September 14, 2020 – Dr. Kelly Diehl talks with Drs. Josh Stern and Ronald Li, Morris Animal Foundation-funded researchers at the University of California, Davis, School of Veterinary Medicine. They discuss how arterial thromboembolism in cats is treated, as well as their efforts to improve diagnosis and treatments.
00:10 Dr. Kelly Diehl: Welcome to Fresh Scoop, episode 24, Arterial Thromboembolism in Cats. I'm your host, Dr. Kelly Diehl, Morris Animal Foundation's Senior Director of Science and Communication. And today we'll have two guests on the program. We'll be talking with Drs. Josh Stern and Ronald Li, both Morris Animal Foundation funded researchers. Dr. Stern is the Chief of the Cardiology Service and an Associate Professor at University of California Davis School of Veterinary Medicine, and Dr. Li is an Assistant Professor in the Emergency and Critical Care Service at UC Davis School of Veterinary Medicine, and the principal investigator for the Comparative Platelet and Neutrophil Physiology Laboratory. And Josh, and Ron, thanks for joining us today.
00:57 Dr. Josh Stern: Thanks, Kelly.
00:58 Dr. Ronald Li: Thank you.
01:00 DD: Before we get into work, we always make everyone tell us a little bit about yourself and kind of how you got into veterinary medicine.
01:07 DS: Great. Yeah, so I can start. So I'm Josh Stern. I am... A little bit about myself. I'm originally from Ohio and did all of my training starting at Ohio State and then moving on to North Carolina and Washington State University. My interest in veterinary medicine started with a love of dogs. I was a kennel assistant for a golden retriever breeder back when I was a kid and just blossomed from there. I spent a fair bit of time working in exercise physiology before I went to vet school, and that's where I found my love for cardiovascular disease and physiology.
01:43 DL: So a little bit about myself. I grew up in Ontario, Canada. I have always been interested in animals; however, my parents never let me have dogs and cats. So I always had fish and reptiles and birds. And it's not until in high school that I volunteer in a local veterinary clinic that I found my passion and then I went to the Ontario Veterinary College where I completed my veterinary degree. That's when I developed an interest in emergency medicine, and then I went on to become an emergency doctor, and then went on to do a residency.
02:25 DD: Cool. And I want to mention I almost forgot that you guys have a golden retriever in our golden retriever lifetime study as well so... And Dr. Stern is actually on our Small Animal Advisory Board, which is a group that reviews our grants and so lots of attachments to the Foundation. Let's begin. For folks, I think if you've ever had a cat and many cats, chances are you've run into heart disease in cats, but for those people who are listening who may not be familiar with heart disease in cats, can you talk to us a little bit about sort of the statistics with heart disease, maybe a little bit about the financial cost, the emotional cost for owners, how often it's diagnosed, all those kind of basic statistics?
03:23 DS: Sure. I'll tackle that question first. So from a standpoint of heart disease in cats, when we think about heart disease in cats, we're thinking about several different cardiomyopathies, but far and away, the most important one of those diseases is known as hypertrophic cardiomyopathy, which results in an abnormal thickness of the heart muscle itself and leads to various outcomes including this arterial thromboembolism that we're going to talk about soon. The reason it's so important in cats is because it's a really common disease process. In one really nice study looking at a large population of cats in a shelter, these were not purebred cats, these were cats of all ages across the shelter environment. They found one in seven cats or 14.5% of the population was affected by hypertrophic cardiomyopathy. So this is a really common disease, and unfortunately, the outcomes of this disease are not good. The disease itself can lead to congestive heart failure, sudden cardiac death or arterial thromboembolism, which we're going to talk more about soon.
04:28 DS: Diagnosis of this disease generally involves a veterinary cardiologist. So the workup for it itself is not an inexpensive venture. Most owners, when they come for an initial cardiology visit, spend somewhere in the neighborhood of $700 to a $1000 to establish the diagnosis. And if they actually have complications of their disease moving forward, that can bring them back to the clinic really frequently and those veterinary costs can ramp up pretty quickly.
04:58 DD: And so you mentioned arterial thromboembolism, which I'm going to abbreviate ATE because it's a mouthful. Tell us a little bit about that particular problem.
05:10 DL: Yeah. So ATE is one of the complications of hypertrophic cardiomyopathy. And as an emergency clinician, I would have to say it's one of the most distressing emergencies for feline owners. As Dr. Stern mentioned before that we really don't know until we look for it. So oftentimes, these cats would go on with their lives. They will have no clinical signs, and suddenly, the owners would find these cats in agony, in pain, unable to use their back legs. And that's a result of clot formation within the heart, and that clot dislodged and disrupt blood supply to the back legs. And so, oftentimes, we not only have to deal with a very painful cat in the emergency room, but we also have to deal with a very distressed owner. We have to give them potentially a very poor prognosis associated with the disease. The disease itself can be controlled, but most of the time, it's associated with high recurring rates. We would say at least more than 50% of the time, it will come back. And so, owners are left with very distressing information, a poor prognosis, and oftentimes can't make the right decision.
06:44 DD: Right. And can you... Some folks listening are going to know this but... Ron, could you talk a little bit about the typical clinical signs? You mentioned pain, they can't use their rear legs, but what are some of the things you see with cats when they present in the emergency room with ATE?
07:02 DL: Sure. So the most common clinical sign that we see in the emergency room is the inability of the cat to use both hind legs. Some of the clinical features would be low rectal temperature, abnormal pulses. So sometimes it would range from abnormal pulses from one leg than the other to absent femoral pulses. Those legs, the muscles of the hind legs, would also become really firm. Nail beds oftentimes will look cyanotic. Foot pads would also look pale to cyanotic as well. But that's not... That's like the typical clinical signs. Remember that blood clots can eventually travel everywhere in a body so sometimes it may affect just one limb, one thoracic limb. Sometimes it may go to the kidneys causing acute kidney injury. Sometimes I've seen blood clots traveling to the brain causing acute onset of neurological signs or sudden death.
08:16 DD: Okay. And how, historically, have cats been treated for this disease?
08:22 DS: So, historically, cats with this disease have been treated with mostly supportive care, which involves to a large degree pain management as a principal therapy. We also need to keep them from being in a hypercoagulable state. And so they've already formed a blood clot, and we need to stop them from forming additional blood clots. And so we'll use drugs to stop blood clot formation moving forward. We'll also have to support them if they are in congestive heart failure. And so many of these cats, because of the stress of the event or because of their concurrent heart disease, will enter during the course of therapy or already be in congestive heart failure and have a requirement for oxygen support and diuretics.
09:13 DD: I think for folks who are listening who aren't veterinarians or vet students, they're going to say, "Well, this sounds like a stroke in people." And can you talk a little bit about... You know, people again are probably used to treatment for that. How do cats differ from people when they have strokes and how they're similar?
09:35 DL: Sure. Yeah. In many ways, it's similar because stroke is also arterial thrombosis. But what's fascinating about cats is this is a massive thromboembolic event. We're talking about obstruction of blood flow to an entire part of the body. And if you can imagine, a lack of blood supply means a lack of oxygen to vital tissues, and essentially, it can cause massive amount of inflammation. So not only is the obstruction of blood flow very concerning, but the aftermath for that is also extremely concerning because it can also set up a massive inflammatory reaction or something called ischemic-reperfusion injury. What happens is that once the body is trying to form collateral circulation around that blood clot, the reperfusion or the reintroduction of oxygen to those dying tissues can set up a massive inflammation. And so, some cats, even though they can survive the initial episode, will later on succumb to this inflammatory reaction.
10:49 DD: Right. Thanks. Let's move on now to your grants focused on ATE and both the completed ones and the ones in progress. And why did you decide to look more closely at ATE and this problem in cats?
11:07 DS: Yeah. That's a great question, Kelly. I think this disease, HCM as a whole is super common, and so anything we can do to move treatment forward within HCM is really, really important. But then, when we drill down on what we're dealing with in terms of HCM, we're really talking about three main outcomes: congestive heart failure, thromboembolic disease and sudden cardiac death. Sudden cardiac death is exquisitely hard to predict. Congestive heart failure, we're pretty good at treating. And then, ATE is this nebulous thing that is hugely important in terms of quality of life. It's a big problem and hugely distressing for owners. And so, we really found that area of HCM therapy to be one that needed work.
11:58 DD: And you guys focused in on it some more just as you were talking about, and can you... So this is putting you on the spot a bit but can you try to summarize from a high level first what your grants were focused on?
12:12 DL: Well, yeah. So, one of my main research interest is... Well, it's a little bit off topic but one of my main research area, it's called neutrophil extracellular traps. And from our understanding in human medicine is that these neutrophil extracellular traps, which are produced primarily by neutrophils, they are released once neutrophils are activated. And these traps are formed by essentially neutrophil proteins and mostly DNA. These DNAs are sticky substances in the bloodstream, and what they've found in and well we have some evidence in dogs as well that these DNA that are free floating around in the blood can exacerbate clot formation. These DNA structures bind to clotting factors, it binds to platelets, it binds to red blood cells. So not only does it increase clot formation but it also prevents clots from breaking down. And so, going on from that perspective, I wrote a grant looking at whether cats with hypertrophic cardiomyopathy or cats with ATE had increased circulating levels of this cell-free DNA.
13:34 DL: As Dr. Stern was saying that the diagnosis for HCM and ATE, it's pretty difficult. And so one of the goals of the grant is whether we can use these circulating levels of DNA as biomarkers. So instead of reactive, we want to be proactive in terms of diagnosing this disease early and treating this disease early.
14:00 DD: So this would be something that maybe you would look at as Josh mentioned, it's a pretty common problem in cats. So do you envision this would be an easier test maybe than taking your cat to the cardiologist, for example, if you had an older cat?
14:17 DL: Yeah, certainly. It's a blood test. And so we are looking at the amount of cell-free DNA so that means that DNA that are not within the cell but in fact are free-floating around in our circulation. And so the DNA can be measured quite easily in plasma or whole blood.
14:45 DS: Yeah. Kelly, I think if I can jump in there for a second, I think when I step back and look from a bird's eye view at what we're doing or interested in doing in terms of these diseases in cats, I kind of see us going in two big areas. And one of those is in predicting disease outcome because if we can predict what's going to happen to these cats, we can then go the next step to look at preventative therapies that might make a big difference. As Ron mentioned earlier, I think many of the cats that we see with ATE, it's the very first time they've come into the clinic for their disease. We had no idea they've had HCM likely for many years. And so predictive things in this disease process are important to us. Then the other big area that I think we look at is therapeutics for this disease and is there anything that we can learn about what would make therapy more or less effective because when we treat ATE in cats, not all cats respond ideally. And so we know that there are some cats that appear to be resistant to drugs and so that's another big area that we decided to look into. In fact, we identified some mutations that do appear to have an impact on whether cats respond to the typical drugs that we use to slow down clot formation. And so if we can learn that information upfront, we can choose better drugs for the individual cat and maybe make a real difference there.
16:17 DD: Right. And I think you guys have looked at, for those listening, you may be familiar with Plavix. That's the trade name, a common drug that people who've had strokes or have heart disease... And you looked at that in cats because the cats do act differently to clopidogrel. And can you talk a little bit about what happens when cats are given that particular drug, what the challenges are?
16:48 DL: Yeah. So the challenges are that we gave a quarter of a pill and think that it would work in every cat. And the reality is that that's not true. And in fact, my laboratory specializes in different ways to look at how cat platelets respond to the drug. And we found out persistently study after study that cats no matter whether they have HCM or not, it was about 30% of these cats are resistant to clopidogrel. And this resistance is not uniform so they have different levels of resistance. And that led to a project performed by Dr. Stern's PhD Student looking at the genetic polymorphisms or other variants that leads to their different responses to Plavix. So maybe Dr. Stern can give us a little bit more information about what he found in that study.
17:50 DS: Yeah. I think we now know that there are at least some different genetic mutations that play a role in how cats can respond to this really common drug like Plavix that cardiologists around the world have been relying on to prevent blood clots. And we now know that perhaps there are a significant number of cats that need more than just Plavix or need something, a different drug compound altogether. And so we've been kind of moving that momentum in the lab forward to build upon it in different studies. We're moving into these neutrophil extracellular trap areas because there are novel drugs that work on that target. We're moving into different anticoagulant type drugs because there are more novel drugs out there than Plavix alone. And I think what we're trying to do is figure out when you have a patient in front of you with ATE, what's going to work best for that individual patient at that time and how can we prioritize which patients really should think about moving forward for those additional treatments?
19:01 DD: So, I mean, you guys have been working on this for quite a while as a team and as you look more into this disease, what surprised you that you found out that you were not expecting? We all want to be open-minded with our experiments, but most of us have some idea or some hypothesis that we think that we're testing it and what has surprised you about cats and ATE?
19:30 DL: Well, I guess what surprises me is the more I look into it, the more I don't know about it. [chuckle] And it just seems like we thought we knew what's going on, but in reality, the pathophysiology of it, it's really quite complex. And so, it's one of the areas that I'm thankful that every day I get to wake up and get to study because I'm learning literally something new. Every single time we try to answer a question, there's another new question that pops up.
20:09 DS: Yeah. I think for me, what's been really surprising is we were looking at compounds that appear to be pretty well studied in humans, and we know a lot about them. And there's pretty good evidence about which ones work the best in the human population, and you would think that that might translate over into our companion animals, and that has not been the case. I think we're learning a lot about how drug A, if you think it does one very specific thing, it turns out in the research lab, when you really do an in-depth look, it's actually also impacting the pathway of drug B and perhaps of drug C. And so, we're really gaining some insight here that this is not going to be a one-size-fits-all. I don't think we're going to conclude that drug X is always better than drug Y, and that personalized medicine in cats might have an even bigger role than we see it playing in humans right now.
21:14 DD: Wow. So how do you think your finding so far, and I know this is a stretch, will either have already influenced how people treat ATE in cats or in the future? And you alluded a little bit to it but expand on that how you think what you’re finding will change how we look at this disease.
21:35 DS: Yeah. I'm really hopeful that by the end of this, when we've kind of wrapped up a couple of more studies and get a little collection of manuscripts out there, that people are willing to consider that taking this personalized medicine approach is really worthwhile. So it might be a pipe dream, but I hope when people have one of these cases in their clinic, they're treating it and the cat's doing well, that they say, "Well, let's look at the genetic signature of this cat and decide, when it goes home, which medication cocktail is best." That's one of the things I hope. I also hope, and I realize that it's a long way off because we don't have a veterinary specific compound yet, but I hope that what we've learned from Ron's lab about NETosis or the neutrophil extracellular traps, provides us with another immediate pathway to target in the ICU. We've been really stagnant in things that we've added to ATE care over the years. I don't think it's changed really very much at all since I was a vet student, and this would be a very novel pathway for somebody to target and hopefully make a real dent in improving the number of cats that get through this disease process.
22:55 DL: Yeah. And I would add to that that our lab has looked at the actual molecular structure of clots whether it's in the heart or clots that have been dislodged in cats, and these are biopsied samples that we stain to look for neutrophil extracellular traps. And what we found is that the distribution of the type of cells and the distribution of these NETs are completely different. It depends on where the clot is. And so, I think even just the disease progression may dictate what type of drugs, what's the most appropriate drug to use because it seems like, from my findings, that the structure of the clots are different. It depends on where it is and the disease progression.
23:47 DD: Yeah. That's kind of a big thing to wrap your head around because I think we think like a blood clot is a blood clot. And the idea that blood clots could be different is, I think, really not how most of us were taught to think about a blood clot. So that's really, really interesting. And I know you guys have ongoing research, but are you thinking ahead like where you want to go next with your research program?
24:15 DL: Well, yeah. Recently, I got funded for... This is a project of my dream, and I've always wanted to do this. It's we're creating basically an in vitro model that mimics ATE in cats. And so, this model uses advanced biomedical engineering to mimic the environment inside a blood vessel. And so we want to see what are the influences of changes in these environments that can facilitate blood clots and that allows us to really better understand the molecular interactions between the cell types. And potentially, we're actually testing a novel therapy, trying to see if we can block some of these blood clots from forming inside this model. So I'm very, very excited about this project. It's something that's, I think, really going to change how we see this disease.
25:22 DD: Alright. Well, that's really exciting because I think it's... That's not been easy, right? I mean, all we have are cats throwing clots right up to this point. So having a model like that where we can really dissect out maybe what's going on I think is really, really cool. So my last question is, I'm going to split it into two, which is the take home message for our listeners. What would you tell veterinarians and vet students who are listening and what would you tell owners who are listening about this disease?
25:54 DS: For veterinarians and students that might be listening, I would say that this is an area of rapidly evolving knowledge in veterinary medicine right now. And so what you might have been taught in vet school or what you may have seen in the ER a couple of years ago may very well not be applicable going forward. And so, I think this is a really important area to look at when you have upcoming CE. Pick up your journal articles and look for things that come out about this because I actually do think this is an area where prognosis and treatment are going to be evolving very rapidly. And so I'd love to make sure that we make a progress on a profession-wide level.
26:41 DS: And for owners, I guess I would like to ensure that they understand that making the decision on treating or not treating cats that have ATE is a very personal decision. And it's often very hard to make that decision in the moment because all you see as an owner is an emergent situation with a cat that's not moving its hind limbs and may be very painful, and then they get whisked away to the back of an emergency room to be triaged. And so I would say, knowing that this disease exists and understanding what the treatment options are ahead of time is really smart, and I would encourage owners to know that veterinary medicine is really good at managing pain in these cats now. And so, if they're willing to try, this is not going to be an experience where the patient is suffering at all, and they may very well have a good outcome. We have many cats that we've been following now for quite some time that have lived more than a year after having one of these major thromboembolic events, and I think sometimes people get the impression that that would not be possible, and it is.
27:52 DD: That's really great to know. I was going to say back in the dark ages, when I went through vet school, it was almost a death sentence, I think, was how it was presented unfortunately as a student if it was into the rear legs as you mentioned. Sometimes you had like a front leg or maybe people would be willing to try it. And I think we have made advances and I am so excited about it because it is a pretty common problem. Many of us who are in practice... You're going to see one. I was in specialty practice and I saw them and I wasn't even a cardiologist. They would come in through medicine sometimes. And certainly, as a cat owner, I have experienced it unfortunately too, and I'm really, really pleased with what you guys are doing, and I'm really optimistic that you'll be able to help these guys...
28:43 DS: Kelly, I tell owners that with the current state of where we are in treating ATEs, at least one in four of those cats does really well and goes home and has a really great quality of life. And so, if the odds of winning the lottery are one in four, we'd all be playing every day. And so as long as we can keep all of those cats really, really comfortable and doing well in ICU until we can figure out whether your cat is one of those four, we're in really good shape.
29:15 DD: I think that's really great advice for everyone who's listening. So I'll be really interested in hearing more from your group. I'm really excited for what you guys are doing. And I want to thank you so much for joining us today and telling us about ATE in cats, and we'll look forward to reading more of your work on this topic. And I'm hopeful we'll make a big difference for a lot of cats and their owners. So thanks for joining us again today.
29:48 DS: Thanks, Kelly. We really appreciate it.
29:49 DL: Thank you.
29:50 DD: Well, that does it for this episode of Fresh Scoop, and once again, thanks to Drs. Stern and Li for joining us. And we'll be back with another episode next month that we hope you'll find just as informative. The science of animal health is ever-changing and veterinarians need cutting-edge research information to give their patients the best possible care, and that's why we're here. You can find us on iTunes, Spotify, Google Play Music and Stitcher. And if you like today's episode, we'd sure appreciate it if you could take a moment to rate us because that will help others find our podcast. And of course, to learn more about Morris Animal Foundation's work, again, go to morrisanimalfoundation.org, and there you'll see just how we bridge science and resources to advance the health of animals. You can also follow us on Facebook, Twitter and Instagram. And I'm Dr. Kelly Diehl, and we'll talk soon.