Sex-differences in brain activation patterns during emotional stimuli have been reported, particularly in the amygdala and ACC, with women demonstrating greater activation during negative emotion ( 56 ). In particular, heightened amygdalar activity appears to be related to increased risk of Takotsubo syndrome, a condition that is often triggered by emotional or physical stress and predominates in women ( 57 ).…”