In a study of 300 people, those with higher activity in the amygdala were more likely to develop cardiovascular disease - and sooner than others.
Stress could be as important a risk factor as smoking and high blood pressure, the US researchers said.
Heart experts said at-risk patients should be helped to manage stress.
Emotional stress has long been linked with an increased risk of cardiovascular disease (CVD), which affects the heart and blood vessels - but the way this happens has not been properly understood.
This study, led by a team from Harvard Medical School, points to heightened activity in the amygdala - an area of the brain that processes emotions such as fear and anger - as helping to explain the link.
The researchers suggest that the amygdala signals to the bone marrow to produce extra white blood cells, which in turn act on the arteries causing them to become inflamed. This can then cause heart attacks, angina and strokes.
As a result, when stressed, this part of the brain appears to be a good predictor of cardiovascular events.
But they also said more research was needed to confirm this chain of events.
The Lancet research looked at two different studies. The first scanned the brain, bone marrow, spleen and arteries of 293 patients, who were tracked for nearly four years to see if they developed CVD. In this time, 22 patients did, and they were the ones with higher activity in the amygdala.
The second very small study, of 13 patients, looked at the relationship between stress levels and inflammation in the body.
It found that those who reported the highest levels of stress had the highest levels of amygdala activity and more evidence of inflammation in their blood and arteries.
Dr Ahmed Tawakol, lead author and associate professor of medicine at Harvard Medical School, said: "Our results provide a unique insight into how stress may lead to cardiovascular disease.
"This raises the possibility that reducing stress could produce benefits that extend beyond an improved sense of psychological wellbeing.
What does the amygdala do?
It's the part of the brain that prepares you for fight or flight, becoming activated by strong emotional reactions.
The amygdalae (because there are two of them - one on each side of the brain) are almond-shaped groups of cells located deep within the medial temporal lobes of the brain.
In humans and animals, the amygdala is linked to responses to both fear and pleasure.
The term amygdala - which means almond in Latin - was first used in 1819.
Dr Tawakol added: "Eventually, chronic stress could be treated as an important risk factor for cardiovascular disease, which is routinely screened for and effectively managed like other major cardiovascular disease risk factors."
Commenting on the research, Dr Ilze Bot, from Leiden University in the Netherlands, said more and more people were experiencing stress on a daily basis.
"Heavy workloads, job insecurity or living in poverty are circumstances that can result in chronically increased stress, which in turn can lead to chronic psychological disorders such as depression."
Emily Reeve, senior cardiac nurse at the British Heart Foundation, said reducing the risk of heart disease and stroke from stress normally focused on controlling lifestyle habits such as smoking, drinking too much alcohol and overeating - but this should change.
"Exploring the brain's management of stress and discovering why it increases the risk of heart disease will allow us to develop new ways of managing chronic psychological stress.
"This could lead to ensuring that patients who are at risk are routinely screened and that their stress is managed effectively."