Heightened Brain Activity With Stress Tied to Takotsubo Syndrome

Pauline Anderson

March 29, 2021

A new study is providing what researchers are calling "unique and important insights" into potential mechanisms contributing to the Takotsubo syndrome (TTS) also known as "broken heart syndrome."

Results from the retrospective case-control study suggest that chronically heightened stress-associated neurobiological activity may affect both the risk for, and timing of, subsequent TTS.

Dr Ahmed Tawakol

"The findings suggest that this stress-related acute syndrome doesn't start simply upon exposure to a stressor, that preexisting brain wiring predates it by quite a while," study author Ahmed Tawakol, MD, director of nuclear cardiology and co-director of the Cardiovascular Imaging Research Center at Massachusetts General Hospital and Harvard Medical School, Boston, told Medscape Medical News.

The study highlights the need to "pay close attention" to stress reduction in patients who develop TTS as they may face ongoing problems, said Tawakol.

"We should test whether reducing stress leads to health benefits in this subpopulation of patients who develop this syndrome," he added.

The study was published online March 26 in the European Heart Journal.

TTS is a relatively rare heart failure syndrome often triggered by acute emotional or physical stressors. It usually resolves, but not always, with some patients suffering lingering effects, said Tawakol.

"We have learned that it's not completely benign; those who have TTS are more likely to develop other cardiovascular complications including recurrences of TTS."

From a large patient data registry, researchers identified 41 cases of TTS and 63 controls matched for age, sex, race, and health status. All participants had suspected malignancy and had undergone whole-body fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scanning at Massachusetts General Hospital from 2005-2019.

The median age of the study population was 67.5 years, 72% were female, and most (89.4%) were White. In the TTS group, four patients had recurrence of this condition.

About 86% of all participants had a malignancy. The authors noted that controls were "carefully" matched to those who developed TTS by type and stage of malignancy as well as malignancy treatment.

Individuals with TTS and controls had similar baseline characteristics, except autoimmune diseases were more common in the TTS group (29.3% vs 6.3%; P = .002).

The median follow-up was 2.5 years after imaging.

To examine stress-related neural activity, researchers used what they called "AmygA," or the ratio of amygdalar metabolic activity divided by activity of regulatory brain regions.

The amygdala, which is part of the limbic system, is very active in the stress response, noted Tawakol. "The more activity in the amygdala, the greater the physiologic response to a stressor."

But he pointed to the importance of a balance between the "pro-stress" amygdala and the "anti-stress" upper control levels of the brain, notably the prefrontal cortex.

In this study, female sex, diabetes, and chronic kidney disease were associated with higher AmygA (>mean + 1 SD).

The study linked AmygA to risk of TTS. In an adjusted logistical regression analysis, higher baseline AmygA was associated with greater odds of developing TTS (standardized odds ratio [OR] 1.64; 95% CI, 1.03 - 2.61; P = .036).

A time-adjusted Cox regression analysis showed that AmygA independently predicted subsequent TTS (standardized hazard ratio [HR] 1.643; 95% CI, 1.189 to 2.270; P = .003) after adjustment for TTS risk factors.

Thus, each standard deviation (SD) increase in AmygA was associated with a 64% increase in TTS risk, which remained significant through other multivariable adjustments.

Those with the highest AmygA developed TTS about 2 years before those with lower AmygA (P = .028) after imaging.

That higher AmygA predates TTS is somewhat surprising, said Tawakol.

"In the past, we used to conceptualize TTS as a syndrome that occurs to people who are unlucky enough to encounter an absolutely dreadful stressful event, the classic one being the unexpected death of a spouse or child, and that would lead to this massive stress response resulting in this heart abnormality."

Interestingly, the insults that primed patients to develop TTS were not those dreadful events, said Tawakol. "Some people developed TTS as result of an endoscopy or a foot fracture, so yes, those are stressful but not the once-in-a-lifetime stressors."

People who are most predisposed to develop TTS may have greater amygdala activity, said Tawakol. "In response to any given stressor, the physiologic output that results from that is more severe."

It's possible that with higher amygdala activity, "the less dramatic the stressor needs to be and so it happens earlier as a result," said Tawakol.

The research suggests that stimulation of the stress response that results in high sympathetic nervous system activity is one potential mechanism leading to TTS.

Another possible mechanism is inflammation. Researchers observed a significant association between autoimmune disorders such as lupus and TTS.

Tawakol stressed the importance not only of having a moderately active amygdala but also a robust prefrontal cortex. "The higher your prefrontal cortical activity, the better control you have of your stress response."

He used the example of a door slamming. "If you have an active amygdala and it's not counterbalanced by other areas, your brain would be jolted and you would start running through a whole bunch of dreadful possibilities — is it a car crash, am I in danger, could it be a gunshot?"

But if that same amygdala activity was counterbalanced by a robust prefrontal cortex, "you would have a quick signal saying, 'I got this, I categorized it as something benign, don't worry about it, move on,' " he said.

Although, he added, a "completely quiet amygdala" is not necessarily a good thing on its own. "That means you're not perceiving potential threats."

The study also showed a significant relationship between higher amygdala activity and bone marrow or leukopoietic activity.

"The bone marrow gives us an insight into production of immune cells," said Tawakol. "When the stress portion of the brain is activated, the sympathetic nerves coming from the brain trigger the production and release of immune cells by the bone marrow."

As bone marrow produces different types of blood cells involved with carrying oxygen, mounting immune responses, and clotting blood, stress-related brain activity may influence the activity of cells that affect cardiovascular health.

The authors note that bone marrow activity was not associated with TTS risk in the study.

Although the researchers adjusted for clinically diagnosed depression and anxiety, researchers were unable to assess perceived stress or evaluate for subclinical psychiatric symptoms.

They were also unable to study all brain regions involved in the stress response. Other important regions — eg, insular cortex, anterior cingulate cortex, and hippocampus — should be evaluated in future studies, they note.

For his part, Ankur Kalra, MD, medical director of clinical research and staff interventional cardiologist at Cleveland Clinic, Cleveland, Ohio, praised the study and the "great hypothesis" it investigated using a "sizeable repository."

"The way the study was conducted was very neat and the investigators were really smart in thinking they could look at FDG PET scans that were available to them retrospectively," Kalra told Medscape Medical News.

While there may have been confounding and selection bias as per any retrospective study, Kalra thought the researchers did a good job of matching controls to cases. "They sort of meticulously did everything they could do to match the two cohorts."

That the amygdala activity ratio was higher in patients who developed TTS makes sense, and sheds important light on the heart–mind–body connection, said Kalra.

He noted that meditation and mindfulness practices have been shown to lower this amygdala activity ratio. He also referred to a recent study he and his colleagues authored, published March 11 in the European Heart Journal, that underlines the importance of spirituality in cardiovascular medicine.

The study received support from the National Institutes of Health and the American Heart Association. Support also came from the Harvard Medical School Osher Center and from A. Curtis Greer and Pamela Kohlberg. Tawakol reported receiving institutional grants from Genentech for research outside the submitted work.

Eur Heart J. Published online March 26, 2021. Full text

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