Identifying the relationship between mental stress and physical health, including cardiovascular disease

In June 2016, the German national soccer team was preparing to take on Slovakia in the European Championships. While thousands of fans were excited about this crucial match in host France, a group of German scientists were watching with interest.

Their aim is to investigate the link between short-term, acute mental stress and physical consequences such as heart attacks and strokes. Cardiovascular disease, related to such medical emergencies, is the leading cause of death worldwide, claiming 18 million lives per year.

Risk triggers

Hendrik Sager, a professor of cardiology at the Technical University of Munich in Germany, said that while there have been advances in treating risk factors such as diabetes and obesity, much is still unknown about stress-related triggers.

“This urgent need for action motivated us to investigate the contribution of atypical risk factors, such as psychological stress,” Sager said.

He led a research project investigating how acute psychological stress can lead to severe coronary artery disease, called STRATO, which is due to finish in January 2024 after six years.

The Germany vs Slovakia soccer match took place a year and a half before the start of STRATO in February 2018. Germany won 3-0.

A group of scientists, including Sager, arranged to take blood samples from 35 healthy fans before and immediately after the game, as part of the information gathering for STRATO, which will analyze the results.

When the team tested blood samples, they found a rapid decline in white blood cells, called leukocytes.

Plaque attack

Further investigating, the scientists found that inducing mental stress in mice by restricting their movement had a similar effect: Using cell-tracking techniques, the team found that the lost white blood cells were relocated to tissues, including the heart.

This can cause fatty deposits called plaque in the arteries to rupture, leading to a heart attack or other coronary artery diseases. Causes of plaque buildup include a high-cholesterol diet, smoking, obesity, and diabetes.

“Plaque rupture occurred twice as frequently in stressed mice compared to non-stressed mice,” Sager said, “providing a fundamental biological mechanism for how acute stress causes cardiovascular disease.”

He thinks that redistribution of white blood cells to the heart, lungs and skin may have evolved in our human ancestors to improve their chances of survival when under threat, by providing more oxygen to organs and priming damaged tissues to regenerate.

STRATO also looked at measures to reduce stress-related effects.

The team found that pre-treating mice with a specific anti-inflammatory antibody achieved this by blocking a molecule that helps white blood cells move.

Early influences

On the other hand, there are long-term associations between early childhood stress (ELS) and conditions later in life.

Another project trying to unravel these connections is called EarlyCause, and is scheduled to finish in four and a half years, on June 30, 2024.

EarlyCause researchers have focused on three mental and physical illnesses associated with ELS: depression, coronary artery disease and diabetes.

These stressors include maternal depression during pregnancy, child abuse, parental loss, socio-economic poverty, etc. A 2022 study found that more than half of children may be experiencing some form of ELS.

EarlyCause is run by Karim Rekadir, a professor at the University of Barcelona in Spain who studies artificial intelligence in healthcare.

Knowledge about how stress affects life in later life is limited, in part because it’s difficult to pin down links to diseases that can develop decades later, he said.

“It’s not necessarily intuitive that suffering psychological adversity in childhood would lead to cardiovascular disease 50 years later,” Recadir says, “and it’s not easy to study.”

Surprising discovery

Researchers on the project conducted experiments in mice, rats and cells, analysed existing human data and employed machine learning techniques.

The study uncovered biological pathways that may link ELS with subsequent disease, including impaired glucose response, altered metabolism and tissue inflammation, and changes in gut bacterial composition.

One finding is that people suffering from ELS are more likely to develop multiple symptoms rather than just one.

“This is surprising because intuitively it would seem easier to have just one illness,” Recadir said, “and it also suggests that early life stress has powerful long-term mental and physical effects.”

The findings add to the urgency of tracking the impact of ELS, and the team built a machine learning model to track people at risk.

“These models are promising,” Recadir said. “They showed that we can bring all the data together to do risk profiling. We need to look further at prevention through screening, identifying people at risk, and monitoring.”

The presence of multiple symptoms in people who experience ELS suggests a close link between the causes, which Recadir said could help address multiple causes at once.

“In some ways, this is good news because it means we may be able to attack a single mechanism rather than attacking the disease individually,” he said.