The Genetics of Aortic Dissection

One of these people who I surround myself with is Bijal Panja who is going to come and speak to you about the genetic factors and how we look after the whole family and she She is a cardiologist who specifically concentrates on grown-up congenital heart patients, and she's going to tell you about this. We work very closely in this expert group. So a quick change of laptop, sorry, because I'm the awkward person who doesn't use PowerPoint. So I've been asked to talk to you this morning about treating the whole family with regards to aortic dissection and the genetic risk factors. To start off with, I just want to say that our genetic constitution makes us our individual people. And it predicts whether we're going to be tall, short, male, female, healthy, or diseased. And we think that our genome is unique to us. But in fact, we share a big, significant part of our genome with the people that we love, i.e. our family members. And more importantly, we pass on those genes to our progeny, to our children. So when it comes to genes implicated in aortic dissection, we need to look at the whole family. But there are other caveats within this. So, although we know some of the genes identified in causing dissection, some of the genes remain unidentified. And we see trends in certain families that can't pin down a certain gene. And there's also a definite overlap between the genetic factors affecting a patient's aorta and their lifestyle. So maybe overweight and hyper high blood pressure, have diabetes, smoke, and all those other factors in their lifestyle have a detrimental effect in the aorta as well. And it's a big overlap in that, especially as people are aging. And then we have questions we don't know how to answer really. When should we be treating, how should we be treating the patient, should we be using tablets, should we be offering prophylactic surgery, and how best to manage the whole family in this setting. So just a little bit of information about the aorta initially. I'm sure you probably all know this as a very well-educated audience. However, the aorta is the largest oxygen-carrying artery in the body. It arises from the left ventricle above a valve called the aortic valve. and it has a very unique tissue pattern. So it's made up of three layers, like an onion skin, but one of the really important layers is the middle layer, the media, which is made out of smooth muscle cells, so it's a very muscular layer. And within those smooth muscle cells, the smooth muscle cells move by a sort of ratchet movement. So remember that for later. And what happens when the left ventricle contracts is the blood is propelled into the aorta, some of that energy is kept in that smooth muscle wall, And then as the heart relaxes, the smooth muscle releases the energy and propels the blood forward into the body. And that's a very unique property of the aorta, which carries all the oxygen-rich blood around the body and all the arteries that come off the aorta. We know that disease of the aorta can affect all parts of the aorta, not just the aortic root, which I think may be focused on a bit more today, but also the arch of the aorta, descending aorta. You can see on the right-hand panel here, even below the diaphragm, so into the abdomen as well, all the way down to your groins. And why do we worry about disease of the aorta? Well, we know that if you have reached a certain dimension or in certain disease processes, you can get tears in the aorta, which then allows blood to track in the onion skin layers, if you like, and it can shear off the arteries coming off the aorta and deprive those organs or tissues of oxygen-rich blood. And it can be, as we mentioned earlier, fatal. Some facts about the aorta, though. The thoracic aorta is not usually as diseased as much as the abdominal aorta in the normal adult. The aorta naturally grows with age, so it's an aging process that occurs throughout the aorta from the age of about 40. And dissection of the aorta is very rare in children, but Elena will go through that a little bit further with you in this session. The most commonest cause of aorta dissection is not genetically related, actually. it's more to do with degeneration, as I mentioned earlier, the lifestyle things. In young people, the most common cause still remains traumatic injury due to the aorta causing death, but we're now also seeing that in younger people, other drugs such as amphetamines and cocaine affecting the aorta. So, the American Task Force guidelines have shown that, quite nicely, that all parts of the aorta, which is the panel on the left, the ascending arch descending aorta, as you age from your 20s to your 80s, naturally grows around one to two millimeters over the 10 years. But also, it's directly related to your size, your body surface area, which is shown in the right-hand panel. One thing we look at is the stress on the wall of the aorta, which is a little bit of physics for you, Laplace's law, which shows that the stress on the wall of the aorta is related to both the radius of the aorta, so the size of the aorta, but also the wall thickness of the aorta, and the pressure against that wall. Now, medically, we can't really do much about the wall thickness of the aorta. we can manipulate the pressure, which is why a lot of patients are given medical therapy to lower the blood pressure and reduce that stress on the wall. And one way of monitoring the stress of the aorta is by measuring the radius of the aorta. So you can see that as the aorta expands and the radius grows, we know that there's going to be more stress on that aortic wall. And this is quite an easy thing for us to measure with echocardiography, CT scan, MRI, and my colleague Kate von Klemper is gonna discuss a bit more of those imaging modalities with you later. But we do know from the data that there are certain numbers in normal people and in people with diseases of the aorta and genetic predisposition, there are some magic numbers that we have, such as six centimeters where the aorta is more likely to tear or dissect or rupture even. So which genes are implicated in diseases of the aorta? Well, most of them affect that wall integrity and that muscular wall that I was talking about earlier within the three layers of the aorta. Here's a list of some of the genes implicated and where they're actually at. And some of these will be well-known to you, so the fibrillin gene that results in Marfan syndrome, TGF-beta gene, which results in Lois Deet syndrome, which we now know, well, we now picked up six types of Lois Deet syndrome, different mutations of the TGF-beta receptor. But there's a whole list of genes identified, the COLD3A, which is implicated in vascular ALS Danlos, and we really don't know whether some of these genes result in a disease of the aorta or not, whether they're pathological or not. When we send a genetic panel, we often get results back saying we've identified this gene in this patient, but we don't really know if this is going to result in a higher risk of dissection, whether it's going to result in a higher risk of the aorta dilating. And so some of it is down to our clinical acumen and surveillance of these patients to find out how these particular genes will be behaving. And those are the genes that we may have identified so far, but there are still, as I mentioned earlier, a whole number of unknown genes to us. So we do know that some of the genes that result in a diseased aorta gave us quite typical agent presentation and outcome data. So we know that the bicuspid aorta valves, which is the valve that should be tricuspid, i.e. have three leaflets, if it's developed with two cusps, they have a predisposed predilection of dilating the aorta, and there's data to show that they have some risk of dissecting the aorta. Lois Dietz syndrome is one of the conditions which has a mean age of presentation that's much lower, and Lois Dietz, in his original paper, described the mean age of death at around 26, and these patients with dissection, or their first dissection. Vascular Ehlers-Danlos is very rare, and we don't really have any great data for vascular Ehlers-Danlos, but we do know these patients at higher risk of aneurysm formation in all parts of their arterial vasculature, which can result in death and fragility. So, just to talk about some syndromic aortopathies and non-syndromic aortopathies. Lois Deet syndrome, of which we know there are approximately six. This is a patient classical for Lois Deet's one. And there's quite a large crossover between their phenotype, by that I mean the way that they look, with Marfan syndrome. So they have long, thin fingers. They have hypermobile joints, very bendy. They have often curvature of the spine and chest wall as well. but they classically have arterial tortuosity, so the blood vessels are very wiggly and bendy. Patients with Marfan syndrome, a very well-known patient with Marfan syndrome was Abraham Lincoln, and you can see here that because his aorta had stretched so much, the valve underneath it was leaking, so where the blood was going in and out of the heart, up the aorta, his head used to bob up and down, and the early stages of photography, where it took a long time, exposure time, to capture a photograph, his head was never kept still in the photograph and was always blurred. Not really a problem with the iPhone X these days. But these patients classically also have a high arched palate, dislocated lenses, which we now know is a risk factor that can predict their risk of dissection as well. And then we have non-syndromic aortopathies, and the classic one for that is the bicuspid aortic valve. This is a bicuspid aortic valve. You can see two leaflets opening and closing. It should be three leaflets. And we know that this is quite a common condition. There hasn't been a single gene yet identified to pick this up, but we do know it tends to follow clusters within families. And these patients also end up with surgery at a much younger age than those patients with trileaflet valves. And when you actually look at their aortas, they seem to have an abnormal aorta, which reflects that of those patients with Marfan syndrome or Loews-Dietz syndrome as well. So a little bit more about the bicuspid aorta valve. Although it's a different disease process and we haven't got the genetic factors there, the aortas dilate up quite significantly and they do have a risk of dissecting earlier than those patients with a tricuspid valve. And there are some guidelines on when we should be operating those patients with percuspid aortic valves and aortic root dilatation. When we look at the types of aortas, you can see quite nicely here with the syndromic and non-syndromic aortopathies, the percuspid aortic valve usually, at the valve R level seems to maintain its integrity, but it's the ascending part of the aorta, that's the bit before the first branch comes off, that's dilated. The Marfan's patients typically have a root that's dilated, so just above the aorta valve, and you can see on the right-hand panel, the Lois Dietz patients have very wiggly vessels. They look much more wiggly than the other two patients, and in fact, the aorta there after the arch is very tortuous there, and they also get root dilatation of the aorta. So how do I manage the aortopathic family? So in our service here, we have a different number of referral streams. Dr. Elena Chirby, who's talking a little later, sends her adolescent patients to our service, and we have a joint adolescent service with Great Ormond Street Hospital. Our genetics are based at a regional center at Great Ormond Street Hospital. Dr. Kate von Klemperer, who's talking later, also runs a quarterly Alice Danloss clinic here in collaboration with a geneticist from Norfolk Park Hospital. We get referrals from adult cardiology teams, adult medical teams as well. We provide both an inpatient service and an outpatient service for our patients. We provide pay-operative care management, so advice for the intensive care teams, how to manage patients' blood pressures around time of operation. But most importantly, and I think this was something Steve mentioned earlier, we have a multidisciplinary team that involves a very large group of people where we're hopefully identifying patients before they reach a stage where they're at risk of dissection and they are kept under regular surveillance and we can offer them prophylactic surgery to lower their risk of dissection and those terrible outcomes. And we have a regular fortnightly MDT, or JCC as we call it in cardiology, where we as a wider team discuss certain select patients we think are nearing those thresholds where we offer surgery with the whole team. We also provide a family screening service in our clinic. Our family screening service has grown by three to four fold in the last year. We're thinking that people are becoming more aware that their brothers, sisters, aunts, uncles, et cetera, once you have an index case, should be screened. And that's all aimed to carry out preventative surgery. But more importantly, our patients, we like to offer lifelong follow-up too, because you do need lifelong follow-up with us. Now I think this picture will be used a lot throughout the course of the day, but this is the family, as you can see, with Marfan syndrome. And Antoine Marfan first described Marfan syndrome in 1890s, and he picked up that it's a genetically inherited condition, that if you have the syndrome, there's a 50% chance that your children will inherit it. But we know that about 25% of cases are also sporadic, which means you don't have to have a relative with the syndrome. So how do we manage the family? The most important thing is once you've identified a patient you think is at risk, taking good history from them, and that's taking good family history as well, which I'll come to in a moment. Examining the patients, looking for those features on their body to see if they have any of those features associated with any of the syndromic autopathies and performing some baseline investigations. Once I've carried out those baseline tests, if a patient I think is susceptible to a genetic autopathy, refer them to genetic team and offer screening. It's always good to document the pedigree of your family and that's something that needs to be repeated as things change in the family. A surveillance screening, so regular follow-up on a six monthly, four monthly, annual basis and knowing when to treat your patient. And also with the female patients, or even male patients with autosomal dominant diseases, how to plan for their families in the future. As I mentioned, the pedigree's really important. So all of our patients have a pedigree done in clinic, and that's going back at least three generations and identifying patients who might be affected with the disease. You can see the red square on the right-hand panel here is my index patient here, for example, and you can then track back with their cousins, other members of the family, aunts, uncles, who may have died, who may have been affected, who may have had emergency surgery, who may have needed a pacemaker, et cetera, and that can give you a trend of what's happening within the family. What's really important is that you keep updating the pedigree, though, so if someone dies consequently in two or three years' time, you need to add that to the pedigree. If the child is born who looks like they're affected or a nephew is born, you need to add that to the pedigree as well. And we know that when we risk profiling our patients, there are certain patients, regardless of the genes, if they have a family history that suggests that they're going to dissect early, that will make and have an effect on our decision-making as to when to offer surgery for them. Kate's going to talk a bit more about surveillance imaging in the dissected aorta, but to say that when I am imaging patients, the way I'm imaging patients, we use a number of different modalities, echo, CT, MRI. And there have been many controversies in the literature over the past about where to take the measurements, which part of the cardiac cycle, as in when the heart's contracting or when it's relaxing, do we acquire the data. And a lot of the literature out there uses different types of modalities and different timing of the cardiac cycle. And what treatments can we use? Well, again, there haven't been any massive, robust clinical trials as they have with heart attacks, for example, and aspirin and statins, et cetera. So there are medical therapies we can offer which seem to show reduction in the growth of the aorta. And as I mentioned earlier about blood pressure being really well controlled, we have surgical therapies which I think you can all look at later on in the virtual reality. And the nearest group of patients I have who have perhaps vascular Ehlers-Danlos syndrome who don't want to take any medical therapy, don't want to know anything about what's inside them and they're managed conservatively. So in practice what do we do? We do imaging, six to 12 monthly usually. Sometimes more frequently, there's quite dynamic growth in the patients. Have to remember that a patient who's had a repaired aorta is repaired, but it's not cured. They still require surveillance in the long term, whether that be six monthly or annually. We offer patients lifestyle advice in clinics. That's avoiding certain types of exercises and isometric exercises such as weight training. Our specific country indicated if you have a diseased aorta, they raise your blood pressure in a bad way and put extra stress on the wall of the aorta. And when you're considering surgery, we're thinking about whether we offer mechanical valve replacement or tissue valve replacement that has to be individualized to the patient in their care. And what we're trying to avoid really is our patients undergoing emergency surgery which carries a high mortality. So it's offering timely prophylactic surgery, but many gray areas remain. And that's probably because the guidelines have changed so much. In 2001, there were very basic guidelines. The dimensions were much higher, 5.5 centimeters, Not many syndromes were mentioned in the guidelines then. In 2010, the AHA and ACCF developed further guidelines, a little more comprehensive now. They actually had put some genes in there, and they actually put some further syndromes in there, and they brought down the dimensions that we should be offering surgery. And then there was also connective tissue disease repair at 4.5 update in 2011. And then of course there are other genetic syndromes where we see diseases of the aorta, but the dissection is very rare, And we don't really know what we should be doing with them. So for example, Bill's syndrome, allergical syndrome, and familial thoracic aneurysms. So who looks after families with aortic diseases? As Steve mentioned earlier, we're a very large team. They consist of the physicians managing the patient. We depend on excellent imaging for these patients and serial data that we can compare to. We are very dependent on our genetical colleagues. Counseling required for these patients. a patient who's got a lot of physical disability sometimes, and young people that feel embarrassed going out sunbathing or going out with their friends. So there's lots of psychological issues involved as well. They may have a number of scars on their body. Obviously our surgical colleagues are required in the team, our vascular colleagues as well. And we're also dependent on our GPs providing follow-up in the community, monitoring patients' blood pressure, et cetera, offering the lifestyle advice and reinforcing it, and also fertility teams as well. And eventually, it'd be nice to have a clinical environment where we can offer patients a one-stop shop where they can access all these services really easily. So my take-home points in my last slide is when managing the whole family, firstly, you've got to identify the patients at risk and their family members. Offer the genetic testing and counseling. Go to your multidisciplinary team so you can risk stratify and profile your patient. And then offer the relative medical or surgical therapies. Think about the future for these patients and their family planning. Remember, you're gonna have a lifelong relationship with these families. Thank you. Thank you. you