- This retrospective study analyzed 18F-fluorodeoxyglucose positron emission tomography/computed tomography brain scans of 41 individuals who subsequently experienced Takotsubo syndrome (TTS) and 63 matched controls
- Stress-associated neural activity (Stress-ANA) was derived as the ratio of metabolic activity in the amygdala (a brain region that plays a key role in the stress response) vs. activity in brain regions involved in counter-regulating stress (i.e., the temporal lobe or the prefrontal cortex)
- Stress-ANA was significantly higher in individuals who developed TTS than in controls (0.98 vs. 0.95; P= 0.04)
- Elevated Stress-ANA was sometimes present years before TTS onset and may represent a previously unrecognized TTS risk factor
- Stress-ANA may eventually be a useful target when prescribing pharmacologic interventions, stress reduction measures and other non-pharmacologic interventions to individuals at high risk of TTS
For years, a heart–brain connection has been proposed to underlie the development of Takotsubo syndrome (TTS, also called stress cardiomyopathy and popularly called "broken-heart syndrome"). Chronically elevated stress-related neural activity may "prime" an individual to mount a more vigorous neurophysiologic response to subsequent stressors, thereby increasing the risk of TTS.
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Functional MRI studies of individuals who previously experienced TTS have supported this hypothesis by demonstrating altered neural connectivity in the amygdala and other key stress-related brain regions. However, that research couldn't determine whether the alterations predated TTS or were a consequence of it.
Azar Radfar, MD, nuclear cardiology fellow, Shady Abohashem, MD, Cardiovascular Imaging fellow at the Cardiovascular Imaging Research Center, and Ahmed Tawakol, MD, co-director of the Cardiac MR PET CT Program in the Cardiology Division at Massachusetts General Hospital, and colleagues have now analyzed 18F-fluorodeoxyglucose positron emission tomography/computed tomography scans made on individuals who subsequently experienced TTS.
In European Heart Journal, the team reports additional evidence that increased stress-associated neural activity (Stress-ANA) predates the development of TTS. This activity does appear to prime the limbic system to respond more vigorously to acute stressors, thus increasing TTS risk.
The researchers identified 41 patients with a diagnosis of TTS who had undergone 18F-FDG-PET/CT imaging at Mass General between 2005 and 2019. These patients experienced TTS a median of 0.9 years later (IQR, 0.1–4.1 years).
Baseline Stress-ANA of the TTS patients was compared with that of 63 controls who were matched on age, sex, race, health care usage and oncologic history. 86% of the total cohort had malignancy, a known risk factor for TTS.
The primary method of calculating Stress-ANA was the ratio of amygdalar metabolic activity and metabolic activity in the temporal lobe, which regulates the stress response.
- In a model adjusted for TTS risk factors, mean Stress-ANA was higher in individuals who developed TTS than in controls (0.98 vs. 0.95; P=0.04)
- Higher Stress-ANA (greater than the mean plus one standard deviation) was associated with greater odds of developing TTS (OR, 1.64; P=0.04) and remained significant in multivariable models
- In time-adjusted Cox regression analysis, Stress-ANA independently predicted TTS, with each standard deviation increase in AmygA linked to a 64% increase in TTS risk (P=0.003)
- Among patients who eventually experienced TTS, those with higher Stress-ANA developed the syndrome about two years before those with lower Stress-ANA (P=0.03)
Hope for Improved Care
Stress-associated neural activity may eventually be a useful target when prescribing pharmacologic interventions, stress reduction measures and other non-pharmacologic interventions to individuals at high risk for TTS. The same might be true for patients at risk of many other stress-related chronic diseases, including atherosclerosis.
Recurrent TTS is associated with considerable morbidity and mortality, so secondary prevention is equally important.
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