Focus on stroke: Predicting and preventing stroke
There will be about 150 000 strokes in the UK in 2012, among a population of 62 million. Crude arithmetic suggests your chance of having a stroke this year is, therefore, 0.24 per cent. But a variety of factors can make us more – or less – likely to experience stroke. Is it possible to put a number on an individual’s risk? And if you found out you were at high risk, what could you do about it? Michael Regnier investigates.
A blood vessel in the brain is blocked or bursts. Without their blood supply, brain cells are left gasping for oxygen. They die, breaking neural circuits and shutting down brain functions. Every stroke is different but whatever the precise effects are, they begin immediately.
Strokes are sudden but many of the disease processes that precede them take a long time to develop. This is why age is the most clear-cut risk factor for stroke: the chance of blockage or breakage rises with every passing year, so – although it can strike at any age – stroke is much more likely the older we get.
We won’t all have a stroke, though, even if we live to be 100. What makes some people have a stroke early in life while others never experience its often devastating consequences?
Professor Hugh Markus, an academic clinical neurologist at St George’s, University of London, is studying people’s genes to see whether the answer lies in our DNA. A number of single-gene disorders significantly increase the risk of stroke. At St George’s Hospital, Hugh runs the national clinic for people with a condition called CADASIL. Caused by a mutation in a gene called Notch3, it is the most common form of hereditary stroke.
“People who come to us have typically had a stroke, or a history of migraines, for example,” says Hugh. “If their family history of stroke is very strong, we will do genetic tests and offer counselling. We can also do a scan using magnetic resonance imaging (MRI), which can show up patterns of disease associated with CADASIL. Some years ago we identified characteristic appearances on MRI scan and many referrals we receive are now from patients who have had these appearances noted on MRI.
“At the moment, there is no specific treatment for CADASIL, but conventional factors like smoking are still very important: someone with CADASIL who smokes will have a stroke ten years before a non-smoker with CADASIL, while high blood pressure also seems to make the disease progress more quickly. So we give people advice on how to reduce their risk, but often we find just having a diagnosis and information on prognosis is important to patients. When we started, people had sometimes been going round hospitals for years trying to find out what was going on, but now the disease is becoming much better recognised.”
Disorders like CADASIL are rare. Could there be other genes that contribute less starkly to the risk of stroke? Hugh co-led the biggest ever investigation of stroke and genetics, the Wellcome Trust Case Control Consortium 2 (WTCCC2), which involved thousands of patients from across three continents and published its findings in February 2012.
“We identified a completely novel gene associated with stroke: HDAC9,” says Hugh. “There is already a lot of interest in HDAC inhibitors, and some animal models have shown the effect of those inhibitors on stroke, but we now need to find out how it mediates its effects, and see if HDAC inhibitors could really prevent stroke in people.”
Variations in the HDAC9 gene by no means account for all strokes. However, advances in technology mean new tools are becoming available to search more thoroughly for clues. “Our study was a genome-wide association study,” Hugh explains. “It revealed significant associations between genes and disease; markers for further study. Next-generation sequencing, where you can sequence the complete genome, is likely to uncover many more genes involved in influencing the risk of stroke.”
WTCCC2 also showed that different types of stroke have distinct genetics. The study was on ischaemic stroke – the blockages, not the bursts – but by performing detailed imaging to work out what caused each individual patient’s stroke, the researchers could separate the three major subtypes: blockages caused by disease in the large arteries in the neck, blood clots from the heart getting lodged in the brain, and disease of the small arteries in the brain itself.
“WTCCC2 shows that these types of stroke have different mechanisms,” says Hugh. HDAC9 was associated only with stroke caused by large artery blockages, whereas other genes have been associated with the other subtypes of stroke. “This has implications for treatment and suggests there may be treatments that are useful for one type of stroke and not others.
“To a degree, treatment is already personalised. If you have a narrowed artery in the neck, you can have that cleaned out with surgery. But people haven’t really looked at whether drug treatments have different effects on these different types of stroke.
“The HDAC9 association, and other new genetic associations with stroke, may tell us completely new information about stroke that can help us develop better ways to prevent and treat stroke. These are badly needed as stroke remains a major health problem.”
Hugh thinks it is unlikely that we will be able to make accurate predictions about individuals’ stroke risk based on genetics alone in the near future: “For prediction to be important, you have to be able to predict a large proportion of overall disease. At the moment, known genetic risk factors only account for a small proportion of stroke risk: most stroke is multifactorial, involving multiple genes, multiple environmental factors and interactions between the two.”
This interplay between genetics and environment is likely to be behind the significant differences in stroke risk between ethnic groups. UK mortality data show that, compared to white Europeans, Indian-Asian people are about 1.5 times more likely to die of stroke and the risk for African-Caribbean people is doubled. Professor Nish Chaturvedi, principal investigator on the Southall And Brent REvisited (SABRE) study, and her colleague Dr Therese Tillin explain how a unique cohort of Londoners is providing insights into why ethnicity should have such influence on stroke risk.
Twenty years ago, the original Southall and Brent studies compared the health of white Europeans with first-generation migrants from South-east Asia and the Caribbean. Researchers took measurements such as blood pressure and asked the participants for information about their lifestyle. Their health has been followed ever since to see what effect various factors have on certain diseases. SABRE is an opportunity to go back to the participants and see how their lives have changed – including whether or not they have had a stroke, which should shed more light on the ethnic differences in risk.
“Blood pressure is a strong risk factor for stroke,” says Nish. “If you were looking for an explanation of the ethnic differences, you would look first at blood pressure. But ethnic differences in blood pressure do not map to the differences in stroke.” In fact, while African-Caribbeans had the highest blood pressure of the three groups, Indian-Asians had equivalent or even lower blood pressure than white Europeans on average. Other factors, such as alcohol consumption and smoking, which are in any case more favourably distributed in the minority ethnic groups, also failed to account for the different stroke risks. “Everything was stacking up the wrong way round.”
They then looked at diabetes, which is more common in African-Caribbeans and Indian-Asians than in white Europeans. “The original diabetes rates from 20 years ago are the baseline,” explains Therese. “Among people who had no diabetes then, there is not much difference in stroke mortality. But among those with diabetes, there is a large ethnic gradient, even after accounting for other factors.”
Diabetes is a known risk factor for stroke. The mechanism for its effect is not clear, but it could be that it reduces the body’s ability to damp fluctuations in blood pressure. Without damping, there could be greater blood flow through the cerebral artery, increasing resistance and damaging the brain’s fragile small blood vessels.
But why should the size of the effect of diabetes be so different between these ethnic groups? Nish is not sure of the answer, but she is willing to speculate: “There is some evidence that the onset of diabetes occurs at a younger age in African-Caribbeans and Indian-Asians. This might increase their length of exposure to the detrimental effects on stroke risk, or perhaps the effect occurs at a critical time in their development.”
The SABRE analysis so far relates to deaths from stroke. The next step is to look at non-fatal strokes and subclinical disease visible with brain imaging to see whether that yields any additional insights. “The picture is becoming much more complicated than was thought,” says Nish. “But there is a clear emphasis on diabetes and that it could play a role in the increased risk we see in both ethnic minority groups.”
As with the genetics, understanding the contribution to stroke risk made by diabetes and other risk factors could help shed more light on the mechanisms underpinning stroke. In turn, this should lead to better strategies for preventing stroke through primary prevention, which will usually occur at the level of general practice. Doctors can identify people potentially at risk and recommend behaviour changes, such as stopping smoking or drinking less alcohol, and treat conditions like high blood pressure, obesity and diabetes.
The GP’s surgery is not the only opportunity for prevention, however: “In hospital, we see patients who are by definition at high risk because they already have something wrong,” says Professor Martin Brown. Often this means people who have had a stroke or a transient ischaemic attack (TIA, or ‘mini-stroke’), or have other cardiovascular symptoms that make them very likely to have a major stroke. For many of these people, medical or surgical interventions would be beneficial, and this is called secondary prevention.
Martin was one of the first professors of stroke medicine in the UK; today he runs the Stroke Research Group at University College London’s Institute of Neurology. He explains that secondary prevention is a high priority: “We try to prevent another stroke or to stop the disease getting worse.”
Treatments can be general or specific: “In general terms, we treat the risk factors. We treat high blood pressure, try to lower cholesterol and, for ischaemic stroke, stop the patient’s blood from clotting again with an antiplatelet drug – this used to be aspirin but is more likely these days to be clopidogrel. We also advise lifestyle changes such as giving up smoking.
“For the focused treatments,” he continues, “we are looking for diseases we know increase the risk of stroke even further. This requires investigation, which makes it more expensive, so tends to be focused on patients who have already had a stroke or a TIA.”
The diseases they look for vary according to what type of stroke the patient has had. Martin’s research focuses on atherosclerosis, which particularly increases the risk of ischaemic stroke when it narrows the large blood vessels of the neck. “Atherosclerosis is the build-up of cholesterol plaques. As these plaques develop in the carotid and vertebrate arteries, they can reduce the flow of blood to the brain, but the plaques can also become inflamed and rupture, which causes a clot to form in the artery. If the clot breaks up, bits can get lodged downstream in the smaller arteries in the brain, triggering a stroke.
“We can open up these narrowed arteries in the neck with an operation called an endarterectomy, which involves removing the inner lining of the artery where the plaque is formed. Removing the plaque prevents further problems from blood clots forming in the artery, but until the artery lining grows back over the next two weeks or so, there is actually a slightly higher risk of stroke, which then falls back to the level of a normal healthy artery.”
Other procedures used to treat atherosclerotic arteries include using balloons or stents to enlarge the area of narrowing in the artery. “A stent is a wire mesh – like chicken wire,” explains Martin. “A thin catheter is inserted into the artery with the collapsed stent over it. Once in place across the narrowed section, the catheter is removed and the stent opens up a bit like an umbrella.
“Stenting is slightly riskier than endarterectomy because the stent might knock bits off the plaque. But once in place, the body’s cells grow over the stent, incorporating it into the wall of the artery and sealing the plaque off from the bloodstream.”
Because these surgical procedures carry a risk of stroke, the decision to operate is based on the narrowness of the artery. The Medical Research Council European Carotid Surgery Trial (ECST) compared surgery with drug-based treatment some 20 years ago. It showed that endarterectomy was better than aspirin for preventing stroke once an artery had become narrowed beyond a certain threshold.
However, medical treatment has improved since then and different drugs are available – not just clopidogrel for use alongside or instead of aspirin, but also better antihypertensives and statins to lower cholesterol. Martin and his team have therefore started a second ECST to compare today’s surgery with today’s best medical treatment. They will focus on patients with an intermediate or low risk of stroke recurrence.
The new trial only recently began recruiting participants and it will be several years before it yields answers. When the results are in, however, they might lead to a change in the threshold for surgery or the way patients’ risk is assessed. “We use a scoring system and base treatment on the score,” says Martin. “The problem is, we need to test our score in the context of the trial because it is based on the 20-year-old data.
“Hopefully, we can avoid some people having unnecessary surgery or we may say some people need the operation who are currently not getting it. And a particular group where there’s a lot of uncertainty is people who have got carotid narrowing but no symptoms at all. It would be very useful to know whether we should be operating on these patients or not.”
That is something that Alun Davies, professor of vascular surgery at Imperial College London, would also like to know. He is running a trial to improve risk prediction for ‘asymptomatic’ patients with atherosclerosis: “We are trying to identify the high-risk group among them,” he says. “We want to know who would be likely to benefit from surgery, as the criteria for operating seem to be slightly different to symptomatic cases. We currently need to operate on 20 asymptomatic patients to prevent one stroke, as opposed to between seven and ten symptomatic patients.”
People in the asymptomatic group don’t know they are on the path to a stroke until, for example, they happen to have a scan that shows a potentially dangerous atherosclerotic plaque and get referred for further investigation.
Alun explains that his study, called Contrast Ultrasound for Stroke Prediction (CUSP), is assessing whether imaging the plaque using ultrasound can give a better idea of its potential for rupture. “There are many different imaging techniques we could use but ultrasound is quick and relatively cheap, and we can use ‘microbubbles’ to enhance the picture with information about plaque biology.”
Microbubbles are tiny phospholipid shells filled with an inert gas. Injected into the patient, they circulate in the blood where they tend to stick to the endothelial cells lining the blood vessels before being washed out of the system. While in the arteries, they can reveal on an ultrasound scan how active an atherosclerotic plaque is. The hypothesis is that the more activity there is, the greater the risk of a stroke.
“Ultrasound also shows how the blood is flowing,” adds Alun. “You can see the arterial wall, you can see whether there’s an ulcer on the plaque and you can get a feel for whether there is a high lipid content, which also seems to be associated with greater risk.”
The aim of CUSP is to stratify asymptomatic patients into higher and lower risk groups. “What everybody is working towards is trying to personalise risk for the patient,” says Alun. “So that you can look a patient in the eye and say, ‘The best we know, your risk of having a stroke is x per cent. Whereas if we operate, your risk will be y.’ We will need some sort of predictive model to take account of the patient and the plaque’s features – we think this will be useful for patients trying to decide about surgery.
“I think there will be a way of stratifying these patients, as we have done with those who have just had a TIA,” he concludes. “I’m not 100 per cent sure that microbubbles will be the answer, but I definitely think we can develop and validate an ultrasound technique to stratify them within a model.”
It seems that the closer someone is to having a stroke, the more accurately we will be able to assess their risk. This, in turn, will help them to decide on the most appropriate treatment.
For those at low risk of stroke, it may be that the interplay between our genes and our environment will always be too complex to say exactly how likely we are to have a stroke. But we already know the most important risk factors that we can watch for and do something about: high blood pressure, high cholesterol, obesity and, in some cases, diabetes.
Continuing research into genetic and environmental risk factors will help shed light on the chronic, progressive but usually hidden disease processes that predispose some of us to having a stroke. Although the outcome of such research may not be a precise percentage risk for each of us, it should lead to new policies and interventions that will help to lower the incidence of stroke, reduce the number of people dying of stroke, and leave fewer people living with the disabilities it causes.
Notes and references:
International Stroke Genetics Consortium (ISGC), Wellcome Trust Case Control Consortium 2 (WTCCC2) et al. (2012). Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nature genetics, 44 (3), 328-33 PMID: 22306652
Tillin T, Forouhi NG, McKeigue PM, Chaturvedi N, & SABRE Study Group (2012). Southall And Brent REvisited: Cohort profile of SABRE, a UK population-based comparison of cardiovascular disease and diabetes in people of European, Indian Asian and African Caribbean origins. International journal of epidemiology, 41 (1), 33-42 PMID: 21044979
European Carotid Surgery Triallists’ Collaborative Group (1991). MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. European Carotid Surgery Trialists’ Collaborative Group. Lancet, 337 (8752), 1235-43 PMID: 1674060
WTCCC2 and SABRE are funded by the Wellcome Trust.
Image credits: Wellcome Images
This article is part of the Wellcome Trust’s Focus on stroke, a series of articles, interviews and videos running throughout May 2012, which is the Stroke Association’s Action on Stroke Month.
For more information on stroke, visit the Stroke Association’s site or call its helpline on 0303 303 3100. If you or someone with you is suspected of having a stroke, call the emergency services immediately.