Brain Differences Suggest Therapeutic Targets in Takotsubo

January 17, 2023

A new study has identified differences in the brain present in patients with the cardiac disorder Takotsubo syndrome vs control scans, which may lead to new therapeutic targets.

Takotsubo syndrome is an acute heart failure cardiomyopathy mimicking an acute myocardial infarction (MI) in its presentation, but on investigation, no obstructive coronary disease is present. The syndrome, which mainly affects women, typically occurs in the aftermath of intense emotional or physical stress and has become known as "Broken Heart syndrome."

The mechanism by which emotional processing in the context of stress leads to significant cardiac injury and acute left ventricular dysfunction is not understood. So, the current study examined both structural and functional effects in the brain in patients with Takotsubo syndrome to shed more light on the issue.

"The abnormalities in the thalamus-amygdala-insula and basal ganglia support the concept of involvement of higher-level function centers in Takotsubo syndrome, and interventions aimed at modulating these may be of benefit," the authors conclude.

The study was published online January 11 in JACC Heart Failure.

Lead author Hilal Khan, MB BCh, BAO, from the University of Aberdeen, United Kingdom, explained to | Medscape Cardiology that patients with Takotsubo syndrome have a substantial drop in heart function and show an apical ballooning of the heart.

It is a relatively newly defined condition and was first described in 1990 in Japan, and so named because the heart was thought to resemble the Takotsubo pot used by Japanese fishermen to trap octopus.

Although uncommon, the condition is not rare. Khan estimates that about 1 in 20 women with suspected MI turn out to have Takotsubo syndrome, with cases increasing in times of global stress such as in the recent pandemic.

While patients tend to recover in a few weeks and the pumping function of the heart usually returns to normal, there are some long-term cardiac complications including a reduction in global longitudinal strain, and patients have similar long-term outcomes as those with MI.  

"It is believed that these cardiac changes may be triggered by changes in the brain caused by emotional stress, so we wanted to look at this more closely," Khan said.  

There have been a couple of studies published previously looking at brain changes in Takotsubo syndrome, but they haven't reported patients in the acute stage of the condition and they havent compared the patients to controls, he noted.

For the current study, the researchers looked at brain scans for 25 acute Takotsubo patients and in 25 controls matched for age, gender, comorbidities, and medications. All the patients and controls were examined using the same MRI scanner in the same hospital.

"This is the largest structural and functional brain study of acute Takotsubo syndrome patients compared with matched control subjects," Khan said.

The researchers looked at many different factors including brain volume in different regions, cortical thickness, small vessel disease, and functional and structural connectivity to try and obtain a complete holistic view of the brain.

Key findings were that patients with Takotsubo syndrome had smaller brain volumes compared with matched controls driven by a reduction in brain surface area. In contrast, the insula and thalamus regions were larger.

"A reduction in brain volume could be caused by inflammation; this is often seen in depression," Khan commented.  

The researchers also found that certain areas of the brain had a reduction in functional connectivity, particularly the thalamus — the central autonomic area of the brain, which regulates the autonomic nervous system — and also the insula region, which is also involved in the autonomic regulation of the heart.

They suggest that there may be a loss of parasympathetic inhibition in Takotsubo syndrome, which would fit the theory that Takotsubo brings with it a surge of catecholamines, which could injure the heart.

Reduced functional connectivity was also seen in parts of the basal ganglia, abnormalities of which have been associated with an increased risk of both arrhythmias, and in the amygdala, similar to patients with a tendency to catastrophize events.

The other observation was that there appeared to be an increase in structural connectivity in certain areas of the brain. 

"Structural pathways seem to be increased but functional connectivity was reduced, so while physical pathways are enhanced, they don't seem to be doing anything," Khan said. "We don't know why this occurs, or if this has happened over time and made the brain and heart more vulnerable in some way."

One possibility is that under a significant emotional stress, the brain may divert function from some areas to others to be able to cope, and that this results in reduced functioning in areas of the brain responsible for regulating the heart, Khan suggested.  

"We believe this study confirms that the brain is involved in Takotsubo syndrome, and we have identified markers in the brain that may be contributing to the condition," he said.

The researchers are planning to further study these markers and whether it might be possible to modulate these changes with various interventions such as exercise or mindfulness.

"We believe there is some interface between the brain changes and the impact on the heart. We don’t think it is just the release of catecholamines that causes damage to the heart. We think there is something else happening as well," Khan commented.  

It is also posisble that the hearts of patients with Takotsubo syndrome are predisposed in some way and more vulnerable to this condition occurring. 

"It will be important to obtain a greater understanding of the triggers and identify people who may be vulnerable," Khan noted. "Around 10% of individuals who experience Takotsubo syndrome will have a recurrence, so we need to try and develop preventative strategies to reduce this."

He suggested that possible preventive or therapeutic approaches may involve interventions such as exercise or mindfulness.

This work was supported by National Health Service Grampian Endowment. The authors report no relevant financial relationships.

JACC Heart Failure. Published online January 11, 2023. Full text

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