 So, for this, the basics are going to be pretty short because we don't know a lot about the etiology of these diseases. I want to remind you that there's a number of non-atherosclerotic, non-inflammatory vascular diseases that are much more common in women, and here's a list of those diseases. So, I'm going to talk about fibromescular dysplasia and spontaneous coronary artery dissections today, but please remember that intracranial aneurysms, cerebrovascular dissections and Moyamoya disease, all are more common in women for reasons that we don't understand. And so, it's interesting because many of these conditions affect primarily the cerebrovascular arteries. In contrast, men are more likely to have, than women, to have disease of the large arteries like the aorta. So, if you look at abdominal aortic aneurysms, thoracic aortic aneurysms, aortic dissections, that has a male predominance. You start looking at these non-atherosclerotic vascular diseases that affect this primarily the cerebrovascular circulation. It tends to affect women, and once again, these sex differences we don't really understand. So fibromescular dysplasia is an interesting disease and we really don't understand much about the etiology. It's clearly a non-atherosclerotic, non-inflammatory disease. It results in stenosis or complete occlusions of the arteries, and then there can also be within the same artery aneurysms or dilatations, enlargement of the lumen, and that can lead to, and this condition can predispose to dissections of arteries. The most commonly affected arteries are the renal arteries. About 60% of the patients will have renal artery involvement and present with hypertension. The second most commonly affected arteries are the extrachranial carotid arteries and the vertebral arteries, and in those individuals, they can present with strokes, TIA, and sort of non-specific findings like headache, dizziness, and tinnitus. Because these features are kind of non-specific, you know, presenting with hypertension or headache. Sometimes the patients, the diagnosis is delayed and then sometimes up to 10 years. So think about these when you see a woman with really hard-to-control hypertension or persistent migraines that are associated with pusiltile, tinnitus, or dizziness. We don't really know what the incidence or prevalence of fibromuscular dysplasia is. We do know that if you take renal donors that all have imaging of their kidneys prior to donation, that 4% to 6% of renal donors will have evidence of fibromuscular dysplasia changes in their kidneys. So that puts the incidence extremely high. Do we think it's really that common for individuals to come in with symptoms? No. We know these changes aren't occurring at a very high rate in the general population with the most likely a minority leading to symptoms. And as already mentioned, this is very much a woman predominant disease, 9 to 1 woman. And there on the image there, I show your sort of typical bead on the string appearance of the arteries where you've got these stenosis, then an aneurysm, and it leads to that unusual angiographic appearance. The classification is sort of with classically based on the histopathology. And more recently it's then flipped over to be based on the imaging. And the histopathology, there's basically just two changes. In our arteries, we have that thin intimal layer, which is typically just one endothelial cell thick. And then we have a thick medial layer made up of smooth muscle cells. So it can be that the layer of smooth muscle cells is disrupted. And that in thickened, and that can be shown here. Where the wall, this smooth muscle cell area gets thickened. And in other places it'll be thinned out. And so this would be the bead part and this would be the aneurysm part here. And typically with this medial fibroplasia, there's not much change in the endothelium. And then a second rarer cause is intimal fibroplasia. And that's where the medial layer looks normal. But you've got this incredible proliferation of cells within the lumen. Once again, no lipid deposits, no macrophages. So these are not atherosclerotic lesions. And what leads to this kind of lesion, we don't know. Interestingly enough, patients with Moyanoia disease all have this type of fibro, intimal fibromescular lesion. So more recently it's been, because of the improvement of imaging, it's been suggested that these be classified based on the imaging appearance. Also we don't often have histopathology on the arteries that are involved. And in this case, this is called multifocal lesions, where you have just this artery that has diffuse changes throughout. And then in arteries where you just have one stenotic lesion, that's unifocal. And just if we look at what correlates, this typically is that intimal lesions and these are the medial lesions. So by far this is the most common presentation of fibromuscular dysplasia. So presenting sign and symptoms. Here's probably the largest cohort of patients with fibromuscular dysplasia and going through their symptoms. Hypertension is the most common. As I already said, the renal arteries are most commonly involved. So hypertension is the most common presenting feature. If you start talking about the cerebral vascular involvement, you can have headaches. Half the patients will have headaches on presentation. And then the other features I talked about, pulsotelotinitis, dizziness. But note that stroke is way down here at the bottom. TIAs and strokes are actually uncommon in fibromuscular dysplasia. So you are much more worried about controlling, in long term, controlling the hypertension in these individuals. And with less of a worry that the cerebral vascular involvement will progress to stroke. So renal artery involvement is suspected in anybody with early onset hypertension or anybody that has resistant hypertension, but especially in women. Renal insufficiency and progression to end-stage renal disease is extremely uncommon. And on physical exam, in some cases, you can hear a burry, but that's very rare. In the cerebral vascular, as I already said, the presenting symptoms are highly variable. Much more often you can hear that cervical artery burry than with the renal lesions. And here is the list of the presenting symptoms, which the most common symptom is headache. So it's not surprising that the actual diagnosis of this condition is often delayed because headache is such a common occurrence. As I said, strokes are rare. Cervical artery dissections do incur, and these will often lead to strokes. Those individuals will present with a sudden onset of neck pain. So if you have an FMD patient, you need to tell them if they have a sudden onset of neck pain, they need to go to an ER. Because once that dissection is there, it becomes a nidus for clot formation, and they can throw a clot which can lead to a stroke, so they need to get on anticoagulants as quickly as possible. Aneurysms can lead to subarachnoid hemorrhage and a hemorrhagic stroke, but this is also, once again, extremely rare in patients within most of the clinical status saying this only occurs in 1% of patients. Interesting is, tortuosity is common where the vessels end up with a tortuous path, and we don't really understand why this tortuosity is there, but we know it's there in many of the vascular-connective tissue diseases like Marthen's syndrome and Lowestief's syndrome. So it certainly implies that there's an underlying defect in the artery that's leading to these diseases. Imaging, I think most people in the room know that there's multiple ways of imaging. The catheter-based angio is still the gold standard for this, but it's becoming less and less common as we move to CTA and MRI, and when we can get the beautiful images and 3D reconstruction of these arteries. Treatments, treatments based obviously on the location of the lesions, the symptoms, whether or not they've actually had prior vascular events and that's most pertinent for the cerebral vascular involvement, and the presence of the aneurysms because if they have large aneurysms they need to be treated because of that risk of rupture and dissection. Medical therapy, antihypertensive drugs, and antipyretic therapy if there's, in particular, there's cerebral vascular involvement. You have to modify the cardiovascular risk factors like you do with any cardiovascular disease, and then there is a very prominent role for renal revascularization in angioplasty and the treatment of this disease. You really want to focus this on individuals with resistant hypertension, people that have a new onset of hypertension. If they've been hypertensive for many, many years, the clinical trials say that the revascularization is less successful. If they have renal artery dissections, you really want to go in and treat them and aneurysms, but in this case it's not angioplasty, you need to put the stent in, and if you have children with early onset hypertension, there's often renal vascularization to try to preserve renal function because they are so young and the onset is so early. So here's the results of renal angioplasty in patients with FMD. Overall, there is a wide range of success. If we just look at the cure rates, it goes from like 13% to 74%. On average, if you look at a large number of these trials, 50% of the patients are cured. Their hypertension is reversed. Once again, it's less likely if the hypertension has been there for many, many years and the diagnosis was delayed. And in older individuals that are affected. Common misconceptions about fibromuscular dysplasia. Once again, it's not an atherosclerotic disease. Another misconception is that it only affects the carotid and renal arteries and this is not the case. It commonly does affect the coronary arteries and I'll talk more about that in a minute and can also affect the ciliac arteries and other arteries, muscular arteries in the body. The ultrasound velocities predict the degree of carotid or renal artery severity. That is not the case. And that you really can't tell how severe the lesion is based on the velocities. People with renal or carotid artery FMD undergo intervention should receive a stent. That's not the case again. That we don't... Angioplasty in most cases is enough to open this only if there's those aneurysms or dissections that we need to think about stentplasing. And the most common presentation for carotid FMD is TIA or stroke. As I mentioned, that's a very rare, not rare but not... It's an uncommon complication with these conditions. The etiology, we don't know. There are studies that say that smoking increased your risk but there's other studies that say it doesn't. So even just a common, you know, cardiovascular risk factor like smoking, we don't have clear data that it does increase the risk. Hormonal factors, we think it may be hormones but at the same time oral contraceptive use does not increase your risk nor is it associated with multiple pregnancies. So in these conditions where we know the hormones are high there doesn't seem to be an increased risk. Which really makes us think that maybe it goes back to the genes and the fact that women have two X chromosomes and men only have an X and Y. Most of the X chromosome is inactivated but we know there's breakthrough of inactivation of that X chromosome that may be part of the reason that women... A hypothesis as to why women are more affected. We know that there are genetic factors that predispose to this disease, about 10%. Patients will have another family member who's affected and I want to talk briefly just this week we're publishing the first gene for fibromuscular dysplasia and I'll go through this data very quickly because I know you guys aren't geneticists or basic scientists. But we used a family that had a syndrome called grain syndrome and in this family which had autosomal recessive inheritance they had very severe and early onset fibromuscular dysplasia with hypertension starting in childhood due to renal involvement and then strokes and TIAs by the time they were teenagers and in addition some of the affected family members went on to have carotid and celiac artery involvement. Here's a little girl with grain syndrome, she looks pretty normal. They also have problems with their bones, osteopenia and actually brachyldactyly which just means short fingers and then the lesions typically were unifocal with either stenosis or occlusion of the arteries and here's the cerebral vascular involvement and here's the renal artery involvement in the patient with grain syndrome. So we took this family which is actually the original family described with the syndrome. There were four affected children and five unaffected children in this family. The parents were unaffected with the exception that the mother was recently diagnosed with fibromuscular dysplasia of her renal artery and she had the imaging because of persistent hypertension. So in these kids as I said the fibromuscular dysplasia is early onset. This woman actually died of coronary artery disease at 18 and all these children presented very young. What we found were mutations in a gene called YY1 AP1 and they were recessive mutations. We used exome sequencing to find these mutations and then went through other patients with grain syndrome. All of them had recessive mutations which means both genes in the genome were defective. In all cases the mutation led to no protein being made from this particular gene. Well there wasn't a lot known about this gene but we were able to confirm that it was expressed specifically in the smooth muscle cells and that when we knocked it down the smooth muscle cells did not differentiate. They did not become complete smooth muscle cells as defined by making all the contractile proteins that's required for contraction of the smooth muscle cells. And we went on to show that this protein is actually in the nucleus. It interacts with another protein called YY1 and they go into these huge complexes that we have in our nucleus that help open up the chromatin. So in this case they all go into this complex called ION80. This is a strand of DNA and when our DNA is turned off and a gene is not expressed like the genes for the contractile proteins in the heart are not expressed in the liver. So in the liver you'd have the heart genes the contractile protein genes would have the DNA wrapped up on these nucleosomes and transcription turned off. The gene would not be expressed but in a heart cell these complexes come in and either evict these nucleosomes or slide them aside so the DNA becomes open and you can actually come in and turn on the gene expression. So YY1, AP1 is a component of the ION80 complex and now we're working and we know if you don't have that protein that the cells do not differentiate properly. So we think when you don't have YY1 in this complex that in smooth muscle cells the genes important for differentiation are not being opened up and transcribed properly and that can lead to the smooth muscle cells not assuming that differentiated quiescent phenotype that they have in the artery wall that may instead leave them in a more stem-like state and prone to proliferation in the arterial wall and these stenotic lesions. So we're going forward with a hypothesis that may be similar changes, maybe in patients present in patients with fibromuscular dysplasia that don't have YY1 mutations. We did identify YY1, AP1 mutations in patients with fibromuscular dysplasia, heterozygous mutations and they were very rare. So it's a rare cause of FMD in the population but we can actually test this hypothesis by getting blood cells from patients with FMD taking them back to pluripotent stem cells, those iPSC cells you hear about then trying to differentiate them into smooth muscle cells. So we're going forward with this grant that Stephanie mentioned to ask that question. Is this... here we have the first gene for this disease and is this what's going on and are we having our patients with FMD? Do they also have problems opening up the chromatin when in their smooth muscle cells and fully differentiated the cells? And so we can ask that question even without knowing the underlying cause in patients with FMD. So it also shows that for the first time that you can alter just one gene in the human genome and predispose to this disease. So I suspect going forward that more genes will be identified for this condition and hopefully I don't know how much in these families it helps us tell who's affected the day they're born and we can prevent the condition using prenatal genetic testing. We can prevent it being passed on in the family but I will see if additional genes will allow us to do that sort of pre-symptomatic and prenatal diagnosis. And is this a condition that we really need to do it? I'm not so sure because although it does cause problems it's not as deadly as the Marfan gene and other genes where we know they can lead to vascular diseases that can cause sudden death. I'm just going to talk briefly about spontaneous coronary artery dissections. They're once again non-aslioscopic, non-inflammatory, 9 to 1 woman ratio, once again very specific and very common in women. Average age of onset is around 50 years of age. They're associated with FMD. 30, 40% of the people with spontaneous coronary artery dissections will have FMD. They're also associated with pregnancy. They can show up in pregnancy. Pregnancy is in general a risk for vascular diseases, most likely because the vascular volume goes up by a third so that the woman can perfuse the placenta and provide nutrients to the embryo. And a most likely that puts stress and strain on the arteries throughout the body. There's probably underlying remodeling that occurs with pregnancy that may also trigger this. And I say that because if you look at something like aortic dissection, half the cases occur in that last month of pregnancy, but half occur in the month after the baby's born when the volume acutely goes down. So that's why I'm bringing up this proposal that maybe it actually is triggered by the vascular remodeling that occurs with increased volume. Extreme stressors, we heard an excellent talk immediately before this one on how it can cause coronary-based cardiomyopathy, coronary artery-based myopathy. And extreme stressors can also cause dissection. And then we know there's a number of connective disorders that lead to coronary artery dissections. And I will go through those quickly in a minute because those are the people you really want to diagnose because they will have the coronary artery dissection and go on to have other problems. Women with spontaneous dissections, they're at a low risk for having additional dissections. And that's just like any MI they can present with any of the features of a classic coronary event. The dissection, it's just when the blood enters the wall and that can occur. But in some cases it's an intramural hematoma. We don't have evidence of the blood flowing through the wall. And as I said, this is very different from your atherosclerotic plaques. Here's a case of an intramural hematoma. I think you can see there's a little blood there of blood. And here's just an example of the false lumen and the true lumen that you get with dissection when the blood's actually flowing through. The connective tissue disorders that predispose to SCAD are vascular EDS and Lois Dietz syndrome. We diagnose these now based on genetic testing. We just run a panel of these genes that include all these genes that cause vascular non-atherosclerotic vascular disease and we can pick these up. Patients with vascular EDS, this is that you can pick them up often physically. They have deeply sunk eyes and awfully, you know, the bluish marks around the face. They have very thin skin so that you can see the veins through their skin and they have poor wound healing. Their wounds typically do not close properly and they end up looking very atrophic and abnormal. And it's due to mutations in the type III collagen. These individuals will go on to have additional vascular events in other arteries and on average they die in their mid-40s due to the recurrent vascular events. So you really want to be able to pull out these patients. The very first patient I saw, I never saw her, but I diagnosed with the Co3A1 mutation and was a young woman. She was pregnant with her second child in the eighth month of pregnancy when she dissected her coronary artery, dissected her left anterior descending, had a massive cornea vent. They took her emergently to the oar to try to revascularize her, but she died. They were fortunate to save the child and it was delivered, the young boy was delivered after her death and they came to me and said, what could have caused this? And I said, and the woman was only about 26 years old and I said vascular EDS is a possibility. Why don't you let me see the young man in my clinic and we were able to diagnose type 3 collagen in the child because this is heterozygous and the child was at a 50-50 risk for having the condition. So you want to pick this up not only because your patient is at risk for additional events, but there may be other family members. We do have a treatment for vascular EDS, that's soliparolol, which will delay the age of onset of the events, but not prevent them. We don't have anything that prevents them. The other thing is lowestete syndrome. This is due to mutations in the TGF beta pathway, TGF B or 1 and 2. These patients have a wide range of phenotypic features. They can look very dysmorphic due to hypertylerism and craniosynostosis. They can actually look like they have classic Marfan syndrome or the vast majority look completely normal. And in this population of TGF B or 1 and 2, I've only seen coronary artery dissections in women. So once again, if you see a woman that looks slightly morphinoid or has features, these individuals can also have those features of vascular EDS, the poor wound healing and the thin skin. And if you see a woman with a coronary artery dissection that has a brother that had an aortic dissection, think about these TGF beta pathway genes. So just in summary, these are, we're sort of starting to understand some of the genetic components that trigger to these diseases. It's my feeling that both conditions are affecting mostly the smooth muscle cells in the artery of the wall that we're still working on proving that. And there definitely are genetic triggers and it's important to make the diagnosis just to know what's going to happen to your patient going forward and whether there's other family members at risk. So thank you very much.