Scientists in Switzerland have for the first time identified a tangible link between how different areas of the brain communicate with each other, and Takotsubo syndrome (TTS), a rare heart condition called that is also known as “broken heart” syndrome. The team, headed by researchers at University Hospital Zurich, compared magnetic resonance imaging (MRI) brain scans of patients with TTS with those of healthy controls. They found that those parts of the brain that control emotions and motivation, and which are involved in the autonomic regulation of heart function, didn’t communicate well in the TTS patients.

“We found that TTS patients had decreased communication between brain regions associated with emotional processing and the autonomic nervous system, which controls the unconscious workings of the body, compared to the healthy people,” commented Christian Templin, PhD, principal investigator at the University Hospital Zurich InterTAK Registry. “For the first time, we have identified a correlation between alterations to the functional activity of specific brain regions and TTS, which strongly supports the idea that the brain is involved in the underlying mechanism of TTS. Emotional and physical stress are strongly associated with TTS, and it has been hypothesized that the overstimulation of the autonomic nervous system may lead to TTS events.”

Templin is lead author of the researchers’ published paper in the European Heart Journal, which is titled, “Altered limbic and autonomic processing supports brain-heart axis in Takotsubo syndrome.”

This is a Takotsubo heart, showing the typical shape resembling a Japanese octopus trap. [Christian Templin, University Hospital Zurich]
TTS is a rare, potentially fatal cardiac disorder that occurs when sudden weakening of the heart muscle causes the heart’s left ventricle to balloon out at the bottom. The resulting shape is akin to a Japanese octopus trap, the word for which—tako-tsubo—has been adopted as the name for the condition. The symptoms of TTS include chest pains and breathlessness, and the disorder can lead to heart attack and death. Ninety percent of cases occur in women.

TTS was first described in 1990, when accumulating evidence indicated that the condition is triggered by severe emotional distress, including grief, anger, or fear, or by reactions to joyful events, hence its colloquial name, broken heart syndrome.

The University Hospital Zurich researchers and colleagues in Switzerland and the U.K., including both neuroscientists and cardiologists, carried out MRI brain scans in 15 TTS patients from the InterTAK Registry, and another 39 healthy control individuals. The scientists were particularly interested in areas of the brain including the amygdala, hippocampus, and cingulate gyrus, which are involved in controlling emotions, motivation, learning, and memory. The amygdala and cingulate gyrus are also involved in autonomic nervous system control and heart function regulation, while the cingulate gyrus, in addition, plays a role in depression and mood disorders, which TTS patients commonly experience. “We were interested in four specific brain regions that are spatially separate from one another but functionally connected, meaning they share information,” Templin commented.

broken heart syndrom
Brain and heart may be connected in more ways than previously imagined. Here a Japanese octopus trap, from which Takotsubo syndrome derives its name because of the shape of the “broken heart,” is shown in the heart with the connections to the brain.
[Professor Christian Templin, University Hospital Zurich]
Interestingly, Templin’s team had previously demonstrated that TTS patients and healthy controls exhibit structural differences in areas of the brain including the limbic network, which comprises the insula, amygdala, cingulate cortex, and hippocampus, “all of which might contribute to the emotional processing and the autonomic nervous system,” the researchers noted.

The latest comparative study of MRI scans aimed to identify resting-state functional connectivity patterns in TTS patients at the whole-brain level, and in subnetworks of brain regions. The overall findings indicated decreased strength in connectivity (hypoconnectivity) in all of the analyzed networks—including the parasympathetic- and sympathetic-associated networks—and at the whole-brain level. “Reduced functional connectivity reflects a decreased or altered communication between brain regions constituting a subnetwork,” the authors wrote. More specifically, the findings indicated that those brain regions that are believed to control responses to stress communicated less with each other in the TTS patients than they did in the control participants. “Therefore, this decrease in communication could negatively affect the way patients respond to stress and make them more susceptible to developing TTS,” Templin suggested.

“The present study demonstrates that patients with TTS have altered functional connectivity patterns during resting state in comparison to healthy age- and gender-matched controls,” the authors concluded. “Key nodes identified in this study, like the amygdala, hippocampus, and cingulate gyrus, are structures of the limbic system that control emotions, motivation, learning, and memory.” Interestingly, the authors pointed out, the reduced connectivity pattern in TTS patients was evident in similar brain regions to those in which they had previously identified structural alterations relating to TTS.

The team acknowledged that their study has a number of potential limitations, and also pointed out that the heterogenic nature of TTS is suggestive that there are “likely many causes of TTS.” Nevertheless, they state, the findings do indicate that alterations in the function of certain parts of the central nervous system may result in the onset of a TTS event in response to a stressful trigger. “Our findings might represent a neurological substrate involved in TTS and thereby reinforcing the current concept of the involvement of the brain–heart interaction.”

“Of note, this study presents the results of a collaboration between neuroscientists and cardiologists,” commented co-author Jelena Ghadri, PhD, senior research associate at the University Hospital Zurich and co-principle investigator of the InterTAK Registry. “One problem in TTS research is that usually cardiologists only focus on the heart; we believe that approaching TTS in a multidisciplinary way might help to uncover the real nature and causes of this disease. The methods we used are mainly neuroscientific in nature, but the findings we uncovered are, in our view, of major importance for cardiologists in understanding TTS.”

The MRI scans of the TTS patients’ brains were carried out on average about a year after they experienced a TTS episode. The scientists didn’t have MRI scans of the patients’ brains before or immediately after they developed TTS, so it wasn’t possible to conclude whether the decreased brain communication was causal for TTS, or whether TTS may even have caused the reduced communication.

Further studies should be carried out to determine whether there is any causal link, and its direction, Ghadri added. “We hope this study offers new starting points for studying TTS in terms of understanding that it much more than ‘broken heart’ syndrome and clearly involves interactions between the brain and the heart, which are still not fully understood. We are at the beginning of learning more about this complex disorder. Hopefully, one day new findings can be translated into developments in preventive, therapeutic, and diagnostic strategies to improve patient care.”

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