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.

Keywords: 18F-FDG-PET/CT; Amygdalar activity; Stress; Takotsubo syndrome.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Figures

Relationship between stress-associated neurobiological activity on 18F-FDG-PET/CT imaging and risk for subsequent Takotsubo syndrome. 18F-FDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography/computed tomography; TL, temporal lobe; TTS Takotsubo syndrome; vmPFC, ventromedial prefrontal cortex.

Figure 1

Consort diagram for the selection of cases and controls. ESC-HFA, European Society of Cardiology-Heart Failure Association; FDG PET/CT, fluorodeoxyglucose positron emission tomography/computed tomography; HCM, hypertrophic cardiomyopathy; MGH, Massachusetts General Hospital; RPDR Research Patient Data Registry; TTS, Takotsubo syndrome.

Figure 2

Amygdalar activity among subjects with and without subsequent Takotsubo syndrome. (A) Axial 18F-FDG-PET/CT of the amygdala shows increased uptake in a patient with (right) vs. lower uptake in a patient without (left) subsequent TTS. Amygdalar activity is adjusted for regulatory TL or ventromedial prefrontal cortex (vmPFC) activity. (B) Between-group differences in amygdalar activity in models adjusted for TTS risk factors are shown. Individual values are shown. Mean and 95% confidence intervals (error bars) are depicted. SUV, standardized uptake value; TL, temporal lobe; TTS, Takotsubo syndrome; vmPFC, ventromedial prefrontal cortex.

Figure 3

Hypothesized neurobiological pathway linking stress to Takotsubo syndrome. Individuals with a higher ratio of amygdalar to regulatory activity are primed to have a heightened response upon encountering subsequent acute stressors, resulting in greater activation of the sympathetic and immune system and increased Takotsubo risk.