Each year our medical review panels carefully assess the many applications we receive from the teams in the hospitals and universities around the UK needing grants to help them progress their work into understanding, diagnosing and treating heart disease.
Heart Research UK is a national charity which spends its funding on research across the country, which means what is raised locally is used to help hearts near you.
Novel and Emerging Technologies (NET) Grant (PhD studentship) - Prof David Firmin and Dr Andrew Scott, Royal Brompton Hospital and Imperial College London
This project will develop an advanced MRI technique that can provide information relating to the cell structure in thin heart muscle tissue, which is a feature of many heart diseases. This technique may provide earlier diagnosis, new information on how diseases affect the heart and novel insights into treatments.
Diffusion tensor MRI is a unique, well-established and safe technique which is used to examine connections in the brain. In the heart, this technique can be used to provide information on the arrangement of muscle cells, which could provide earlier diagnosis and new insights into the many diseases affecting the heart. This team has recently used such MRI techniques to look at changes in the heart muscle as the heart is beating, and has studied how this is abnormal in patients who have a disease which causes thickening of the heart muscle. However, due to the movement of the heart when it beats and as people breathe, diffusion tensor MRI in the heart is difficult. Images must be collected during a short period of the heart beat where there is minimal movement while the patient holds their breath. This limits the detail that can be provided with these techniques and means that they cannot be used in patients with thinned heart muscle, for example after a heart attack.
Professor Firmin’s team also has considerable experience of using a technique known as spiral MRI which is a very efficient way to collect image information and is very resilient to the problems usually caused by movement. In this PhD project, diffusion tensor and spiral MRI techniques will be combined to produce a technique which will give greater detail, and provide reliable and accurate information on the microscopic structure of the heart muscle, for example in cases of thinned heart muscle after a heart attack. Initial work by the team has shown that this combination of techniques has potential, and the project will build on this, aiming to improve the detail shown in the images and the reliability of the method. The combined MRI techniques will be tested in a group of healthy volunteers and compared to existing techniques before applying them to the hearts of patients who have had a heart attack.
This technique also has the potential to be used to study other conditions where the heart muscle is thinner than normal, for example dilated cardiomyopathy where the heart muscle is stretched and thinned. As well as new insights into the way these diseases affect the heart, it is hoped that it will also provide earlier diagnosis of some conditions and be used to monitor the response of the heart muscle to treatment.
Novel and Emerging Technologies (NET) Grant - Prof G André Ng, University of Leicester
This project aims to develop a simple, accurate and cost-effective test, to predict which patients are at risk of sudden cardiac death and whose lives could be saved by implanting an ICD.
Sudden cardiac death (SCD) is responsible for over three million deaths per year worldwide and is frequently caused by lethal heart rhythm disturbances. These deaths could be prevented with implantable cardioverter defibrillators (ICDs) – devices similar to pacemakers which detect life-threatening heart rhythms and deliver therapy or a shock to the heart to restore normal rhythm.
However, choosing the right patients for ICDs can be extremely difficult. Patients who are thought to be ‘high-risk’ may have ICDs implanted without making use of them, while most cases of SCD occur in a large population regarded as ‘low-risk’. The current tests to measure risk of SCD are inadequate, and balancing the risk of SCD against the potential harm and cost of unnecessary ICD treatment can be guesswork.
The electrocardiogram (ECG) is a simple everyday test performed to record the rhythm and electrical activity of the heart, and Professor Ng’s team has developed two new tests based on the ECG, for measuring the risk of SCD.
The tests involve recording the ECG while performing a series of tests on the heart and the data is then used to work out numerical values of cardiac risk. They have already shown these tests to be effective in predicting which patients are at high risk of SCD in a series of small studies at Leicester.
Building on the earlier work, this project will look at the predictive value of these tests in larger numbers of patients which is necessary before the tests can become routine clinical practice.
The study will recruit 440 patients from 11 of the leading specialist cardiac centres in the UK. Suitable patients will include those enlisted for ICD implants who also have coronary heart disease.
Taking part in the study will involve an extra test performed on the heart during the ICD implant; an ECG will be carried out and later analysed to calculate numerical values for cardiac risk. These cardiac risk scores will then be compared with how often abnormal heart rhythms occur during an 18-month follow-up period.
The aim of this project is to develop a simple, accurate and cost-effective test which can more accurately identify people who need ICDs. It is hoped that this new technology could be applied in future studies to other groups for which there is no tool to assess sudden cardiac death risk.
Trustees Discretionary Award - Mr David Barron, Birmingham Children’s Hospital and University of Birmingham
The normal heart has two pumping chambers - but in babies born with hypoplastic left heart syndrome (HLHS), the main pumping chamber of the heart does not develop. Without treatment, HLHS is lethal within days of birth and accounts for a quarter of all cardiac deaths in the first week of life. Life-saving heart surgery can be performed to create the ‘Fontan circulation’ using the single pumping chamber to pump blood to the body, so that these children can now survive into adulthood.
The way in which the Fontan circulation adapts to the demands of exercise is poorly understood, and it is not known whether training protocols and rehabilitation schemes can influence the performance of the Fontan circulation.
Using some of the latest non-invasive tests, the research team will measure performance and response to exercise in a much more detailed way than ever before.
The project will study how children aged 11 – 14 years with the Fontan circulation respond to exercise, and compare them with children of the same age with healthy hearts. This will build up a picture of the muscle mass, exercise ability and cardiovascular response to exercise in these two groups of children.
In the Fontan circulation, many of the normal systems that control cardiovascular function are very different and it will be important to define how the cardiovascular parameters in these children compare with what would be expected in healthy children.
The project will also look at the adrenaline and stress hormone levels in the body to see if these vary between HLHS and the healthy population, and also compare the children’s own assessment of their quality of life in relation to their actual exercise performance.
Once the baseline performance has been established, the researchers will then use this information to examine whether exercise training and rehabilitation schemes can bring benefits equivalent to those seen in the normal circulation during fitness training.
Motivating children to exercise is an important part of this research and the work may have a wide-reaching impact by demonstrating the potential benefits of exercise, particularly in children who have been labelled as having ‘heart disease’ but also in the wider population.
Translational Research Project Grant - Dr Nicolette Bishop, Loughborough University and University Hospitals of Leicester NHS Trust
A kidney transplant can transform the life of someone with kidney failure, but these patients have a high risk of heart disease which can damage their new kidney and stop them living life to the full. Regular exercise is an important part of a healthy lifestyle for everyone and can lower the risk of heart disease, but there are no exercise guidelines designed specifically for kidney transplant patients. Recent research by this team has shown that these patients want to become active in an enjoyable way, but they're not sure how much and what type of exercise is best for them and they are worried about ‘overdoing it’ or damaging their new kidney.
This study will assess the suitability of three different exercise programmes for kidney transplant patients. All three programmes are known to help lower heart disease risk, but we don’t know which will be most effective for people with a kidney transplant and which of the programmes the patients will like best.
Patients will take part in one of the exercise programmes, all of which will be done three times each week for eight weeks, in state-of-the-art gym facilities at Loughborough University. Two of the exercise programmes involve alternating short bursts of high and low intensity exercise, which is known as High Intensity Intermittent Exercise or HIIT. For HIIT Programme 1, patients will do four bouts of four minutes high intensity with three minutes low intensity exercise in between. For HIIT Programme 2, patients will do a mixture of four, two and one minute high intensity bouts with two minutes of low intensity exercise in between. Both of these programmes last for 30 minutes per session. The third exercise programme is a steady brisk walk for 45 minutes per session.
Before patients start their exercise programme, they will have a series of tests of fitness and heart health, and answer questions about their quality of life and general health. These tests will be repeated at the end of the eight week exercise programme, and at the conclusion, patients will be asked for their opinions of the exercise programmes and about their experience of taking part.
This study will give us vital information on the willingness of patients to start each of these different exercise programmes, whether they manage to do three sessions a week, and whether they will stick at it for eight weeks. This will help the team to choose the most suitable exercise programme for kidney transplant patients, so they can then go on to do a larger study to find out how effective the chosen exercise programme is for lowering heart disease risk. In the long term this work will help to develop safe and effective exercise guidelines that transplant patients will be able to include as part of a healthy lifestyle. Dan, a participant of the study, has written his first hand account on his blog, 'Pedalling to Paris with PKD.' Read the latest post here.
Translational Research Project Grant (PhD studentship) - Prof Annette Graham, Glasgow Caledonian University
Atherosclerosis involves the accumulation of fatty deposits in the walls of major arteries and is the underlying cause of both coronary heart disease and stroke. Initially, the fat accumulates within white blood cells, called macrophages, which enter the artery wall in response to chemical damage. The fat is taken up from low density lipoproteins or LDL – the so-called ‘bad’ cholesterol - which is recognised by specific receptors on the surface of the macrophages. This can be reversed when the fat is removed from the cell, via different receptors, and transported to the liver by high density lipoprotein or HDL – the so-called ‘good’ cholesterol. These processes are dependent on the activity of particular genes which code for the receptors and enzymes involved, and the balance between the two processes determines the rate at which atherosclerosis develops.
Recent evidence suggests that a class of small RNA molecules, called microRNA, regulates the activity of clusters of genes involved in different processes within the human body. The aim of this project is to investigate microRNAs that regulate genes involved in atherosclerosis and to see if their activity can be altered to slow or even reverse the accumulation of fat in the artery wall. Using human macrophages, the research will investigate the ability of two microRNAs to regulate fat build-up in these white blood cells, and whether inhibitors or mimics of these molecules can alter fat accumulation.
Despite substantial decreases in deaths from cardiovascular disease over the last two decades, coronary heart disease and stroke are still major causes of morbidity and mortality in the UK. Also, the rise in the numbers of people who are overweight or obese is expected to cause considerable healthcare problems in the future. This project explores the exciting idea that the development of atherosclerotic plaques in arteries may be altered by microRNAs, and that mimics or inhibitors of these molecules may lead to treatments to prevent, or even reverse, atherosclerosis.
Translational Research Project Grant - Prof Faisel Khan, University of Dundee
Inflammation is a protective mechanism activated by the body’s immune system to fight infection, remove harmful toxins and help in the healing process. However, inflammation can also harm the human body, especially when it does not resolve and becomes persistent. It is now known that chronic inflammation plays an important role in the development of cardiovascular disease, particularly atherosclerosis - the build-up of fatty material inside blood vessels. In the presence of risk factors for cardiovascular disease, such as obesity, high cholesterol and high blood sugar, the lining of blood vessels becomes damaged, and this leads to the production of inflammatory chemicals. Some of these chemicals are harmful to the blood vessels and promote atherosclerosis, while others are protective. Understanding the mechanisms that lead to persistent inflammation and cause damage to blood vessels is therefore very important so that steps can be taken to counteract them.
Prof Khan’s team has recently identified a group of enzymes, called salt-inducible kinases or SIKs, which inhibit the production of protective anti-inflammatory chemicals. Importantly, they have shown that when the SIKs are switched off using drugs, there is an increase in the production of protective anti-inflammatory chemicals and a reduction of harmful pro-inflammatory chemicals. Using laboratory models of atherosclerosis, this project will investigate the role of SIKs in the development of atherosclerosis. Importantly, they will test whether switching off the SIKs helps to reduce the development of atherosclerosis.
The findings will help to determine whether inhibiting SIKs can protect against processes responsible for the early development of atherosclerosis. By inhibiting the harmful pro-inflammatory pathways and promoting the protective anti-inflammatory pathways, drugs that inhibit the SIKs could lead to new treatments for cardiovascular disease. It is hoped that the findings may pave the way for clinical trials of SIK inhibitors in patients with cardiovascular disease.
In future studies, the research team hopes to extend the findings from the laboratory models to patients admitted to hospital with an acute heart attack. Previous studies show that such patients have high levels of inflammation in the body that contribute to the complications linked with acute heart attacks, and the team plans to examine whether high levels of SIKs play an important role in cardiovascular disease in these patients.
Translational Research Project Grant - Prof Khalid Naseem, University of Leeds
People with angina have a narrowing or blockage in the coronary arteries of their heart. There is a risk that a blood clot may form inside the blood vessel, blocking the blood flow and causing a heart attack. The disease processes leading to a heart attack involve inflammation.
Small blood cells called platelets play a major part in blood clotting and recently it has been found that platelets can cause inflammation in blood vessels by releasing particular chemicals. Professor Naseem’s team has previously shown that patients with angina and heart attack have increased levels of inflammation chemicals in their platelets. There is also evidence that their genetic codes have been changed to produce more of these chemicals.
The aim of this project is to find out if the platelets of patients with heart disease have and produce more inflammation causing chemicals compared with other patients. The team will also see if the platelets of patients with heart disease have higher levels of genetic codes for these inflammatory chemicals.
The team will compare blood samples from three groups; patients admitted with a heart attack, patients with stable angina and people who do not have any heart disease. They will measure levels of these inflammatory chemicals, their genetic codes and the proteins that are involved in the manufacture of the chemicals. They will also measure these levels before and after mixing the platelets with substances that are known to cause inflammation, to see how the platelets react.
The findings will help us to understand the role of platelets in causing inflammation in the blood vessels of patients with heart disease and how they are already prepared for an inflammatory reaction. This project will support future research into new medicines for patients with heart disease.
Translational Research Project Grant - Dr Daniel Bailey, University of Bedfordshire
Prolonged periods of time spent inactive and sitting increases the risk of heart disease even if the person is active at other times. This means that even people who meet the government guidelines of 150 minutes of moderate physical activity per week may have a higher risk of heart disease if they spend long periods being sedentary (sitting). Heart disease is the leading cause of death in people with spinal cord injury which may be because they are highly sedentary.
In this project, markers of heart disease risk will be measured in 20 inactive people with spinal cord injury in the following three situations to show whether breaking up prolonged sedentary time is effective at lowering their heart disease risk:
1. Uninterrupted sitting; volunteers remain seated in their wheelchair at a desk for a 5.5-hour day
2. Prolonged physical activity; volunteers will carry out a 30-minute bout of activity in the morning followed by uninterrupted inactivity (sedentary time) for the rest of a 5.5-hour day
3. Sitting plus activity breaks; volunteers will carry out short 2-minute bouts of exercise every 20 minutes over a 5.5-hour day
During the inactive periods the volunteers will carry out desk-based activities on a computer, read, talk, or watch DVDs. Before and during the trial, the researchers will measure each participant’s levels of blood sugar and cholesterol after eating, insulin levels and blood pressure. These are all good indicators of heart disease risk. Breaking up prolonged sedentary time with regular short activity breaks may be an effective way to lower the risk of heart disease in people with spinal cord injury and a simple strategy that they are more likely to take part in. In the long term, the results will help to inform new physical activity and clinical care guidelines to reduce the risk of heart disease in people with a sedentary lifestyle including those with spinal cord injury.
Translational Research Project Grant (PhD studentship) - Prof Paolo Madeddu, Bristol Heart Institute
In the UK, at least 1 in 180 babies is born with congenital heart disease which means a heart defect that develops in the womb, before a baby is born. So that these babies can survive, cardiac surgeons often have to perform complex surgery to replace and correctly position defective arteries and valves. The grafts currently used to repair hearts are made of non-living materials. This means that as the baby’s heart grows rapidly during the first years’ of life, the grafts do not grow and the child will need further surgery to replace the grafts.
The aim of this project is to isolate and use special cells from the baby’s umbilical cord to grow ‘blood vessels’ that behave like a life-like artery and grow with the child’s heart. These cells, called pericytes, will be grown in the laboratory and then placed in a special incubator where they will be grown to form tube-shaped ‘biomaterials’ that behave like blood vessels. This ‘living graft’ can then be used by a cardiac surgeon to correct the child’s heart defect.
If this research is successful it will significantly improve the lives of babies born with heart defects, as babies could have their heart defects corrected shortly after birth, without the need for multiple traumatic operations as they get older.
Translational Research Project Grant - Prof Stuart Cook, Imperial College London
Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and is the biggest cause of sudden death in young adults. In HCM, the wall of the heart becomes thickened and a build-up of fibrous tissue (fibrosis) causes the muscle to stiffen, making it harder for the heart to pump effectively.
The thickness and stiffness of the heart muscle varies from one person to another and is used by doctors to predict how the disease will progress and to choose the best treatment for each patient. It’s important that doctors identify muscle stiffening as soon as possible, so that they can begin early treatment to slow down the progression of the disease. However, while the thickness of the muscular wall can be measured easily, it is much harder to measure muscle stiffening. Currently, cardiac MRI is the best way of measuring muscle stiffening, but it is expensive and waiting times can be long. Also, cardiac MRI can only detect muscle stiffening after it has already occurred and cannot be reversed.
To increase a person’s quality of life and chance of survival, we need a test that can effectively identify people at risk of heart stiffening – before it occurs – because that means it is much more likely to be treated successfully. HCM is a genetic disease, which means it runs in families and early detection is especially important so that care can be given to people who carry the disease-causing gene but who have not yet developed HCM.
A simple and affordable alternative to cardiac MRI would be a blood test that measures ‘biomarkers’ of heart muscle stiffness. Professor Cook’s team has discovered five new markers which are involved in the very early stages of heart muscle stiffening. This project will investigate whether blood levels of these markers are related to the degree of muscle stiffening in the heart.
To do this they will use cardiac MRI data from 750 people with HCM to assess the amount of heart muscle stiffening. They will also sequence their DNA for genes involved in heart disease and develop new, highly-sensitive tests to measure levels of the potential markers in their blood.
This blood test would help doctors to identify and monitor patients at high risk of developing heart muscle stiffness, benefitting those with HCM and perhaps others with related conditions, such as heart failure. Also, the research will give insights into the mechanisms of tissue stiffening, helping us to understand how HCM progresses and how it may be treated.
Novel and Emerging Technologies Grant (PhD studentship) - Dr Vivek Muthurangu, University College London and Great Ormond Street Hospital
In the UK, at least 1 in 180 babies is born with congenital heart disease which means a heart defect that develops in the womb, before a baby is born. Not all of these infants will need treatment, but in those that do it is important to understand the structure and function of the heart. There are several ways this can be done, including creating images of the heart, and cardiovascular magnetic resonance (CMR) is recognised as one of the best methods of imaging children with heart disease. In an ideal world CMR would be used routinely in all cases but CMR takes a long time to perform, requires an expert to do the scanning and is very costly. Also, due to the long scanning time and because it can be a distressing experience for young children, in many cases a general anaesthetic must be used.
The aim of this project is to develop an imaging technique that can be carried out rapidly – in 5 minutes - and which doesn’t need expert input. The research team will build on their experience in the technical aspects of CMR, computer science, mathematics and performing CMR in children.
The new technique involves imaging the whole of the heart multiple times throughout the heartbeat which will allow any part of the heart to be assessed after the scan has been carried out. However, this approach is time consuming, often taking more than 30 minutes. Therefore, they will attempt to speed up the scan by combining the most efficient methods of collecting CMR data with computer algorithms that generate high quality pictures. Also, they will use cloud based computing to more rapidly generate images. The new technology will then be tested in children undergoing conventional CMR.
It is hoped that the new technology will dramatically reduce the cost and patient discomfort of CMR, so that more children can benefit from CMR. Also, the better information may help doctors to decide on the best ways to treat these children. The new technology could have benefits in other areas of medicine and science, for example for scanning children with diseases such as cancer and epilepsy.
Novel and Emerging Technologies (NET) Grant - Prof Ashok Handa, Prof Eleanor Stride and Dr Regent Lee, University of Oxford
The use of ‘keyhole’ procedures to treat heart or artery problems has increased over the years. These procedures involve the insertion of a needle into the artery in the groin which allows access to other parts of the body, such as the heart or arteries elsewhere in the body. At the end of these procedures, the hole in the artery needs to be closed in order to stop the bleeding. If the hole is not fully closed, bleeding from the hole is initially contained by the surrounding tissue creating a ‘pseudoaneurysm’. If left untreated, a pseudoaneurysm can become bigger as the bleeding continues, resulting in swelling, pain, and sometimes skin ulcers. Very rarely, the surrounding tissue can give way and result in sudden massive blood loss.
Keyhole surgery is often the preferred way to treat patients who are frail and elderly, and have other medical problems such as heart disease. This is because the risks associated with a general anaesthetic and open surgery tend to be higher in these patients. However, the conventional treatment for pseudoaneurysm requires open surgery to repair the bleeding hole which exposes these vulnerable patients to the increased risks of surgery, general anaesthesia, bleeding and infection. There are alternative treatments for pseudoaneurysm which do not require open surgery, however not all patients are suitable for such treatment.
The aim of this project is to develop a novel treatment for pseudoaneurysm. The research team will develop a medication which can be injected into the pseudoaneurysm to make the bleeding stop. This new treatment would eliminate the complication or traditional treatment methods and avoid open surgical repair. This is particularly important in vulnerable patients with multiple medical problems.
Northern Ireland Grant - Dr Chris Watson, Queen’s University Belfast
Coronary heart disease (CHD) is the most common cause of heart attack and is the UK's biggest single killer. Understanding the disease processes involved in coronary heart disease is key to the development of new drug treatments. A better understanding also helps in the development of new blood tests for diagnosis and for monitoring how well treatments are working. Dr Watson and his team will study ‘DNA methylation’ - a process that affects how your genetic code is activated or ‘expressed’. DNA methylation can change due to environmental factors including reduced oxygen levels, called hypoxia, which is a characteristic of coronary heart disease due to reduced blood flow to the heart muscle. Changes in DNA methylation in the diseased heart is potentially reversible and may form the basis of new treatments in the future.
The aim of this project is to better understand the DNA methylation pattern in the heart and link this to how coronary heart disease develops and becomes worse. The team will examine human heart tissue from patients with CHD and study the methylation patterns of their genetic code and how this relates to disease. They will also take these findings into lab-based studies to further study the roles of changing DNA methylation in hypoxia and the subsequent development of disease. They will look at changes in blood levels of some of the newly-identified genes relevant to CHD in heart attack patients and also in patients undergoing surgery to improve blood flow to the heart. This will show whether these gene markers in the blood could be used as valuable new blood tests to identify coronary heart disease or used to monitor improved heart health. If successful, the findings may ultimately help to improve the lives of patients through improved treatment, care strategies and survival.
Translational Research Project Grant - Prof Derek Steele, University of Leeds
The rhythmic beating of the heart is controlled by the co-ordinated opening and closing of ‘ion channels’ in the heart cells which allow electrically charged particles – ions – to move in and out of the cells. If this electrical activity is disrupted, the resulting abnormal rhythms, called arrhythmias, may prevent the heart from pumping effectively and be life-threatening. The most common form of arrhythmia is ‘atrial fibrillation’ which is thought to affect 1-2 million people in the UK. In many cases of atrial fibrillation, the arrhythmia is partly due to a disruption of the activity of an ion channel called Kv1.5.
Most, if not all cells in the body, naturally produce gases including, surprisingly, carbon monoxide and hydrogen sulfide. These gases are well known for their toxic actions, both being highly poisonous at high levels, but in fact have important roles in controlling lots of normal processes within cells. Professor Steele and his team have discovered that both gases control the activity of the ion channel Kv1.5 and appear to protect it from disruption of its activity in atrial fibrillation.
The aim of this project is to understand how Kv1.5 is regulated by carbon monoxide and hydrogen sulfide, and how these gases protect Kv1.5 from being disrupted. The team will also manipulate the production of these gases within cells and see how this affects Kv1.5, both under normal conditions and those which mimic atrial fibrillation. This will tell us whether drugs which increase the formation of these biological gases can prevent the disruption of Kv1.5 in atrial fibrillation, and so treat this dangerous form of arrhythmia.
Atrial fibrillation dramatically increases the risk of stroke, heart failure and other life-threatening cardiac complications but current treatments are inadequate and new approaches to this common problem are needed. The ion channel Kv1.5 may represent a new target for drugs to treat this dangerous type of cardiac arrhythmia. If successful, the findings could lead to rapid development of new drugs to treat atrial fibrillation, because drugs designed to release carbon monoxide and hydrogen sulfide into the bloodstream in a controlled manner are currently under development for other conditions.
Translational Research Project Grant - Prof Sarah George, University of Bristol
Heart attacks are usually caused by blockage of the coronary arteries supplying blood to the heart muscle. One of the treatments for blocked coronary arteries is heart bypass surgery using sections of vein from the patient’s leg to bypass the blockage. Unfortunately, these vein grafts suffer from unacceptably high failure rates, with approximately 50 per cent failing within ten years. This means that some patients will go on to experience recurrent angina or heart attacks, and need further operations.
Vein graft failure is caused by increased activity of cells within the vein graft which causes thickening of the inner layer of the vein. Professor George’s team has been studying a protein that plays an important part in ‘cell adhesion’ – the binding of cells to one another. They have shown that the ‘adhesion protein’ reduces over-activity of cells within the vein and graft thickening, without harmful effects on the blood vessel wall. They have also found that a very small part of the adhesion protein can act as a mimic for the full-length version and has similar effects on the vein graft.
They will package the mimic in small biodegradable spheres called ‘microspheres’ to deliver the mimic in a continuous way. The microspheres may prolong release and therefore could be used in patients to slowly deliver the mimic to the vein graft. By studying human veins that are used for bypass surgery they will test whether microspheres can improve delivery of the mimic and reduce graft thickening.
If the mimic reduces over-activity of the cells within the vein graft without adverse effects on the blood vessel wall, it may have potential as a treatment to prevent vein graft failure following bypass surgery. If successful, it could be used to improve the outcome of heart bypass surgery and reduce the need for surgery to be repeated.
Translational Research Project Grant - Prof Julia Gorelik, Imperial College London
A heart attack is usually caused by the blockage of a coronary artery which cuts off the supply of blood to the heart muscle. This starves the heart muscle of oxygen and the heart may be permanently damaged. After the onset of damage, repair starts and special cells appear which form scar tissue. However, extensive scarring, or fibrosis, impairs coupling between muscle cells in nearby areas and the heart may start to beat irregularly.
The aim of this project is to test whether a drug that has shown beneficial effects in other organs can reduce the scarring of the heart. The drug, called UDCA, is a component of bile and is already used to treat other conditions and so is known to be safe. UDCA prevents the appearance of cells that play a part in the formation of scar tissue and also improves survival of muscle cells that have been subjected to a lack of oxygen. The team will use human donated hearts; some of them healthy and some failing and discarded after the patient has received a transplanted heart. They will culture isolated heart cells and slices of heart tissue in the lab, treat them with UDCA and compare signs of fibrosis in tissue from healthy and failing hearts.
Also, a small trial will be carried out involving patients with chronic heart failure, who are suffering from extensive fibrosis in their hearts. The patients will be divided into one group who will receive UDCA for three months and the other who will receive a placebo. At the end of the three month period, they will compare the distribution and amount of fibrosis in the heart muscle by cardiac MRI scans in the two groups of patients. The findings will show whether UDCA has potential as a protective treatment in heart failure patients.
Translational Research Project Grant -
Coronary angiography is a type of x-ray test which is used to look at the coronary arteries in the heart and help in the diagnosis of a number of heart conditions. It can also help in the planning of procedures such as balloon angioplasty and stent insertion to widen narrowed or blocked arteries in the heart.
During angiography, a special dye is injected which allows the blood vessels to show up on the x-ray. However, the dye can cause acute kidney injury called contrast induced nephropathy (CIN). In fact, CIN is the third most common cause of kidney failure that occurs in hospital. It is an important problem, as it is associated with a longer stay in hospital, higher healthcare costs, and a much worse outcome for patients with higher rates of complications and death.
There is evidence that contrast dye may cause kidney damage by reducing levels of nitric oxide (NO) in the kidneys. Dietary nitrate, which is abundant in vegetables such as beetroot, can increase the levels of NO in the body and this project will test whether taking nitrate in a capsule form can replace the lost NO in the kidneys and prevent CIN.
Patients will be divided into two groups; one group will take nitrate capsules and the other group ‘placebo’ or dummy capsules that do not contain nitrate. The researchers will then measure kidney function before the procedure, and two days and three months after, and compare the two groups to see if dietary nitrate makes a difference.
This study will show whether dietary nitrate capsules reduce kidney damage caused by coronary angiography. If successful, the benefits to patients with heart disease would be substantial with reduced rates of kidney damage, less need for treatments such as dialysis and better long term survival.
Translational Research Project Grant (PhD studentship) - Dr Tom Van Agtmael, University of Glasgow
A better understanding of how heart function is controlled and what goes wrong in heart disease will help in the development of new and better treatments. Tissues in our body including the heart are made up of cells which are surrounded by a material called the extracellular matrix. Within this matrix there is a structure called the basement membrane which forms a sheet-like structure that surrounds the muscle cells of the heart. However, the role of the basement membrane in the function of the heart and heart disease is unclear.
One of the major components of the basement membrane is a protein called collagen and Dr Van Agtmael’s team has previously shown that small changes in this protein, called mutations, cause eye, kidney and blood vessel defects. They have now shown that mutations in collagen also lead to defects in the structure and function of the heart. New data suggest these mutations cause the mutant protein to accumulate within cells leading to defects in the matrix including the formation of scar tissue in the heart, a process called fibrosis which is linked with heart failure.
The aim of this project is to understand more about the role of the basement membrane in heart biology and the development of heart defects due to these mutations. Recent work by the team suggests that treatment with a drug can reduce the accumulation of abnormal collagen. They now plan to exploit this exciting result by testing whether they can prevent or reduce the severity of heart defects due to collagen mutations. Since the drug is already approved for other clinical uses, if successful, the project could lead to a more rapid development of new treatments for heart conditions such as cardiomyopathy, heart failure and damage following heart attack.
Novel and Emerging Technologies (NET) Grant - Dr Erica Dall’Armellina University of Leeds
Small blood vessels in the heart, called microvessels, deliver blood to the heart muscle. Each microvessel supplies a small number of heart muscle cells with oxygen and nutrients. When the supply fails, the tissue can suffer and cells can die. For a good blood supply and healthy heart, two factors are crucial - the vessels need to be unobstructed and function well, and the surrounding structure has to allow for the microvessel to reach the tissue. However, this is not the case in patients with heart disease such as hypertrophic cardiomyopathy (HCM).
About 1 in 500 of the UK population has HCM, although most HCM patients have few, if any symptoms. In HCM patients, the muscular wall of the heart becomes thickened, making the heart muscle stiff and preventing the microvessels from delivering enough blood to the cells. This can have serious consequences and may lead to death.
Cardiac magnetic resonance (CMR) imaging is used to image the muscle of the heart in detail and detect the presence of dead tissue. However, it does not tell us how an abnormal muscle structure impacts on the delivery of oxygen. The aim of this project is to develop a new CMR method to assess how severely the blood supply is affected by the disarray of the microstructure in patients with heart disease including HCM. The technique is called intra-voxel incoherent motion (IVIM).
After optimising the imaging technique in the lab, Dr Dall’Armellina’s team will test it on 10 healthy volunteers to establish normal values for heart structure and blood flow. They will then use the technique on 30 HCM patients to measure how well the heart muscle is supplied with blood and see how this correlates with standard measurements such as the thickness of the heart or the amount of scar tissue.
If the project is successful, the new imaging technique may benefit patients with HCM and other types of heart disease. It may help doctors to assess whether the microvessels are functioning efficiently to supply blood to the heart muscle tissue. By determining at an early stage whether there is poor oxygen delivery due to an abnormal microscopic structure of the heart muscle, doctors could test new medicines to treat the abnormal function of the microvessels. This may lead to new ways to treat the condition early and to avoid serious consequences.
Novel and Emerging Technologies (NET) Grant - Prof Ioakim Spyridopoulos, Newcastle University
The coronary arteries supply the heart muscle with oxygen-rich blood and a heart attack is usually caused by the blockage of a coronary artery. This starves the heart muscle of oxygen and the heart may be permanently damaged. The death rate from heart attacks has significantly fallen over the last decade and more people are surviving heart attacks than ever before. This is thought to be partly due to advances in treatment, including coronary angioplasty and stent implantation to re-open the blocked coronary artery. However, 20 per cent of patients who undergo this procedure need to be readmitted to hospital in the first year after a heart attack due to heart failure and 40 per cent have enlargement of the left side of the heart, showing that they are at risk of developing heart failure in the future. This may be because the treatment has failed and the blood flow to the heart muscle has not been restored.
Current blood tests used in the NHS do not identify patients at high risk of developing problems in the future. Professor Spyridopoulos and his team have discovered very small molecules, called microRNAs, in the blood stream that are increased soon after patients have undergone stent treatment to re-open the blocked artery. These microRNAs may be useful as ‘biomarkers’ to predict which patients are at future high risk. However, current technology to measure these small molecules is unfortunately not accurate enough to replace the conventional NHS-based blood tests.
A new technology is now available at Newcastle University, called ‘droplet digital PCR’. With this technique the blood sample is divided into 20,000 small droplets and microRNAs are measured in each droplet, so that every single molecule in the blood stream can be counted. A similar approach has been used to develop a precise and reliable blood test in cancer patients, but so far no studies have been carried out in patients with heart disease or who have had a heart attack.
If this project is successful, a new and affordable blood test could replace current blood tests for patients who have had stent treatment for heart attacks. The test may help doctors to identify which patients are at higher risk of developing heart failure so that they can be closely monitored prior to discharge or given further treatments. Those patients with a small increase in the biomarker and therefore low risk could potentially be discharged early, whereas those at high risk would undergo additional tests and follow-ups.
Novel and Emerging Technologies (NET) Grant - Dr Jack Lee, King’s College London
Coronary heart disease (CHD) is where the coronary arteries that supply the heart muscle with blood become narrowed by a gradual build-up of fatty material. This can lead to angina and heart attacks, and is the leading cause of death in the UK. When a patient is admitted to a catheter lab for treatment for CHD, doctors must decide whether the artery should be re-opened physically with a stent, or in less severe cases, treated with medication.
There is much evidence that measuring the pressure drop across the coronary artery narrowing is a highly accurate way of deciding the best treatment. The test involves inserting a wire into the coronary artery which has a sensor to measure pressure. However, the majority of catheter labs in the UK do not currently measure pressure routinely. The reasons for this include risks to the patient, and extra time and cost of the procedure. The aim of this project is to make the pressure-based assessment of coronary artery narrowings safer, quicker and easier, using advanced computing processes.
Coronary angiography is the conventional method for looking at the coronary arteries and involves taking x-ray images of the blood vessels. This information can be combined with a computer model of blood flow to estimate the pressure drop, without carrying out invasive measurements on patients. There are already accurate methods to simulate the blood flow through blood vessels but they are time-consuming and require special training to perform.
In an alternative approach, this project will use an advanced computing algorithm known as ‘deep learning’. This is a type of artificial intelligence technique which will identify patterns from blood flow simulations in thousands of coronary arteries, so the computer ‘learns’ how the geometry of the narrowings affects the pressure pattern. In turn, this information may allow the pressure drop across the coronary artery narrowing to be calculated directly and in real-time from the angiography images. The team will then test the new method on real patient data to demonstrate its clinical usefulness.
The successful outcome of this research may help doctors decide on the best treatment for CHD using a test with reduced risk and less discomfort for patients. A fast and automatic method may also lead to shorter waiting times and cost savings for the NHS.
Novel and Emerging Technologies (NET) Grant - Mr Steven Tsui, Papworth Hospital NHS Foundation Trust, Cambridge
There are not enough donor hearts for everyone that needs a heart transplant. This project will test whether a combination of machine perfusion before and after donor heart retrieval can restore the function of donor hearts that would otherwise be rejected by transplant teams. If proven to work, this approach would increase the numbers of suitable donor hearts available so that more patients with severe heart failure can benefit.
It is almost 50 years since the first successful human heart transplant and it remains the gold standard treatment for severe heart failure. The increasing demand for heart transplants, however, vastly outstrips the limited number of usable donor hearts. In 2014/15, there were 547 patients in the UK on the heart transplant waiting list but only 180 heart transplants were carried out.
Worryingly, less than 3 in 10 of all the donor hearts made available from ‘donation after brain death’ (DBD) are transplanted. This is due mainly to the harmful effects of brain death on the donor heart leaving it too damaged to be transplanted.
The aim of this project is to limit the injury to donor hearts after brain death, so that more are available for transplantation. This would give more patients on the heart transplant waiting list the chance to undergo this life-saving operation.
How the donor heart gets damaged:
The process of brain death in the donor has many harmful effects on the heart. Also, in order to maintain an adequate blood flow to the other vital organs in the donor, intensive care doctors often have to use powerful drugs to drive these already injured hearts to work harder. This causes further damage.
After a donor heart has been removed from the body of the donor, it is placed in a ‘cool box’ packed with ice and transported to the recipient hospital to be transplanted. The heart receives no oxygen during this time and deteriorates further. This makes it hard for the transplant surgeon to be confident that after it has been transplanted, the donor heart will function well enough to keep the recipient alive. In fact, as many as one in three of the carefully selected donor hearts that are transplanted go on to develop so-called ‘primary graft failure’. This is a devastating complication where the newly transplanted donor heart does not work properly and this is the leading cause of death in recipients during the early period after transplant surgery.
At Papworth Hospital in Cambridge, Mr Tsui and his team have recently set up a world-leading ‘donation after circulatory determined death’ (DCD) heart transplant programme. These DCD hearts are very different to DBD donor hearts in that they have suffered even more damage and have already arrested in the donor. Over the decades, cardiac surgeons have dismissed the possibility of transplanting hearts from DCD donors. By using a mechanical circulatory support system, called ‘ECMO’, the team has been able to restore good function in a high proportion of DCD hearts. To avoid further injury to these carefully reconditioned DCD hearts during transportation, they are placed in a specially designed machine, instead of a cool box with ice. This technique is known as machine perfusion which provides the donor heart with warm blood enriched with oxygen and nutrients continuously.
This project will use the same approach to recondition and retrieve injured DBD hearts that are rejected by transplant teams. By using ECMO to provide blood flow to vital organs in the DBD donors, the need to use powerful drugs to drive the donor heart might be avoided while allowing the injured donor hearts to rest and recover. Once retrieved from the donor body, machine perfusion will maintain the recovering DBD hearts during transportation to avoid further injury.
This exciting research may lead to better use of valuable donor hearts, fulfilling the wishes of more donors and their families who have generously offered organs for transplantation. Above all, it would give more patients who are dying from severe heart failure the chance of a life-saving heart transplant.
Translational Research Project Grant - Dr Markos Klonizakis, Sheffield Hallam University
There are 10 million cigarette smokers in the UK and the electronic cigarette or e-cigarette is considered as the number one aid to stop smoking. This project will investigate the health benefits and risks of using e-cigarettes.
It is estimated that there are 10 million cigarette smokers in the UK and 1.3 billion in the world. Smoking is the leading preventable cause of death worldwide, with the majority of these deaths due to cardiovascular disease.
Cigarette smoke contains more than 9,000 chemicals. While nicotine is thought to cause the greatest harm to the heart and blood vessels, there are other chemicals present that also have damaging effects. In fact, the effects of smoking on the blood vessels are so powerful that cigarette smoking can have immediate harmful effects on the small blood vessels, whilst ‘passive smoking’ can increase heart disease risk by as much as 30 per cent.
Nicotine can be highly addictive and if it cannot be avoided, it is important to encourage replacement of cigarettes with ‘cleaner’ nicotine-based products as an aid to stop smoking. The NHS has adopted this approach and supports the use nicotine replacement therapy (NRT). However, its appeal to smokers is quite low and 75 per cent of ‘quitters’ start smoking again within six months.
The electronic cigarette (or e-cigarette) has been embraced by the public, with an estimated 2.8 million users in the UK in 2016. It is currently considered the number one aid to stop smoking among those who want to quit. Although e-cigarettes have been found to successfully support reduction in the numbers of cigarettes smoked and appear to have a relatively small number of side effects, little is known about their effects on the heart and blood vessels, or their effects on cardiovascular disease risk.
This project will involve 267 smokers who want to stop smoking and will be randomly divided into the following three groups:
Group A will receive nicotine-rich e-cigarettes and behavioural change support
Group B will receive nicotine-free e-cigarettes and behavioural change support
Group C will be referred to NHS smoking cessation clinics (with a view to receiving nicotine replacement therapy and behavioural change support)
The researchers will study the effects of these three aids to stop smoking on the cardiovascular system. They will assess the health of the small and large arteries, cardiovascular disease risk, degree of nicotine addiction and also compare the cost of the three options. Finally, they will interview a number of participants to find out the effects of these approaches to their lives, and explore what encourages and what deters them from quitting smoking.
E-cigarettes are becoming increasingly popular but little is known about their safety and health effects. More research is urgently needed and the findings will help smokers who want to quit to make an informed decision about which option to choose.
If you live in Sheffield and want to take part, please contact Dr Gareth Jones on 0114 225 4312 or email firstname.lastname@example.org
Highlights of completed research projects
The following research projects are among those completed over the last few years which have had an interesting and successful outcome and in the future, may contribute to prevention, treatment and cure of heart disease. Heart Research UK awards medical research grants of around £1 million every year and there are ongoing projects in hospitals and universities across the UK worth more than £3 million.
Research highlights 2017
This project involved an advanced imaging technique called positron emission tomography (PET) and studied a new ‘probe’ which may be useful in imaging human heart and blood vessel cells.
An exciting finding was that the PET imaging compound had ‘cardioprotective’ effects. This compound has already been shown to protect against degenerative conditions of the brain and an early clinical trial is taking place in Australia to test it as a treatment for motor neurone disease. In this HRUK-funded study, Dr Siow and his team showed, for the first time, that the compound also protects heart muscle and blood vessel cells from damaging processes, called oxidative stress, that contribute to heart disease.
Importantly, they also studied the behaviour of cardiovascular cells when exposed to different oxygen levels in the lab. Most scientific studies take place in room air which means that cells are exposed to higher oxygen levels than in the body. Using a special oxygen-regulated workstation purchased with HRUK funding, this research highlights the importance of maintaining the correct biological oxygen levels when studying cardiovascular cells in the lab, to reflect lifelike conditions.
In most cases, a heart attack happens when a coronary artery becomes blocked and the resulting lack of blood supply to the heart muscle can lead to a damaged heart. One of the treatments for heart attack is coronary artery bypass surgery. This uses blood vessels from the leg, or elsewhere in the body, to bypass the blocked artery and improve blood flow to the heart muscle. This is invasive and major surgery, with a long recovery time. Professor Madeddu and his team have been studying new ways to improve blood supply to the heart muscle after a heart attack.
Earlier research by Prof Madeddu’s team showed that cells which surround blood vessels, called pericytes, can stimulate the growth of new blood vessels. This follow-on project provides important new information about the mechanisms involved and demonstrates that the hormone ‘leptin’ has a central role. Leptin is produced by fat cells and helps to regulate energy balance in the body by inhibiting the appetite.
The research, published in Scientific Reports, showed that pericytes produced 40-times more leptin when exposed to low levels of oxygen and that this continued until oxygen levels returned to normal. This may help tissues to build more blood vessels to increase blood flow and oxygen supply.
In the longer term this research may help in the development of an alternative treatment to major surgery for heart attack patients. It may also have implications for cancer treatment, where the growth of new blood vessels plays a central role in the growth and spread of the disease.
Coronary heart disease causes narrowing or blockage of the arteries that supply blood to the heart muscle which may damage the heart and lead to heart failure. Stem cell treatment has the potential to treat damaged heart tissue by encouraging the growth of new blood vessels and improving the blood supply to the heart muscle. However, clinical trials have shown mixed results with only some patients benefiting from the treatment.
This project investigated the genetic make-up of patients’ cardiac stem cells, with the aim of developing a test to predict and improve the success of stem cell treatment. Dr Martin-Rendon and the team found that stem cells isolated from cardiac tissue of patients undergoing heart bypass surgery could be classified into two types:
(1) those that grew well in the lab and were good at supporting new blood vessel growth
(2) those that did not grow well in the lab and aged quickly.
Interestingly, if patients had other conditions, such as high blood pressure, the cells were less able to support new blood vessel formation, whilst cells from patients with severe heart failure were better at supporting new blood vessel formation.
The team identified genetic differences between these two groups which in the future may help with predicting the best cells to use and selecting patients who are more likely to respond well. Such a personalised approach would improve the success of stem cell treatment giving better outcomes for patients with coronary heart disease.
Infective endocarditis (IE) is a serious infection of the inner lining of the heart. It affects around one in 10,000 people every year in the UK and can be life-threatening. People with certain heart conditions are thought to be at increased risk of IE and this project assessed the risk of developing or dying from IE, in patients with different predisposing heart conditions. Patients with heart conditions are categorised as high, moderate or low risk of IE but there is a lack of evidence about the risk of IE in these patient groups.
Using a national database that records every hospital admission in England, Professor Thornhill identified patients admitted to hospital between 2000 and 2008 that had a diagnosis, or had a procedure, that could have put them at risk of developing IE. Patients were then followed until 2013 to see if they developed IE later and what the outcome was. The study, published in the European Heart Journal, showed that:
• Those at highest risk of developing or dying from IE are patients who have had IE before, and those with artificial or repaired heart valves
• The risk for those with congenital valve defects or acquired valve disease, previously considered only moderate-risk, was nearly as high
• Patients with certain repaired congenital heart conditions previously considered to be at high-risk of IE are actually at a much lower risk
• Patients who have had an electronic cardiovascular device inserted, such as a pacemaker or defibrillator, have a significantly increased risk of developing or dying from IE - this was not known before.
These important findings challenge the current grouping of patients into high, moderate or low risk of IE and may influence national and international guideline committees including NICE. The results may allow preventative treatments, such as antibiotics, to be targeted at individual patients, as well as helping with earlier diagnosis and better treatment for heart patients.
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