Beating Heart Disease
This week we’re delving into the science of heart disease; with help from the British Heart Foundation (BHF), we’ve been to the UK’s leading heart conference to hear from the researchers trying to discover the causes and new treatments for one of the world’s most important diseases. We hear why air pollution and heart attacks are linked, about the role of salt in high blood pressure and learn about a new vaccine for heart disease...
In this episode
What is a heart attack?
with Adam Murphy & Marika Ottman, The Naked Scientists
What is a heart attack? Marika Ottman and Adam Murphy throw some quick fire facts our way...
Marika - Is your chest a bit tight? Feeling short of breath? Sweaty and nauseated? Possibly a bit lightheaded? Maybe you’ve noticed an odd pain crawling down your arm and up your neck? If so, you might be having a heart attack.
Adam - Heart attacks get a pretty bad press… and with good reason. According to the British Heart Foundation 180 people a day in the UK will die of a heart attack.
Marika - Heart attacks happen when one of the blood vessels supplying the heart becomes blocked a blood clot called a “coronary thrombus.”
Adam - This cuts off the flow of oxygen and sugars to the affected part of the heart muscle causing it to run out of energy and the muscle cells begin to die.
Marika - When this occurs, heart attack victims experience a feeling of being crushed or squeezed, accompanied by a dull aching pain in the centre of the chest.
Adam - Someone having a heart attack usually looks pale, sweaty and clammy, and their pulse rate might become irregular, be going too fast or running too slowly.
Marika - The first thing a doctor or a paramedic will do to investigate is an ECG or Electrocardiogram. This is an electrical tracing of the heart.
Adam - Heart attacks often produce characteristic changes to the normal ECG pattern which can also reveal where in the heart the damage is occurring.
Marika - Doctors can also use blood tests to confirm when a heart attack has taken place.
Adam - One of these is called a “troponin test.” It looks for molecules called “troponins” that leak in the bloodstream from damaged heart muscle cells. Patients who have suffered a recent heart attack will have high levels of troponin in their blood.
Marika - Following the diagnosis, doctors will quickly try to reopen the blocked artery to restore blood flow and reduce the damage done to the heart.
Adam - This is called an “angioplasty procedure.” It involves placing a fine cannula from a wrist or leg artery into the heart arteries and using X rays to spot where the blockage is.
Marika - A balloon is then inflated inside the clogged artery to squash the blood clot out of the way so blood can flow again.
Adam - The balloon is removed and replaced with a small metal cage called a “stent,” which is inserted to prop the vessel open so that it cannot close up again afterwards.
Marike - Patients are then given blood thinning drugs, like aspirin, to ensure that further blood clots don’t form and block the stent.
Adam - Usually, people recover quite well, but the area of muscle damaged by the heart attack can form a scar which can reduce the ability of the heart to pump, which means some people are at risk of heart failure.
Marika - After a heart attack, patients are given help to reduce their risk factors, which includes advice to take regular exercise, control their cholesterol and blood pressure, eat healthily, and not to smoke.
03:43 - How to diagnose a heart attack...
How to diagnose a heart attack...
with Dr Tom Kaier - St Thomas' Hospital, Dr Tian Zhao & Dr Sharon Wilson - Addenbrooke's Hospital
Most people are aware of the pressures that face Accident and Emergency Departments, and a significant workload for emergency doctors is the assessment of patients with chest pain. Now this can be one sign of a heart attack; so it’s important to take seriously; but this takes a long time, and the majority of people coming in to hospital with chest pains aren’t actually having heart attacks, meaning that acute care beds can be occupied for long periods of time unnecessarily. Chris Smith spoke to Tom Kaier, from St Thomas’s Hospital in London, who has developed a new blood test that might be able to help speed things up. Plus, Addenbrooke's cardiologists, Tian Zhao and Sharon Wilson, explain the different between a heart attack and a cardiac arrest.
Tom - My name is Tom Kaier. I’m a British Heart Foundation Clinical Research Fellow, and I work at St Thomas’s Hospital in central London.
We’re looking at the diagnosis of myocardial infarction, so in layman's terms a heart attack. It’s a huge public problem; it affects about 2.2 million people a year that present with chest pain to the emergency department in England alone. And only 10 percent of them actually have myocardial infarctions, so have a heart attack that warrants further treatment.
Chris - But the other 90 percent, because they’ve got the symptom, might end up with a whole bunch of unnecessary investigations and possibly even treatments?
Tom - Exactly. Big heart attacks show themselves on the heart trace, but the heart trace abnormalities are only present in about a third of all patients with a heart attack. And the two third of patients that don’t have any ECG abnormalities, we have to perform blood tests in the Emergency Department and often admit them to hospital for ongoing observation and treatment. As you can imagine, because 90 percent of people have actually presented with chest pains do not have a heart attack, it places a huge burden on the health cares system. But, more importantly, also for the patients who sit in an Emergency Department and simply want to have an answer to the question: did I have a heart attack or not?
Chris - The present generation of blood tests that we have, are they not any good?
Tom - The blood tests we use at the moment, which is cardiac troponin, is excellent. It helps us diagnose a heart attack very clearly. The problem with cardiac troponin is that it comes out from the heart muscle at a relatively late stage. So if you look at the guidelines that many of us use, they advocate the use of those blood tests only in patients that had symptoms for more than three hours.
Chris - What’s the new test?
Tom - The new test is called “cardiac myosin-binding protein C.” It’s a mouthful; we abbreviate to MyC. It’s similar to troponin; it’s a protein that forms part of the heart muscle.
Chris - What, and that comes out of injured heart muscles? So when someone has a real heart attack, damage to the muscle releases that into the bloodstream and you can pick it up?
Tom - Exactly. Any sort of damage to the heart muscle would release these proteins. But, in particular, in patients with a heart muscle injury due to a heart attack we see very high levels of MyC. We also see high levels of cardiac troponin but at a later stage. So by having a protein that comes up in the bloodstream much earlier we can, in essence, test more patients and give them an earlier answer.
Chris - How quickly does the concentration of the MyC come up in these people, and how much faster is it than the existing troponin test you do?
Tom - You probably have a twice as quick release of the MyC protein comparing it with troponin. If you look at the time until you can safely make a discharge decision, that is also brought down to probably two hours rather than three hours with the cardiac troponin I’d say. Using MyC, we have shown that we can tell about 17 percent more patients, double the amount of patients than with cardiac troponin, that they didn’t have a heart attack with the first blood test at presentation to the emergency department, and, therefore these patients can be already reassured that they don’t require any further assessment.
Chris - I was thinking also, it might be very useful in primary care settings like General Practice? Because lots of people don’t go straight to the hospital when they have chest pain, they go and see their GP and say: oh, by the way, been up all night with indigestion do you think this could be a heart attack? And the GP then has to make a decision and this could help them?
Tom - It certainly could. The problem we have at the moment is that to bring this to a handheld device is very complicated. You’re trying to detect the equivalent of a few molecules of a protein in the finger prick blood sample, for example, which so far, no handheld troponin device has managed to achieve. Because there is so much more of MyC in the heart muscle, and it rises to much higher levels after the injury to the heart muscle, we are confident that we could translate the MyC onto a handheld device and, therefore, allow the measurement in a primary care environment like at the GP. But also be done by paramedics when they get called out to patients who are complaining of chest pain they could essentially do a risk assessment then and there with a finger prick blood test.
Chris - Tom Kaier. He’s based at St Thomas’s Hospital, in London.
Now also with me today are two heart specialists, or cardiologists. They’re Tian Zhao and Sharon Wilson; they’re both based at Cambridge’s Addenbrooke’s Hospital.
In a moment we’ll hear about how salt can affect your blood pressure, but first, Tian, can you just tell us when Tom was referring to chest pain there, why do people with heart problem classically get chest pain?
Tian - The reason is the heart, like any other muscle in the body, needs blood for it to function. And the three vessels supplying the heart with blood, and if there’s a narrowing in any of these blood vessels, the blood can’t get through and you don’t get enough oxygen and energy to the heart and it gets, essentially, like a cramp-like state where it can’t function well enough. The reflection of that is you get chest tightness; it may go down your arm and it may go up your neck and that’s what classically people call Angina.
Chris - Why does it go all over the place: neck arm and so on if it’s happening in your heart in the centre of your chest?
Tian - The organs in your body aren’t supplied by nerves that feel like the skin does. So sometimes when you get distress in the heart the body perceives it in different ways; for example, in heart patients they perceive it up the neck, in the left arm, and across the chest.
Chris - That pain is classically referred to as Angina. Does angina mean though that you’re actually having a heart attack or is it possible to have that pain and not actually be doing heart attack damage to your heart?
Tian - Exactly. Angina is typically pain that is rather predictable. So, for example, if you walk too briskly or you’re rushing upstairs you get chest tightness and also going up into your arm, but it you stop that goes away. Or if you use a puff of GTN which is a drug that…
Chris - Glycerin trinitrate?
Tian - Yeah. That relieves the pain. A heart attack is when you get chest pain that doesn’t go away, and it’s continuous, and it lasts for a long time or often at rest as well.
Chris - Sharon, when someone has a cardiac arrest, how does that relate to this story? What is one of those?
Sharon - A cardiac arrest is an electrical fault of the heart rather than a heart attack which is a plumbing problem.
If you’re having a cardiac arrest, your heart electrically has stopped. For the patient, who’s usually unconscious, they will not have a pulse that you can feel and this is a more significantly serious situation because you don’t have time.
If you have had a patient who's had a heart attack, you’ve still got blood supply to other parts of the heart and they can get to a hospital or to medical safety, but a cardiac arrest you need to respond to in a more urgent way.
Chris - So you can have a heart attack but not necessarily have a cardiac arrest? But you might do if you have a very serious heart attack and it causes an electrical problem in the heart?
Sharon - Yes. If it’s a significant heart attack it can cause damage to the main pumping chamber of the heart, which actually causes the heart to get into a stunned state. It doesn’t pump effectively and then you go and have a cardiac arrest. Or you can have a heart attack which causes direct damage to the electrical circuits within the heart which can cause a cardiac arrest.
But you can also have a cardiac arrest without having a heart attack. So people who’ve had previous damage to their heart can get abnormal electrical circuits within the left ventricle which can cause some problems and they can go on and have cardiac arrests without having a heart attack at the specific time.
Chris - And Tian, after someone’s had a heart attack how does the heart recover, and is the damage to it permanent or does it get better?
Tian - Unfortunately, the heart does not regenerate itself, so the cells that have died or have become permanently damaged usually stay that way and become scar tissue. Some parts of the heart which have been partially damaged can recover so you do get some recovery of the heart but, unfortunately, a large part of it is permanent.
12:01 - The link between air pollution and heart disease
The link between air pollution and heart disease
with Professor David Newby, University of Edinburgh
Now one of the reasons why someone might suffer a heart attack, slightly surprisingly, is air pollution. And according to the World Health Organisation (WHO), "air pollution is now the world's largest single environmental health risk", and rates of heart attacks and strokes surge on days with low air quality. Why though was always a mystery, until scientists in Scotland began asking volunteers to breathe in gold nanoparticles, Chris Smith spoke to David Newby, British Heart Foundation Professor of Cardiology at the University of Edinburgh.
David - What we know about the particles of air pollution is they’re tiny. They behave like a gas so they get really deep down right into the alveoli of the lungs, which is the base sack right at the very bottom. And we believe that some of these particles, either within cells or on their own, jump across into the bloodstream.
Chris - When you say jump across; so I breathe in some particulates from the street out there they’ll get right into the bottom of my lung and then they’re actually getting into the blood so particles of traffic pollution are travelling around my body, you think?
David - So that’s been one of our challenges actually to design a study to see whether they can actually get into the bloodstream. So we did this study taking gold nanoparticles and got people to breathe in a fine aerosol of these particles, which were the same size as you get out of a diesel engine, for example. The reason we chose gold is it’s not harmful; it’s inert. But the second reason is the body shouldn’t have any gold inside it so if we can find evidence of gold inside the body then it must have come from these inhaled particles.
So what we did is we got various people, healthy volunteers to begin with, to breathe in a very fine aerosol vapour of gold. And what we found was that when we took blood samples for them for days and hours after they breathed it in, we could start to detect the gold. And it’s present in their blood and it’s present in their urine, so not only had it gone into the blood, it had been filtered out by the kidney, gone into your bladder and there it was in your urine.
So the next thing we did was say well, that’s a bit scary, what about patients who’ve had a stroke or something like that? Because when you’ve had a stroke, if you have disease in your neck - your carotid artery - there’s often a furring up and plaque which is what causes heart attacks and strokes and these people often have that removed surgically. So what we did is we got them to breathe in the day before their operation some of the gold particles. They went through surgery and they took out this plaque, and then we analysed that plaque to see if we could see any gold in it and, low and behold, we did.
So what that’s telling us, is okay gold’s not the same as what comes out of an engine, but they’re the same size and we could prove that these particles have gone from the lung into the bloodstream, and actually gone to the diseased areas of the body. And that’s quite a powerful message really.
Chris - It doesn’t tell you though that when they get to that site in the body that they’re the cause of the mischief though?
David - Absolutely not, no. And what it’s just showing is that it gets to there. Now we have done some experiments looking at how blood vessels behave when you’ve been exposed to diluted diesel exhaust. So we did some studies in Sweden, they had an exposure chamber where we diluted down diesel exhaust and got people to cycle in it.
Chris - Hang on a minute. So you put people in a shed and pipe in diesel exhaust and say just breathe this on an exercise bike?
David - Yeah, it’s… yes. Some people have challenged us with that. In fact, the BHF, some of the office staff raised it with me, and I pointed out to them that the dilute exposure that we’re giving was the same as the pollution monitoring station round the corner from the British Heart Foundation headquarters.
Chris - So the average person wandering around in London is breathing in equivalent air quality to what your victims, if I can call them that, in your study were breathing?
David - Yes, essentially. I mean, on a polluted day, if you’re walking down Oxford Street that’s what you would be exposed to, so it is within the realms of real world. Now in some parts of the world it’s lower what we put in the chamber than what people will be exposed to walking around a major mega city.
Chris - And what happens?
David - What we found was when we tested their blood vessels, the blood vessels don’t relax as much. They don’t release as much of a certain protein which helps dissolve blood clots. And when we looked at how much the body forms blood clots, you're much more likely to form blood clots when you’ve been exposed. And all of these things we know are associated with why you have a heart attack.
The final thing that we did, we got some patients who’d had treatment for heart disease to wear a heart monitor. And when they cycled in the presence of the diesel exhaust then we could see two to three times higher stress in the heart than when they did the exact same exercise when it was filtered air and not dilute diesel exhaust. So there’s clearly a huge connection between an acute exposure and the physiology of the body and how it behaves.
Chris - Does that argue then that there’s not really any safe level of exposure?
David - At the moment what we have is associations. But the associations that we’ve looked at there doesn’t seem to be a bottom level that people have identified as yet, which is slightly worrying because you could say well you know, this is just a problem for the third world countries and mega cities that are polluted. But actually, even within current air quality standards, there’s evidence of still some residual risk and that if we get the air quality better, the risk will go down further.
Chris - London’s on that list. It’s got one of the worst air qualities in the world and this is a first world country. It’s one of the most important cities in the world.
David - It is. And we do need to do something about it. We need better active transport. We need people to get out of their cars, get on their bikes, walking, using vehicles that are low emissions. We need to do this together as a society.
18:44 - Can your gut bacteria cause high blood pressure?
Can your gut bacteria cause high blood pressure?
with Dr Dominik Mueller - Max-Delbruck Centre for Molecular Medicine, Dr Sharon Wilson and Dr Tian Zhao - Addenbrooke's Hospital, Cambridge
Doctors have cautioned us for decades that increased salt intake leads to high blood pressure, and there are lots of studies that support the association. But why this happens no one really knows. Could it be though, Dominik Mueller from the Max-Delbruck Centre for Molecular Medicine in Berlin, wonders, that dietary salt affects our gut bacteria, which in turn affect the immune system and this causes the high blood pressure? He doesn’t know for sure, but it does look like low doses of microbes might reduce the risk of hypertension, because mice fed on high salt diets - or chow - and probiotics don’t get high blood pressure. Plus, cardiologists Sharon Wilson and Tian Zhao explain other risks to high blood pressure...
Dominik - We know that salt promotes cardiovascular disease and a rise in blood pressure, and whether this is somehow related to any interaction with the bacteria was the aim of the study.
Chris - What did you do?
Dominik - We started in mice and gave mice a standard control with normal salt and one with high salt and we wanted to find out whether we get changes in these bacteria.
Chris - When you say changes, do you mean as in the types of bacteria that live there or do you mean the way those bacteria behave, or both?
Dominik - Both. The first thing is that you screen the abundance of bacteria, the composition of the different bacteria to identify which bacteria reacted and we came up with a short list of eight bacteria, and then we could focus on the top listed candidate, which was a lactobacillus. And then we focused more specifically if we would use this one for a kind of treatment whether we could improve cardiovascular health and affect the blood pressure regulation.
Chris - When you give the salt diet, and then you see these changes in bacteria, is this reflected in a change in the blood pressure of the animals though?
Dominik - This is a tough question because we cannot definitely say that if you decrease the lactobacillus that this increases the blood pressure. It could also be that both happen in parallel. We did the other way round. We supplemented with lactobacillus and we could prevent the increase in blood pressure.
Chris - What about if you take animals that don’t have any bacteria in their intestine, the so called “germ free” mice? They’re born, they’re never allowed to be colonised by bacteria. Do you seen any influence if you do the experiments there?
Dominik - We could not, at the moment, measure their blood pressure because you have to do surgery to implant the blood pressure measurement device, and as soon as you do a surgery you open the possibility for contamination with bacteria and, therefore, this experiment was not done yet.
Chris - Putting all this together then, would your idea be that high salt in the diet changes the spectrum of bacteria that live in the intestine this, in turn, in some way, signals to the cardiovascular system and translates into changes which include an increase in blood pressure? Is that a reasonable summary of where you think you are?
Dominik - Again, we have to be careful about causality. We know that the chain you have mentioned exists. Whether one depends on the other is not clear yet. However, if you turn it around and if you think of strategies to supplement the missing bacteria by taking a probiotic you can prevent the increase in blood pressure. And we are currently setting up a clinical study where we want to test this in humans.
Chris - Do you have any theories as to how this is protecting the mice when they have the right spectrum of bacteria or the right levels of bacteria so that in these animals, at least, they don’t appear to get the high blood pressure?
Dominik - We learn more and more that cardiovascular disease and hypertension depends on the immune system. In the gut we have a big number of immune cells and it is known that the microbes affect the immune system in the gut. And new research in the cardiovascular field also demonstrates that the immune system plays an important role in the regulation of blood pressure. So we speculate what we eat might have an influence on the gut, on the gut immune cells and, therefore, on the development of high blood pressure.
Chris - And that’s a trial you’re doing, is it? You’re actually taking adults and supplementing them to see if you can get a change in their blood pressure in response to giving them more probiotics?
Dominik - Yes. We are currently in the preparation phase of this clinical study, and this will be exactly the question we will want to ask.
Chris - Be interesting to see what that shows won’t it? Dominik Muller; he’s from the the Max-Delbruck Centre for Molecular Medicine in Berlin.
Now, in the studio with me this week are Cambridge cardiologists Tian Zhao and Sharon Wilson:
Sharon, we were talking about high blood pressure there, but why does high blood pressure damage arteries and increase your risk of heart disease?
Sharon - Well, if you’ve managed to think about your blood pressure, the harder your heart has to work the more strain you’re putting on your heart. You’ve got basically changes that are based on the vessel wall, so the wall is getting stiffer and everything is sort of getting a little bit harder for it to distend or to change in shape. You also have the effect directly on the actual heart muscle where if it has to maintain a higher blood pressure, it gets thicker. As it gets thicker, the heart doesn’t relax particularly well so it has to work harder again to relax and contract and fill with blood in order to get blood to go forward. So there’s a couple of effects of why we prefer your blood pressure to be within the target range.
Chris - Also, it intuitively feels to me as though blood rushing through blood vessels which are tighter at higher pressure is more likely to damage the blood vessel than blood which is flowing in a more sedate way? Is that a reasonable synopsis?
Sharon - We more say with valvular disease from a heart rather than actual blood pressure changes. It’s more the distensibility of your vessel is the main issue with having a higher blood pressure.
Chris - And it’s not just your heart that’s at risk from hypertension is it. Tian? You could get other bits of your body which are going to get damaged by blood pressure that’s too high?
Tian - Indeed, yeah. The organs that mainly are affected are the brain, in which case we get strokes. The heart, that we’ve discussed and also the kidneys. We know that every 2 mm of mercury increase in your blood pressure you get a 10 percent increase in your stroke risk, a 7 percent increase in your heart risk. So the closest correlation actually is with stroke.
Chris - And normal blood pressure is 120 over 80 give or take?
Tian - Well, give or take, yeah. It’s what we aim to achieve. Often patients don’t achieve that, but the closer we get to that the lower your risk.
Chris - Now, Dominik was talking about salt in the diet and his theory is that this, or at least is partly attributable to its effect on microorganisms in the gut which might make the immune system make you have higher blood pressure. What other theories are there for why salt intake puts your blood pressure up?
Tian - We know quite well that the more salt you eat the higher the blood pressure, but the reason of that is not well understood. When that’s the case in medicine, often the reason is it’s that there’s a number of reasons all coming together. We know that, as you eat more salt, the more salt in your body, the body retains water to balance the concentration of salt in the body. And, as more water is retained, there’s more volume and therefore the blood pressure goes up is one idea.
Chris - The thing that I find wrong with that is that actually it appears to be how long you’ve been exposed to salt over your lifetime that determines your blood pressure, doesn’t it? Because I could eat shovelfuls of salt tomorrow, I might get a short term increase in my blood pressure but then it would go back to normal. But if I carried on doing that day after day after day relentlessly, I’m not going to swell up like a balloon so I can’t continually be taking on board water, there must be something else going on?
Tian - Well, the idea is that there’s a thermostat in the body which controls how much salt one should take in. With a prolonged exposure of salt over time that thermostat is adjusted to retain more and more salt, and the result of a number of years the blood pressure goes up. That’s probably why we see it as a disease of ageing as well. As people get older, people get high blood pressure.
Chris - And linking that to what Dominik Muller was saying, is it possible then that that thermostat for salt could be being influenced by what the dietary conditions are, or what the microbes in the gut are saying to the brain and the cardiovascular system?
Tian - Exactly. There’s several factors which could be influencing the thermostat and gut bacteria could certainly be one of those.
27:36 - Do Zombie cells promote arterial disease?
Do Zombie cells promote arterial disease?
with Professor Martin Bennett - Cambridge University
It’s a fact of life that we’re all ageing, all the time. And as we age, an increasing proportion of the cells in our tissues become “zombified”: they aren’t dead, but they’re no longer properly alive either, and they’re definitely trouble makers. Speaking with Katie Haylor, Cambridge University’s Martin Bennett studies how these so-called "senescent cells" might be linked to heart disease...
Martin - Cell senescence describes a point in a cell’s life where it can no longer divide. It’s basically reached old age in cell terms but it hasn’t quite yet died. The importance of that is that the cell can’t fulfil its function, and is also at that stage generates inflammation. There’s a lot of excitement about cell senescence at the moment. A whole range of diseases. So senescent cells have been identified in heart disease, in dementia, in liver disease, in kidney disease, in arthritis. And increasingly we’ve been able to work out the consequences of having senescent cells. What that means is there may be potential treatments based upon eliminating these cells in the future.
Katie - Can you explain how this relates to a concept of a whole person ageing?
Martin - As we age, a greater proportion of our cells become senescent. There are certain tissues in the body which constantly regenerate, so your bone marrow for instance regenerates forming blood, but many other tissues can’t regenerate if they get damaged, particularly the brain and heart. What that means is that as the cells age, they are not replaced and you have more and more of these sort of almost like zombie or undead cells around the body. They’re not killed, they’re not cleared, but they can cause damage.
Katie - So they’re kind of dormant?
Martin - No. They’re not dormant because they’re very, very active. They can’t fulfil their function, so if they’re a liver cell they can’t perform a normal function to the liver cell or a kidney cell, likewise, or a heart cell or a blood vessel cell. But what they do do is lots of detrimental other things. They signal to other cells causing inflammation.
We’re particularly interested in cells that make up the blood vessel lining, because when those become senescent, again, they can cause problems with the blood vessel function. But we study patients who have heart attacks or have strokes and those diseases are caused by what’s called “atherosclerosis.” Increasingly, we can find senescence cells in those atherosclerotic plaques. They cause a problem because they promote inflammation and they stop the normal blood vessel cells functioning properly.
What’s exciting is some fairly new data that’s come out that suggests that if you clear those cells, then you can improve the functioning of many many organs in the body, and you may even be able to prolong lifespan. So we talk about lifespan and healthspan. Healthspan is the number of years that you have of healthy living. Lifespan is, obviously, until you die. And removal of senescent cells may actually promote and improve function of many organs as well as potentially improving lifespan as well.
Katie - Wow, okay. So there is the potential to extend the life of organs? Even ourselves, or is that in the realm of science fiction?
Martin - No. It’s not in the realms of science fiction. Certainly, in animal models, removal of these senescent cells has been shown to improve function of many many organs. To slow, or in some cases, partially reverse particular diseases and, in some creatures, can actually extend their lifespan as well.
Katie - Is there any possibility of instead of removing these senescent cells, these cells that are no longer dividing, of reactivating them in some way?
Martin - Yes. Another option is instead of removing them is just switching them off. So if you don’t get rid of them but you just stop them producing things that cause inflammation; that may be just as good. Switching them back on again is more challenging because they have irreversibly reached this state, and if you try and kick them back into making them divide, then the danger is you might generate cancer. So we would prefer to either get rid of them or just switch off the proinflammatory side of things.
Katie - What would you envision for the next 5/10 years in terms of finding these senescent cells and getting rid of them?
Martin - We’re getting much much better at finding them. And we’re getting very much better at working out how they signal, how they’re controlled, and what their consequences are. There’s also major interest now from industry, to design drugs to remove these cells silently. Because you can imagine, if they’re present throughout the body, and if you can remove them, then you may improve functioning of many many organs associated just with ageing.
33:35 - How to prevent heart disease...
How to prevent heart disease...
with Adam Murphy & Marika Ottman, The Naked Scientists
Adam Murphy and Marika Ottman have more quick fire facts; this time on simple ways you can reduce your risk of having heart problems. Plus, Addenbrooke's cardiologists Sharon Wilson and Tian Zhao join Chris Smith and explain what drugs are available for treatment.
Marika - Heart attacks are very common: one person in three will be directly affected by heart disease during their lifetime.
Adam - There are lots of factors that increase the risk of developing heart disease.
Marika - Smoking is probably the most important one. Toxins in cigarette smoke damage the walls of arteries, increasing the chances that they will furr up and block. Nicotine, meanwhile, puts up blood pressure. So don’t smoke!
Adam - Family history is also a huge factor. If you have close relatives who developed heart disease or suffered heart attacks at a young age then there could be a genetic component, and that means you might have a higher risk too.
Marika - This includes being affected by a condition called “familial hypercholesterolaemia.” This is where the levels of cholesterol are too high in the blood, making it more likely that the cholesterol will build up in the walls of arteries, causing them to narrow.
Adam - You can have a test to monitor your cholesterol levels and tell whether you are at a higher risk.
Marika - ...and if your levels are high, fortunately there are drugs called “statins” that can reduce the production of cholesterol in the body, lowering the level and cutting your risk.
Adam - Statins are very safe and very effective: they can reduce your chances of having a heart attack by up to a third.
Marika - High blood pressure - or hypertension - is another major risk factor for heart disease.
Adam - Blood pressure that is regularly too high damages the linings of our arteries, increasing the chances that fatty deposits, called atheroma, will build up and narrow the artery.
Marika - You should ask your doctor to check your blood pressure next time you visit.
Adam - But don’t be alarmed if it’s apparently high the first time you take it: you might just be stressed, or one of a number of people with a condition called “white coat hypertension” which means their blood pressure goes shooting up whenever they go near a doctor!
Marika - If that turns out to be you, you can buy a home blood pressure monitoring machine and take your own blood pressure regularly when you’re relaxed at home.
Adam - If it’s still high under these conditions, you might need drugs called “antihypertensives” to bring your blood pressure back down to normal levels, which will dramatically cut your heart attack risk...
Marika - Another good way to reduce blood pressure and benefit your health overall is to take regular exercise.
Adam - This doesn’t mean that you need to go mad: park your car a bit further from work and walk the rest of the way; take the stairs rather than the lift when you can; cycle to the station; or get a dog and take it for a daily 20 minute walk. It all adds up.
Marika - And exercise is a great way to stay in shape, which is also important…
Adam - ...because being overweight is also a big heart attack risk factor: it increases cholesterol levels, puts up your blood pressure and you’re more likely to develop diabetes, which is a serious cardiovascular risk factor in its own right.
Marika - Diet is also very important: regularly eating fresh fruits and vegetables, reducing red meat consumption and avoiding fatty foods like chips, fried and fast food all helps, and alcohol in moderation of course!
Chris - Of course. Just the one bottle of shiraz then, rather than two!
With me are cardiologists Tian Zhao and Sharon Wilson. Now Sharon, we’ve heard people talking on the programme about high cholesterol and we heard Adam and Marika mention statins to control cholesterol. What are statins and how do they actually work?
Sharon - Statins basically interfere with a way that the body processes cholesterol to block it from being produced within the liver. So if you’ve got a reduced amount of cholesterol coming out of our liver, your blood levels naturally drops, but then you don’t go on to develop atheroma within the vessels of interest such as those within the heart.
Chris - What about how well tolerated they are?
Sharon - Statins are relatively well tolerated; the problem that we have is when people are on very large doses of statins. There’s a large range of the medication so that we can start at a fairly low dose up to a very very high dose. When people come into the hospital after having a heart attack we start them usually on a very high dose, and you need to go back to your local doctor or your local cardiologist to adjust your dose back to an appropriate number, depending on how your cholesterol responds.
Chris - Does everyone respond to a statin or are there some people that just can’t be dealing with them?
Sharon - The majority of people actually do respond quite well to statins but there is a subset of population that do have quite significant side effects. We’re talking about muscle pains with the top of your legs - you’re unable to get out a chair. And there are other alternatives of different medications that are available on the market that can help these people as well.
Chris - Now Tian, some people say that they regularly take aspirin - just a baby aspirin 75 milligrams a day. And they do that despite not having had a diagnosis of heart disease or heart attack, they do it because they believe it will reduce their risk in the long term. Is there merit in that argument?
Tian - That’s not the advice I would give to the public. I think if you’re worried about your risk of having heart disease, I think you should go to your primary care doctor - your GP - and have a discussion about it. And there are quite sophisticated ways we can try and calculate your risk, and depending on what that risk is there’s different advice we can offer. Aspirin is a very good drug but it’s not without side effects, and it is unfortunately an irritant of the stomach, for example, and can cause stomach ulcers. So it’s something, I think, that people should discuss with the doctor. Doing that consultation there are great alternatives to medication; for example lifestyle changes. Things like that to reduce your risk and not just taking tablets.
Chris - Many of the interviews that we’ve heard here have talked about inflammation in your arteries as a cause of arterial disease. Since aspirin is an anti-inflammatory, is there not one school of thought that could argue, "if I take an anti-inflammatory, I could slow down the progression of the inflammation and, therefore, the progression of arterial disease, particularly in people who might be at high risk of a heart attack". For example, they’ve got a very strong family history or very high cholesterol, high blood pressure, stressful job, etc?
Tian - That’s a great thought. We’ve looked at aspirin as an anti-inflammatory in heart disease. Unfortunately, most of the data which shows it acts as an anti-inflammatory is at much higher doses than prescribed clinically and, therefore, I think the majority of the effect is not there...
39:47 - A vaccine against heart attacks
A vaccine against heart attacks
with Professor Jan Nilsson, Lund University
One in three people is destined to develop vascular disease - meaning furred-up arteries - that can cause heart attacks and strokes. But might it be possible to vaccinate people against this happening? Speaking with Chris Smith, Swedish heart specialist Jan Nilsson, at Lund University, explains how has a way of doing just that…
Jan - The disease I’m interested in atherosclerosis where fat accumulates in the arteries; this is mainly cholesterol. And we know that this cholesterol is being oxidised and that induces inflammation in the artery and the inflammation activates scar process which give rise to plaques which are focal thickenings of the artery. The worst outcome of this they may rupture and then you get the thrombosis which occludes the artery and that’s the main cause of myocardial infarction or a stroke.
Chris - How do you think we might be able to intervene? Because there are drugs that will lower the cholesterol level, and that’s one approach, but how else might we be able to intervene to reduce the risk of this happening?
Jan - Yes, that’s correct. We have the statins which reduce optimally the risk by 50 percent. We have the remaining 50 percent where we need to find new types of therapies and we think that one could be to get the immune system to help.
Chris- So what, like a vaccine against arterial disease?
Jan - Yes. What happens is that when the cholesterol is oxidised in the artery, it changes structure so the immune system can’t recognise this, so it assumes this is something that comes from a bacteria virus and it attacks it.
Chris - Oh, that’s intriguing. So if you could therefore what: educate the immune system that it’s not harmful when it’s in the oxidised; it wouldn’t be so harmful? Is that the rationale for your approach?
Jan - Exactly. The optimal way for the immune system to react is to recognise this as damage self substances, and try to clear it away and we can try to educate the immune system to do just that.
Chris - How?
Jan - You take a piece of the bad cholesterol molecule, which is called “LDL” and with adjuvants that directly stimulate the generation of these protective immune cells, then you can get the immune system to act protectively.
Chris - Right. So by introducing the immune system to what the oxidised bad form of the cholesterol looks like, with something to make the immune system get excited, that’s the adjuvant, you should get what: an antibody, or immune cells, or both in response to that?
Jan - Yes, there are two types of protective responses that you can activate: one is the antibodies which can then just help to clear away these oxidised LDL. The other one is to activate a form of immune cells which are suppressive, so the go in and act anti-inflammatory and by that way they can stabilise the vascular wall.
Chris - So this is like a two-pronged approach then? On the one hand you’ve got the immune system being able to remove the bad cholesterol and, on the other hand, you’ve got the immune system saying: now don’t get too excited by this cholesterol, it won’t harm you?
Jan - Yes. That’s a very good way to describe it. Actually, rather than making the immune system making thing worse, you can get the immune system to help.
Chris - If one considers a different approach though, which is for Alzheimer’s disease one pharmaceutical company had a vaccine which made a person’s immune system go into the brain and find the protein that was building up that was causing Alzheimer’s disease. The idea being it would remove that protein. The trial for that had to be stopped because the brain became inflamed when they did that. Is there not a danger that with what you’re doing, if you’re programming the person’s immune system to recognise the bad cholesterol, if they’ve got arteries full of it throughout their body could they not get worse inflammation?
Jan - Yes. We learned a lot from that study. And the mistake they did was to choose an adjuvant that made the immune cells very aggressive and that ended up that the immune cells did more harm than protection. So we learned a lot there so we can now choose adjuvants to get milder responses for the immune systems; for example focussing on generating antibodies rather than an aggressive immune cells.
Chris - What stage are you at; are you actually doing this now? Do you have a vaccine that can do what you’re suggesting you’d like to achieve?
Jan - We have a vaccine which we can show works well in experimental models. We’re now developing so it’s safe to give to humans. Then we hope to be able to do a first clinical trial in a couple of years.
Chris - When you say an experimental model, what are these; mice or something?
Jan - Yes, these are mostly mice that we use as experimental models for atherosclerosis.
Chris - So what did you actually do with the mice, and how were they affected by the vaccine?
Jan - We gave the mice a high cholesterol diet.
Chris - What’s that like rodent junk food?
Jan - Sort of!
Chris - And what happens when you do this?
Jan - In the mice we can see that the formation of the astherosclerotic plaques is reduced by about 50 percent.
Chris - That’s a lot!
Jan - That’s a lot. And we are quite optimistic that that could be something that makes a difference clinically.
Chris - But if you can get such a dramatic difference, why is this not already in clinical trials? Why has a pharmaceutical company not chewing your arm off for access to the technology, or are they?
Jan - Unfortunately, not at the moment. There are safety concerns that we have to take seriously. Nobody has used this type of therapy before so there is obviously a risk that we could induce some sort of adverse immune response which we can’t stop, so we have to be sure that we’re doing the right thing. The safety tests that we need to do before needs to be done carefully, and they take time.
45:51 - Diabetes drug prevents heart attacks
Diabetes drug prevents heart attacks
with Dr Ify Mordi, University of Dundee
Developing new drugs is extremely costly: the estimate test-tube to needle time for a new agent is ten years and the price tag is billions. But, it might not always be necessary to invent a new drug if you can find an existing drug that happens, as a side effect, to have a beneficial effect on the heart, which is what Ify Mordi, from the University of Dundee, has done with the diabetes drug metformin. Katie Haylor spoke with him...
Ify - Metformin is used a treatment used for Type 2 diabetes. It reduces insulin resistance, causes you to lose weight and this is obviously beneficial in terms of your general health. It also is associated with improvements in the metabolism of the heart. One of the pathways that we do know about and is more well understood is that metformin acts on a substance called AMPK, which is Activated Protein Kinase. This substance is involved in molecular signalling within the heart and is associated with the fibrosis and enlargement of the heart muscle. Metformin reduces this and, therefore, this is one reason why it may have beneficial effects on the heart.
Katie - First of all, how do you go about linking a drug that’s being used routinely in diabetes with a heart condition?
Ify - Numerous studies have been done which have shown that metformin is beneficial in patients with diabetes and large studies, including done in the UK, have shown that metformin use in patients with diabetes is associated with reductions in heart attacks. In fact, in one study there was a striking 33 percent reduction in heart attacks and strokes in patients using metformin compared to other diabetes drugs.
So this suggested to us that perhaps metformin was having beneficial effects on the heart muscle. What we wanted to do was to try and translate this to use this in patients without diabetes. It’s something that hasn’t been done before and this is the really exciting bit of our research.
Katie - So how do you go about doing that then?
Ify - The research was done in two parts, and the first part was to look at electronic health records of patients that were using metformin that has a condition which predisposes to thickening of the heart muscle called “aortic stenosis.” This is a condition where there is narrowing of the main heart valve that lets blood out of the heart. This increase in pressure causes the heart to have to do more work. The heart muscle thickens up, which includes fibrosis and scarring of the heart muscle.
Katie - Okay. So take us back to your study.
Ify - The first part of the study was a retrospective study where we looked at people with this condition called “aortic stenosis.” In this condition, diabetes is associated with worse outcomes, so people with diabetes and this thickening of the heart muscle are more likely to die because of this. And what we found was that the diabetic patients in the study on metformin had a similar outcome as the patients who were not diabetic. In contrast, diabetic patients who weren’t taking metformin had a 44 percent increased likelihood of having a heart attack or a stroke that lead to death. This suggested to us that metformin use was associated with better outcomes and less likelihood of dying of a heart problem.
Katie - Presumably now you need to do this with people who don’t have diabetes at all, so is that what you did next?
Ify - Yes, exactly. What we did in this study, which was called “The MET REMODEL Study,” was to look at patients with previous heart attacks, and they also had thickening of the heart muscle. One group were given metformin treatment for a year and the other group were given placebo, and we studied the thickening of the heart muscle at the start of the study and at the end of the study after one year.
What we found was that the patients in the metformin group had twice as much reduction in the heart muscle size compared to the patients in the placebo group, proving for the first time in humans that metformin use was associated with the reduction in this adverse thickening of the heart muscle.
Katie - What happens next then?
Ify - This has provided us with some evidence that metformin could be used in this purpose. What we need to do now is to look at this in a large group of patients to see if this truly does lead to improvements in heart attacks and strokes in patients without diabetes.
49:36 - Nanoparticles tackle heart disease
Nanoparticles tackle heart disease
with Dr Patrick Hsieh, Academica Sinica, Taiwan
When a person has a heart attack, it’s usually because a blockage has formed in one of the coronary arteries that supply blood to the heart muscle itself. This cuts off the supply of oxygen and nutrients to the tissue, which begins to die. One consequence of this is that the immune system moves in triggering inflammation, which can add further insult to the injury and exacerbate the damage. But drugs that can damp down inflammation can’t currently access the injured tissue very well. So a canny scientist from Taiwan has designed nanoparticles loaded with an anti-inflammatory drug cargo that can piggy back on the very same immune cells that migrate from the bloodstream into the damaged heart. Chris Smith spoke to Patrick Hsieh.
Patrick - What we’ve been trying to do is improve cardiovascular repair and regeneration after injury, particularly for a heart attack. Because after the cardiovascular event they will have ischemia which will cause tissue damage, and eventually they also have inflammation that will cause more and more damage to the tissues.
Chris - So when someone has say a heart attack and there’s a lack of blood flow to the heart muscle, that directly causes damage. But you also get inflammation and the inflammation causes damage and you’re saying you want to find a way to stop the inflammation?
Patrick - Right. Because the ischemia or lack of blood flow is short term damage. Information can prolong for weeks or even months and that causes progressive damage to the tissue.
Chris - So how are you trying to do this? How can you control the inflammation?
Patrick - We are tried to develop an anti-inflammatory drugs into the tissue but, as you can imagine, it is very difficult to directly deliver drugs into the injured sites, so we need some new technologies to help us.
Chris - But we’ve got lots of anti-inflammatory drugs - things like aspirin which we’ve had for a 100 plus years, so why is it a problem getting the drugs into the tissue?
Patrick - Because, as you can imagine, whenever you take a drug or you receive an injection of drugs they will be circulating into the whole body with very few going to the heart. So we need to develop a new technology to help them get to a specific area; one to deliver the drug for the heart.
Chris - And how are you doing that?
Patrick - We use nanotechnologies. We formulate nanoparticles and we load the anti-inflammatory drugs in the nanoparticles. And then we can add new targeting materials outside of the particles so once we inject it, the new nanodrugs, they will be specifically targeted to the heart.
Chris - Right. So you build a new nanoparticle that's got the drugs inside, but your problem is still how you get the nanoparticle to do where it’s needed. So you’ve got some crafty way of making the nanoparticle do that, so did you get the nanoparticle into say the injured heart then?
Patrick - We learned from mother nature. There are cells in the circulation called “monocytes.” They naturally we will go to the site of damage of the heart and we developed the nanomedicines which can stick to the monocytes so they will be brought into the damaged areas for delivering of the therapeutic drugs.
Chris - That’s crafty! So because there are these cells naturally going to damaged areas you’re piggybacking those cells with your nanoparticles to get your drug only where it needs to go?
Patrick - Exactly.
Chris - How do you persuade the nanoparticles to stick to the monocytes?
Patrick - During the monocytes targeting to the heart platelets and other type of cells, they will stick to the monocytes. So we fabricate the nanomedicines with similar sticking abilities of the platelets so once we inject them into the circulation they will stick to the monocytes and be brought to the injury sites.
Chris - So let me make sure I’ve got this correct: there are monocytes in the bloodstream and they naturally go where there’s damage. There are also bits of cells called platelets in the bloodstream which naturally stick onto monocytes, and where the monocytes go the platelets will go?
Patrick - Right.
Chris - So you’re stealing what the platelets do, putting that on your nanoparticles so your nanoparticles will stick to the monocyte and then be carted off into the heart to access the damaged area?
Patrick - Right. That's the power of what we said: we learn from mother nature.
Chris - Does it work? Do you actually get more drug going in by doing this?
Patrick - Yes, we did. We can increase 50 fold or more drugs to be delivered into the injury site.
Chris - 50 fold: that’s a lot. So if you were just to measure how much drug if you popped a pill versus if you did it the way you’re doing it, you’re saying at least 50 times more drug goes in?
Patrick: Typically, if you just simply inject a drug into the circulation, then less than 0.1 percent of a drug would be in the heart. But by the technology we’ve developed we can achieve 5 percent or even more of the drugs to be delivered to the heart.
Chris - And when you do these experiments, if you take a heart that’s been experimentally damaged by a heart attack, do you actually see a reduction in the level of damage when you use these particles that you’ve developed?
Patrick - We created animal models for heart attack and we find that by delivery of these drugs we can reduce the heart damage size by 50 percent. We can improve the cardio functions by 50 per cent as well, so such doings we can prolong the heart functions and the animal life as well.
Chris - As anyone tried to do what you’re doing before or is this a first trying to do it this way?
Patrick - This is a first.
55:20 - The future of heart research
The future of heart research
with Dr Tian Zhao and Dr Sharon Wilson, Addenbrooke's Hospital, Cambridge
The final word went to Cardiologists, Tian Zhao and Sharon Wilson, from Addenbrooke's Hospital. Chris Smith asked them what areas do they think are the most promising, or the most important, to surmount matters of the heart...
Tian - I think inflammation is the next frontier, right. These narrowings in the heart which cause heart attacks; they’re made of lipid or cholesterol or fat, we know that.
Chris - In the arteries that supply the heart muscle?
Tian - In the arteries, exactly. But it’s more complicated than that; it’s about how the body reacts to this lipid, and inflammation is a major part of that. And we’re here in Cambridge doing great work trying to treat that inflammation. We saw Professor Bennett talking about the senescent cells that are causing the inflammation and he’s doing great work trying to treat them. And I think that goes back to the very nature of human beings, of ageing.
Chris - Sharon?
Sharon - I’m more a clinical cardiologist, so I’m more interested in the new work that’s happening with biomarkers and actually getting the patient sorted out. So it’s very worthwhile to have lots of work within research in the basic science, but we also need to remember the person at the end of the equation is a patient.
Chris - Indeed. Now when you say biomarkers, what does that mean?
Sharon - So that’s looking at assays like troponin or what you’ve previously mentioned of the myosin C, of ways of detecting is a person in front of me having a heart attack or having damaged their heart at this exact point? How can I prevent them from having a major issue, and how we can treat them through the system efficiently and effectively?
Chris - Many people argue though that by the time you’ve got a person with a heart attack in front of you it’s a bit late, we should have intervened sooner. Are there any things on the horizon that enable us to make better predictions of the people who are at risk?
Sharon - So even using the biomarkers in a different way. So they’re using the biomarkers with myosin C primarily looking at diseases such as aortic stenosis, which is a valvular problem, rather than a heart attack. Then looking to see where is the point when intervene before the heart is actually sustaining damage? And that’s where I feel this is quite exciting. There’s also a lot of work with people who’ve had a heart transplant, looking at biomarkers there to see are we treating these patients effectively? How can we prevent them from rejecting their organs, and how can we made sure that the organs we have available are being utilised appropriately?
Chris - What about the role of genetics? We’ve got the Hundred Thousand Genome project in the NHS, for example. There’ve been enormous strides made in sequencing people’s genomes. Are we seeing strong associations between certain combinations or cocktails of genes and people who are at risk of certain types of heart outcome?
Sharon - We are. The Hundred Thousand Genome project is fantastic initiative, which the NHS is behind, and we have seen benefits even in our clinical practice to some of our patients who’ve had problems with a dilated aorta, or the big tube that come out of the heart. You’ve got particular association which you may not have a specific gene that’s been identified, but you can put their information in, get particular panels, get particular genes to identify new targets. You might have a person who’s in Swansea who has a problem, you might have a person in Cambridge who has a problem, and their clinical data you can try and get them to overlap to identify new targets. And I feel that that’s very important.
Chris - Yeah. The whole big data of being able to look at very large numbers of people, all at once across a population, that’s very valuable isn't it?
Sharon - Yeah. I think that’s where some of our greatest gains in cardiology is going to come from in the next couple of years.
Chris - Well I tell you what, we’re going to find out whether you’re right aren’t we? Because we’ll have to have you back in about five years time and see if actually your predictions have come true.
Sharon - That would be very interesting and I’ve a feeling I will probably win against Tian and his inflammation.
Chris - Well, I think the thing is you’re solution, Sharon, is slightly more attractable in terms of looking for markers and that can predict things. Whereas actually trying to intervene and change things is always going to be a bit more risky and that’s going to take a bit longer for you isn’t it?
Tian - We’re doing work already in Cambridge trying to get the next step, so we’re hopeful!