 So good afternoon and welcome and thank you to Dr. Rich for this opportunity. I also want to thank Dr. Chaturvedi who besides mentoring me provides me lozenges for my lingering cough, so thank you. So our title today is new avenues and stroke prevention for women and I will be discussing atrial fibrillation and Dr. Chaturvedi will be discussing carotid stenosis. I have no disclosures. So here are the objectives for our talk. We're going to look at the differences in atrial fibrillation treatment by sex, learn a little bit about screening for atrial fibrillation and then sex differences in carotid stenosis. Okay, so talking about AFib. So the educator and me, the way I thought about this presentation, it's a capsule review. So I'll be touching on three important points. The first is just AFib epidemiology in men and women. The second will be disparities in clinical presentation and medical and surgical treatment. And then the third will be avenues or future directions. So just talking about epidemiology, as we all know, AFib is the most common arrhythmia in men and women worldwide and it's detected in about 30% of patients with a schemic stroke. The prevalence is estimated to be lower in women than in men, but I'll talk a little bit more about that. And the incidence of AFib increases with each decade of age and it increases disproportionately and prevalence doubles after the age of 60 with each decade. So this is just a graphical abstract looking at the prevalence of AFib in women. And in the U.S., you can see the prevalence is greater in men than in women. But we also know that the women are aging and they tend to live longer and the absolute number of women with AFib is going to surpass the number of men living with AFib. There are some intrinsic differences. This is a busy slide, but I'll summarize. There are some intrinsic differences in cardiac electrophysiology between men and women. So women are known to have a shorter PR interval, a higher resting heart rate and longer QT intervals. Structurally, they also have smaller left atria and ventricles, less left ventricular wall thickness and increased inflammation. So baseline CRP and ESR levels are higher in women. And this plays into their symptomatology and stroke. So what are some of the key differences in clinical presentation between men and women with AFib? So women have higher frequency of symptoms such as palpitations, fatigue, light-headedness, and chest discomfort. They're also older than men at the time of presentation with AFib and have a higher prevalence of underlying risk factors, which is hypertension, valvular heart disease, and heart failure. And due to these differences, the CHADS VAS score, which provides an annualized risk for stroke in patients with AFib and risk factors, factors in an additional point for the female sex. So here's the CHADS VAS score. So if you are between the ages of 65 and 74, you get a point. If you're older than 75, you get two points. And then there's points factored in one for female sex, and the remainder of the points are for risk factors. So if you have heart failure, it's one point. Hypertension gives you a point. Prior stroke or TIA gives you two points, and vascular disease and diabetes gives you a point each. Let's look briefly at the percentage of patients that are anti-quagulated that have a diagnosis of AFib. So this is data from the National Cardiovascular Data Registry. There is a practice improvement part of it called the Pinnacle Registry. And this is from 2016. So obviously this has changed somewhat over the years, and a new publication is on the horizon. But looking at this data, so on the right-hand side, if you look across the x-axis, this is your CHADS VAS score. So with each interval, there's an increased risk for stroke. On the y-axis is the proportion of patients that are receiving some sort of therapy. And the therapy is classified as warfarin or DOAC, or NOAC, in the blue and the brown bar. The light, I guess, cream bar represents treatment with anti-platelets. So if we just look at the blue and the brown segments here, we can see that overall, only about 50% of patients are receiving anti-quagulation for atrial fibrillation. When we break this data down by sex, and women are in red, men in blue, you can see that women across all CHADS VAS groups are under-treated as compared to men. This is another graph, and this is looking at the use of oral anti-quagulent per year between the years of 2010 and 2014. And while there's been an increase of oral anti-quagulent use both in men and women, women are under-treated as compared to men. And if we break that down by decrease in warfarin use and increase in newer oral anti-quagulent use, we see that the women are somewhat under-treated as compared to men. Although that difference is less and less with more use of newer oral anti-quagulants. If we talk about rhythm control, so we talked about anti-quagulation, if we discuss rhythm control, women are less likely to receive beta blockers for rhythm control. There are these two large cohorts, the Outcomes Registry for Better-Informed Treatment of AFib and the European Cohort. In both those cohorts it was found that women are more likely to be prescribed Dijoxin for rate control. And Dijoxin has been independently associated with increased cardiovascular mortality. So women are less likely to be treated with anti-quagulants, less likely to be treated with beta blockers, and more likely to be treated with Dijoxin. Again, this is a review paper looking at the association between race and sex and the receipt of AFib-related health services. And across the board you can see that women are less likely to see an electrophysiologist, less likely to visit with a general cardiologist, less likely to receive catheter ablation, and we'll get into this a little bit more, and less likely to receive a rate controlling medication. And this is significant across all groups. So what are some of the surgical options for AFib? So there's two main surgical options. One is catheter ablation and the second is left atrial appendage occlusion. With regards to catheter ablation, women are generally older at the time of referral for cardiac ablation, and referral is made much later after symptomatic presentation. Women that undergo catheter ablation have higher in-hospital complications, including cardiac tamponade, and they have higher rates of AFib recurrence postcardiac ablation. This is a graphical abstract looking at left atrial appendage occlusion. So the Watchman device was one of the first devices approved as a left atrial appendage occluder. When we look at men and women across the U.S. between 2016 and 2019 who received this device, and it's a fair number, 16,000 women versus 21,000 men, these patients, the women that underwent the Watchman procedure had a higher inpatient mortality, increased prevalence of respiratory failure in this group, increased bleeding complications, cardiac complications, and barocardial complications. So women generally do poorer than men when they get these devices placed. So very quickly, this brings me to future directions and key questions. I've highlighted the inequity in medical and surgical treatment and sort of the disparity in clinical presentation. So some of the key questions that we are asking now are, should we be screening for AFib as a primary prevention strategy? Obviously there's the bigger issue of inclusion of women in clinical trials, and this is not just in neurology or cardiology, but across all specialties. And how do we go about improving access to anticoagulation, community engaged research in community physician education, improving access to surgical options for those women who we identify are at a higher bleeding risk. And then the new kid on the block is AI and wearables. How do we integrate this technology in monitoring and screening for AFib? So we're at this juncture where we know that women are more likely to be symptomatic and have severe symptoms, and female sex is an independent risk factor for death, stroke, and cardiovascular risk. Women live longer and hence the absolute number of women with AFib is going to be higher than men, and women are less likely to be treated. We're also at the juncture of having newer technology for monitoring. We now have loop recorders as compared to traditional event monitors, and we have better treatment for AFib. We have the newer oral anticoagulants as compared to warfarin. So our goal here is to find a key population that would benefit from early screening and treatment for AFib. So this is a pilot project, a study that we have embarked upon here at the University of Maryland. It's called SAFEW. It's screening for AFib in elderly women who are older than 70 years of age. So I'm just going to present a little bit about the study. So the inclusion criteria is women who are older than 70 years of age who do not carry a diagnosis of AFib and have a CHADS VAS score greater than four. Why did we choose the score of four? Because you get one point just for age, if you're between 65 and 74, and two points if you're older than 75. You get a point for being a woman, and we wanted to include high-risk women. So the fourth point is for any of the risk factors that they may have. We are screening patients from cardiology clinics, primarily from heart failure clinics. And the inclusion criteria, as I mentioned, female sex, no previous diagnosis of AFib, age greater than 70, CHADS VAS greater than four. We are excluding patients who have a lower life expectancy and cannot be followed or have other factors for which they may not be compliant with treatment or with wearing the monitoring device. So the study procedures, women will be consented and enrolled and asked to wear a wearable cardiac monitor called a ZEO patch. Some of you may be familiar with the ZEO patch. It can be worn for up to two weeks at a time. IRhythm is the manufacturer of ZEO patch, and it's FDA approved and is being used across the board in primary care and cardiology. And subjects who do have AFib diagnosed during this time will be referred back to the primary care physician or cardiology for anticoagulation and other treatment options. And then we will be calling these patients up at six months and 12 months to determine if they were diagnosed with AFib after they wore the patch, if they had any further monitoring or symptoms and were started on any anticoagulation. This is a smaller study with a limited number of patients, but we are looking at the rate of detection of AFib in these patients. We will also be looking at predictors of AFib in women who are older than 70 and erase ethnic disparities, device adherence and compliance with wearing the ZEO patch and anticoagulant use after detection of AFib. So I will conclude here. So what I discussed briefly today in my little capsule was that women have increased mortality from AFib. They are likely to have more symptoms and increased morbidity. They are likely to have more underlying risk factors. They're less likely to receive anticoagulation and rhythm control. They're less likely to be referred for cardiac ablation and increased procedural complications from cardiac ablation. And yes, there's that overarching issue of less inclusion in clinical trials. So there is a need for women-specific clinical trials and there is a need for inclusion of more women in clinical trials. And when there's evidence for differential response to treatment by sex, which is perhaps in this case, then we should power trials to address sex-specific results. And in a trial that includes both men and women, perhaps closing the arm that's recruiting men to include more women is an alternative strategy. Okay. That's all I have. And I will hand it off to Dr. Chiravidi. Okay. So in terms of chronic stenosis in women, I was going to review a little bit about clinical trial data and talk about the characteristics of men versus women. And we'll also discuss some insights that we've gained from imaging studies and should there be a difference in treatment approach and also future directions. Regarding this first bullet point, I was chatting with Dr. Rich a few weeks ago and he was saying, you stroke people are always discussing your clinical trials. Don't you have anything else to offer? And so sorry, Dr. Rich, we have to mention a few of the trials. I'm just jealous. Okay. Now one of the reasons why the topic of stroke in women is gaining more importance nationally and internationally is because of some of the statistics. And so if you, many of you know that with the aging of the baby boomers, one statistic is that 10,000 baby boomers are turning 65 every day. And so that's going to lead to a large number of strokes, a lot, many doubling of the incidence of Alzheimer's disease, large increases in the number of patients with Parkinson's. And if you look specifically at the deaths related to stroke, here we are in 2020. And you can see that there's already a difference between women and men with more women having disability or death from stroke each year. And then in the coming decades, due to the aging of the population and more women surviving past 80 and 85, this is actually going to be continued to be magnified. Now how did the interest arise in terms of carotid stenosis in women and are there any differences by sex? And so one of the pivotal trials that all the stroke faculty know is the ACAS trial. And so this was a study looking at patients with asymptomatic carotid stenosis where they were randomized to either endarderectomy or medical therapy. And this was an old study published way back in 1995. And what they found was that for endarderectomy, there was a 66% relative reduction in stroke for men, but only a 17% reduction for women. And the conclusions were that women did not have a clear benefit from endarderectomy. But then the caveat was that the study was not really powered to look at differences according to sex. So therefore the next large study which came along was the asymptomatic carotid surgery trial. And here there was some benefit for women. This had the same design looking at once again at asymptomatic patients randomized to surgery or medical therapy. And this study showed that there was some benefit for women, but it was significantly less compared to men. And so overall for men about an 8% difference and for women about half that. And the comments from the writing committee were that the results were not as definite for women. And you can see that about one third of the population enrolled were women. Now later Dr. Rothwell and Goldstein did a combined analysis of these two trials. And you can see that overall there was about a 50% relative reduction with endarderectomy for men, but really no clear convincing evidence that women benefited from surgery. And once again you can say that the studies weren't powered to look at these subgroups, but this is sort of the best information that we have in terms of the two largest studies dealing with asymptomatic carotid stenosis. Now on the symptomatic side we also have some information that there could be significant differences for men compared to women. And when you look at a combined analysis of NASA plus the European carotid surgery trial, you can see that there was significant difference in terms of how many patients do you need to operate on to prevent one stroke. And you need to operate on nine men compared to 36 women. And so once again women tended to have less benefit from surgery even in the symptomatic realm. And another interesting finding which was observed is that in addition to the decreased benefit, it was noted that they had a higher perioperative stroke and death rate, about two points higher for men compared to women in their combined analysis. And if you look at the absolute risk reduction at five years, you can see about 3% for women and 11% for men. And once again the authors commented that for women there is some benefit above 70% symptomatic, but not in those with 50 to 69% stenosis. So the conclusions from these trials were that for asymptomatic patients women didn't have clear benefit. If they were symptomatic they had reduced benefit. They were noted to have higher perioperative risk. And so that led to some additional questions. Do women do better with medical therapy alone or is it a combination of these factors? Now what about timing of carotid revascularization? And so if a patient is symptomatic we usually like to do the revascularization procedure relatively early. And for many years the guidelines have said that you should do the surgery within two weeks. And so this is a pragmatic tool that I've been using for the last several years which is the 1314-28 rule. Which is that if it's a TIA you operate relatively quickly within one day. If it's a mild stroke within three days, moderate stroke within 14 days. And if it's a more severe stroke you reevaluate them at 28 days. Look at their extent of recovery and see that is it worth doing the procedure at all. Because if the patient still has global aphasia and right hemiplegia four weeks afterwards you really have to wonder what you're trying to accomplish by doing the revascularization procedure. So how are we doing in terms of timeliness of offering and our direct to meet? And so as I mentioned Dr. Kittner and I were on the 2021 guidelines for secondary stroke prevention. Where it was recommended that the surgery be done within two weeks of the last symptomatic TIA or stroke. And in this study where they looked at from 19 different emergency departments. You can see that women on average were older at the time of surgery. And they were less likely to be diabetic or be past smokers. But if you look at the delay to end our direct to me it was really terrible for both men and women. It was 26 days for men and shockingly 53 days for women. And so you have to raise concerns about whether people would actually benefit from the surgery. By doing the surgery this many weeks after the last symptomatic event. So a few years ago one of my former fellows and I we wrote this paper on crowd stenosis in women. And considered a few different factors. And one is that there appear to be differences in plaque morphology and composition. And this may explain why women benefit less from carotid revascularization compared to men. And they may do better with medical therapy. And then if they have more stable plaques that are less likely to cause emboli to the brain. Then removing this plaque may have a less clinical benefit. So what do we know about some of the biologic and anatomic characteristics. And so some of these are listed here and I'll mention a few of these in the coming slides. Including the fact that women have smaller arteries. And so that may make them more prone to re stenosis after endardarctomy or after carotid stenting. And also there can be differences in intra plaque hemorrhage and other vulnerable plaque features. And there have also been interesting studies where they've looked at the endardarctomy specimen. And done pathological analysis of the endardarctomy specimen following the surgery. And this was one study from the Netherlands where they found that the plaques from women had a less macrophage infiltration and more smooth muscle compared to the plaques from men. And so overall the plaques from women had a more stable phenotype compared to those from males. Now in terms of the radiology side there's a lot of interest these days in high resolution imaging of the carotid plaque. And for many years we've used a duplex ultrasound to look at the plaque. But MRI can also offer us some important insights. And so one of the features that can be valuable to detect is intra plaque hemorrhage. And this was the paper from Annals which showed on the upper left a patient with no evidence of intra plaque hemorrhage. Here you can see a bright area and these are bright on the T1 weighted scans. And then you can see a more larger area of intra plaque hemorrhage. And intra plaque hemorrhage has been linked with a higher incidence of future stroke. And so therefore identifying it can be important prognostically when you're seeing the patient with TIA or stroke or even with asymptomatic disease. And so from the Netherlands they did this analysis of sex differences in plaque composition among symptomatic patients with 30 to 70% chronostenosis. And what they found is that intra plaque hemorrhage was more common in men by about three fold. It was about 50% in men compared to about 16% in women. And these other abbreviations refer to lipid rich necrotic core, thinner ruptured fibrous cap and then ulcerations and calcifications. And so these top three are really the characteristics of plaques that are considered more vulnerable and which have greater stroke potential. And so these top two especially were more common in men compared to women and then there was no major difference in terms of calcifications. And so in this study they adjusted for plaque volume which is important because there could be some differences in the size of the arteries. And after adjustment for plaque volume you can see that the men were more likely to have intra plaque hemorrhage and lipid rich necrotic core and also a combination of high risk features. And so the authors commented that we might want to consider having sex-specific tailoring of risk factor management using the plaque characteristics. Now what about if you've decided to go ahead and do a revascularization procedure should the sex of the patient determine which procedure that they undergo and if you have a choice between endoderectomy and stenting. Some studies have reported higher complication rate with carotid stenting in women and one analysis from New York State, a statewide registry showed a very high complication rate for symptomatic women of close to 11%. And for the current guidelines say that the upper limit of morbidity and mortality for symptomatic patients should be in the range of 4 to 6% and so 11% is extremely suboptimal. Now so putting all this together should we change our management strategy for men compared to women. And so here you see a difference in the prevailing opinion in the literature. This was one review article from Stroke where the author commented that there should basically be no difference and that the indications for carotid revascularization are the same in women as they are in men. On the other hand this paper is much more consistent with what I believe where it says that I think there are clearly differences in plaques isolated from women and that they're undeniably different in morphology and composition compared to men. And as a result women may require different treatment and especially considering their reduced benefit from revascularization. Now in terms of future directions a couple of the important areas are increasing the representation of women in carotid stenosis trials and also studying intensive medical therapy as a treatment modality. In terms of the representation of women in trials this is as Dr. Menderato is mentioning in AFib it's suboptimal and it's also suboptimal in the carotid stenosis area. And these are several of the trials that we love and once again for Dr. Rich. I won't ask Dr. Rich to explain all these acronyms but these are trials showing that the representation of women ranges from about 25 to 35% in these various carotid trials. And so that's suboptimal and hopefully that can be boasted in the future. In terms of ongoing studies one of the ongoing studies sponsored by NIH is the Cres-2 trial and the Cres-2 trial is looking at asymptomatic 70 to 99 and looking at endarid rectomy or stenting versus intensive medical therapy. And it's currently close to the finish line it's enrolled over 2,300 patients and it's looking at aggressive and protocol driven medical therapy. One piece of good news is that there has been some special emphasis on enrollment of women and so thus far Cres-2 is enrolling close to 40% women. Now in terms of medical therapy this is guideline driven and so that all the patients in Cres-2 we aim for an LDL less than 70 milligrams per deciliter we aim for systolic blood pressure less than 130 and the protocol in Cres-2 does seem to be working if you look at the baseline compared to the last follow-up only about half of the patients were in target at the beginning and at the last follow-up close to 70% were in the target range and so that shows the value of following a consistent algorithm and consistent protocol. And this slide shows the studies that in 2023 which have shown conclusively that revascularization is better than intensive medical therapy. And so I'm waiting for a reaction to see about this wealth of evidence and so there is no evidence. And so in 2023 we have no evidence that endarderectomy is better than intensive medical therapy for either symptomatic or asymptomatic patients. Now to help get some information on symptomatic patients we've started a multi-center registry called SCORE and here we're trying to evaluate the outcomes of modern medical therapy in symptomatic patients who have additional features. And so here we're using a combination of clinical and radiologic criteria and the hypothesis is that with intensive medical therapy similar to what's used in Cres-2 that the one-year stroke risk will be less than 5%. And so in terms of the clinical criteria the important one related to this talk is that we're including women who have recent TIE or stroke. We're also including patients with retinal events such as amorosis fugax because those patients have a lower stroke risk compared to hemispheric ischemia and then also those with the last stroke or TIA more than two weeks ago. And so as an example this is a 72-year-old woman with multiple risk factors and she presents with central retinal artery occlusion on the right side and she has 60 or 70% stenosis on the CTA. And so this patient has less than 70% stenosis which would put her in a lower risk category. She's a woman, she has a retinal event and so all of those features would suggest reduced benefit from revascularization and so this patient would be an excellent candidate for intensive medical therapy alone as well as enrollment in the score registry. For the registry we recommend that all patients get dual anti-pleo therapy for at least 21 days and along with high potency statins and adjunctive medications. Interestingly the LDL goal has been shifting downwards in recent years. Many of the residents know that I always say get the LDL less than 55 and if the patient is very high risk some of the guidelines say even less than 40 and so that has been a moving target but it's gradually shifting downwards. Cystallic blood pressure less than 130 and then dietary modification we recommend elements of the Mediterranean diet along with regular physical activity. And so here are some of the sites that we have in the score registry thus far and we have enrolled one patient thus far from University of Maryland. We have a second patient under surveillance who we're hoping to enroll next week and then we have a few sites in Canada that have also started to get started once they have their ethics committee approval. So in terms of crowd stenosis we know that women tend to be older at the time of crowded revascularization. Previous studies have suggested uncertain benefit for asymptomatic women, reduced benefit for symptomatic women in terms of pathological studies, reduced infiltration of inflammatory cells, radiologic differences as well and putting all these together. These plaque features could explain in part some of the clinical observations. Also representation of women in trials has been suboptimal but hopefully the current trials will do better than the historical trials from the 1990s or 2000 decade. Now in terms of one I always also mentioned to the residents that one major problem that we have in the crowded field is that many of our trials are very old. As I mentioned ACAS was published in 1995 and NASA was published way back in 1991. And so unless you're a real politics nerd you would have very, you might have a hard time identifying some of these world leaders from 1991. And so I always tell the residents and students that we shouldn't really rely on data from which is 32 years old. And if I told Dr. Harrison that he could only treat his MS patients with options that were available in 1991 he would say that I'm crazy. And yet it seems strange that some of the stroke community are still content to use the data from 1991. So don't rely on ancient and obsolete data. Don't rely on 32 year old data from NASA to our 28 year old data from ACAS and contribute to the modern studies. So in addition to what we've discussed before there are many other areas pertaining to stroke and women that are receiving increased attention and deserve to be studied in the future. One is that we know that brain aneurysms are more common in women compared to men. And so there have been some additional recent studies looking at the outcomes and treatments in women compared to men. Is there a difference in how unruptured aneurysms are treated? Is there a difference in subarachnoid hemorrhage outcome? Also there's an increasing interest in preeclampsia as a stroke risk factor in young and middle-aged women. And those who've had a previous pregnancy with preeclampsia are believed to have suffered endothelial damage which puts them at higher risk for having hypertension and future heart disease or stroke. And so as part of the Young Stroke Clinic I think this should be a focus to try to identify women with later stroke and see whether there was any previous preeclampsia and see whether other studies could be designed in this realm. For the third item, a believer or not, perimenopausal hormone therapy is not dead. And many years ago after the Women's Health Initiative the Women's Health Initiative showed that postmenopausal hormone therapy was associated with increased risk of stroke, DVT, cancer, and dementia. And so you would think that after that the pendulum definitely swung against use of postmenopausal hormone therapy. But recently some groups have said that short-term use is safe for treatment of vasomotor symptoms and have suggested that maybe using it for five years or 10 years from age 50 to 60 might be safe. But then other studies have shown that any use beyond age 50 or beyond the natural time of menopause is associated with increased risk of stroke. And so this is still an area of debate. And then finally, what about something that we encounter on the outpatient side a lot is women with migraine with aura. And so is it safe for women with migraine with aura to use oral contraceptives? And some guidelines say that women with migraine with aura should avoid estrogen-containing contraception because it has an increased risk of stroke. But on the other hand, the absolute risk is relatively low. But some guidelines do recommend avoiding oral contraceptives if you have migraine with aura. Now, as I said, this has received increasing attention the topic of stroke in women. And so I'm working with Virginia Howard and Louise McCullough and Cheryl Bushnell and several others for this conference, which is going to be in April of next year and which is going to be hopefully supported by a conference grant from the NINDS. And so we'll send more information about it as the data approaches. So just to summarize what we've discussed, we know that more women than men are disabled each year from stroke. Screening for atrial fibrillation could be of great value because if you can identify the AFib early, if you can then place the patients on anticoagulants, that could be a very useful method for reducing a future potential embolic stroke. We've seen numerous treatment disparities in atrial fibrillation and crud stenosis treatment should likely be sex-specific and more trial data are needed for women with crud stenosis, especially using intensive medical therapy. And then as I showed on that other slide, there are many other areas pertaining to stroke risk in women which need further study. So I think I'll stop there and we'll be happy to take any questions.