Monday June 23 2014
Stress may cause inflammation of the blood vessels
"Stress is already known to be bad for the heart, but now scientists have discovered why it is so harmful," The Times reports.
A new US study now offers a plausible model of how chronic psychological stress could lead to heart damage. It involved both mice and junior doctors.
Researchers checked the blood of a small group of doctors after a week at work in intensive care. After a week of this stressful work, their white blood cell count had increased.
Similarly, when mice were exposed to chronic stress (tilting their cage for an extended period of time), they also showed increased levels of white blood cells.
This finding is of interest and possible concern. Previous research suggested inflammatory white blood cells might be involved in the process of causing the rupture of fatty atherosclerotic plaques in the arteries of people with heart disease, which causes a heart attack.
However, this research is very far from providing conclusive proof that stress leads to the development of heart disease, or directly causes heart attacks.
Where did the story come from?
The study was carried out by researchers from Harvard Medical School in the US and the University Heart Center in Germany, and was funded by the US National Institutes of Health and Deutsche Forschungsgemeinschaft.
It was published in the peer-reviewed medical journal, Nature Medicine.
The Daily Mail's topline suggestion was that "groundbreaking research" provides proof, but this "proof" is far from definitive. Only later on in the article does the newspaper explain that the only human element to the study involved examining the blood cell counts of a small sample of medical staff exposed to chronic stress.
None of these people had a heart attack or stroke, and a change in their white blood cell count is not proof that they were more likely to develop heart disease or have a heart attack. Directly attributing stress as the cause of these changes in their white blood cell count is even harder to prove.
What kind of research was this?
This was a laboratory study that aimed to look at the association between psychosocial stress and atherosclerosis, where a fatty build-up of cholesterol and other cellular material leads to hardening and narrowing of the arteries.
When atherosclerosis develops in the arteries that supply the heart muscle, this is known as coronary heart disease.
The researchers looked at the effect stress has on the white blood cells of the immune system. They did this by analysing blood samples from a small number of medical staff exposed to stressful situations, as well as examining the immune cells of mice exposed to stress.
A heart attack is caused when atherosclerotic plaques rupture or break apart, leading to a clotting process that can then completely block the artery. This cuts off the oxygenated blood supply to an area of heart muscle.
The chest pain of angina often develops in situations when the heart is trying to work faster (when exercising, for example) and so needs more oxygen, but it cannot get enough oxygen because of these blockages in the arteries. The pain is the result of the muscle being starved of oxygen.
Triggers of angina can therefore include not only physical activity, but also emotional stress such as anger, as this can cause the heart rate to speed up.
However, a plaque rupture causing a heart attack can happen at any time and will not necessarily be linked to any trigger.
This scientific study is loosely concerned with stress and plaque ruptures, though it did not directly look at coronary heart disease or heart attacks.
Rather, it looked at whether stress could alter the activity of the hematopoietic stem cells, which give rise to all other blood cells. This includes:
- red blood cells, which carry oxygen
- platelets, which are involved in blood clotting
- white blood cells, which form the immune system (the researchers were particularly interested in these)
The theory was stress may be associated with an increase in white blood cells levels, possibly because of an increase in the activity of hematopoietic stem cells.
The researchers say previous research has suggested the infiltration of atherosclerotic plaques with certain inflammatory white blood cells may be involved in the process of plaque rupture, and so lead to a heart attack.
What did the research involve?
This research involved both human and animal study.
In the first part of the study, the researchers recruited 29 medical residents (equivalent to registrar grade [specialty trainee] doctors in the UK) working in a hospital intensive care unit. As you can imagine, this is a challenging, fast-paced work environment that frequently involves the responsibility of life-or-death decisions.
The researchers asked the doctors to complete the Cohen's Perceived Stress Scale (a widely used method of assessing self-reported levels of stress) both on and off duty. At the same time, the researchers also took blood samples to look at their white blood cell count.
The second part of the study involved mice. The researchers exposed mice to different levels of chronic stress in behavioural experiments to see what effect this had on their white blood cell count. These stress tests included tilting the cage at an angle for an extended period of time and periods of isolation in a confined space followed by crowding.
The researchers wanted to see whether any increase in white blood cell count was actually being caused by an increase in the activity of the hematopoietic stem cells. To do this they examined samples of the mice's bone marrow.
The researchers next investigated whether any increase in hematopoietic stem cell activity could be being caused by the stress hormone noradrenaline, which is involved in the "fight or flight" response.
Noradrenaline is a very similar hormone to adrenaline, with very similar functions, although they are not identical chemicals.
A final part of their study involved looking at mice genetically engineered to develop atherosclerosis.
What were the basic results?
The researchers found the medical residents' perception of stress was, not surprisingly, higher when they were working compared with when they were off duty.
Comparing blood samples taken on and off duty, they also found that they had higher numbers of certain white blood cells (neutrophils, monocytes and lymphocytes) after they had spent one week working in intensive care.
When the researchers further explored the theory in mice, they found that they similarly demonstrated an increase in levels of certain white blood cells (neutrophils and monocytes) when they were exposed to stress in behavioural experiments.
There was also increased activity of hematopoietic stem cells in the bone marrow of stressed mice. The researchers found noradrenaline levels increased in the bone marrow of stressed mice compared with non-stressed control mice. This suggests the hormone may be involved in increasing hematopoietic stem cell activity.
When the researchers carried out further tests in stressed mice genetically engineered to lack noradrenaline receptors, these mice didn't demonstrate the same increases in stem cell activity, suggesting that they were "protected" from stress.
The researchers then looked at mice genetically engineered to develop atherosclerosis, exposing them to six weeks of chronic stress. They found stress was, as expected, associated with increased stem cell activity and increased numbers of certain white blood cells.
When they examined their heart blood vessels in the laboratory, they found the atherosclerotic plaques were infiltrated with increased numbers of white cells.
How did the researchers interpret the results?
The researchers conclude that chronic stress interferes with the production of blood cells, and has interactions with the immune system and the process of atherosclerosis.
They say that with their observations in mice reflecting those in humans, "These data provide further evidence of the hematopoietic system's role in cardiovascular disease and elucidate a direct biological link between chronic variable stress and chronic inflammation".
This research investigates the widely held perceived wisdom that psychological stress is associated with coronary heart disease.
It found 29 medical residents working in a stressful intensive care unit setting had increased levels of white blood cells, which form part of the immune system. The researchers also found exposing mice to chronic stress similarly increased their levels of certain white blood cells.
When they examined the bone marrow of stressed mice, they found this increase in the number of white blood cells seemed to be mediated by an increase in the activity of hematopoietic stem cells, which produce all other types of blood cells.
In further study of the mice, the researchers found evidence the chemical noradrenaline (very similar to adrenaline) seemed to be responsible for this increased stem cell activity. They also found there was an increase in white blood cells in the fatty plaques of stressed mice predisposed to coronary artery disease.
Overall, these observations in mice and humans provide a plausible model of how chronic stress may lead to increased hematopoietic stem cell activity.
This in turn may lead to an increased white blood cell count. These white blood cells may possibly then infiltrate the fatty plaques of coronary heart disease (if they have built up), leading them to rupture and cause a heart attack.
However, there are a lot of maybes:
- We don't know what these people's white cell counts looked like in the longer term over the full duration of their working life.
- We do not know whether the activity of stem cells in their bone marrow was responsible for the slight increase in white cell levels. If it was, we do not know whether stress hormones were directly responsible for this activity.
- As far as we know, none of these participants actually had heart disease. If fatty atherosclerotic plaques were present in the heart arteries of these people, we do not know whether an increase in white blood cells would actually be involved in the process of causing these plaques to rupture and so cause a heart attack.
- We also don't know whether the elevation of white blood cells as a result of chronic stress could be involved in the development of heart disease in the first place. Still, the most well-established risk factors for the development of atherosclerotic plaques are high cholesterol, smoking and high blood pressure, in addition to unmodifiable factors such as being male, increased age and hereditary factors. A person's white blood cell count does not have a firm association with the development of heart disease.
- These results do not alter the well-established association between emotional stress and coronary heart disease. In people who have atherosclerotic plaques built up in their heart arteries, emotional stress, like physical activity, causes an increase in heart rate and so an increased demand for oxygen in their heart muscle. The blood cannot flow past the blockages in the heart arteries well enough to meet the oxygen demands of the muscle, which causes angina pain in people with heart disease.
Overall, this is a valuable scientific study that furthers our understanding of how stress – through white blood cell count – could potentially be involved in plaque rupture, which causes heart attack.
However, the study is far from conclusive. Other lifestyle risk factors for heart disease, most notably high cholesterol and smoking, are well established.
Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.