Stroke Alert January 2022

On Episode 12 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the January 2022 issue of Stroke: “Efficacy of Intravenous Mesenchymal Stem Cells for Motor Recovery After Ischemic Stroke: A Neuroimaging Study” and “Cumulative Concussion and Odds of Stroke in Former National Football League Players.” She also interviews Dr. Mike Sharma about his article “Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source: NAVIGATE ESUS Trial.”

Dr. Negar Asdaghi:

1) Can repeated concussions increase the risk of stroke in professional athletes?

2) Does stem cell therapy enhance the recovery from ischemic stroke?

3) ESUS stands for “embolic stroke of unknown source.” Is ESUS just a fancy new term, or is there more to it than meets the eye?

These are some of the topics that we will discuss in today's podcast. We're covering the best in Stroke. Stay with us.

Dr. Negar Asdaghi:         Welcome to a new year of Stroke podcasts. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The January 2022 issue of Stroke covers a host of topics, from molecular biomarkers and drug targets in brain arteriovenous malformation to examining the role of calcium in atherosclerotic carotid disease, which I encourage you to review in addition to listening to today's podcast. Later in the podcast, I have the honor of interviewing Dr. Mike Sharma from McMaster University in Hamilton, Ontario, on his work with embolic stroke of unknown source and some of the therapies to soon be studied in this population, including the new Factor XI inhibitors. But first with these two articles.

Dr. Negar Asdaghi:         Stem cells are truly the new kids on the block of therapies to potentially enhance stroke recovery. There's now four decades worth of experience with preclinical research and studies with animal models to evaluate the safety and efficacy of stem cell therapies and stroke. Now, this is a complex topic, and I will try to simplify it as much as possible. So, what are the things that we need to know about stem cell therapy and ischemic stroke? Well, first, in humans, the bone marrow has emerged as the widely used source of stem cells, primarily because of its long track record of safety profile. In fact, bone marrow derived cell populations, some examples being mesenchymal stem cells, mononuclear cells, endothelial progenitor cells, are the leading candidates for stem cell therapies in ischemic stroke. Number two, stem cells can be practically delivered to the brain through a variety of pathways. Intravenous and intra-arterial treatments have been and are currently being studied, but stem cells can also be delivered intranasally and, of course, surgically transplanted in the brain.

Dr. Negar Asdaghi:         So, with these in mind, there are two recently concluded clinical trials of mesenchymal stem cells in adult stroke patients. The STARTING-2 trial, which stands for the Stem Cell Application Researches and Trials in Neurology-2, was one of those two trials. This trial evaluated the safety and efficacy of intravenous autologous, meaning from the same individual, mesenchymal stem cells in patients with moderate to severe neurological deficit originating from the middle cerebral artery territory infarct within 90 days of symptom onset. The primary results of the trial was published in Neurology very recently in February of 2021, and if you missed it, well, luckily, you are listening to the podcast today. So, here's a quick recap of the trial. Fifty-four patients were enrolled in the trial with mean stroke onset to randomization of 20 days. Patients were randomized 2:1 to either receive intravenous mesenchymal stem cell treatment or placebo.

Dr. Negar Asdaghi:         Well, in terms of the primary outcome, stem cell therapy did not improve the primary outcome, which was improvement of modified Rankin Scale at 90 days after treatment. So, disappointing, but secondary analysis showed a significant improvement in lower extremity motor function in the stem cell group as compared to the control group. So, in the current issue of the journal, in the study titled "Efficacy of Intravenous Mesenchymal Stem Cells For Motor Recovery After Ischemic Stroke: A Neuroimaging Study," the STARTING-2 collaborators, led by Dr. Jungsoo Lee from the Department of Physical and Rehabilitation Medicine from Sungkyunkwan University School of Medicine in Seoul, South Korea, aimed to look at this improved motor recovery in more detail using advanced neuroimaging. So, of the original 54 patients in the trial, 44 were eligible for the current neuroimaging study. Participants underwent a variety of testings, including diffusion tensor imaging and resting-state functional MRI studies, at the time of enrollment and then 90 days afterwards.

Dr. Negar Asdaghi:         So, not surprisingly, at baseline, patients in both the stem cell and control group had comparable demographics, clinical characteristics and infarct volumes, as well as similar motor function, which was measured by the Fugl-Meyer, or the FMA, score. So here's a look at their main findings. So, number one, the FMA scores that were comparable at baseline were significantly higher at follow-up in the stem cell-treated group. Number two is the interesting results; they looked at the motor pathways using diffusion tensor imaging. So, they looked at fractional anisotropy values of the corticospinal pathways and the posterior limb of the internal capsule. Now, just a quick review of a somewhat complex concept of the fractional anisotropy for our listeners. In general, FA is one of the calculated parameters in DTI with a value between zero to one, and what it does is that it defines the degree of diffusion directionality.

Dr. Negar Asdaghi:         A value of zero means that the diffusion is isotropic, meaning it is unrestricted or equally restricted in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all the other directions. So, it's easy to understand in terms of axons creating white matter tracts. When the tracts are intact, then the FA values would be high because the diffusion is occurring only in one direction as the tract is intending it to do so, whereas if the white matter tracts are damaged, then the uni-directionality of the tract would be disrupted and the molecules would diffuse freely in various directions and the FA values for that white matter tract is then, as expected, reduced. So, in the stroke model, for example, if a neuron in the motor cortex is damaged, the white matter tract related to that region will, over time, degenerate, a process which we know as Wallerian degeneration and, as such, the FA values of that tract is expected to decrease as we go from the acute to the chronic stages of stroke.

Dr. Negar Asdaghi:         So, back to the current study. At time zero, FA values for the corticospinal tract and the posterior limb of internal capsule were fairly similar between the two groups, but interestingly, at 90-day follow-up, those in the control group had a significant and expected drop in their FA values, whereas those who had received stem cell therapy did not show a significant drop, meaning that intravenous administration of mesenchymal stem cells did modulate and perhaps prevented degeneration of the motor tracts after stroke. The third and final interesting finding of the study was the findings of the resting-state functional MRI. They used RS, or resting-state, fMRI as a measure of functional motor connectivity and found that stem cell treatment increased the strength of ipsilesional connectivity in the motor network and prevented a drop in the strength of intrahemispheric connectivity, whereas these findings were not seen in the control group.

Dr. Negar Asdaghi:         So, what does this all mean? We now have some detailed neuroimaging evidence that indeed stem cell treatment can facilitate motor recovery possibly by reducing degeneration, which is what their DTI data showed, and potentially by leading to positive motor network organization or reorganization, which is what the resting-state fMRI findings showed. So, obviously, lots still to come in this topic and a reminder to our listeners that there are ongoing clinical trials on this topic. So, we will stay tuned as the neuroprotection and regeneration paradigm is truly changing for ischemic stroke with stem cell therapy.

Dr. Negar Asdaghi:         Sports-related concussive symptoms typically resolve within a few weeks of the injury, but there is now ample scientific evidence to suggest that repeated concussion can cause long-term neurological disorders extending way beyond the short-term post-concussive period. How can traumatic brain injury, or TBI, be a cause for stroke? Well, in the more severe forms of TBI, it can actually cause damage to the large vessels and cause dissection, but there is more and more research showing that even milder trauma can lead to microvascular disruptions and even alterations in coagulation pathway, which will then increase the risk of stroke. So, how about repeated mild trauma or repeated concussion in professional athletes? Is concussion a risk factor for stroke in this population?

Dr. Negar Asdaghi:         Well, in the current issue of the journal, in the study titled "Cumulative Concussion and Odds of Stroke in Former NFL Players," Dr. Benjamin Brett and Zachary Kerr from Department of Neurosurgery, Medical College of Wisconsin, and Department of Exercise and Sports Science, University of North Carolina at Chapel Hill, and colleagues report on a cross-sectional study that included professional football players who had at least played for one year in the National Football League and were over the age of 50 at the time of the study.

Dr. Negar Asdaghi:         Now, before we go over the results, there are a few important definitions from this study to note. Number one, concussion was defined as a blow to the head followed by a variety of neurological symptoms, such as headache, dizziness, loss of balance, etc. Getting knocked out or being unconscious was not necessary to define concussion. For our listeners, this is an important shift from the original definition of concussion that required some alteration of level of consciousness. Number two, the participants were asked as part of the study survey about a history of stroke, which was defined as any health provider giving the participant the diagnosis of stroke at some point in their life. So, there were no mandates of any neuroimaging or particular testings to confirm this diagnosis as part of the study. So, with these in mind, 979 participants met the study inclusion criteria and were included in the study. The mean age was 65 years ranging from 50 to 99, self-reported lifetime concussion history was recorded, and the participants were then divided into five categories of zero, meaning never had experienced concussion, to those with over 10 concussions.

Dr. Negar Asdaghi:         So, the first important finding was that over a quarter of their study population actually were in the over 10 concussions category. The second finding was the overall prevalence of stroke was 3.4% amongst the pro-NFL players, which was significantly lower than that expected from age-matched normative population, meaning the prevalence of stroke amongst U.S. men over age of 50. So, in simple words, being athletic is a good thing and not surprisingly is associated with a lower risk of vascular disease. But what they found was that NFL players with a history of 10 or more prior concussions had five times the odds of stroke as compared to those with no prior concussions in the adjusted models. So, what we learned from this study is that traumatic brain injury, specifically repeated TBI, however mild, seems to be an independent risk factor for stroke. Microvascular disruptions and potentially alterations in coagulation pathways have been proposed as potential mechanisms for this association.

Dr. Negar Asdaghi:         About a quarter of patients with ischemic stroke do not have a clear cause for the stroke and fall under the cryptogenic or unknown category. In 2014, an international panel of experts developed a criteria to define a group of patients with cryptogenic stroke that are likely to have an embolic, but yet undefined source for their ischemic event and called them ESUS, which stands for "embolic stroke of unknown source." These were operationally defined as non-lacunar brain infarcts without significant proximal arterial stenosis or known cardioembolic sources of infarct. Now, the idea behind the development of this new term, ESUS, was to identify a more homogenous subgroup of cryptogenic stroke patients that would perhaps benefit from preemptive anticoagulation therapy over the standard antiplatelet treatment for secondary prevention of stroke.

Dr. Negar Asdaghi:         Indeed, since 2014, ESUS has become a rather commonly used terminology in the stroke literature with multiple ongoing and a few already completed randomized trials examining the efficacy and safety of the newer oral anticoagulants in patients with ESUS over antiplatelet therapy. Similarly, much has been done to further study the clinical and radiographic characteristics of patients with ESUS. In this issue of the journal, in the study titled "Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source," the NAVIGATE ESUS randomized control trial investigators set out to examine the radiographic characteristics and infarct patterns of ESUS patients enrolled in the NAVIGATE ESUS randomized trial.

Dr. Negar Asdaghi:         Joining me now is the first author of the paper, Dr. Mike Sharma, to discuss the findings of this paper. I always say that my guest needs no introduction, and today's guest is, of course, no exception to that. Dr. Sharma is well known to our Stroke readership. He is a stroke neurologist and a scientist at the Population Health Research Institute at McMaster University in Ontario, Canada. He is truly a leader in the field of clinical epidemiology in secondary stroke prevention with an interest in randomized trials, covert stroke, and economics of stroke care. He holds the Michael G. DeGroote Chair in Stroke Prevention and is the immediate past chair of the Canadian Stroke Consortium and also leads the Hamilton McMaster Stroke Program. Good morning, Mike. It's so good to connect with you after so many years. Thanks for being with us.

Dr. Mike Sharma:            Good morning, Negar. It's a pleasure to talk to you again, and thank you for that kind introduction.

Dr. Negar Asdaghi:         Well, thank you so much. Can you please start us off with a brief summary of what the NAVIGATE ESUS trial set out to do, and what were the main findings of the trial?

Dr. Mike Sharma:            So, in NAVIGATE, we really wanted to advance the care of patients with cryptogenic stroke. Cryptogenic has been a somewhat nebulous term for decades, and care really hasn't advanced beyond using aspirin. The problem with that term is, there is no agreed upon criteria to define cryptogenic stroke. Sometimes it means that the workup is incomplete, where there are multiple competing causes or indeed there is a disagreement as to what the cause is. So, in NAVIGATE, we took a different approach, which was to look for markers which would identify patients who had strokes which were embolic. Our feeling was that they might respond better to anticoagulation than antiplatelet therapy. So that was the main goal in NAVIGATE, was to use this construct of ESUS to test the hypothesis that anticoagulation will be more effective in preventing stroke recurrence than antiplatelet therapy.

Dr. Negar Asdaghi:         And what did the trial find?

Dr. Mike Sharma:            So, NAVIGATE randomized over 7,000 patients with ESUS, and it was stopped, unfortunately, at the time of the second interim analysis after about 67% of primary events had occurred. At that point in time, our mean follow-up was only about 11 months. It was stopped because there was a difference in the risk of bleeding between the rivaroxaban arm and the aspirin arm and, at that point in time, no evidence of benefit. So, the DMC reasonably halted the trial. So, at that point, we saw an excess of hemorrhage with rivaroxaban without an offsetting benefit in preventing recurrent ischemia.

Dr. Negar Asdaghi:         Okay, so to recap for our listeners, NAVIGATE is an early terminated randomized trial that basically looked at the safety and efficacy of rivaroxaban over aspirin in secondary prevention of stroke in ESUS. Now, the dose of rivaroxaban used in NAVIGATE ESUS was slightly lower than the current standard of care for treatment of embolic stroke patients with known atrial fibrillation. So, you used 15 milligrams per day rivaroxaban, whereas the standard is 20 milligrams per day. Was there a reason why a slightly lower dose of rivaroxaban was chosen for the trial?

Dr. Mike Sharma:            That's a great question. So, 20 milligrams a day in atrial fibrillation is approved in the U.S. I must say that many guidelines, including the AHA guidelines, suggest 15 milligrams for patients with renal impairment and creatinine clearance that is less than 50. Now, in other countries, as the label is slightly different recommending the lower dose. So, in planning this very large international trial, we had a variability in dosing and the complexity of possibly having to change the dose during the course of the trial if a patient's renal function changed. When we looked at the drug exposure between the 15 and 20 milligrams, it turns out that they were very similar. So, taking 15 milligrams, you get very close to the drug exposure with 20 milligrams. The lower dose, we felt, would eliminate the need for dose adjustments during the course of the trial and make running the trial simpler and possibly have a slightly lower risk of hemorrhage than the 20 milligram dose. So, for all those reasons, 15 milligrams was chosen.

Dr. Negar Asdaghi:         Mike, I love these interviews mainly because of these valuable background information we get on trials that is otherwise impossible to easily access. Now, coming back to your current paper, the current paper in the January issue actually is an MRI sub-study of the NAVIGATE ESUS trial. Can you please walk us through the details of the current study?

Dr. Mike Sharma:            Sure. You know, in NAVIGATE, in the parent trial, we included people who had embolic strokes of uncertain source, and those were operationally defined as either visible on imaging, the majority were, or having symptoms that lasted greater than 24 hours. You couldn't have atrial fibrillation, and we required at least 20 hours of monitoring. Now, 20 hours sounds like a funny time period to request. Originally, we asked for 24 hours, but it turns out that when you put a monitor on for 24 hours, it's never exactly 24 hours. It's often just slightly less. So, we had to make a practical decision as to how much was enough, and in addition, you had to have less than 50% extracranial stenosis. We didn't require imaging of the intracranial vasculature; however, if it was imaged, the stenosis had to be less than 50% to the affected area.

Dr. Mike Sharma:            You needed an echocardiogram. We didn't specify a transesophageal echo. Most were transthoracic, which excluded left ventricular thrombus or left atrial appendage thrombus. People who had prosthetic mitral valves were excluded as well. So, from that population of about 7,000, our aim was to select 1,000 patients who met those criteria, but in addition had no contraindication to MRI, and the plan in the MRI sub-study was to look at what happened to covert infarcts, infarcts we didn't identify clinically during the course of the trial, if there was a treatment effect on those and also with MRI, a very sensitive, I would say, exquisite measure of hemorrhage that occurs in the brain. Because the trial was closed early, we ended up at baseline having 918 usable images and participants from 87 sites across the world, less than our original target. You know, our goal really was to see what would happen to these MRI lesions and if treatment affected them.

Dr. Negar Asdaghi:         Okay. So we are talking about baseline MRIs of a subpopulation of the patients who were enrolled in NAVIGATE ESUS, and I think we are ready now to hear about your main results.

Dr. Mike Sharma:            Thanks very much. I'm bursting to talk about them. You know, in spite of the fact that this was a subset of the whole ESUS population, 918 out of 7,000, roughly 13%, the characteristics of these patients was very similar to the main trial. So, I think that with the usual caveats of the subgroup, I think it's reasonable to think that what we found is representative of the ESUS population in general. The most exciting finding for us was that, so we set out to define clinically a group that would be embolic. The majority of the MRIs that we had first off had visible infarcts, and secondly, 70% of these were multiple infarcts often in multiple vascular territories. So, the clinical construct, I would say, worked. We did identify a group of patients who have embolic lesions and often proximal sources, as we see with these multiple vascular territories affected.

Dr. Mike Sharma:            So, this clinical construct works really very well in identifying them. The second thing we found, which shouldn't have been overly surprising but really stood out, were the number of lesions that these people had. The ones with multiple lesions, on average, had four infarcts visible on their MRI, and these were present even in patients who did not have a previous history of TIA or stroke. So, this was their first symptomatic event, and I think that tells us a lot about what's happening in this condition. It's an embolic disease with multiple events, which seems to be very active over time, even when these lesions aren't identified symptomatically.

Dr. Negar Asdaghi:         So, Mike, you've already alluded to what I was going to ask you in this question, but I want to recap and repeat for our listeners again, some very pretty impressive findings you have in the study, 93% of ESUS patients with evidence of infarcts, 70% in multiple vascular territories. What I find very interesting is that two-thirds of your patients without even a history of TIA or stroke had multiple infarcts on their neuroimaging. Does that represent to you this clinical radiographic dissociation in the ESUS population?

Dr. Mike Sharma:            You know, I think that's a really great question. So, it certainly does. What we know in the number of other covert studies and some other work that colleagues have done epidemiologically is the proportion of covert infarcts. These are infarcts without clinical symptoms that have been identified as stroke, is roughly 5 to 10 times symptomatic events. And we are seeing this recapitulated in this population.

Dr. Mike Sharma:            In looking across literature, I suspect that some of these and perhaps a majority had symptoms which were transient, which they didn't appreciate the significance of, or were not identified as stroke at the time. So, this is similar to what's been seen in other populations, just more striking, I think, because of the embolic nature of this condition. You know, I think this really points to the significance of identifying these patients. We expect them to continue to have these covert infarcts, and I prefer the term "covert" to "silent." Silent means it's not really having any manifestation, whereas covert indicates a hidden and nefarious purpose. So, these things do detract from cognition, from motor function, they correlate with disability and recurrent stroke. So, this condition seems to us to be very dynamic and really needs to be addressed.

Dr. Negar Asdaghi:         So, striking indeed and definitely concerning findings, Mike, as you pointed out. I think it goes along with all the continuous efforts of increasing public awareness about mild or transient neurological symptomatology along the lines of what you were mentioning. For our listeners, what should be the top two takeaway messages from your study?

Dr. Mike Sharma:            So, you know, I think from this study, the really important things are when you identify one of these patients where there is an infarct that you cannot comfortably identify the etiology of, please know that it is likely to be embolic often from a proximal source, but not exclusively, and that patient has an ongoing risk of recurrent infarcts, which may not present symptomatically. So, I think that what this underscores is the need to pay a very serious attention to these patients, look carefully for underlying causes, and we really do need a better treatment.

Dr. Negar Asdaghi:         Fair enough. Now I want to end by something that I derived from your study, and I wanted your opinion on that. ESUS is truly proving to encompass a more heterogeneous group of ischemic stroke patients than I think previously recognized. Can you please tell us what's the future for the ESUS trials? Are you going to more elaborate on the etiology of ESUS, again truly cardioembolic versus others, and can you please share with our listeners some of the work that you are currently doing in this field?

Dr. Mike Sharma:            Very exciting future, I think, for this. If you consider where we are with this condition, it's similar to where we were with mechanical thrombectomy with the early trials, which were negative but taught us a lot, and so has this one. Our approach with mechanical thrombectomy, we did two things. First, we honed in on the patient population that was likely to respond, and secondly, we improved the treatments, and I think our approach to ESUS, and this goes along with what we are doing currently, is along the same lines. So, in terms of honing down on the population likely to respond, there is now a number of interesting trials being done. One of these is ARCADIA, and I would encourage everybody to refer patients for this trial. In a post hoc analysis of NAVIGATE, we found that patients with markers of atrial myopathy, particularly a large left atrial diameter, seemed to respond to anticoagulation.

Dr. Mike Sharma:            So, in ARCADIA, which is being run from Columbia University through NIH StrokeNet, is looking for patients with ESUS who have markers of atrial myopathy, randomizing to anticoagulation or aspirin. So, really honing in on a population likely to respond. The other thing that we are working on are better treatments. So, at the same time NAVIGATE was being done at our institute, we were doing COMPASS. Now, COMPASS used low dose rivaroxaban 2.5 milligrams BID with aspirin, and one of the startling findings in COMPASS was a 50% reduction in ischemic stroke occurrence in that trial. And if you think about it, emboli can be fibrin rich or platelet rich or some combination and we really don't know. So, if there is a safe dose to combine aspirin with an anticoagulant, that is a promising approach. So, currently what we are doing is a trial using Factor XI inhibitors.

Dr. Mike Sharma:            Now, you know, if you think broadly across stroke prevention, we have made advances using dual antiplatelet therapy, but they seem to be hitting a ceiling in terms of efficacy with some risk of hemorrhage, and it certainly seems to be the case from NAVIGATE and also RE-SPECT ESUS, which used dabigatran, that anticoagulation by itself won't work. So, from COMPASS, we have this dual pathway approach combining anticoagulation and antiplatelet agents. The novelty here that we are pursuing is using anticoagulants, which have a much lower risk of hemorrhage. So, Factor XI, unlike Factor X, which is affected by rivaroxaban, is not involved in hemostasis, but rather amplifies thrombi, and we know that Factor XI-deficient patients have a low rate of stroke, lower than matched controls, and really no significant spontaneous hemorrhage.

Dr. Mike Sharma:            So, there's a number of trials currently in DVT. We are running really the first trial ever done in stroke at phase two to develop an appropriate dose of anticoagulation for these patients. So, I think the future is going to be combining anticoagulants with antiplatelet agents to reduce these patterns of embolic stroke. Holds a lot of promise after what we saw in COMPASS, and indeed we did a similar MRI study in COMPASS, which taught us a lot about how to do these trials. So, currently, we are working on those, and the first results from two trials using Factor XI inhibition. This approach should be available to us next year.

Dr. Negar Asdaghi:         So, wow, a lot of information, and we look forward to reading about all of this and perhaps collaborating with you on this. Now, Mike, one question that came up along the lines of what you were mentioning is that, what about the duration of therapy? Do you think that much like CHANCE and POINT, where dual antiplatelet therapy is beneficial for shorter period of time and not for long period of time, that you might choose that as well for ESUS patients, that a short period of anticoagulation or combined anticoagulation and antiplatelet therapy might be beneficial and then not continuing them indefinitely for this population?

Dr. Mike Sharma:            You know, it's an entirely reasonable approach to consider. The problem really is what we found in the MRI study, which is that infarcts continue to occur over the long period. We have data now for about a year. But, in other trials and COMPASS, we saw it over many, many years. So, I think that if we focus on the short term, we will have success in reducing the recurrence rate, and the payoff might be a lower risk of hemorrhage, but at the cost of leaving patients vulnerable to recurrences over the long term, you know, and NAVIGATE, we saw recurrence rate of about 5% per year. So quite a significant recurrence rate of symptomatic stroke, and we won't have touched the occurrence of covert infarcts and all that means for the brain.

Dr. Negar Asdaghi:         Dr. Mike Sharma, thank you so much for joining us on the podcast this morning. We look forward to covering more of your work in the future.

Dr. Mike Sharma:            It's a pleasure, Negar, very nice to talk to you.

Dr. Negar Asdaghi:         And this concludes our podcast for the January 2022 issue of Stroke. Please be sure to check out this month's table of contents for a full list of publications, including an organizational update from the European Stroke Conference, which highlights some of the top science presented as part of the plenary sessions at this year's meeting to give us that extra motivation to start the year. Now, speaking of motivation, starting the year, in my view, is much like running a long distance race. Anyone who has done it would tell you that this is as much about mental fitness as it is about physical fitness. So, I think it's only fitting to end the beginning of this year's podcast remembering one of America's inspirational distance runners, Steve Prefontaine.

Dr. Negar Asdaghi:         As a kid, he was told that he's too short and perhaps too slow to be played in any of his school's sport teams. Later, when he became a runner, people would say that they had never seen anyone run like him, a runner who never slowed down nor paced himself. And he famously said "to give anything less than your best is to sacrifice a gift." All of 2022 is now ahead of us. Let's not sacrifice the gift. There is no time to pace ourselves, and what better way to do this than staying alert with Stroke Alert?

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org