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At the Heart of Research: From giraffe & metronomes to 3D printers

This Science and the Healthier Heart presentation by Presentation by Professor Julian Paton PhD FRSCNZ, Manaaki Manawa, Centre for Heart Research, Medical and Health Sciences, The University of Auckland addresses the latest research into understanding and treatments for heart disease.

Watch the video and read the transcript of Prof Paton below and keep watching for more heart health research from Dr Nikki Earle.




First of all I'd like to start by thanking the Auckland Medical Research Foundation for this fantastic opportunity to talk about my research. It gives me a great pleasure to share what we're doing in terms of heart research. The title of my presentation “At the Heart of Research: From giraffe and metronomes to 3D printers” and that title will become obvious as we go through the presentation.


I want to start off by telling you a little bit about cardiovascular disease in New Zealand. I think most of us know of somebody with cardiovascular disease and the consequences of that particular disease. In New Zealand we have about one death every 90 minutes from cardiovascular disease and that means one in three deaths in our country is caused by cardiovascular disease. The mortality in our Māori population is at least twice that of our non-Māori population and that presents an unacceptable inequity and that's something we'd really like to resolve. Currently there is no treatment for heart failure which of course is a major goal and aspiration of what we're trying to do here at the University of Auckland.


So how do we go about doing that? To resolve that we have set up a new Heart Research Centre established in July 2019 called Manaaki Manawa. This is the Centre for Heart Research located and hosted at the Faculty of Medical and Health Sciences at The University of Auckland. I want to give a big shout out to our fantastic Research Operations Manager Lisa Wong, who together with myself directs Manaaki Manawa, and has played a vital role for mobilising this new Heart Research Centre.


I'm just going to spend a little bit of time telling you about the centre before I explain some of the exciting research that's going on.


The mission for Manaaki Manawa is “in partnership with Māori and Pacific People, create a vibrant world-class centre for heart research underpinned by evidenced based and multi-disciplinary research that delivers clinical benefits and equity to all in Aotearoa New Zealand”.


One aspect of that mission statement is the multidisciplinarity and that's quite unique because for the first time under our centre we've been able to bring together researchers from different avenues. Classically these researchers have always worked in silos and so we've gone around breaking down the silos and throwing everyone into the same mix. We have clinical scientists, biomedical scientists, epidemiologists, analytical scientists, bioengineering scientists, biomarker scientists and genomics scientists all working under the same roof together with our Māori and Pacific cardiovascular researchers. We are fully integrated into a multi-disciplinary approach to resolving some of the issues around cardiovascular disease inequity in New Zealand. This gives us an enormous strength.

Manaaki Manawa actually stands for “preserving the life force of the heart” and that name was gifted to us by Dame Naida Glavish.


I'm going to tell you a little bit now about some of the exciting research that we're doing and I'm going to block this into three compartments. I'm going to talk to you about a silent killer, then listening to nature, and growing your heart valve. These are three examples of some of the research that we're currently doing.

I'm going to start with high blood pressure which is a leading risk factor for death and disability in New Zealand. Around 20 percent of the population in New Zealand have high blood pressure which is similar in other countries globally. As you may know it's asymptomatic - it has no symptoms. Unfortunately it's 32 percent higher in our Māori population and remarkably 50% of the hypertension in our communities can be prevented. It is indeed a modifiable risk factor.

Let me talk a little bit about risk factors. I think the first thing to say and, as you can see below from this plot of blood pressure against age, is that blood pressure rises as you become older. As blood pressure rises it does indeed contribute to increasing the risk of a cardiovascular event such as stroke, a heart attack or heart failure, renal failure and can worsen diabetes. Now this risk obviously increases with age because blood pressure has increased and high blood pressure is a risk factor for these comorbidities. However, if you also smoke or drink excessive alcohol, are overweight, you lead a sedentary lifestyle, you have a high cholesterol or have a high salt intake, and/or have a family history this further increases your risk of a cardiovascular event. That's the epidemiological evidence for cardiovascular events and it's really now a matter of trying to understand what we can do about this.

Firstly, I want to tell you something that's come from some very recent data published this year about a disease called heart failure with preserved ejection fraction, which is a disease that's caused by high blood pressure. As you can see in the top left hand panel (next slide) we have a schematic of the heart. What high blood pressure can do to the heart is thicken the walls of the main chambers of the heart - these are the so-called ventricles. Not only do they become thicker but they also become stiffer which means when the heart tries to fill properly it can't fully dilate to allow new blood to come into the heart before it then contracts. Now it may well be that under resting conditions, where you're not exerting yourself you're okay, but it's when you start to exercise - when you need your heart to start pumping more blood - that the heart really struggles because it cannot fill to accept more blood, to pump more blood, because it's become stiff as a result of the high blood pressure.

Now we know this stiffening is caused by something called fibrosis, and it's an increase in fibrosis, and you have underneath the heart a picture of the heart at very high magnification (showing in red the muscle cells and in blue the fibrosis). You can see in somebody with heart failure with preserved ejection fraction there is a lot more blue - a lot more fibrosis. Now I'll tell you in a moment what that fibrosis is.


First of all I just want to let you know that if we look at a single heart muscle cell as depicted in the slide below (top right), every heart cell has little tubules that project into the inside of the heart cell. This is important to allow the heart cells to contract properly. What we've detected, and this is work from David Crossman's group, is that in these tubules there is a lot of fibrosis and that fibrosis is due to something called Collagen 6. Collagen 6 is a peptide - it's an important protein that helps hold things together. In the healthy condition you can see in green the tubules running in to the heart cell and you can see there's a little bit of red and that's the Collagen 6; but in heart failure with preserved ejection fraction you can see that the amount of collagen here is greatly enhanced which is causing it to become stiff.

The new finding is that we've detected a new biomarker for heart failure with a preserved ejection fraction and this is really exciting and important because, if we can catch it early, we can do something about it before it's too late. During the formation of Collagen 6 it releases a protein into the blood called endotrophin and we can now detect endotrophin in the blood. This recent study shows very nicely that if we look at survival of patients with heart failure with preserved ejection fraction against time over about four or five years, you can see those with high amounts of endotrophin don't survive too well, those with lower endotrophins survive much, much better. So the early detection of heart failure with preserved ejection fraction is now possible by measuring endotrophin in the blood. This will help preventing worsening of this condition but clearly further research is needed to assess what we can do to actually lower Collagen 6 in the first place and prevent stiffening of the heart.

I’m going to move on and ask a question now. What was the greatest invention to lower blood pressure? Surprisingly it was refrigeration and the reason it was refrigeration is because the development of cooling food prevented its preservation by addition of salt. This tells you something about a major cause of high blood pressure which is high salt. The other thing that helps to reduce high blood pressure is exercise and I just show this 24-hour fitness centre here in the United States with a bit of a tongue-in-cheek because you will notice that there is an escalator up to the fitness centre - both up and indeed back down again too. I think only in America would you have a fitness centre with escalators.

Now regarding the salt and high blood pressure - most of our drugs that are given to control high blood pressure are acting on the body to try and help remove salt and reduce the amount of blood volume by excreting water from our body. So if we look at treatment which is typically a, b, c, d standing for ACE inhibitors or angiotensin receptor blockers, beta blockers, calcium channel blockers and diuretics. You can see below how these drugs relate to different parts of the body and the main organs that are affected are the kidneys, the arteries, the adrenal glands and the heart. A, b and d will all help reduce the salt and water in the body and they will counteract a hormone called Angiotensin II which I want to come back to in a moment.


Angiotensin II is a hormone. It's been in animals for many many years. It originally evolved when animals moved from an aquatic environment out into land. Because when you move from water dwelling to land dwelling you need to preserve water and salt because you don't want to lose water through dehydration. However Angiotensin II is a major culprit for cardiovascular disease. Unfortunately, both in New Zealand and many other countries around the world, blood pressure is poorly controlled and there are a number of reasons for this. First of all we noticed that 50% of those that are treated for their blood pressure, so they're taking their drugs, still remain with hypertension, although blood pressure may be lowered they remain hypertensive. Those that are treated and controlled, that have normal blood pressure, remain at elevated risk for disease and that is quite an alarming fact. This would suggest that our current drug armoury is not preventing causes of high blood pressure but rather treating symptoms. So the question then becomes so what are possible causes of the high blood pressure? And, if we were able to treat those causes, we ought to be able to have a more effective way of lowering blood pressure in patients.

So I want to return to the idea that the nervous system, the so-called autonomic or automatic nervous system within our body, is contributing to high blood pressure. Indeed the heart as you can see on the slide below is covered in nerves. The nerves are in red. This doesn't matter if it's a human heart or an animal heart, there are nerves. These nerves are part of the parasympathetic nervous system because there are two types of nerves that innervate the cardiovascular system. Those that are parasympathetic and those that are sympathetic. We see clearly here a very rich innovation by the parasympathetic nerves carried in the vagal nerve that goes to the heart and originates from the brain.


Now I'd like to demonstrate with a short video the connection between the brain and the heart and the way I'm going to do this is, I'm going to activate the vagus nerve to the heart and the vagus nerve causes a slowing of the heart. The way that we can activate that vagus nerve is to stimulate cold receptors around your face - around your nose and your lips. These cold sensors are connected to a different part of the brain which eventually connects to the vagus nerve and activates it to slow the heart and this is called the diving response. So when you put your face into water your heart rate will slow down and the reason it slows down is to preserve oxygen usage because the body realises that you can't breathe underwater. This is a video of a participant that's going to put the head into a bucket of cold water while we record heart rate using an oximeter that's connected to the index finger of her right hand and what I want you to do is I want you to listen to the beeps that this machine makes which indicate her heart rate. Continue listening despite the fact that she will lift her head out of the water after about 20 seconds because her heart rate continues to fall.

What happened was her heart rate fell from a heart rate of 115 down to 54. That's a reduction of 61 beats per minute and that is due by activation of this vagus nerve.

Now the other nerves I want to talk about that connect the brain to the cardiovascular system are the sympathetic nerves and in the slide below, what we've got is a blood vessel. Every blood vessel in the body is connected to the brain via these sympathetic nerves and they are the green wiggly lines.


What do those nerves do? Well those nerves if activated as you can see in the schematic below, cause your blood vessels to constrict, to become narrower, and as you constrict those blood vessels that increases blood pressure. The analogy I would give is like putting your finger over the end of a hose pipe - you do that and you increase the pressure in that hose pipe which means now you can squirt the water further from the end of the hose. You also know that the pressure is increased in the hose pipe because if your hose pipe is like mine the other end of the hose connected to the tap normally blows off. If we could find a way of reducing that activity in those sympathetic nerves that should dilate vessels and lower blood pressure.

What we've discovered is an organ called the carotid body and the carotid body drives up sympathetic activity in those nerves to cause hypertension. We demonstrated this for the very first time some years ago, by selecting patients with drug resistant hypertension, that means they were not responding to drug treatment and had huge pressures of around 180 to 200 millimetres of mercury. We remove one carotid body for the very first time. Here it is seen below and we reduced blood pressure in those patients by around 20 millimetres of mercury which is quite a substantial lowering. The exciting news that I bring today is that we have unearthed a natural way to temper the activity of this carotid body that means we do not advocate going around and removing carotid bodies. So we sought to try and find a natural occurrent compound to block those receptors and have found one, but I can't tell you exactly what it is because it's under patent.

The giraffe has also been a fascination of ours for quite some time because it has high blood pressure but this is natural for it. It has blood pressure that's twice that of humans - typically at the level of the heart our pressure would be around 95 millimetres of mercury - but it needs that high pressure in order to push blood up its neck into its brain. We've wondered for many years what it is about the giraffe that allows it to be able to adapt to high blood pressure because it never dies of cardiovascular disease. Normally, unfortunately, giraffes die from being caught by lions.


So what is it that we can learn? Well the first thing we know is that the neck artery is wide and open as you would expect, but those arteries in its leg are very very narrow and this is how it generates its high blood pressure - through a narrowing of the arteries in the leg. Those that are supplying the brain such as the neck arteries are nice and wide and open and in fact, if you remember, if you increase the resistance to flow you will get higher blood pressure as we saw in the hose pipe.

Very recently the genome of the giraffe has been fully sequenced and what's come out of that is something called fibroblast growth factor receptor like 1 or FGFRL1. This is a novel gene that's been identified and is related to high blood pressure. What's recently been published in science is that that gene has a number of mutations and those mutations, relative to the human FGFRL1, are of unknown function.

In order to determine what the function of those mutations in that gene might be, the giraffe FGFRL1 Gene has been snipped out of the giraffe genome and has been replaced in the mouse genome as indicated by the schematic above. Now we are going to look at what happens in a mouse that now has the giraffe FGFRL1. Here you see the mouse in the lower panel (slide below) relative to a mouse containing its own FGFRL1. Interestingly enough you don't see a long neck. In fact you don't see too much difference. If anything the mouse is a little bit shorter at the same age. What we do know is that the bone density is massively increased which you would expect in a giraffe that's bearing all that weight but there's something very important that's been discovered and that is this.


Remember I told you that Angiotensin II is a major culprit for raising blood pressure and indeed if you look at the mouse with its own FGFRL1 and you give that mouse Angiotensin II you can see you can raise its blood pressure relative to giving vehicle control. If you then take the mouse that has the FGFRL1, surprisingly Angiotensin II is completely ineffective. That was something that had not been predicted but what that tells us is that the giraffe is desensitized to Angiotensin II probably to protect itself from generating further high blood pressure. This opens up huge avenues for us now to exploit and to try and understand how we might be able to modulate FGFRL1 in humans.


The next thing I want to briefly mention about blood pressure is renal denervation and this is a one-time procedure to lower blood pressure that may help to combat issues around accessing clinical treatment for blood pressure. It may also address a compliance of drug taking (people don't like taking pills) and also tolerance issues around drugs that gives nasty side effects. What you can see on the left of the slide below is the catheter that's placed into the renal artery - it's an ablation catheter. It's a two or three hour procedure and it ablates all the nerves going to the kidney. Now when you do that, as you can see here, very recent data. After three years you can see quite a nice fall in blood pressure approaching 20 millimetres of mercury. We are currently hoping to set up a trial in New Zealand very shortly to be able to form renal denervation.

I want to move now to listening to nature which is a new pacemaker that we're developing. Most pacemakers are situated as a device just under the skin on the chest and have a lead that goes down into the heart as you can see in the slide. That's very standard. The other thing that's very standard is that the pacing is typically metronomic. The heart never beats metronomically and so we've raised the question very early on so why are we pacing hearts metronomically? I want to demonstrate that hearts don't beat metronomically by looking at this participant and the way he breathes and how his breathing is affecting his heart rate. What he's going to do is he's connected up to the same device used in the first video so you will hear beeping again. Every beep is a heart rate and I want you to listen to how his heart rate increases as he raises his hand that's because he will inhale, he's indicating breathing in through raising his hand, and then as he breathes out he will lower his hand and he's going to take three breaths and those three breaths are going to be related to changes in heart rate (decreasing) as you will hear.

So we have developed a pacemaker that allows us to modulate heart rate every breath and we found some spectacular results in a large animal model of heart failure. This is a sheep model of heart failure. We fitted our novel pacemaker such that every time the animal breathes its heart rate increases and every time it breathes out its heart rate decreases just as we saw in the video. If we do that for a number of weeks, four weeks in total, you can see how the pumping, which is rather reduced because of the heart failure, dramatically increases by about 25 percent. That increase in heart pumping efficiency is three times that of current pacemakers which really is a very exciting and novel observation.

The question is how is it doing that? What we've seen when we look at the heart tissue and these are pictures of the heart tissue (below) that have been labelled with antibodies connected to fluorescent markers. One is red indicating the T tubules - those are those tubes that I was talking about earlier on - they're in red - and associated with them is something called Ryanodine receptors in green. These Ryanodine receptors are really important for contractility of heart muscle, they give it the power to contract. You can see in a healthy situation the green and the red are beautifully aligned tubules with the Ryanodine receptors. In heart failure the tubules become fragmented and the Ryanodine receptors lose their location with those t-tubules but after our pacing you can see this beautiful realignment of the t-tubules and the Ryanodine receptors. Which means to us that we're actually beginning to see a way of reversing heart failure, reversing the damage to heart muscle cells.

I'm delighted to say that we're able to start a trial in the first quarter of next year which will be performed by Dr Martin Styles in Waikato Hospital. We will be using this new pacemaker and connect it to an external pacemaker device which they use in the hospitals already. This will connect it to patients after they have had coronary artery bypass grafting. The reason for selecting those patients is that they have exteriorised pacemaker leads which allows us to connect our pacemaker device directly to the patient without having to implant it.

Hopefully this time next year we'll have some positive data on this new form of pacing but what this does mean is that New Zealand has an opportunity here, if this works, to demonstrate to the world a completely new revolution of cardiac pacemakers.

I want to end with rheumatic heart disease and rheumatic heart disease is something that this country, as a developed country, really should not have. You may know that rheumatic heart disease is due to repeated streptococcal or sore throat infections. After replication of these infections an autoimmune disease is triggered which means that one's own immune system now begins to attack the body. The part of the body that it attacks unfortunately are the valves within the heart. Now a valve in the heart plays an essential role because it allows the correct direction of blood to flow through the heart. Rheumatic heart disease basically destroys these valves which no longer operate and therefore there is poor directional movement of blood. It doesn't know whether to come forward or back and as a result the heart becomes a really very weakened pump. Currently to address this patients undergo operations to either fit a titanium valve - a metal valve - or a valve from an animal such as a pig or cow. This is a real world problem.


Matt Johnson who's a retired Blues midfielder was diagnosed with rheumatic heart disease not so long ago. He no longer is able to play rugby because he has now been fitted with a titanium valve and indeed I met Matt not so long ago after his operation and you could hear this valve click opening and closed with every heartbeat. The other thing that Matt unfortunately has to do is take a blood thinning drug called Warfarin, because with a valve such as this it can cause blood to clot. Being on a blood thinner means he cannot play contact sport because he's very prone to bruising and large bleeds under the skin so this is hugely problematic for people clearly throughout their life.


Rheumatic heart disease if caught early typically can be found in young children and here we have a young man who has just had his rheumatic heart disease valve repaired and this is six weeks since surgery. Unfortunately for this young man he's going to have a lifetime of operations to replace his heart valve. The reason for this is that there are a number of problems. The first is the current valves don't grow. I showed you a metal valve and a porcine valve - they simply don't grow but his heart will grow and as his heart grows so the valve will begin to leak because it will remain the same size. Very often animal valves are rejected eventually by the body or simply wear out after a period of time. So repeated heart surgeries are needed and every time this child comes back in for a heart surgery the surgeons are faced with technically more challenging operations.

What can we do to address this? I think this is a nice example now of how Manaaki Manawa with its interdisciplinary approach to cardiovascular disease really demonstrates its power. Recently a colleague in engineering, Olaf Diegel, has received a 3D printer which allows us to print growth matrices and scaffolds that will support human tissue growth. This will be ideal for making personalised body parts and as I said interfaces engineering with medicine very beautifully.

Here's what we're planning on doing. We're trying to grow your own heart valve. Let's imagine we have a young child that has been diagnosed here with rheumatic heart disease. We take a skin biopsy from that child and we reprogramme the cells to produce from their skin cells pluripotent stem cells. We can then take those stem cells and drive them into heart valve cells. At the same time, the child's heart can be scanned using a high-powered magnetic resonance imaging so that we can get an exact copy of the size and shape of the heart valve needed for that particular individual - so-called personalised medicine. Once we've got an image, a 3D image of the valve, we can then set up the 3D printer to print an exact replica of a heart valve. Printed in this growth matrix gel scaffold and now that gel will be impregnated with all the right growth factors that are needed to stimulate the stem cells to grow into heart valve cells.


Those heart valves will then be implanted back into the heart of that recipient and the beautiful thing here is that those heart valves will not only fit perfectly, because they've been personalised, but because they have been grown from cells that originated from the patient there will be no rejection of those valves.


That is an aspiration, that is something that we would love to be able to progress to do with funding that could come from the Auckland Medical Research Foundation.


Thank you very much for listening. It's been a great pleasure to be able to update you with some of the fantastic research that's going on in Manaaki Manawa. Thank you.

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