RAJIV GULATI: Hello, everyone. It's fantastic to be here for another one of Mayo Clinic's Department of Cardiovascular Medicines webinar. I am Rajiv Gulati. I'm an interventional cardiologist here in Rochester, Minnesota. And I'm joined today with my colleague Marysia Tweet, who's also a cardiologist who specializes in imaging. And both of us are going to talk on spontaneous coronary artery dissection, top five facts that you need to know.

Our learning objectives are number one, to differentiate SCAD from other causes of acute coronary syndrome on angiography, to identify key SCAD management strategies, and to distinguish what is known and what remains unknown regarding spontaneous coronary artery dissection.

Before I hand over to Dr. Tweet, I just wanted to alert you to the QA button at the bottom of your screens. Please feel free to click on that, press it, type in a question. We'll try and get to as many, if not all of those, probably mostly at the end of the webinar. But if something really important and pertinent comes up as we go along, we can interrupt each other, Dr. Tweet and myself, and try and address those questions. Great to have you here. At the last count, we had about 450 signed in from all over the world. And with that, I'll hand over to my colleague Marysia Tweet. Marysia?

MARYSIA S. TWEET: Thank you, Rajiv. Very happy to be here and talk to you about one of my favorite topics, which is spontaneous coronary artery dissection. And that is an emerging cause of non-atherosclerotic acute coronary syndrome, which essentially causes what is currently classified as a type 2 myocardial infarction and can also cause sudden cardiac death.

And you can see the graphic to the right shows a normal coronary artery. And with spontaneous coronary artery dissection, there's either hematoma or a tear within the coronary artery. And it occurs mostly in women about 80% of the time. The average age is between 42 to 52 years of age with a range as young as 14 years of age to greater than 70 years of age. It is a cause of myocardial infarction commonly in younger women. So up to a third of women less than the age of 50 years of age is also a common cause of myocardial infarction in pregnancy.

And I'll start with a case. And we'll have several cases throughout this presentation. This is a 40-year-old female a couple of years ago with no atherosclerotic risk factors who presented to the emergency department with atypical chest pain. Her troponin was mildly elevated. And the decision was made to take her to the coronary angiogram. And as you can see here on her coronary angiogram images, she has really non-obstructive coronaries. There's maybe a lesion in the ramus artery that was thought to perhaps not necessarily be significant. But everything else looked rather satisfactory.

Of note, she did undergo a cardiac CTA the next day. And the report said that there was a small distal left anterior descending artery. And just one thing I'll point out to you which is easier to see in retrospect is there was a haziness here in the proximal LAD that you could follow down when doing recons of this study.

She was dismissed with medical therapy but then came back at one month with worsening chest pain. At that time, if you look on the left hand side of the screen, you can see her coronary angiogram images. The coronary caliber actually improved quite a bit, including that ramus area that I pointed out earlier. To the right, you can see her optical coherence tomography imaging.

And for those who are not used to looking at these, essentially, where this yellow arrow is is where there's an intramural hematoma. And you can see on her OCT imaging, as we call it, where she has segments of normal coronary and then segments where there's this hematoma. And at the end of the day, this was a dissection, which presumably is in the process of healing but even at one month was detectable with the optical coherence tomography.

So the first of our five facts about SCAD is that SCAD is not always obvious. You should consider it as a etiology of myocardial infarction, especially in younger women without atherosclerotic risk factors and especially for indeterminate findings would consider use of intracoronary imaging if that can be safely performed.

These illustrations really show to us the different types of SCAD which essentially were first introduced by doctors [INAUDIBLE]. And it's really helped us communicate about SCAD, because classically I think most people thought of a type 1 SCAD as being the only SCAD. And with time, and intracoronary imaging, and awareness, we're realizing that this type 2 SCAD which is a long extensive hematoma is likely the most common cause or subtype of SCAD. And then the type 3 SCAD can also be quite tricky, there to the right. And it commonly will appear very similar to atherosclerotic coronary disease.

So when trying to discern the etiology of myocardial infarction, one thing that you may recall with this patient was that she actually had coronary tortuosity. So her coronaries were somewhat curly, for lack of a better term. And when we looked at over 200 patients with SCAD and compared them to controls, similarly aged woman, as best as we could, on coronary angiography, we found that the SCAD patients much more commonly had coronary tortuosity in all three major epicardial vessels.

Now, what about CT? Because this patient did have CT, and it's tempting to want to do CT in these patients, which I think can be very useful, particularly if there's an initial concern about pulmonary embolism. This is a very small study of 14 studies that were done with CT performed within two days of a cath among SCAD patients. And the one thing I want to highlight there is most of the patients did not have a dissection. So that was only 14% of the imaging. But rather, SCAD on CT looked more like an abrupt luminal stenosis or intramural hematoma, which is not always obvious or might even look like non-calcified plaque.

This is another study performed by our colleagues in Spain where they point out the intramural hematoma with those white arrows on CT, again, a hazy appearance which is important to be aware of. Down on the bottom panel here, you can also see the abrupt luminal change that was described on the prior slide.

So here's a patient, 42-year-old female with no risk factors who presented with non-ST elevation myocardial infarction. And I hope that you can appreciate-- you only get one movie here-- but that there is a proximal LAD lesion here. And at that time, she was told, we think this is SCAD. And the study was stopped, and she was medically managed and was not treated with PCI.

There was some concern, however. So she was brought to the coronary catheterization lab again. And this is actually several months later in the setting of some persistent left ventricular dysfunction and concerns regarding symptoms. You see here in the proximal LAD that one, it hasn't resolved as we often expect with SCAD, but it looks actually more consistent with atherosclerosis related MI. And the intravascular ultrasound imaging is consistent with atherosclerosis.

And as a result, she was stented with a very good final TIMI flow and a really good result overall. But I think this case really illustrates the importance of getting the etiology right. And this is an algorithm from the 2018 AHA SCAD statement. And here, you can see that the management of acute SCAD can be conservative for many patients. We do revascularize in certain cases as outlined here, but it is different management algorithm than you would have for atherosclerosis. So really, for these patients, it's critical for us to diagnose the acute cause of myocardial infarction correctly.

And SCAD will heal in many cases. So this is a study from Canada where 86% of the patients had angiographic healing. And if the patients were over 30 days post SCAD, their angiographic healing was occurred or apparent in 95% of patients. What about fact two? Well, now, I'll pass it on to my colleague Dr. Gulati.

RAJIV GULATI: Thank you, Marysia. So as you say, conservative treatment has evolved where it's the mainstay treatment for spontaneous coronary artery dissection, particularly when there's normal flow and no large vessel occlusion. But there is a caveat. And I do want to spend this number two fact talking about that caveat, because I fear there has been this linkage between SCAD and conservative therapy that doesn't really account for the short term after presentation of SCAD.

So why is conservative therapy the mainstay? Well, here's just one clinical example. You see this patient who had awful looking dissection of the left main, underwent coronary artery bypass grafting, which I think was very reasonable. This is many years ago now. A year ago had some atypical symptoms that led to another angiogram.

And look at the left main that has completely healed without any intervention, so complete resolution of this ugly SCAD. And one of the grafts is open [INAUDIBLE] LIMA graft is occluded because of the competitive filling. The point here is the beauty of this native healing one year after coronary artery bypass grafting. What this doesn't show, however, is what happens in the first few days after spontaneous coronary artery dissection. All right.

So with that point that I want to underscore here, with this case from not long ago, just a few months ago, a woman who had-- 47-year-old-- severe chest pain comes to the emergency department, atrial fibrillation, which was a new finding for her, and ST elevation here in AVR, and ugly looking ST depressions throughout the rest of the ECG leads here, concerning for, I think, left main or multivessel disease.

Well, here's her angiogram. And at the time this was taken-- so I would say maybe an hour after initially presenting to the outside department-- her pain had eased considerably. There was TIMI 3 flow in the circumflex and LAD. But there is this focal 60% stenosis in the mid left main over here. The etiology of this cannot be determined on this angiogram. There is no intimal dissection flap scene. Could be atherosclerosis. It's not spasm, because it stayed after nitrates. It could be spontaneous coronary artery dissection.

This is a perfect case for where intravascular imaging will make the diagnosis. And here, we did OCT. You saw the one that Marysia Tweet showed. This is a similar one, the catheter artifact here. Here is the lumen that I'm going around with my arrow. This is some shadowing artifact. This lumen is clean, no plaque, no thrombus. The abnormality is this dark shadowing, which is bleeding in the media intramural hematoma compressing this lumen, causing this 60% stenosis. So this is classic intramural hematoma which is synonymous with spontaneous coronary artery dissection.

Now, how to treat this? There is no clear evidence based pathway. You can make a case for anything. You can make a case for coronary artery bypass grafting. And I have to say, that was really one of the things that we were leaning toward. You can make a case for some creative intervention, maybe a cutting balloon or a regular balloon to deliberately tear the intima and decompress that bleeding into the lumen. You can make a case for conservative therapy based on the case I just showed you with that incredible healing at one year.

After due discussion, we did elect to manage medically or conservatively but keep a close eye on her in hospital. And day zero, I've shown you this angiogram here. Of note, on day four, she had recurrence of chest discomfort that was relatively minor. We did elect to proceed with another angiogram. And look at this incredible change over four days. Dramatic worsening, near occlusion of the left main extending into the circumflex, extending into LAD. So this is acute SCAD extension, acute extent to the intramural hematoma to both daughter vessels over here. And at this stage, we sent her to coronary artery bypass grafting, from which she has recovered very well.

So that's the case that illustrates the point I'm trying to make about conservative therapy is that there's not a failsafe treatment. There are risks in the first few days. Here's some data that support that anecdote from our group. This is 240 patients who were managed conservatively. We just wanted to look at the first 14 days. What happened to that group of patients? Well, 15%, or one in six, deteriorated significantly within the first few days of presentation.

At what stage did they deteriorate? Well, most was early in the first couple of days but extending out to day four. By day five, six, seven, eight, just an occasional patient who did worse. And when we say worse, we're talking about clinical deterioration together with a repeat angiogram showing worsening to either near occlusion or loss of flow, just like the patient I showed you.

Who is at risk for worsening, and who is less at risk? The highest predictive the odd ratio, the hazard ratio of three was patients who had an intramural hematoma alone. So an intimal tear, if that was present on the angiogram, that was a protective feature. IMH alone, just like the patient I showed you, was a higher risk of progression. Also at higher risk are, not surprisingly, but a higher grade stenosis at baseline or multivessel spontaneous dissection.

So here's that patient again, day zero, and then progression with minor pain, underscoring the point that SCAD is dynamic in those first few days. Conservative therapy may well be appropriate, but it's critical to keep a close eye on deterioration given that one in six risk of something seriously changing.

Here's another example of a change that I think helps us understand the early dynamics of what may be going on in SCAD. So here's day zero. You see an abrupt caliber change in the LAD, just after the origin of this large diagonal. This diffuse intramural hematoma then plumps up again over here but normal flow. Well, she worsened on day two. And now you see how that LAD has completely occluded, going down here.

Another example here. So there's the axial compression. As that intramural hematoma continues to push down on the lumen, we see extension to occlusion downstream. The eagle eyes amongst you may also note that things have gone upstream. So look here, a big fat plump vessel here that is now much narrower, so proximal extension longitudinally of the intramural hematoma, excellent compression and occlusion, so three pathways of SCAD extension in the first few days.

So when we look at multiple early repeat angiograms, we see the natural history of SCAD in those first few days. Typically, it will start as an intramural hematoma with compressive narrowing. It then may extend longitudinally. It may cause axial compression and even occlusion.

And in some of the cases we see, the intramural hematoma evolve into an intimal dissection, suggesting that an intimal dissection is actually a secondary phenomenon, a decompressive aspect of the hematoma. Hematoma first, then splitting and decompressing into the lumen, not the other way around, which is what we see with aortic dissection. And of course, the majority will subsequently heal. But these first few days is when the risk occurs.

So how do we manage SCAD conservatively? Remember, there's no randomized controlled trials that will support us. But we will typically manage here at Mayo and we recommend this single antiplatelet therapy. You can make a good theoretical case for dual antiplatelet therapy. You can make a good case for no antiplatelet therapy. We have settled on, and perhaps we can talk about this later, single antiplatelet therapies. They're a halfway house.

Beta blockers, we do use because of the Canadian study registry retrospective that suggested a lower risk of recurrence in patients on beta blockers. It makes sense. Statins, well, this is a controversial area. I won't spend too long on this, but there's limited data. Some registry data are suggesting no benefit, no harm. Our very early study, small numbers suggesting maybe a higher risk of recurrence, but there's an awful lot of potential confounding. So we have limited data. We don't routinely use it if the lipids are very good. If the lipids are abnormal, we do use it.

You can think about giving nitrates or calcium channel blocker if there is persistent pain that is non-ischemic, a non-infarct, on the assumption that some of the pain may be spasm. Well, we don't really know that for sure, to be honest. It could be that the pain is just coming from the vessel wall. A tear can be uncomfortable. And standard other medication for left ventricular dysfunction. We can maybe talk some more about this down the line. But right now, I think I'll hand over back to Marysia Tweet for point number three.

MARYSIA S. TWEET: [INAUDIBLE] who may have had a SCAD years ago, over a decade ago, they were told it was a fluke. Don't worry about it. Go live your life. We have learned, though, however, that early outcomes are not always favorable. And one of the primary drivers for this is recurrent SCAD. So what I mean by that is a patient has their acute coronary syndrome. They're diagnosed with SCAD. They recover. And then they have another separate acute coronary syndrome.

So this isn't progression of the initial lesion but rather a separate one, often in a different coronary artery at a different time, sometimes even years later, due to another SCAD. And depending on the cohort study you're looking at, the rates of this is between 10% to 29%. And in our current registry data is about 15% at five years among a little over 1,000 patients. And we're really at this point unable to predict who is going to go on to have more SCAD, and some up to three or four times, even maybe five, versus who will just have one and then never have another SCAD in their lifetime.

I wanted to share a case to illustrate this point. So this is a dear patient of mine. He's a 59-year-old gentleman, again, no risk factors, does have chronic hypertension, though. Presented with non-ST elevation myocardial infarction. And this is his coronary angiogram. I do want to point out on him that coronary tortuosity. But this lesion in the LAD was very suspicious, and it was uncertain as to the significance of it, as to whether or not it was SCAD. Perhaps it was athero. And the decision was made to conservatively manage him.

Well, he was brought back to the catheterization laboratory about five days later with worse chest pain, which is de facto very similar to this progression or this early change of the SCAD during the initial process. And as you can see, his LAD-- this is a slightly a different view. But you can see that it's changed. And at one point, it's very stenotic and narrowed. Again, he was medically managed, did well. I saw him in outpatient, continued to do well, titrated some medications.

Now, about one year later, a different physician decided that he didn't need his antihypertensives and discontinued all of them. And so the patient followed that advice. And at 60 years of age, he presented with another myocardial infarction. And to the left, you can actually see that prior lesion is completely healed. It looks fantastic now in regards to the LAD caliber. But on the right, you can see that there is actually a new region of SCAD. And again, for those of you who may be paying attention, we did query about a branch vessel SCAD here, so essentially multivessel SCAD.

So recurrence, we're still trying to put our finger as to how frequent it is, who is at risk? This particular patient essentially had a recurrent SCAD in the setting of very high blood pressure, after being taken off of his medications. And when we look at our Olmsted County population based data, which is relatively recently reported, we find that at about one year, the risk is 4% in our Olmsted County, so patients like this one. Two years, risk is 5%. And then the five year risk is 10%.

This is from the Canadian cohort. But when they included not only recurrent heart attack, whether or not that was progression of SCAD or instant thrombosis, death, revascularization, stroke or TIA, or heart failure, at 30 days, that adverse event rate was 8.8%, so not negligible, and emphasizes the importance of watching these patients and keeping tabs on them.

What are the approaches currently to prevent another SCAD? Well, obviously, this is a topic of ongoing study and interest. We're still trying to determine the actual incidence rates of this. We have found in the past that percutaneous intervention doesn't necessarily prevent another SCAD, partly because it tends to occur in a different vessel when it does happen, even among those who are conservatively treated.

Dr. Rajiv Gulati mentioned the beta blocker therapy, which has been associated possibly with less additional SCAD, if tolerated. Blood pressure control is also something we achieve or try to achieve as best possible. And again, from that same study looking at the beta blockade, which was a cohort study by the Canadian group, they found that the patients with a history of high blood pressure tended to have more recurrent SCAD.

Work to minimize possible triggers. And I'll go into more detail about this on the next slide, but that might include extreme exercise, stress, and pregnancy. And then again, just getting back to the beta blockers, so this is just the Kaplan-Meier curves from that study. It didn't give a whole lot of granular data, because this is more of a retrospective study. It wasn't a randomized controlled trial. But you can see here that there was a definite difference over time.

Now, granted that there are patients at six, seven years were about 20 to 30 in each arm. But over time, there was a separation of the curves with a suggestion that those on beta blockers had less additional SCAD. The one thing I will point out is it's not foolproof. There were still patients who were reported as being on beta blockade who did go on to have another SCAD. So we do have our work cut out for us in this regard.

So let's talk about these possible triggers. So I'll focus on the first, intense exercise. So about a third of patients report an intense activity at the time of the onset of their SCAD. So examples that I've heard in clinic have included moving a big fan in the barn. We live in our area where there's a lot of farms nearby. Another one I've heard is moving the refrigerator up a flight of stairs. So really heavy Valsalva, unusual activities.

I have had some patients who were doing their usual exercise routine, though, when they had the onset of chest discomfort preceding their diagnosis of SCAD, say, later that day. And it's uncertain as to whether or not those were related or coincidental. Emotional stress is another one that we hear in about a third of patients reporting, perhaps a little more than that. And it is often extreme stress, single most stressful day in my life. My mom died. I was applying for a job and didn't get it, other crises, or a lot of things going on.

Sex hormones, that's a question. There's some suggestion that they may play a role, particularly since this predominantly affects women and also occurs in pregnancy. Whether or not they're beneficial, say, in regards to exogenous hormones versus harmful, we don't really understand. But there is some concern about the role of sex hormones and the pathogenesis of SCAD.

What about medications and drugs? So there are some medications that have been commonly associated with SCAD, such as Imitrex or triptans. Those drugs that cause vasoconstriction are thought to perhaps contribute to the pathology. In regards to illicit drugs, things like cocaine would be something to think about. And then, this overlaps with the intense exercise one, but the Valsalva and straining maneuver. Some patients report doing that shortly before the onset of their SCAD symptoms.

Now, let's think about associated predisposing conditions. So fibromuscular dysplasia is probably the most commonly associated condition with SCAD and occurs in anywhere between 40% to 80% depending on your cohort. And this is a non-inflammatory arteriopathy that often appears as beating of the vessels. We've also found other arteriopathies that perhaps don't meet diagnosis criteria for fibromuscular dysplasia, say like an intracerebral aneurysm. And that is also common. We have found among patients with SCAD.

Connective tissue disorders that are inherited, such as Marfan's disease or Ehlers-Danlos, have overlapped with SCAD as well. Although, the overall percentage is a little lower than the FMD group. That's probably more like 5% to 8% in the reported series. Lifetime prevalence of migraines, which is thought to perhaps have pathology related to the vasculature, is 40%, which is considered relatively high, even compared to other young women.

Pregnancy associated heart attack is thought to be the etiology in either less than about 5% of cases, which is more consistent with the data in Canada, and then our recent Olmsted County study, versus up to 18%. Hypertension is present in about a third of patients and sometimes can be associated with fibromuscular dysplasia, specifically of the renal arteries. And then there's this whole catch-all of other, including some patients who cannot think of any associated condition or any trigger that occurred prior to the start of their myocardial infarction.

A topic hot for research-- and I'll go into this just a little bit-- are the susceptibility genes, and whether or not there's a genetic predisposition. We think there is, but it's probably not a single SCAD gene mutation, but rather a complex polygenetic abnormality or set of abnormalities that are affected by the environment.

So fast fact number four, fibromuscular dysplasia, which we commonly refer to as FMD, is commonly associated with SCAD. And arterial imaging for FMD is standard of care for SCAD patients. So I do this at least once. And it can be outpatient. It doesn't have to be while the patient is in the hospital. And our current practice at Mayo is actually a single protocol with CTA with a single contrast injection with radiation modulation techniques to look at that vasculature in the head, neck, abdomen, and pelvis.

MRA could be a suitable substitute, particularly if there's concern regarding radiation. Although, in my experience, I have noted that sometimes mild fibromuscular dysplasia isn't as easily detected. It is also a longer study. While ultrasounds, such as renal ultrasound or carotid ultrasound, can be really helpful and can help detect if there is significant stenosis related to maybe some of the webbings of the fibromuscular dysplasia, it's particularly helpful in follow-up. It might not detect mild fibromuscular dysplasia. And you're really unable to detect the intracranial abnormalities which are occasionally present in some of these patients and do require monitoring.

RAJIV GULATI: Marysia, can I ask you a question?

MARYSIA S. TWEET: Of course.

RAJIV GULATI: So with regards to FMD screening, that comes up quite a lot. You get asked this question an awful lot. Two questions. One is, what should you do? And I think you've really nicely suggested that CT is the preferred imaging modality. But other people ask, so why should I do the FMD screening? What's your answer to that question?

MARYSIA S. TWEET: So there is a couple of reasons. The first reason is because of that intracranial aneurysm, or aneurysms that we find elsewhere. Sometimes, we'll even see splenic artery aneurysms. And depending on the size, many cases we like to monitor those. And I can think of a very clear example of a woman in her 30s who did not undergo screening, actually had a accident with injury to her head, and then had a CT, head and neck. And this is after her SCAD diagnosis.

So had a SCAD MI, recovered, was in a motor vehicle accident. They were concerned about her head. So they did imaging with contrast, so they could see the vasculature. And they diagnosed profound fibromuscular dysplasia with both stenosis and aneurysms. And that was obviously life changing for her, and she did require intervention. So the primary reason why I do it is to ensure that there's not an arteriopathy that we could be missing that might require either monitoring or some kind of intervention.

The second reason is if you've cared for a lot of these patients you find that a lot of them were surprised. They were doing everything right from the heart healthy perspective. They were A-plus student, never smoker, watched their cholesterol. Cholesterol's normal. Blood pressure is normal. Exercise regularly. And yet, still have a heart attack.

And I find it incredibly helpful in regards to them processing what happened, in regards to why it happened. And also I will counsel some patients differently. For example, if they have a large amount of fibromuscular dysplasia in their cervical arteries. And so I find it beneficial for those reasons. And it's so commonly seen that the yield is high with imaging. And it can be incredibly informative. And for some patients, it could potentially be critical.

And it's really interesting that the overlap is high clinically, because at least with some of our preliminary genetic studies, including this one-- so I mentioned that there isn't really a single SCAD gene mutation, but there are some abnormalities we're finding as we study this. And there's a risk, a genetic risk locus, PHACTR1/EDN1.

And the fibromuscular dysplasia as well as patients with SCAD are both found to be the A allele carriers of the specific risk locus RS9349379. And interestingly, people who are prone to coronary artery disease as well as myocardial infarction tend to be the opposite allele carrier. So there is some signal here that there is probably an overlap in mechanisms or at least genetic predisposition.

This is another signal as to what may be going on, because ultimately, we really want to understand the mechanism of disease, so that we can try to find better ways of knowing who is at greater risk, preventing future events, and finding novel treatments better than what we have now. And the PhD, actually, in our lab found a rare TLN1 missense variant.

And so TLN1 here is part of this integrin stability complex which essentially links this actins complex here to this, the integrin in the extracellular matrix. And so the thought is this contributes to the stability within the arterial infrastructure and that this is awry in some patients, both spontaneous SCAD patients but also some cases of familial SCAD.

And then another really interesting finding is the GWAS analysis. And so [INAUDIBLE] analysis here is that identify positional candidate genes associated with SCAD. And these also have established associations with other arteriopathies. And so this is informative, and it's helping us to try to better understand mechanism as well as perhaps risk and the future.

So when we talk about genetics, I do commonly send patients to see a geneticist in clinic, but it's not to discuss those novel findings. And perhaps someday, we'll have a polygenic risk score, or something similar to that to use clinically. But I rather I offer a genetics visit more so to discuss the possibility of connective tissue diseases, which are also associated with SCAD.

So these are things like vascular Ehlers-Danlos syndrome, Marfan syndrome, Loeys-Dietz syndrome, possibly pseudoxanthoma elasticum, and some other arteriopathies that can be found and are associated with mutations in the genes for which we already have panels. And approximately 5% to 8% of patients with SCAD will have one of these. Now, if you think about it, it's relatively low yield. And the patients that I've cared for who've had SCAD in the context of one of these diseases often already knew about their disease before they had their SCAD, commonly because of their family history or the other clinical manifestations.

So I do discuss this with patients. I do routinely offer it to patients. But the yield overall of the genetic panel testing with the typical arteriopathy panels for some of those mutations, the overall yield is low in this group. But yet, sometimes worth pursuing, in part because it will affect management in terms of monitoring as well as counseling of the family members.

When we think about SCAD occurring in the families-- so we currently have this Mayo Clinic SCAD registry currently with over 1,300 patients who have confirmed SCAD on imaging. And when we look at all of these patients, only about 1% of them have a family member who's also had a SCAD. Now, a larger proportion of them will report things like, yes, my brother died of a brain aneurysm, or I have a cousin with fibromuscular dysplasia. But 99% of them do not have a family member with SCAD.

And we did publish this a few years ago. At that time, we had a lower number of total patients. But we had five familial cases among a little over 400 enrollees. And interestingly, you can see here that the relationships were varied. We had mother, daughter, identical twin sister, sisters, aunt and niece, first cousin pairs. And really, this implicates a complex genetic pattern, so both probably recessive and dominant modes of inheritance. We already commented about the polygenic component that may be playing a role in addition to environmental factors that might affect that. And certainly, this is something we're still looking at within our biorepository.

This is a question I get a lot. So I put the slide in on this. And this is a recent publication that we put out. It's really focused using the Olmsted County population. So that's a limitation in regards to the generalizability. But we looked at autoimmune disease among patients with SCAD to matched controls in the population. And 11% of the SCAD patients had autoimmune disease with the subtypes below. Most of it was thyroid disease.

And compared to the controls, we were matched about roughly 3 to 1. There was a similar percentage with autoimmune disease. So it was 12%. And even when we adjusted for things like race and body mass index, autoimmune disease was not associated with increased odds of SCAD. And SCAD patients also, we noted, had the classic autoimmune disease, but we didn't really see a strong signal for autoinflammatory autoimmune disease.

So this study certainly has limitations, but it is a population based data set. And really, what it tells us is, yes, patients the SCAD can have autoimmune disease. But it doesn't seem to be of higher prevalence. So whether or not they're coexisting conditions versus the autoimmune disease triggering the SCAD, I don't think we can say for certain. But we do not recommend routine screening for autoimmune disease unless a patient has other clinical signs and symptoms to suggest that's important doing.

And just as an additional step to this review, we looked at the key GWAS findings from our SCAD cohort. And then we went and looked at the studies that were performed for autoimmune disease to see if there was any overlap. And there was not. Rather, the only overlap that we could find which is we already knew about was the SCAD and FMD overlap.

And then, the fast fact five, number five is dedicated outpatient follow-up is recommended for patients with SCAD, for some of the reasons that I mentioned, but there are even more reasons. So life after SCAD. So first thing first, at the time of dismissal, it's important to refer a patient for cardiac rehabilitation. This has been both shown to be safe and beneficial to patients with SCAD, both from data here but also Canada.

And when we pull our registry patients about why they didn't go to rehab, if they didn't happen to participate, the most common reason was actually failure on our part. It was because they didn't receive a referral for cardiac rehabilitation. So I do think that we can do better for our patients in that regard.

I will mention that chest pain following SCAD is common. It could be a whole talking in and of itself. It can be one of the greatest trials that we deal with. Usually the first few months are the most difficult. Many patients do start to improve with medication modification and perhaps even healing of their SCAD. However, there are some patients, even years out, who are struggling with symptoms, some of whom have normal looking epicardial coronary arteries on follow-up angiogram. And it can be quite the challenge.

Of course, there are mental health concerns that arise. That includes anxiety, depression, post-traumatic stress disorder. There are reproductive concerns. And I will go into this a little bit more. But typically in our current practice-- although, we really have no data to tell us this is the right thing to do-- is we avoid exogenous systemic hormones when possible.

So if we have a post menopausal woman who wants to be on replacement therapy with hormones, we try to discourage that, or lean more towards the topical formulations if at all possible. For women who are trying to determine contraceptive options, for instance, we'll treat perhaps with a Mirena IUD but try to avoid the systemic oral contraceptives.

Certainly, menorrhagia can sometimes be a problem we see in clinic, particularly for those who are on dual antiplatelet therapy or anticoagulation. I already mentioned for contraception, progestin IUD is something that we do use. Patient or partner serialization are also considered. We do discourage pregnancy. But for our women who have had SCAD, of childbearing age, this is a big topic, especially for those who want children. So I'll go into that a little further.

And migraines are common. So we have to adjust our medications. So when the patients are placed on beta blockers, many times that does help with the migraines. But as you can imagine, nitrates make them worse. So I always ask every SCAD patient about their migraines to help me choose what medications to try to manage their chest pain with.

And I won't go into this in great detail in the interest of time. But for those patients with recurrent chest pains, there is a very nice algorithm currently published in the AHA SCAD statement. And then, it is also included in the recent JACC summary of SCAD with greater details about maybe how to approach some of these patients, because this is one of the most challenging aspects of caring for these patients in the outpatient setting.

And for the patients themselves, there are moments of anxiety when they're trying to decide, is this my usual chest pain? Is this reflux? Is this anxiety? Is this another heart attack? I know SCAD can occur again. So it can be very challenging to navigate.

But I will talk a little more about pregnancy after SCAD, because this is a common question I've been receiving recently. And we do have a recent publication on it. So this publication here was from 2015. It only was eight patients with pregnancy after SCAD. And we found that most patients did well except for one, who had SCAD recurrence at two months postpartum.

And it was a significant recurrence, left main multivessel disease, LAD [INAUDIBLE]. They tried to treat percutaneous intervention. Didn't work well. Ended up going to emergency bypass surgery. She ended up getting through that. Currently is doing well. Hasn't had any more events. But there has been some PTSD and a lot of recovery.

Since that study, we did recently publish another study. Again, small numbers, 23 women, I believe 32 pregnancies or so. But I'll share you a little more. So we looked at 990 women with completed surveys and abstracted records in our registry. 354 of them were of non-childbearing status at the time of SCAD. So they were excluded. We did a cohort time to analysis study, which included 636 participants of childbearing potential.

We also did a case series review of the 23 women who did have pregnancy after SCAD. And then we did a nested case control analysis. So what we did is we looked at patients with confirmed recurrent SCAD. And we match those to controls. And these were women of childbearing age without recurrent SCAD. And then we looked for any difference in the prevalence or history of pregnancy after SCAD. So focusing on the results of the cohort analysis. So we had 636 patients.

Now, we use two definitions of recurrent SCAD, because there is some thought that maybe the early recurrent SCAD is actually one in the same and just a progression of the same initial process. So if we include the ones with early recurrent SCAD, there were 122 patients. If we restricted it to after a one month time frame, it was 97 patients. And that one month was arbitrary, by the way. And at five years, the recurrence was approximately 15%. And pregnancy after SCAD did not seem to associate with those who had recurrence when adjusting for age at first SCAD, year at first SCAD, and fibromuscular dysplasia.

When we looked at the case series, there were 23 women with 32 pregnancies. Most of them were older mothers at age 38 years at the time of their pregnancy after SCAD. Seven of them had a history of postpartum SCAD. Five of them had more than one post SCAD pregnancy.

And two women ended up having another SCAD. One of them was that woman in that very initial series. So we followed up with all those eight women, called them all, and then-- or saw them in clinic, and then included them in this cohort. Another one was not in the original cohort. But her recurrent SCAD was many years after her pregnancies, so not thought to be directly related.

And then in regards to the nested case control, so we identified 92 cases with recurrent SCAD. We use that definition of greater than one month. We looked at 158 matched controls, matched as follows. And the women with recurrent SCAD were not more likely to have a history of pregnancy after SCAD when compared to those without recurrent SCAD, the non-significant hazard ratio. And actually, there were more subsequent pregnancies in the control group than the recurrent group.

So what does this tell us? Well, one, we did find that most women tolerated pregnancy and lactation after SCAD without evidence for increased risk of SCAD recurrence. And this study really suggests multiple contributors to SCAD recurrence. So it's not just hormones or just the pregnancy. But being an author of this paper and dealing with the data, this is small numbers. And I'm going to tell you to interpret these results with extreme caution.

Selection bias may have played a role. It was a small total number of women. And there are many unmeasured confounders in this study. And one example of that is all women had a normal ejection fraction at the time of their pregnancy after SCAD. And we know from other data that ejection fraction is closely tied to how women do with pregnancy after any cardiac condition.

And so for that reason, the hemodynamic and hormonal changes that occur with pregnancy, the severe presentation of pregnancy associated SCAD that I didn't get into, but we have shown that there's a difference that women who have pregnancy associated SCAD tend to present sicker-- and this has been shown in our work, but others' work as well-- than those who have non-pregnancy associated SCAD, and the lack of preventative strategies and ways to identify who might have another SCAD are really reasons why I still discourage pregnancy after SCAD, despite this paper overall being somewhat reassuring. But I wouldn't take it as definitive.

And so again, when I talk to patients-- because this is a very personal decision, and if you think about it, we counsel patients with other forms of cardiac disease, congenital heart disease for example, who are considering pregnancy. And so for those patients with SCAD who are considering pregnancy, these are the things I talk about. I talk about SCAD is associated with pregnancy and postpartum. So it's thought to potentially contribute to risk, even though my data didn't show that, or our data didn't show that.

Pregnancy associated SCAD is often severe and life threatening, and that's data that's been shown in multiple occasions. And following an initial SCAD episode, patients might have left ventricular dysfunction. Arrhythmias may require certain medications that may or may not be teratogenic, or at least need to be strongly reviewed. And predictors for recurrent SCAD are unknown, as well as preventative therapies.