oxygen debtLimiting the damage caused by lack of oxygen. A little bit of angina may actually be good for you. |
Heart attacks caused by coronary heart disease kill over 100 000 people in the UK every year. The only way to prevent these deaths is by restoring an oxygen supply to the heart – and quickly. Michael Marber, Professor of cardiology at St Thomas’ Hospital, London, is looking to the heart itself for ways to limit the amount of damage caused by a lack of oxygen, and so reduce this death toll.
When the heart becomes starved of oxygen – a condition known as ischaemia – patients experience crushing chest pain, called angina. Angina is a common symptom of atherosclerosis – ischaemic heart disease caused when fatty deposits build up on the inner walls of the coronary arteries, limiting blood supply to the heart. During severe and prolonged periods of ischaemia, heart muscle cells begin to die causing irreversible damage. When the damage is extensive it results in a type of heart attack called myocardial infarction.
“It is this irreversible injury to the heart that is the most common cause of death in the Western world,” asserts Professor Marber.
Ironically, however, mild ischaemia can protect the heart against further damage. “There is a lot of anecdotal evidence to show that people who have angina before they have a heart attack do much better than those who have an unheralded heart attack,” explains Professor Marber.
And people with ischaemic heart disease who experience angina when they exercise often find that if they have a short rest and then start exercising again, they can push themselves further than if they hadn’t had the episode of angina. This phenomenon is known as ‘warm-up’ angina, and sometimes ‘first hole’ angina, because it often happens at the first hole of a round of golf.
“If you have a very brief period of ischaemia or mild ischaemia that starves the heart of blood, but is not severe enough to kill the cardiac cells, then your body switches on a biological programme that makes the heart resistant to further ischaemia – it’s a form of adaptation,” says Professor Marber. However, the effect is only temporary and cannot be maintained indefinitely.
Professor Marber is keen to understand how the heart adapts during ‘warm-up’ angina to protect itself against further ischaemia, and hopes that therapies can be developed that will mimic the effect of ischaemic preconditioning, and slow the rate of cell death. He and colleagues have used a variety of approaches to understand the events that take place during preconditioning. Ischaemia can be monitored in patients using electrocardiography (ECG). The drop in oxygen tension within cells, brought about by the ischaemia, leads to changes in electrical activity which can be detected on an ECG.
In clinical studies, Professor Marber has monitored heart patients during regimented periods of exertion to track the effects of ischaemia on the heart, and improvements caused by ischaemic preconditioning. He has found that medications commonly used to reduce angina and high blood pressure, such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers, do not protect the heart by the same mechanism as ischaemic preconditioning, although some do enhance the effect.
Mechanism
But pinning down the mechanism involved in ischaemic preconditioning is not easy, not least because the heart also uses other means to protect itself against damage. For example, as well as the main arteries that supply the heart with blood, most people have additional, smaller blood vessels surrounding the heart which can step in and provide a supply if the main coronary artery becomes blocked. Most of us are probably born with at least some of these collateral vessels, and when people get ischaemia, the number of collaterals increases and helps protect the heart against damage.
“People who are fortunate enough to have very good collateral vessels have enough blood supply to keep the heart alive. And even when the coronary artery becomes blocked, they don’t have a heart attack,” explains Professor Marber.
But ischaemic preconditioning happens very quickly after the first ischaemic event, often within five minutes, so there is little time for the heart or surrounding tissue to produce new proteins. This observation has led Professor Marber to look at the proteins that transmit signals within the heart muscle cells following ischaemia.
“We are interested in the kinase signalling cascades that are activated during the first period of ischaemia, and which could give rise to protection,” he says. “We have found that during the first episode of ischaemia, you activate a kinase called P38 MAP kinase. But interestingly, once it has been activated, P38 MAP becomes much more difficult to activate again later on, suggesting that it may be involved in preconditioning. When P38 MAP kinase is activated, it triggers a cascade of events that can lead to cell death. So making the cell resistant to further activation can protect cells from damage.”
Professor Marber’s team is using viruses that express abnormal forms of the kinase to infect cells and explore what happens to this activation pathway during prolonged ischaemia. “We are certain that activating this kinase during prolonged ischaemia increases injury,” he says.
P38 inhibitors are already being tested in large-scale clinical trials, for inflammatory conditions such as rheumatoid arthritis and Crohn’s disease. However, as Professor Marber points out, the P38 MAP kinase activation pathway is important in many situations, and is involved in the way the body responds to stress. It has a good side as well as a bad side. And although in preconditioning, early activation of this protein is important because it prevents subsequent activation, Professor Marber warns, “you can see that as a therapeutic target it is going to be quite complicated”.