Beth Licitra, Current Combined DVM/PhD Student; Phillip R. Fox, DVM, MS, DACVIM/ECVIM (Cardiology), DACVECC
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Listen through headphones in a quiet room for best results.
Jump to Beth Licitra's transcript text.
Well, welcome to the 36th annual Winn Feline Foundation Symposium. My name is Steve Dale and I am on the board of directors for Winn Feline Foundation. I thank you all very much for coming. So, once again, to all of you I say welcome! That’s what I like to hear! So, if we see those slides of clogged arteries, we should have applause. We want enthusiasm.
I have some housekeeping sorts of things to talk about. Please complete the symposium participation survey and return it, especially veterinarians – and there are veterinarians here – since their surveys are used for future RACE program approval, and veterinarians will know what I am talking about. Veterinarians and staff should remember to get their CE certificates before they leave. Turn your cell phones on vibrate or off. Anyone who would like to make a donation to the Winn Feline Foundation throughout the course of the night, Vickie Fisher, our treasurer, she is the lady who is all about the money, up in front; raise your hand again, Vickie. Okay, we are more than happy always to take your money.
I have a couple of announcements to make that I am going to save until later, but my job is to tell you a little bit about – and I am sure most of you know a great deal about – the Winn Feline Foundation. The symposium, as I said, this is the 36th annual symposium that is being held. Pretty much a who’s who of veterinary medicine and we continue that today with Dr. Fox, a who’s who of veterinary medicine, has participated in the Winn Feline Foundation Symposium over the years. This symposium that you are at that has had that who’s who of veterinarians who appear, these symposiums that encourage further research would not have been possible if it wasn’t for a lady sitting in the back of the room, whom I am about to introduce, the great Joan Miller. She deserves that applause and much more for what she has done for cats for all these years. Occasionally I have had the opportunity to work with Joan; a learning experience every time I do. Someone here said she is a smart lady. Whoever said that is very right.
The Winn Foundation is a not-for-profit organization that goes back to 1968. If any of you have cats in the room...By any chance, does anyone here have a cat?
I have one.
A big one.
You might have the fewest!
The Winn Feline Foundation is responsible so much medically for everything about that cat, in fact, more than just medically. Everything from what our cats eat on a day-to-day basis, to the shelter cats we might adopt, to the way in which they are kept in shelters, to the medical care that they receive throughout a lifetime, from vaccines to preventive care, to a whole lot that goes into senior care, to treating diseases like two that we will hear about today. The Winn Foundation, over the years, has had everything to do with funding for that. Here is sort of a best of the best list; I am not going to go through all of these, but the idea is, for any of you who talks to...because I am sure most of you...I’m preaching to the choir here, right? You know about the Winn Feline Foundation, but here is how you can help us. Each and every one of you can be an ambassador to spread the word that all of this stuff and more, having to do with cats, the Winn Foundation, if it was not for us funding the researchers doing the work, well, these things might not have happened or would have happened much later.
So, we are going to hear about two topics that mean a great deal to me personally and a great deal to your average cat owner. You guys are not the average cat owner, but my guess is these topics mean a lot to you too. We don’t know how many cats die of heart disease or not. By the way, anybody know this cat? Or about this cat? Yeah. Do you remember this cat at all? Anybody? So, back in the day...and I will tell the brief story. I had a dog that did animal-assisted therapy and my wife said to me...That is when dogs go to hospitals or nursing homes or rehab facilities to help people feel better and, in some cases, help people to get better. My wife came back one day and said, “You know, we have to teach our dog...” (a miniature Australian shepherd named Lucy) “...we have to teach her something new.” And I don’t know why, but I bought a little miniature piano, that was it, and I began the process of clicker training, if any of you know what that is about. It is operant conditioning. You click the clicker and the cat raises its paw just a little bit toward the piano and you click it again, give a treat, and you get closer and closer; in fact, Lucy was lifting her paw a little bit. We were beginning to shape the behavior. It takes a little while to do that. You cannot become a prodigy overnight, necessarily. I had closed the door so the other pets would not come into the room, but I did not close it all the way, and in walks that little Devon Rex cat that looks at me, looks at the dog, looks at the piano and just goes ping, ping, ping, ping, ping, ping, ping and I thought, “Well, what am I fooling around with this dog for? I’ve got a musical genius here.”
So, Ricky was already a very social cat and what this did...and thank goodness for the breeder. Of course, we had the breed going for us; the Devon rex happen to have a certain personality that kind of lend them that way. She was socialized when she was young. That’s what I mean thank goodness for Leslie Spiller, the breeder of this cat. I was able to take this cat out into the world and Ricky loved it. As a result, we had a bond that I doubt I will ever have with another cat and maybe not even a dog. We did everything together. Before all was said and done, Ricky knew more than just to play the piano.
Any of you have little kids or know any? So, what you could do is line them up one by one by one by one by one by one by one and Ricky would go hop, hop, hop, hop over each one of them. He would jump over them, you know, kind of his own version of feline agility. He would sit and give a high four, not quite a five. I would go through a whole litany of things. I would make up stuff or Ricky would make up stuff. If I wanted Ricky to jump from this chair to this chair, like where you are sitting to this chair over here where you are sitting, I could just, at some point, point and Ricky had never done it before. We knew each other that well. Ricky enjoyed performing. Loved cameras, whenever cameras came around as TV crews did. Then, one day, we went to the veterinarian and my veterinarian’s face just turned white as she was listening to our cat’s heart. Before she said anything, I kind of knew and we went to see the cardiologist. Ricky lived for several more years without any symptoms, began to have a few, and that is when I said, “This is ridiculous. We have to do something about it.” And we did. We began the Ricky Fund.
The Ricky Fund has raised...Why did we? Because there is no cure, there is no really effective – or wasn’t then – really effective treatment. We are going to hear if there is a really effective treatment in a little while for HCM, but it was frustrating and what I didn’t know then is how many cats actually get this. And it is not only pedigreed cats; it is any cat at all, potentially. So, we are going to hear about that. We began the Ricky Fund. It has raised, to this minute, well over $100,000, so I thank you all very much for that. Really, thank you very much for that. As a result of that, as Maine Coon and ragdoll folks know, there is a simple blood test that can be done to determine if the gene defect is there. It is not a perfect test, but what is nice about it is we have been able to save some lives and that is awfully nice, but I want to do more than that.
We can skip past that. Then, a couple of years later, we heard from Susan Gingrich – yes, Newt’s sister – and she said, “I had this lovely sweet cat named Bria.” And, as often happens with feline infectious peritonitis, it is a kitten, and the cat owner has no idea that this disease even exists. Why do people – I am not talking about all of you, but in general – why do cat owners typically get a kitten? Maybe it is because another cat had passed away, right? So, they are grieving that cat that had passed away. They get this little kitten. They go to the veterinarian, who says, “Oh, by the way, this kitten has a disease that you’ve never heard about. Your kitten’s going to die.” It is the most devastating thing. I would argue for veterinarians, it is the most devastating news that a veterinarian can offer a client and the most frustrating thing for a veterinarian to deal with. Cancer, often occurs in older cats. Lots of kinds of cancers can be treated. FIP, that is a tough one and it is something...The good news is, there are so many people who are so passionate about it and, in fact, we have raised, similarly, more than six figures in the Bria Fund.
Dr. Al Legendre spoke – it was two years ago – at the Winn Feline Symposium. He offered some really good news. Niels Pedersen has offered some good news. In fact, the Winn Feline Foundation, with Niels Pedersen and Niels Pedersen independently, are responsible, I would say, for almost everything we know about FIP, but now Gary Whittaker is on the scene as well at Cornell and, in fact, we are about to hear all about it.
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Beginning of Beth Licitra Audio
I introduce Beth Licitra, a current combined DVM/PhD student but about to be a veterinarian in a matter of days, which is very, very cool. Isn’t that nice? I had the chance to talk with her earlier today and wow! What a smart, smart lady who is also committed to do something about FIP. Her research in the Whittaker Laboratory focuses on investigations into the initial steps of the virus infection. This includes binding of the virus to its host receptor, activation of viral attachment proteins by host proteases and fusion of viral and host cell membranes. Please help me welcome soon-to-be-doctor Beth Licitra.
Thank you very much, Steve. It is a real privilege to be here today. I attended the Winn Symposium two years ago when it was held in Boston and I heard Dr. Leslie Lyons speak about her work on feline genetics and I have to say, it is a little surreal to be back today to speak to you all about my work on FIP. I want to lead off by acknowledging the organizations that have made our work possible. Winn has been a great supporter of our research over the years. We have also received funding through the Morris Animal Foundation, through the Cornell Feline Health Center, from ANTECH Diagnostics, and my funding as a combined DVM and PhD student comes from the veterinary college through private endowments.
We have had some excellent collaborators over the years. Dr. Gerald Duhamel is a pathologist at Cornell and he was really instrumental in helping us access immunohistochemistry-confirmed cases of FIP from our pathology archives. Dr. Kornreich, who is over at the Cornell Feline Health Center, has been helpful in connecting us with cat owners who call in with questions about FIP. Scott Moroff was a veterinarian at Angell Memorial Hospital for most of his career and now currently he is the vice president and chief scientific officer at ANTECH Diagnostics and I cannot say enough nice things about Scott. He has been really supportive of our idea to take the mutation that we have identified in FIP and use it as a basis for a test to discriminate between feline infectious peritonitis virus and feline enteric coronavirus. He has really given me some great opportunities. I was able to present ANTECH’s work last year at ACVIM and that is how I met Dr. Thayer and I really could not be more grateful to Scott for that. And there is Ed Dubovi, who is a virologist in our diagnostic lab, who has contributed to our work and a special thanks to all the cat owners, veterinarians and shelter personnel who have contributed to our work over the years.
I have to say on a personal note, I think for us in the lab it has been really eye-opening to be able to interact with cat owners in this way because generally in the lab, you do not have that client interaction that veterinarians have and you do not see the clinical side of FIP. So, having the owners call us very desperately looking for a clinical trial, a potential therapeutic, has really affected the way we approach to this problem. Yes, as virologists, we are really interested in understanding how enteric coronavirus is able to infect macrophages and cause FIP, but we are also interested in development of better diagnostic tests, in testing out new therapeutics and, ideally, one day designing a better vaccine.
I have divided this talk into six parts. I am going to open with a little bit of fun history about FIP research at Cornell, then I am going to talk about coronaviruses in general and introduce the idea of the internal mutation hypothesis. In the third section I am going to delve a little bit into some biochemistry, into some virology, and I really hope that I can communicate the science in a way that helps you to better understand our research. In the fourth section I am going to talk all about the work that was published last year in emerging infectious diseases and what that means for potential therapeutics for FIP, and then we are going to move into what is the ultimate goal for all of us in this room and that is a treatment for FIP. I am going to end on a really clinical note. I am going to talk about the diagnostic tests that are currently available and I am going to present some data that has come out of ANTECH on the tests that we are working on together and give you my perspective of how I think that test may be used in the future.
So, if you have never been to Ithaca, please come visit us. It is beautiful. You can see Cornell is a lovely campus. Try not to come between December and May because that is winter. In the summer it is really stunning.
We are all really proud of Dr. Jean Holzworth. She was the only woman to graduate in her class in 1950 and she went on to be one of the pioneers of veterinarians and feline medicine. In 1962 she was the first person to describe FIP and I want to read to you her description. This is the very first publication of FIP in the literature:
“Some Important Disorders of Cats.
A peculiar entity with a definite predilection for cats is chronic fibrinous peritonitis, in which fibrin deposited on the abdominal organs, especially the liver and spleen, gradually organizes into a tough, pale fibrous coating. The liver and spleen may become contracted into barely recognizable forms. Clinical signs are persistent fever, gradual loss of weight and appetite, and enlarging of the abdomen with a more or less clear fluid. The condition is seen most often but not invariably in kittens and young cats, often in several in a household or cattery. Respiratory infections and lavish dosings of various antibiotics appear in many of the histories. To date no causative organism has been isolated or any effective treatment found.”
This is a really classic definition of effusive or wet FIP and if you fast forward 20 years to the laboratory of Dr. Fred Scott, at this time he knew that FIP was caused by infection with a feline coronavirus. Fred Scott did some really pioneering work to characterize antibody-dependent enhancement. For those of you who are not familiar with it, that is a phenomenon that occurs when some viruses infect macrophages in which antibodies against that virus actually enhance infection of those cells. This is what happens in FIP, it happens in dengue hemorrhagic fever, and the virus is able to coat itself in host antibody and then use those antibodies like a Trojan horse to enter through an Fc receptor, a specialized receptor on the macrophage, like coming in through the back door. So, that has really presented a problem for us in designing an FIP vaccine because the point of a vaccine is to stimulate an immune response, but if you stimulate a strong antibody response, you are going to predispose that animal to developing fulminant FIP.
Dr. Scott also studied FIP’s predilection for macrophages and I have to say that a lot of the work we are doing today in Gary’s lab is just a continuation of things that were started by Dr. Scott.
Back in 1974, he founded the Cornell Feline Health Center. This year they celebrated their 40th anniversary and I wanted to highlight some of their recent achievements. They have recently expanded their grant program so they are able to address more problems in feline medicine and that is really terrific.
I want to introduce to you Dr. Gary Whittaker. Here he is in the back row there. Gary is a biochemist by training. He did his graduate work in the United Kingdom. He came to the United States to Yale for his postdoc where he worked on influenza and he spent probably the past 25 years researching influenza. He really recently began to work with coronaviruses. He studied SARS coronavirus when it emerged in 2003 and recently in the lab we have been working with MERS coronavirus, if any of you have heard of Middle Eastern respiratory syndrome. We actually have that virus in a VSL3 facility and one of our postdocs has been doing some research on that. As an interesting side note, MERS is actually capable of infecting human macrophages, so that is something that one of our postdocs is looking at and it certainly correlates with FIP. What is great about working for Gary is that he approaches this veterinary problem from a new perspective. Since he has integrated what we know about flu, which is a much better studied infection than feline corona and taken that knowledge and applied it to feline coronavirus and I think that is really what allowed us to make the recent breakthrough that we did in research that I will talk about tonight. I also want to point out this man here, Jean Millet, who is a postdoc in our lab. He is the postdoc who is currently working on MERS and he helped me with some of the work in the study. He is coauthor with me on our paper that was in Emerging Infectious Diseases.
Part Two: The internal mutation hypothesis. I want to create for you a paradigm of coronavirus infections as they occur across species, not just the cat. These are endemic pathogens, so animals are exposed and develop some level of immunity at a really young age. MERS and SARS are not examples of classic coronavirus infection. These are examples of recent post-transmission events from other species. They are quite virulent. You may not be aware that in people most coronaviruses cause the common cold; 20% of common colds are caused by a coronavirus. These pathogens, they have an affinity for the respiratory and enteric tracts and there they cause really mild self-limiting infections. You really only see severe disease in immunocompromised animals, so animals that are young, whose maternal immunity is waning, and who have not fully developed their own immune systems. Animals that are under stress like high-density housing situations. In the case of bovine coronavirus, very cold winter conditions for cows or for postpartum cows we can break with bovine coronavirus. In cats, we know immunocompromised FeLV is also a trigger for feline corona.
Coronaviruses are named for the distinctive proteins that project from their surface. The word corona is Latin for crown and these projections right here on the viral envelope are known as spike proteins. I want to introduce spike early in the talk because it is really the focus of our research. Spike is critical for determining which cells in the body will be infected. That is because it binds the host cell receptor and it also initiates fusion of the viral envelope here with the host cell membrane and that fusion event culminates in release of the viral genome into the cell and subsequent infection.
Coronaviruses are really fascinating from an evolutionary standpoint because they are capable of this rapid evolution to infect new cell types and new species. There are multiple reasons why coronaviruses are able to adapt so quickly. I am going to go through each in some level of detail.
First, coronaviruses can swap genes to form recombinant viruses. Second, they have these huge RNA genomes and these RNA viruses, as a general rule, unlike DNA viruses or unlike eukaryotic organisms, have a really error-prone copying mechanism. So, we know that the coronaviruses, feline coronavirus has a very big genome, it is estimated that for every genome that is copies, you have three mistakes, so there is a huge potential for variation in coronaviruses and for selection of mutants that are better adapted to the host, and then coronaviruses are able to use multiple host cell receptors and the type of receptor that is on that tissue type or that cell type helps to dictate whether the virus can infect that cell.
I want to lead off by talking about the propensity of coronaviruses to form recombinant or chimeric viruses. In the rare instance that you have a cat that is coinfected with a feline coronavirus and a canine coronavirus – and this can happen because both viruses are really highly related and they use the same host cell receptor – you can have the production of a canine corona/feline corona recombinant and I must say this probably happens very rarely, but it has happened, and then once that variant is formed, it can start circulating in cats.
It turns out that in cats today, there are two genotypes of feline coronavirus circulating and this type, coronavirus type 2, is a recombinant with canine corona. It actually has a canine coronavirus-like spike protein and it makes up about 10% of cases of coronavirus infection in cats. It is really easy to grow in a laboratory setting, so all of that work that I was talking to you about that Fred Scott had done has been done on type 2 coronavirus. The problem is that is not the clinically relevant form of the virus. Clinically, 90% of cases are caused by a type 1 coronavirus and this virus does not grow in the laboratory. We believe that has something to do with the type of receptor this virus needs to enter a cell. It is not a receptor that you can find on cells that grow in culture. It is a receptor we believe is on only primary cells in the organism. It is the focus of our research a) because it is clinically most important and b) because we do not know as much about it. Things get a little confusing when it comes to coronaviruses and the disease they cause in cats. Whether your cat is infected with a serotype 1 coronavirus or a serotype 2 coronavirus, the outcome can be on a very big spectrum. You can either have feline enteric corona, which is ubiquitous coronavirus that is in the environment that most cats and multi-cat households are exposed to. It is limited to the GI tract. These cats are able to clear the infection and are healthy. You can also see the development as feline infectious peritonitis and this form, as you all know, has systemic consequences; it is pretty much universally fatal.
FIP, to complicate things a little bit more, can present in either a wet or a dry form, so you can have effusion, the wet form, or non-effusive disease, the dry form. It is believed that what form of FIP the cat presents with has to do with that cat’s individual immune response to the virus. To get back to some neat things about coronaviruses that allow them to evolve. Coronaviruses have accessory genes. Why is this important for FIP? Well, it turns out some of the mutations that have been identified by Niels Pedersen that are correlated of FIP are immune accessory genes. We do not really know what these genes do. They are not required for replication and cell culture, but they do seem to have a role in infection and pathogenicity in vivo so that they may modulate the immune response to enhance pathogenicity in that way. Niels Pedersen, you probably are all familiar with the mutation in 3c that correlates with FIP, he has also reported on a mutation in 7b. So, these accessory genes are really unique to coronaviruses and I wanted to introduce that.
Coronaviruses, as I have already told you, have a really high mutation rate, so when your cat is infected with a coronavirus, you do not want to think of it as having a single virus. You want to just think of it as being infected with a quasispecies of viruses. What do I mean by quasispecies? A quasispecies is a group of highly related but slightly different viruses that are competing within the same environment. Like I talked about, every viral genome could have three mutations from a parent genome. I tried to make it so in this little quasispecies cloud here, all the viruses are blue and different shades of blue. These are all really closely related viruses, but they are all a little bit different. You can see in an animal that is immunosuppressed, that is not controlling replication of the coronavirus in the gut, you can have the selection of a mutant ovarian that is able to cause FIP.
I am going to gloss over this a little, but I want to highlight that another thing that is important for coronaviruses in general is their ability to use different receptors and one idea we have in our laboratory is that feline enteric corona might enter enterocytes of the small intestine by using a different receptor than the receptor that it might use when it enters a macrophage. I have already told you in antibody-dependent enhancement there is this Fc receptor, the Trojan horse, that coronaviruses can use, but they can also use a molecule called DC-SIGN. DC-SIGN is best studied in relationship to HIV. It turns out that this is expressed on dendritic cells, which are an immune cell as well as macrophages and other immune cells. HIV is able to latch on to this DC-SIGN receptor and get carried to the lymph nodes where it can infect its target cells, which are T cells in the lymph nodes, and it appears ... Work in our lab has shown that feline coronavirus can also use DC-SIGN to enter host cells and this was done by a postdoc in our lab, Andrew Regan, a few years back. So, it is just to say that when we think about the transition of enteric coronavirus to FIP, there are multiple factors that could be at play. I think that is something that is really coming out now. There is probably not just one mutation that causes FIP. It might be a constellation of changes in the virus and that might explain why it has been so hard to pin down the genetic change in the virus that is linked to the development of FIP.
Okay, so this brings us to the internal mutation hypothesis and I tried to convey the point that the hallmark of FIP is its ability to productively infect and activate in macrophages. It is thought that FIP arises uniquely within each infected animal from an enteric coronavirus. So, if every animal has a virus that experiences a mutation that causes FIP, we do not believe that FIP is transmissible. We believe that is what is transmissible between cats – this is what research shows – is the enteric form of the coronavirus and it is that virus then can lead to FIP based on how the cat responds and controls that infection.
Okay, so I have a little animation here. Feline enteric coronavirus is transmitted by the fecal-oral route, so cat ingests the virus, goes to the small intestine where it begins to replicate. It is excreted in the feces and for most cats, that’s it. Their immune system controls the infection and they clear the virus. Some cats – this is work that has come out of Niels Pedersen’s laboratory – become persistent shedders. The virus persists in their intestinal tract and they continue to shed coronavirus into the environment and these are the cats that in your catteries or in your shelters are consistently reinfecting your queens or your new litters of kittens and they themselves may not end up breaking with coronavirus. However, some cats that cannot clear the infection, young cats, cats with FeLV that are otherwise immunosuppressed, in those cases a mutated variant of the virus can arise that spreads in macrophages and triggers FIP.
An alternative theory to the origin of FIP is the circulating strain hypothesis. In this hypothesis, both pathogenic and nonpathogenic variants are actively circulating among cats. Whether a cat develops FIP is determined by what strain they are exposed to. I have to say that in Gary’s lab, our current thinking really takes these two hypotheses and combines them. They are not mutually exclusive. So, while we think that FECV is transmissible, a mutation does occur within an individual animal to lead to FIP, not all FECVs are the same. Some FECVs in circulation probably carry a number of mutations that make them predisposed or closer to becoming FIP and that could explain why, in certain situations, in certain catteries, in certain shelters, you see what appear to be outbreaks of FIP because those cats are infected with an enteric corona that is very likely to mutate to FIP. That is something that we have not tested, but something that we are looking to test by looking at samples that have come from cats in environments where an outbreak is ongoing.
Okay, this is where we get into some biochemistry and a little bit of virology. All the viruses on this slide have one thing in common and that is that in order to infect their target cell, they need to be activated by a host enzyme or protease and I am going to break this down step by step. So, spike, which we have talked about, is the critical determinant in which cells in the body will be infected and that is because a) it is responsible for binding to the cell receptor and b) it triggers that fusion event where the viral envelope and host membrane fuse and the genome gets released into the cell. None of this can happen until the spike protein is activated by a host cell enzyme. This is a common theme among some viruses, that this is how they control infectivity, and if you look at the coronavirus spike – I have given you a linear depiction of it here – coronaviruses have two regions in the spike protein where they can be acted upon by a host protease to be activated.
I think I was in the lab about a year and a half before I really understood what a protease was because everyone in my lab has a good biochemistry background and coming from more of a veterinary background, this was not readily apparent to me. My idea of protease was an enzyme that catalyzes the breakdown of protein, so you think like in your GI tract, you have proteases that break down proteins into amino acids so you can absorb those amino acids and use them as building blocks in your tissues. What I did not realize was that proteases can also serve to activate other proteins, so this is the zymogen idea for any of you who are familiar with that. Proteases are really powerful at breaking down proteins and you do not want them unrestricted in your body because, as you could imagine, that could be quite detrimental, so the body really tightly controls activation of proteases. It does this by secreting them in an inactive form and then having another protease at the target site act upon them to cleave off a piece so that they can be active themselves. I think the best studied example of this, an example that would be most relevant, especially to the veterinarians in the room, is trypsin, which is secreted in its inactive form by the pancreas and if you, let’s say, have a cat with pancreatitis, what has happened is that trypsin is getting activated before it gets to the small intestine while it is within the pancreas and now it is starting to digest pancreatic tissue and cause a lot of inflammation. So, that is an example of how protease regulation is really important and one role of proteases is to activate other things within the body and viruses take advantage of this.
So, how do viruses do this? Viruses like our coronavirus, their spike protein is in an inactive form on the surface and I say it is inactive because the fusion protein, the region that allows it to fuse, is hidden inside this coil here. A host protease comes along and clips this region so that you can have a conformational change where this area, the fusion peptide, is exposed. A fusion peptide is a string of hydrophobic amino acids that can insert into the membrane and disrupt them, so as the membranes get closer, it allows them to fuse and this is a process that cells do not like to do. To fuse two membranes is quite difficult; it requires energy. So, the fusion protein gets in there. You have a conformational change in the spike to oppose. This is the host cell membrane. This is the viral membrane. This is a nice schematic of what happens next. You get this formation of this core where the membranes have fused and this is the viral genome. It is now able to enter the cell and start using the cell’s machinery to replicate itself. The end result is infection.
Viruses can modulate what cell type they are going to infect by controlling what protease activates them. They do this by selecting certain amino acids at their active site. I think the best analogy I have come up with to explain this is a lock and key analogy, where a coronavirus, at the region where it needs to get activated, has an amino acid sequence that is only going to fit a certain key. For the example of trypsin, which is that protease we talked about in the gut, that likes to see a lock that has one basic residue. Basic residues are positively charged. This is a nice electrostatic interaction for the protease. Trypsin can come in and recognize this basic residue and cleave. So, if a virus has a motif that can be activated by trypsin in the gut and only by that protein, it can restrict its activity to the GI tract. As you can imagine, if a virus is active to infect any cell it encounters, it is going to infect the very first cell that it meets in the body or if it cannot replicate in that cell, that is not its target cell, then that is a dead end for the virus. The virus is much better served to target itself to the tissue where it can replicate in this instance the gut, get activated there and then productively have infection in the GI cells.
I am sorry. This is not showing up very well. For those of you who did not get a color copy of this printout, I will leave you my e-mail and you can e-mail me and I can get you a copy of it printed out because some of this is also very small and hard to read, I realize that.
Furin is an enzyme that is present in every tissue in the body and I think of that as like the master key. If the virus wants to use a master key, it has to have a lock that is going to be opened by that master. So, the sequence for activation by furin is a multibasic residue. So, these are amino acids that are positively charged in a multibasic string and Harrington recognized that and cleaved that. The best studied example of viral pathogenicity that is linked to cleavage activation is avian influenza. So, you have low path avian influenza that has this monobasic one arginine activation site in its spike. It is cleaved by trypsin in the GI tract. It is really limited to the GI tract in birds and that is what avian influenza is naturally in birds; it is a GI disease in birds. Then you can have the evolution of high path avian influenza virus and I am sure you have seen in the news that there are definitely some high path strains out there that are very fatal in birds and do spread systemic. What has happened in those viruses is that they have acquired this multibasic activation site that can be recognized by furin. I have told you furin is that master key; it is in every tissue. Influenza is capable, actually, of replicating in a lot of tissue so what happens in birds that are infected with this virus is the virus spreads systemically and you have death of the birds. So, with that in mind, we are going to approach the problem of feline coronavirus because it is a similar story. We are talking about a virus that, in its benign form, is restricted to the GI tract and in its pathogenic form, it is capable of infecting macrophage. So what is going on?
I have already introduced to you the coronavirus genome and I told you that we know that mutations in accessory proteins are associated with the development of FIP. The problem is we cannot really link how mutation in an accessory protein would explain a switch in tropism or ability to infect. Tropism is just like what tissue the virus can infect from the GI tract to macrophage. We know that a mutation at a viral activation site can explain that for other viruses like avian influenza or Newcastle disease. So, in our lab we took the approach where instead of looking at the entire genome, we were going to focus in on this viral activation site and we were going to sequence activation sites from cats that had FIP and cats that were healthy and we were going to compare the activation site between those two groups of viruses. Our hypothesis is that FECV and FIPV have different activation motifs, that they are activated by different proteases and that this difference in activation targets FIPVs to monocytes and macrophages and enhances its replication in this cell type. So, when I had the opportunity to design this study, I had just taken epidemiology as a first year vet student. This was exciting for me. I wanted to have a pretty rigorous study and I decided we were going to need to have cases that we knew were FIP that were confirmed by the gold standard, which is immunohistochemistry. So, what we did is we collaborated with Dr. Duhamel, our pathologist, and we found cases in the pathology archives where we had IHC-positive cats, and then we took our controls from environments where we know there is a lot of coronavirus, so these are healthy cats that came from shelters and catteries where they were probably exposed to coronavirus and were not showing any signs of FIP that seemed to just have benign run-of-the-mill coronavirus infection. From these cats we had feces and we went ahead and we sequenced the virus from the feces and the tissues of the cats to compare it. When it was all said and done, we had 30 control cats and 11 FIP cases. We tried to get a mix; we got some wet cases, some dry cases, and mixed cases. We were hoping we would see differences between wet and dry FIP based on the virus. I can tell you right now, we did not see that, but that does not mean that there are not differences. There were not differences in the area we were looking at.
Our geographic distribution
We wanted to make sure that we were not just describing coronaviruses that were limited to New York State and the area around Cornell, so we tried to take from a really diverse segment around the United States, so our cats came from all over the US. We had samples sent to us from vets, from cat owners. We had the samples from the pathology archive.
The methods were real simple. We isolated viral RNA. We used a method called reverse transcription to turn that RNA into DNA. You can amplify DNA by the polymerase chain reaction, then you can take that amplified DNA, sequence it, and then we analyzed the sequence we got back.
Before I show you the data, I want to share this picture. This is really beautiful. This is IHC-positive omentum and you can see that the areas where there are coronavirus, the macrophages light up red. This is really beautiful and this particular picture was provided by ANTECH. One of the reasons we had some success with this study, if you are trying to isolate RNA from tissue that has been fixed, which is what we were trying to do with the pathology archives, that RNA is really degraded because formalin really degrades RNA, but Dr. Duhamel went in and he selected and picked out these regions that stained red for coronavirus antigen, so it really enhanced our ability to get viral RNA out of these tissues.
So, to orient you here, what you are looking at is the S1/S2 activation motif in viruses that were sequenced from the tissue of healthy cats. I think what will strike you is that you can see there is this really high conservation of this very basic motif. I colored the basic amino acids here in blue. This is an ideal furin motif and if you have been following me, you are probably like “Beth, I’m a little confused. You just told me that avian influenza, which is spreads systemically, is cleaved by furin, has a multibasic motif. Now you’re going to tell me that cats with enteric corona, which is restricted to the intestine, also have this polybasic motif?” We are going to get to that, but yes. That is what it looks like. It looks like, for whatever reason, in the GI tract, this region, this multibasic furin motif is really important. This is highly conserved. The virus does not mutate in this site. We only saw two mutations in the cats that we had and it turns out that mutations of these residue are not as important as mutations like here, this first residue when it comes to furin activation.
Okay, so now we are going to look at what is going on with our FIP cases. I think you can see immediately that that conservation has been lost. We had 22 different viruses from 11 cases. So, what we did is we sequenced different tissues and we got different quality tissues from the same cat. I am going to highlight all of these we saw. There is a big difference from the previous slide. In 10, 11 cats the furin motif was completely disrupted by the presence of an amino acid mutation that varied from that consensus furin motif we saw in feline enteric corona. I am going to walk you through the findings cat by cat. In this animal, we sequenced two tissues and we saw a mutation, the same mutation, in both tissues. In this animal, we also sequenced two tissues and we picked up two different quasispecies species. Both had a mutation, but they were in different sites. In this kitty, one tissue had the enteric motif that we saw in the feces, while the other tissue had a mutation. Then, in this cat, the last cat, we did not see any mutation that would correlate with FIP. You can see we have that really nice arginine, arginine, serine, arginine, arginine, serine motif. What we did see here is this phenylalanine and we are not really sure ... Phenylalanine is a pretty big, bulky amino acid and we do not know in the context of the feline spike what that amino acid would do with the ability to get furin in there. You can imagine if you have not site your protease needs to access and then you stick something big and bulky next to it, can furin still cleave that site? I don’t know. That is a question that we will have to answer with a genetically modified viruses in the lab. We are planning to do those experiments in the future. But the take-home message, really, is that in FECV, you have this conservation of this multibasic motif and in FIPV, in 14 out of 22 tissues we looked at, that conservation is lost.
So, what does it all mean? What we think is going on is when you look at the amino acids that are taking the place of those basic residues, they all have a different character. They are mostly nonpolar, uncharged amino acids and what we think is happening is that FIPV is being activated by another protease, a protease that does not like basic residues; in fact, it is a protease that prefers these nonpolar amino acids and our working model is that use of that protease to target FIPV to macrophage.
This is where we are going to get into those where we are going from where we have been and, hopefully, talk about potential treatment for FIP. I don’t know if you guys can read this in the back, so I will read it to you. When you do as much reading as I do in my PhD, you go back to old magazines, and this is from a 1995 journal; I think it was Feline Practice. This is an old ad for Primucell and it reads: He survived the neighbor kid’s BB gun, a Doberman, a garbage truck, falling asleep on a car engine and a fall off the roof. Here is his empty collar and it says ‘It’s a shame he wasn’t vaccinated with Primucell FIP.’ This is the saddest advertisement I have ever seen. I don’t know what Pfizer was thinking but what it makes me think when I see this is yeah, so in 1995 we thought we had the magic bullet. We thought we had a vaccine for FIP and it turns out we did not, really we are looking for that, we are looking for that treatment for FIP because it really is a tough disease and although this ad is really sad, the sad part is that it is a reality. So, like I told you, in Gary’s lab we are really hoping that our research will bring us one step closer to that ultimate goal.
We talk a lot about proteases and I just want to share with you that proteases are dysregulated in a lot of diseases. For example, in dental disease you have up-regulation of proteases that start breaking down gum tissue. In pancreatitis, we talked about trypsin; if it is unregulated, it starts digesting the pancreas. In cancer, we have up-regulation of proteases to break down extracellular matrix, so you can get new blood vessels into those tumors that are growing. When you think about FIP, you have infection of macrophages and macrophages secrete proteases to break down matrix. We know that there are vascular changes in FIP, that you do see effusion, and this we suspect is mediated by some of the proteases that macrophages produce when they are activated. On top of that, we are thinking that a macrophage-produced protease may in fact activate FIP. The protease that we have in mind is MMP-9. I have given you the lock-and-key analogy. I like to think of us a little bit like locksmiths. We are looking at FIP and we are looking at all the different locks that FIP has, all the different residues that appear at that cleavage site, and we are trying to make a mold of this key. We are trying to find out what is the protease that activates this virus. Our best lead at this moment is a protease called matrix metalloproteinase 9. It is a metalloproteinase because it has zinc, a metal, in its active site. It is known to be produced by macrophages and endothelial cells to break down extracellular matrix. It has physiologic roles in the formation of new blood vessels, in wound healing and in cell migration, but it is also associated with a lot of pathologies in people. It is up-regulated in arthritis. It is up-regulated in some vascular diseases and in metastasis in cancer. What is really interesting is that it likes these uncharged amino acid residues like the ones that we see in FIP.
So, our first question is: Is macrophage expression of this matrix metalloproteinase 9 up-regulated in macrophages that are infected with FIP? This is a picture here that I had taken of feline macrophages, so what we do, we never infect any cats with FIP in our work. We have cats that we collect blood from. These cats do not have any coronavirus, so we draw blood from them and then there is a process by which you can isolate macrophages from that cat blood. You can bring the macrophages back to the lab and you can culture them and then you can infect those macrophages with FIP and see how they respond. So, we did that. These are macrophages that are infected with a strain of FIP called 1146. These are our control, unaffected macrophages and then these are macrophages that are treated with a bacterial protein called LPS that we know stimulates MMP-9. So, we have our negative control, our positive control to show that we can measure MMP-9 and we can actually get it up-regulated when we see FIP. So, we have seen up-regulation of MMP-9, as compared to the control, and these experiments were done last year by a leadership student who came to us. He is a vet student from Germany, Hendrik Sake, who is really excellent. What I have been trying to do now is repeat some of his work to get ready for publication.
Another thing he did – and this is really pretty interesting – we have been collecting blood from pairs of healthy housemates and their siblings or housemates that died of FIP, and the idea is that both these cats were probably exposed to the same enteric coronavirus because they were in the same household. Well, one of them ended up breaking with FIP while the other cat remained healthy. So, we looked at the blood from these cats and looked at the expression of MMP-9 in the blood. We found that in the FIP cat in this one pair that we looked at had 1.5 times more MMP-9 than the healthy housemate and this something now we want to repeat with other cats to see if it holds true, that MMP-9 is in fact up-regulated in macrophages. For any of you who are associated with Dr. Kipar’s work – she is a pathologist from Germany – she has also looked at MMP-9 and shown that, yes, it is up-regulated in FIP.
Our future work is to answer some new questions that we have. Do elevated levels of MMP-9 in FIP-infected macrophages contribute to the vascular permeability that we see in effusive FIP? And even in dry FIP, you have permeability of the blood-brain barrier because these cats survive long enough now that the virus is able to get into the brain and cause some neurological signs in cats that suffering from dry FIP. We know that MMP-9 causes vascular problems in people but also going on in cats. Does MMP-9 upregulate the migration of infected monocytes and macrophages into tissue? Does MMP-9 enhance infection of macrophages with FIP? And this is really the key question we want to get at because if it turns out that MMP-9 activates the virus, then we might be able to get an inhibitor of MMP-9 to help cats control the infection. This is something that has been done a lot with cancer, so there are actually a lot of MMP-9 inhibitors out there in drug development because they are targets for atherosclerosis and for cancer, so it is something the pharmaceutical companies are looking at and that is exciting because it gives us access to tools that are already out there.
So, this is the future. This is not something we are currently doing, but this would be the idea, is that you could use the inhibitor of MMP-9 as a treatment for FIP. Currently the standard of care in people with viral infections like hepatitis C or HIV is to receive cocktails of multiple different antiviral inhibitors. The reason for that is these viruses mutate, so if you give a patient just one drug, they are going to immediately develop resistance to that drug. We have learned from HIV patients that you need to give multiple viral inhibitors in order to control the infection. I think that if we want to be able to effectively control FIPV, this will also be something we will have to consider. There is probably not going to just be one inhibitor that you can give; you are probably going to want to give a cocktail of drugs, so you can suppress viral replication enough that you do not have these mutants that are resistant to your treatment. And then in people already, you can use doxycycline, which inhibits MMPs in periodontal disease. People who have periodontal disease can take this drug Periostat to inhibit matrix metalloproteinases and help control their periodontal disease. So, you know that kind of thing is an option too. Doxycycline is something that we can try as a potential therapeutic in cats. I did talk to Margie (Scherk) last year at ACVIM. She said that she thought they maybe have tried this with some of their animals and not seen any improvement, but it is an idea that is out there and maybe this is not the exact drug we could use, but it is something along that theme.
I did want to say that I think any treatment for FIP is going to have to be initiated really early. The reason for that is once a virus gets into macrophages, once those macrophages get activated and start producing all these proinflammatory cytokines, you are really at a point of no return. I think even if you add in an inhibitor later on in the infection, it might be too late because you have already got the immune response going and it is ultimately that aberrant immune response that kills the cat.
Lastly, I am going to talk about some of our work with ANTECH. I just want to check how we are doing on time. Okay, good. I want to talk a little bit about how FIP is diagnosed and what current diagnostics are out there today.
Clinical signs of effusive or wet FIP. We have obviously talked about the abdominal effusion and this is usually straw-colored and kind of sticky, really characteristic for FIP. The differentials for abdominal and pleural effusion include other diseases like heart disease, neoplasia, cholangiohepatitis and these are things that vets need to rule out when they see a potential case of wet FIP. The other signs of wet FIP are pretty nonspecific. Chronic fever that is unresponsive to antibiotics. Weight loss. Lethargy. A dull coat. And then we can have some changes on your chemistry panels and your hemogram that are not necessarily specific to FIP but can be seen with a lot of different diseases.
Dry FIP has a lot of the same nonspecific signs as wet FIP and then on top of that, some cats will present with ocular changes. The iris will get darker. You can get these white precipitates on the eye, which are keratic precipitates. As we talked about, these dry cases do not tend to progress as quickly as wet FIP, so the virus is in body longer. It is able to cross the blood-brain barrier and you can start to see some neurologic signs of incoordination, seizures, tremors, that kind of thing. I think this is really nice picture from Niels Pedersen’s paper right here. You can see the iris has become brown and you see that even the pupil is a little bit misshapen. I cannot really see the keratic precipitates on here. I have looked, but I bet you Niels probably could see them. The problem with dry FIP is it can be really hard to diagnose because the cat does not always present with these characteristic signs. They may just be presenting with the nonspecific signs of FIP.
I feel like clinicians are really pretty good at diagnosing wet FIP and a) there is a limited number of things that cause effusion, especially if you have a young cat, which is raising your index of suspicion for FIP, and b) when you have effusion as a clinical sample, any diagnostic test you are going to run is always going to give you better results on effusion than on blood or another sample. That is just something we know from the literature. A lot of that work was done by Katrin Hartmann. I don’t know if she has ever spoken to you all here, but she is really wonderful. She has done a lot of work on diagnosing FIP.
Blood-work-wise, if the effusion has this kind of albumin/globulin ratio, something less than 0.9, if you have a high total protein, (Oh, I am sorry. This is not blood work; this is if you are looking at effusion), if you have elevated gamma globulins. If you have coronavirus antibodies at all, any titer, and an effusion, that is pretty suggestive that it is FIP. If that effusion is positive for coronavirus by RT-PCR, pretty suggestive that it is FIP. If you are in a place where you can do IFA, which is immunofluorescence assay, on macrophages and you see virus in the macrophages, that also raises you index of suspicion that you have FIP. So, for wet FIP veterinarians have a really good handle on that.
There is also this Rivalta test and what does this mean? This is a paper from Katrin Hartmann, the vet I was telling you about, who has done a lot of work on diagnostics. So, the Rivalta test was developed in the 1800s by a human physician who wanted to be able to tell transudates, which are low-protein effusions, from exudates, which have a lot of protein. To do this, you take a little bit of vinegar, you mix it with some water, and then you draw up a bit of the effusion on the top of that and it looks like, I don’t know, eggs benedict, you use vinegar because it helps the protein spread out, so if you have a transudate, as soon as the effusion hits, it is going to spread out. You are not going to see this pellet form, but if you have an exudate, then you are going to see this sort of thing, where you can see there is a pellet of protein and it is diffusing through. The Rivalta test, like for shelters, is really cheap and you can take a little bit of effusion and you get a positive Rivalta, that increases your index of suspicion you have FIP.
Okay, now, if you have dry FIP, then you really are stuck looking at blood, so you are going to look at serum and tests on the serum are inherently a little less accurate, but there are some parameters that we know are associated with FIP in serum. People ask us a lot in our lab, “What about the feline coronavirus antibody test?” They will call us and they will tell us they have a cat that has really high antibody titers to feline coronavirus. Does it have FIP? I think that it has really been shown that the antibody test is not really a good indicator of whether a cat has FIP or not just because so many cats are exposed to enteric corona and do develop antibodies. However, people thought maybe we could use it to rule out FIP and the problem with that is that in FIP, you have formation of antibody and antigen complexes, so antibodies can start to bind up all the coronavirus antigens in blood, so if you are going to go look for a coronavirus antibody, you might not see it because it is all bound to the antigen. We know that titers decrease in some cats as the disease progresses, so you can have a cat with a totally negative antibody titer and 10% of the time that cat is actually going to have FIP. All the antibodies are going to be bound up in the antigen. So, that is neat and that comes from more of Dr. Hartmann’s work.
For those of you who are familiar with the current RT-PCR test for coronavirus, there are a couple out there, but the one that I am going to talk about is...I think the place that does most of it is Auburn University. This test is based on looking at a gene that is only present with coronaviruses that are replicating, so trying to isolate or amplify that gene. So, if you have coronavirus replicating in the blood, you are thinking FIP, right? So, they will look at blood and if they see coronavirus replication by amplification of this gene, it is going to be positive for this test. This was developed in 2004 and the published values have a really good sensitivity of 94% and specificity of 100% on blood, but I am going to tell you, just from my experience in our lab trying to isolate coronavirus from blood, just the RNA itself, I do not really believe this. It is actually really tricky to do and we have had a hard time with it in our test at ANTECH so I think these numbers need some independent verification, but certainly...and, you know, it is a nice test. You can submit...the sample that works best is effusion. I have told you that already; if you have ascites, that is the best diagnostic sample. You can also submit fine-needle aspirates or you can submit on blood and then you can get an idea whether you have replication. So, this is just another test you can run in those tough cases where you are not sure what is going on.
Okay, so, I wanted to provide this for you guys. It is just a flow chart on FIP diagnosis. I adapted it from one that was published in 1993. So, you know the signs of FIP, if you have those, combined with the risk factors and when you do your clinical exam, you see effusion and that effusion is positive on the Rivalta test and you are thinking, “Okay, we have FIP.” If you do not have effusion or you have an atypical effusion...let’s say you have some of those other signs of FIP, the ocular signs, the neurologic signs, then you are going to go ahead and you are going to do some lab work. If they come back and you have a lot of abnormalities, like greater than six abnormalities on your lab work, then you can say, “Okay, we’re in the category; this is probably FIP.” The problem is when you get those difficult-to-diagnose cats and their blood work. They do not really have the typical effusion. The blood work comes back without as many abnormalities as you might expect in an FIP case. What do you do with those animals? Previously what we did was serology and if they had the highest titer, you would say, “Okay, FIP is really likely. Let’s go ahead and biopsy.” The problem with biopsy, that is pretty invasive and most owners and vets do not want to put a sick cat through biopsy to confirm whether it has FIP, so if you go to places where yeah, it would be really nice to have a blood test for FIP that you could submit. So, Auburn has their test that could be useful in that case. We are working on a test with ANTECH that could be useful in that case for diagnosis. It is based on qRT-PCR. Instead of looking for a gene that is present during replication, what we are looking for is our mutation. So, our idea is that you could submit blood. We are going to look for coronavirus. If it turns out to be positive, we are going to sequence that coronavirus and we are going to tell you whether you have a mutation at that S1/S2 site that is associated with FIP.
Here is the data that we have. This test is kind of a two-step test. The first thing we are going to be doing is PCR for coronavirus. We want to see how good are we at detecting coronavirus in the blood and it turns out, in the blood, we are not very good at it. Our sensitivity in blood is really not ideal yet. So, we decided we are going to start, as we are designing this test, with something that we can do better at. We are going to start with ascites and in ascites we are pretty good at detecting coronavirus. We can detect it in 72% of the cats that we believe have FIP and the specificity is 100%. We also looked at effusions from cats that had heart disease that that they had hepatitis or some other reason they had that effusion. We did not detect any coronavirus in those cats, so we feel really nice about the specificity. When we go look at these positive cats and we sequence them and we look at what we find, we find that sequencing itself, 79% of the time the cats that we suspect FIP, we find that FIP would be like mutation, and then specificity in cats that are healthy and we go ahead and sequence the virus, we find 93% of the time that comes back negative for the mutation.
So, that is where we are at with this test now. It is still in development. I am under the impression from ANTECH that they intend to market this test within the next year. But I want to give you my perspective on how I think this test could be used. With a diagnostic test, my concern is that it is really specific because you do not want to give a cat owner a diagnosis of FIP when their cat does not have FIP because that, in many cases, could mean euthanasia. And then what are you going to do if you get a positive result? A lot of owners were going to do the same thing anyway. They are going to give the cat as much palliative care as they can until it is time to euthanize that animal.
Where I see this testing really useful is when we get to the point where we have a treatment for FIP, so in that case you could go into the cattery that is having a problem, you could take blood from those cats, and you could look to see which sets of kittens, which queens, have virus that contains a mutation that we know is associated with the development of FIP, and then you can initiate a palliative treatment or not...You know, you can initiate your treatment in those cats, let’s say, for example, you treat them with doxycycline, which right now is not a treatment, but just as an example. You could start treating those cats and, hopefully, prevent that mutated virus that we see from actually causing FIP in those cats; just giving them a little boost to help their own immune systems take control of the virus. So, that is where I see this diagnostic test being super-useful.
I have also talked to one of our shelter veterinarians and she was saying it could be nice in a shelter setting where you have a kitten that has FIP and now you are wondering what to do with the littermates because for shelters, that is a really tough call. Are you going to adopt out littermates of an FIP cat and then have...we know those cats are more likely to break with FIP and that is heartbreaking for the owner. What do you do with those kittens? Then maybe you can get this test on board and can form your decision or you could even start treatment if you have it available. So, those are my ideas for the future. It is really exciting to work with ANTECH on this test.
In summary, RT-PCR-based tests like the one we are developing are useful tools to aid in making a diagnosis in challenging cases, but IHC biopsy on tissue remains the gold standard for diagnosing FIP. I really wanted to end with some pictures of the cats that have been in our study. We know from owners these are their babies and we definitely really think about them and how they would do in the lab and some of them are really pretty adorable. This last cat, Miles here, was the first kitty to participate in our study and I think he will always stick with me for sure. It is really heartbreaking to get pictures of these guys. They are usually kittens that are usually so adorable and it would be great to have a treatment for FIP.
All right, thank you. This is my contact information, so please feel free to e-mail me...
While we do our little computer dance here and we have to switch computers and do all of that. I do have one more piece of business to take care of. By the way, I will tell you, the Winn Foundation, I am speaking for me, but I really think I am speaking for the board. We are determined to do everything we can to do what we can. Today we just had a grant meeting and I think I can talk about this. Zoetis said (essentially, they used to be Pfizer Animal Health for those who do not know), “Here’s a hundred thousand dollars and we want you to focus in on some things, but, essentially, spend the money wisely.” It goes very quickly. Every time we have our grant meeting, our annual grant meeting, unfortunately, we cannot fund nearly as much as we would like to. I am talking about cat health and behavior in general, but when it comes to FIP, as we just heard about, when it comes to cardiac disease that we are about to hear about, everything means a lot to us, but those two, we are determined to make a difference and to do something about, but we need your help to do that and we need the help of your friends to do that as well. For those on the board of the Winn Feline Foundation – put up your arms in the air – and please help me thank all the board members who do this stuff. Significant others of board members...Come on! Our camera guy over here and Otto is somewhere, maybe out of the room at the moment, but we thank them as well.
We have some announcements to make. The Winn Feline Foundation recently said, “You know what?...” Because we have an executive director who is very wonderful, but she resigned, and our new executive director, I will say, I am so excited about. You may know her. She was the president of the board of the Winn Feline Foundation, a past president of the American Association of Feline Practitioners, and if I went through all of her credentials, all the things she has done in her career, I would be taking up Dr. Fox’s time, so just help me thank Dr. Vicki Thayer for accepting that position and Dr. Glenn Olah, who, unfortunately, just stepped out of the room. How about this for making an entrance? Dr. Glenn Olah, welcome back! The new president of the board of the Winn Feline Foundation. If you will help us to take a minute, we have something very special to do. Please help me again welcome Dr. Thayer, who is going to do that very special something for us.
Dr. Vicki Thayer:
A number of people in the room probably realize that one of our long-time board members and CFA people is retiring this year and I would consider this individual kind of my guide star on board and that is our Betty White. We call her our Betty White and she is immediate past president and, as I say, retiring off the Winn board, but I did take some time to get something to recognize Betty’s number of years of involvement and dedication to Winn. We did something a little different this year. Oftentimes we give a Lenox crystal cat, that goes out with an award, but because Betty was a Siamese breeder, I went searching on eBay trying to find the right figurine that would fit and this says, “In appreciation to Betty White for years of dedicated service. Winn Feline Foundation.”
Oh thank you! It has been a real privilege for me – and that is the only word – to sit on that board. You have no idea what those February board meetings are like, all these wonderful grants, all these wonderful proposals, but only so much money. For someone who has a liberal arts background who knows nothing about science, I would reach, I really reached at those meetings, but they are all so very, very wonderful, so thank you.
Thank you all very much. I will say that – because I am going to talk for a minute until we get our computer issues dealt with here – I will say that being on the board of the Winn Foundation is wonderful. Part of my job is to go out and raise money and I have taken advantage of Betty a little bit because I have said, “Well, we have some amazing veterinarians on our board” because people will ask, “Well, who’s on your board?” and I will say we have some amazing veterinarians on the board. We have Betty White on our board and people will say, “Ooh, Betty White! Really?” And I say, “Yeah!” In fact, once, Betty told me a story – this Betty told me a story – that she used to get mail from that other lady. I host a radio show and what I did was...this Betty White, I am not sure that she knew, but the other Betty White did know, they knew of each other. Of course, everyone knows the other Betty White and I hooked them up and they had a conversation live on the radio. I said, “Betty White, meet Betty White.” It was a promotion for the Morris Animal Foundation, we are friends with them, which that other Betty White is involved in, and this Betty White has given so much to the Winn Foundation for so many years and I also am very grateful. Thank you very much.
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Beginning of Dr. Fox's Audio.
Well, we do have the best of the best that come to the Winn Feline Foundation Symposium. Dr. Phil Fox is known among veterinary cardiologists, not only in America but all over the world. As I mentioned earlier, feline hypertrophic cardiomyopathy is something that means a heck of a lot to me. It means a heck of a lot to most of you because, as all of you know – bless you! – so many cats, too many cats die of this disease. Dr. Fox is among the long list of those who are doing something about it. Dr. Fox.
Dr. Phil Fox:
Thank you for the kind remarks. I appreciate those. That was really a wonderful talk preceding this on FIP. I do not know if you realize how hard it is to do that work when you are trying to get a DVM degree and a PhD. It is really a phenomenal effort, so, I am glad I did not have to do that. Thank you.
Dr. Vicki Thayer:
There are 3 x 5 cards on the table, so if you want to write any questions for our question and answer session – I apologize to Dr. Fox for interrupting – go ahead and at the end we will pass them forward for a question and answer session.
Dr. Phil Fox:
Thanks for the invitation. I have gotten money from this foundation over the years and it makes a big difference. You might say, “Well, it isn’t that much,” but it is enough to get you started and in this particular case, it combined with money from Morris and it made the difference. This was a large study that was very expensive to run and I think you will see how that turned out. We have had this disease...I have been practicing for 35 years and nobody but nobody knows, or knew before this, what the incidence of hypertrophic cardiomyopathy was. So, how many people are veterinarians here? And then the others are bankers and stuff like that? Lawyers?
Dr. Phil Fox:
There you go. I have been privileged...I went to Ohio State University – thank you – out of a PhD, so I did it reverse. I was working on a PhD and I had no clue what I wanted to do. The only reason I went for a PhD is...I woke up one day. I was a senior in college. I had no plans. I went from a little college in Ohio to out of state because it was two hours away; that was the decision process. I cranked along without a plan until all of a sudden I was ready to defend my thesis, which I did not really want to do, and my cubicle mate was doing something. I said, “What are you doing?” He was a farmer from northwest Ohio. He says, “I’m filling me out an application for vet school” because Ohio State had a vet school. I said, “Why would you want to do such a stupid thing like that? After all the work we’ve put in, why would you want to do this?” and he said, “Do you think I want to do all my life being in a laboratory and looking for a fifth postdoc?” and in those days, money was real hard to get NIH had cut down and I said, “Well, that’s a pretty good idea.” So, he had a second application and I filled one out – it took me, like, an hour – and then we went on and I forgot about it. I got in vet school and he didn’t, so...
I have lucked out on a number of things. I had a job in Connecticut. Back then you could do...it was very sexy to do small animal, equine. Gentleman farmers or gentlewoman farmers and you would do their Jack Russells and you would do their horses. I was really worthless for horses, but it was the macho thing to do. One of my professors at Ohio State said, “Why didn’t you ask me for a recommendation for an internship?” and I said, “I didn’t even think of it. Why would you want to do an internship?” He made a call to the Animal Medical Center in New York – things were very loosey goosey then – and he says, “I got a good student (maybe that’s what he said); fit him in” and they said, “Well, we closed. He’s a month late,” and he said, “That’s how he is... ” I went and I had an interview... It was not even a process. I talked to one guy when he was operating, one guy in the cafeteria and one guy says, “I gotta go to the john.” I followed him in. That was the interview. So, I was there one year and I said, “Gosh, how can you leave? How can you leave New York City?” So, I went on to an internship and residencies in those days were two years instead of three and then, all of a sudden, I blinked and here it is.
So, the point of all this is that we have been dealing with HCM and other CMs for...I have been dealing with it for a third of a century and people I learned from have been dealing with it since it was invented because it was not until the early ’70s, mid-70s, that...There was no recognition that cats had heart disease. It was FIP or whatever caused ascites with high proteins, it was mammary gland tumors in cats, which we hardly ever see. It was a whole bunch of stuff, but it certainly was not heart disease and when they could not breathe and died or dropped dead, well, you know, bad air, termites, the guy is spraying the lawn in Jersey, whatever it was, it was all that stuff.
When you listen to speakers – I mean, other speakers – you should really question what the basis is of what they are telling you because what happens is that inadvertently, speakers are at a tertiary care center and the cases they see are the worst of the worst and then they give you this, “Oh my gosh” and you go, “Oh, geez.” So, everything sounds like it is doom and gloom. Nobody had any data in the world as to HCM other than that came out with a few studies. One was NC State, Clarke Atkins; one was John Rush at Tufts; a couple came out of AMC, but they were pathology studies. These animals had no life, they all died and they all got blood clots. So, I got up one day and I said, “Geez, I’d really like to know more about that because that’s how I would lecture” and I had a study that all my buddies...If you work this long, you have a lot of people hate you or they like you and I had half and half. I had enough that liked me that they all said, “That’s a great study, Phil. We will throw in with it.” I went to an agency – it wasn’t Winn and it wasn’t Morris; I am not going to say what other big branding agency there is – and submitted. They said, “Great study” because there were 25 collaborators, the best of the best, and they said, “We don’t give out...” I guess this was about...when? “We don’t give out money” for what I needed and what I needed was money to pay people to do telephone calls and telephone surveys and incredible database management and coordination. This is called an epidemiologic study and if you do not do epidemiologic studies in every disease, you will not have a clue what is going on because all you will know is what you hear from the guy or gal who comes out and tells you all these horror stories. You will not have a clue. And what is worse than that is neither will your veterinarians because then when a veterinarian sees an animal that has an echo-derived diagnosis of HCM, guess what happens? It is a real bad thing that has happened with ultrasound. Ultrasound is safe and effective. It is quick. The bad news is is that everybody has one, most people are not trained, and if the cat gets labeled as having HCM, you damn that cat forever and that whole family to chase it around once or twice a day, at least, and try to jam pills down the mouth, and you would like to know does that make a difference. I mean, wouldn’t you like to know that? So, I got up after 25-some-odd years and said, “I’m mad as hell. I’m not going to take it anymore.” It took me 25 years. Well, this agency said, “Well, we don’t do that.” I said, “What is it you don’t do?” They said, “We won’t fund that. That’s not what we do.” I said, “But I’ve got the best people on the continent.” “No.” So, if I would have bought a piece of equipment, they would say, “Oh yeah, sure, we’ll give you a hundred thousand dollars” because that is what the budget was. I said, “So, I need a hundred thousand for a full-time equivalent veterinary technician that’s really good and good with people” because she or he had to talk to people, call up veterinarians; those people are hard to find. “Oh, we don’t...” So, that really pissed me off. I am not going to say who it is, but anyway, so I ended up getting a big chunk of money from Morris, who says, “That’s a great study. Yeah, we’ll give you this,” but it still was not enough. Winn came by and partnered up. It is nice for Winn to be able to do that and that has resulted in this initiative.
So, I am going to give you a little thumbnail course of what HCM is and I am going to talk about some data, try and focus generically on the data because you are not all researchers.
Here is the Animal Medical Center in the City of New York in 1909. We celebrated the 100th anniversary five, six years ago. The Animal Medical Center is a unique place. It was started by women; I mean, don’t they start everything? Most of the people in this audience are women. And these people were women of education, means and grit. These women had money, at least this core group. They were married to the Mellons and the Carnegies and the Rockefellers and Vanderbilts, you know, blah, blah, and they wanted to make a difference because in New York City at that time, a lot of the foundations – well, you could not get on a foundation if you were a female. They would not take women. Up until maybe...when I got to New York City, a couple of our board members...I remember getting invited to dinner, it was an all-men’s club on 5th Avenue and 54th Street. Great club, you know, sorry you couldn’t go. Anyway, they started this and they called themselves the New York Women’s League for Animals. You should see these annual reports in those days. They really had it together. Here is a guy taking his dog on the transportation available to him at the time, there is a liaison or something going on in the corner we don’t know quite what, it is lost to history and here is the New York Women’s League for Animals. It was a dispensary on the Bowery and advice and treatment free. Horses, dogs, cats, you know, the hours. Well, we changed the free thing pretty well. That is how that started.
Now, if you think a lot is known about hypertrophic cardiomyopathy, you will hit your head and never regret it because here is why that is. If you go on the National Institute of Health PubMed, you can do these free literature searches. Type in HCM man, human, type in HCM and echo, HCM and genetics, these are the numbers of articles published – and I did this a year ago – some 87,000 on cardiomyopathy, 13,000 on HCM in people, 2,700 genetics. That is a lot of articles! But then if you put HCM and feline, 11 articles on genetics and they are the same three authors. I am not saying that in a bad way. I am just saying there is nobody doing work because there is no money. A 165 articles, feline and HCM, and if you put feline cardiomyopathy, 500; that is really not that many. This goes back to the early ’70s when NIH started to do this. To give you a perspective of what is known and if you ask yourself, “Why would we blow your dough, which is hard to get, on HCM, on heart disease?” Not that it is the most important, but it has a level of importance and I want you to feel good to see that the reason why there is not much stuff is there is not much money for it, historically.
Now, heart muscle disease is heterogeneous and it is hard to diagnose correctly. One of the things I do on the side is pathology. I had a mentor. I kind of did a nonconforming pathology. He is a Chinese guy at AMC. He name is Sam Lo. He was the best of the best and he liked me for some reason and I hung out with him. He taught me a lot and the crazy thing is, I am almost the de facto veterinary and cardiology pathologist. It is the damndest thing. People send me hearts all the time If they have heart from sudden death. I am not going to dwell on this, but the important part is that it is not that easy to diagnose. So, if you have a heart with a...I will get to that. I will get to that.
So, the clinical journal in the world with the highest impact factor, it is considered the most important journal that is read by the most important people is this journal called Circulation. This guy named Barry Maron, he is the mogul. He is the glue. He is an unbelievable guy. I met him in New York years ago and somehow he took pity on me or something like that and he has mentored me. I have had a chance to publish a few articles on HCM and actually, thanks to him, he and I and a couple of other colleagues published our first article on HCM in ’95 in this journal. That silly article has turned out to be still quoted, particularly with the cutoff for what constitutes pathologic thickness. So, if you have got HCM in a cat, you have to have H, that is hypertrophy, that is thickness, and it is still 6 mm, the septum or free wall and the left heart is 6 mm when the heart is at the end of its relaxation. So, the reason I tell you that is if you are not a veterinarian and you are a client and someone echoes your cat and says, “Your cat has HCM,” you should say, “What is your criteria for that diagnosis?” You should not just accept that. Why would you do that? If someone said you have got cancer, would you say, “Oh, thank you. I’m good with that.” You would say, “No, give me some more information” and you would get another opinion. Six millimeters. Now, there is some controversy over that. There is a good friend of mine. I have had a beer with him any time of the day or night. I avoid him like the plague at meetings. Conflict resolution is conflict avoidance. He wants to make the cutoff 5 mm because he knows, he knows, he knows a lot. He is a good guy. He is a know-it-all. And that is not the right value. Six millimeters is the right value because what that means is that some cats...if you make the cutoff value 5 mm, you have crucified cats that are 5.2 mm forever. What 6 mm means is that you might miss some cats that have mild hypertrophy, but if they are 6, they got it. If I was a breeder, I would want to not miss the cats that got it because the truth is, you cannot tell with echo, you know, two tenths, three tenths of a millimeter? If someone says they can measure the same segment time after time and get 5.3 mm, they are full of crap. They cannot do that. There is too much variation and there is genetic variability that we do not even have a clue about. So, 6 mm is reasonable and you will miss some mild forms, but you know what? There is a relationship, which I will show you, between the magnitude of thickness of the heart and outcome. There are only three reasons, there are only three reasons to treat a cat. There are only three reasons to treat a pet with drugs, in my opinion. That ought to be: to increase quality of life, to reduce morbidity (meaning the number of times you have to go to the vet with that cat) and number three, it should make you live longer. Live longer, live the better and stay out of the hospital. Those are the only three reasons that all of us who are veterinarians should treat animals. So, when we go to treat, that is what I teach my interns and residents. They look at me like I have got two heads, yeah well he’s got a thick wall, but will treatment make him feel better, live longer, have less morbidity. And if you do not know that, you still may decide to treat, you know, it could be any disease, but tell the owners, admit, ’fess up that here are the controversies, based upon the information we know – and we do not know a lot of stuff – and this is what I would do. They can believe you or not believe you or go for another opinion. So, that is the context that I believe is reasonable in cats with heart muscle disease. I mention this just as, you know, put it on your list of something to consider.
I am going to go over briefly what is feline HCM, how prevalent is it, what is the natural history – that is the data – how do you detect it, can you manage it and we will go with that.
Feline HCM is characterized and defined by hypertrophy, the thickened left ventricle, excluding all diseases that can result in the magnitude of hypertrophy that is designated greater than 6 mm. What are the things you have to rule out, therefore? You guys know what they are. What do cats get that we get in terms of, you know, if you get an IRS audit, what happens to your blood pressure? So, hypertension, right? Hypertension. So, if you got an older cat with mild-to-moderate wall thickness, got to get a blood pressure because if that cat is hypertensive, it does not have HCM, it is different drugs, totally different drugs; amlodipine for hypertension, not amlodipine for HCM. Then, what is that other disease that causes cats to lose weight and they have goiter in their throat? Hyperthyroidism. Nobody should miss hyperthyroidism today, but a lot of people miss it because they do not do a test. We are pretty good at diagnosing. I am really good at diagnosing hyperthyroidism. Guess why? I just run a T4 on any cat that is sick and older than 7 years of age. I do not even have to think about it. It does not occur in cats less than seven. It just doesn’t. I have got a really good colleague in New York. Boy, she is way smarter than I am and she will get a 2-year-old cat and she will run a thyroid panel on it. I go, “Jesus, why are you doing that?” “Well, we want to make sure. I know it doesn’t usually...” Okay, well, is that cost effective? No. So, hyperthyroidism, hypertension has to be excluded. There are a couple of congenital things. You are not going to see them; they are really rare. So, if you have got an old cat that has got a thick heart that is not hypertensive and not hyperthyroid, then you probably have what would qualify for hypertrophic cardiomyopathy.
It is all over the place and you can see, here is a real thick septum. Here is a little focal region of thickness. You have got to be able to have a level of experience or training in order to sort through this. I truly do not mean to say this offensively, but if you are doing echoes, not people in this state but somewhere else and you are not trained, like you are self-trained, you should not be doing it. I mean, would you be doing brain surgery just because you have got, you know, someone dropped off a brain set? Not really. It is easy to make a mistake in these things. If you are a progressive veterinarian in echo, that is okay. If you have gone on courses, I mean, you know, I have taught one for years in North America and it is a good course. There are good ones in all the big names. If you go to those, then that is totally okay, but I get referrals from people all the time who are colleagues – and I appreciate the referrals – but the people come in with a diagnosis and then I have got to dance around and say no, he’s just the most normal cat, you know, thank you, you know, try to make something up so that the vet looks okay. The point is it is a tough modality to use and it should not be used unless one is committed to getting the training. There are a lot of other ways to make a difference in practice than diagnostic ultrasound.
If you use a consultant, some people use consultants, there are some really, really good consultants in every state, there are really some unqualified consultants, and here is the rub with that. Ultrasound is completely unregulated. You do not need a certificate. You do not need baloney. You do not need anything. You just buy a machine. They sell set-ups now that are PC-based. You put your probe in. It has got a USB port into your computer and that is your 5 MHz probe. It is software and the images are terrible. You can get them under twenty thousand. You can charge – just do the math – two hundred each; you can pay that off. It is unregulated. So, if you use people that...Here are a few tips, in my opinion. You should look at the report and you should ask, before they go, tell me...because the report is four fifths numbers; eight tenths of the four fifths, we do not even use them. The machine spits them out. The machine spits them out. I was in a lecture in Rome once; the best lecture I ever slept through. I woke up at the end and the guy says, “In conclusion, beware of putting reliance on machines that spit out numbers. That’s called an echocardiogram.” It is like a gun thing, you know; I’ll give up my echo when you pry my cold, dead hand off the probe. I use it, but it is not the first thing to do. Now, the bad news is in a cat, an x-ray isn’t very sensitive and specific. That is the problem. When you have a murmur or a gallop, you are forced to go to diagnostic ultrasound, largely.
If you use a consultant who just handwrites...Here are reasons to fire a consultant:
- They write it by hand. You cannot even read it. You laugh, but that’s..., I mean, come on.
- Measurements are listed to the tenth of a centimeter. That person – I am sure I am pissing someone off here – but wake up if you are doing it. God did not make – or whoever you believe in – did not make the ventricular septum four possibilities. It is not 0.4, 0.5, 0.6 or 0.7 cm. It just isn’t. Nothing is like that. And those are the readouts you get because these machines are set to where they round up or round down and the people who do that do not even realize that and it makes a huge difference.
- If the person does not listen to the cat’s chest and look at your x-ray, if you have one, out, done. You do not need that person. There is an enormous conflict of interest in diagnostic ultrasound. There are wonderful, incredibly good people, but conflict of interest is out there as well. What do I mean by that? So, if a cat has got a noncardiac cause of respiratory distress, that consultant should – and many do but some don’t – should say, “You don’t need me for the echo. I am not going to stress your cat out. Get a chest x-ray or something. Tap the chest.” But more often, they will do the ultrasound and then, you know what the recommendations are? What are the recommendations? You know them. Re-echo in three months, right? Re-echo in six months. How many people have you had that say, “You don’t need me anymore. You need ... ” whatever. It does not happen. That is a conflict of interest and that is really prevalent. That is an issue.
I had a dog yesterday – yesterday? – that came in for an echo and it was coughing. I did not do the echo. I got into it with the client and they said, “Well, my doctor said he needed an echo.” No, you don’t. Cough, you need a chest x-ray. And it had pneumonia. I did not know it had pneumonia, but I did not know what it had, and the echo would have missed it. So, just be careful about an ice pick focus of the database. There is a good place for an echo. You need good echo for a diagnosis of HCM, but it is a big world out there and pick and choose the people you use. If you have not gone to a meeting, you are doing your own echoes, I can tell you, there are five meetings that are really great that will help get you to the next level, if you are doing your own stuff.
Now, asymptomatic heart disease is the dominant thing that we see. It is those cats that have symptoms. Heart failure, arrhythmias, blood clots, fainting and occasionally sudden death are what gets our concern. Here is what the echo can do. You hear about hypertrophic cardiomyopathy and hypertrophic obstructive cardiomyopathy. Who can tell me what hypertrophic obstructive cardiomyopathy is? The new president said that the first person who gets it right gets a small...gets a Prius. Wayne will do this. Who said that? Okay...Here is a cat. Now, intuitively, would you give me that this looks kind of thickish? Okay, it is thickish. It is a nice young cat and what happens in some cats, left atrium and then here is the left ventricle and we have a free wall and a septum. The septum divides the left ventricle from the right ventricle. That septum is the barrier between them. In hypertrophic cardiomyopathy you can have everything is thick or one portion is thickened and one variant of this, here is the mitral valve. The mitral valve has an anterior leaflet and a posterior. Anterior because the head is that way. Posterior because the butt is this way. So, sometimes this anterior leaflet gets sucked up into the outflow tract that feeds into the aorta. Not a good thing to have in people. Really a disaster in people because as the heart pumps blood, there is less blood going out because of this dynamic blockage, this dynamic blockage. So, that is called the obstructive form of HCM. We call it hypertrophic obstructive cardiomyopathy or HOCM. Now, it has been, for a long time, believed that that was worse, to have HOCM. The study that we did showed there was no difference. So, there was no difference in anything that we could measure, whether you were a hypertrophic obstructive cardiomyopathy cat or a hypertrophic cardiomyopathy cat. That is a huge finding and that came out of this study. Why is it a huge finding? It is a huge finding because the very presence of hypertrophic obstructive cardiomyopathy was a driver, a driver of therapy. In people, we all – I did it – we all said, “Jesus. Hypertrophic. He’s hypertrophied and he’s obstructed. Better treat him!” Now we know that you do not have to, it’s not worse, and it may make a difference in your choice to treat or not, particularly when the magnitude of hypertrophy is not that great. I do not treat these anymore just because they are HOCM and I think a lot of people probably do not do that as well. It is an emerging management development.
Here is the other interesting thing. You see this blood, this yellow and all those colors, so if you take a straw – there are no straws in here – and you take a straw and you take a mouthful of warm water and you blow it into the straw. The straw is the aorta, so you blow the water through the straw (blowing sound) and you can feel at the end, the velocity, you can feel some pressure against your hand. That is because the air or the blood, the velocity that goes through there has some energy against your hand and you can feel it. So, on the color flow echo, you know, there is echo...Echocardiography shows us the walls and we can measure them. Color flow Doppler – half of you know this, half of you maybe don’t – color flow Doppler is when you press another button and it transforms blood flow into color, so if blood is going towards the transducer, it is looking like red. If it goes away from the transducer, it is blue, so color Doppler mapping. The Doppler helps us map the direction and magnitude of the blood flow. Very useful to us as well. So, we have echo, we have color flow Doppler echo and these high velocities...so, you take your regular straw, now you go to the bar downstairs and you spend about $28 for a glass of seltzer and you get this little mixing straw that has a little tiny hole in it. You get that mouthful of seltzer, blow through that and two things happen. One is you cannot blow so much seltzer through that and the seltzer that goes through hits you at a higher velocity, so you can feel it more. That increased velocity creates energy and that energy turns up as a murmur, as a murmur. So, when a veterinarian hears a murmur in a cat and it is different than a dog, one of the possibilities is that the genesis of the murmur is hypertrophic obstructive cardiomyopathy. So, it may be a surrogate marker of underlying heart disease and that is why, as veterinarians, we just cannot blow off a soft murmur like you can on Friday afternoon in a dog because dogs do not get hypertrophic cardiomyopathy, they get leakages, and a soft murmur means a small leakage and we can say probably not a big deal. You cannot say that in a cat. So, you are stuck having to pursue that. You need to pursue it with echo.
We know that in a small number of cats, HCM cats, there is a genetic basis, particularly Maine Coons and ragdolls, and if you have got a Maine Coon, if you are a Maine Coon or ragdoll breeder, the good news is there is a nice test for this. Penn does it. NC State does it. If you are negative, though, it does not mean that your cat is okay; that is the problem because there are other genes, so it is a really limited utility. If you are a breeder...and most breeders are really, really conscientious and they would like us to be able to state that this cat does not have this myosin heavy chain binding mutation, but it does not mean that the cat does not have HCM because of some...or it might not get HCM. So, we are thankful for what we have, but it is not perfect yet.
How prevalent is HCM? Well, I will show you. Here is my ultrasound log from 1984. You see the green. The green is HCM and the other colors are other conditions. You can see that the preponderance of diagnoses that we make is HCM. So, it is clearly the most common disease. The blue was dilated cardiomyopathy; thankfully, we do not see much of that anymore because it was shown to be associated with a deficiency in what? Taurine. I’m preaching to the choir here. And guess when that was reported? It was reported by Paul Pion and his colleagues, incredibly excellent work at UC Davis. At first, Paul got a lot of pushback from pet food companies and they said, “Well, it’s not our diets,” and then mysteriously...that article came out in ’87 and by 1990, all of a sudden, all the big commercial diets were reformulated and look what happened to the blue bars, and it stayed that way. So, it was not them but somehow they changed their diets anyway and it did go away. So, happily, we do not have this because that is just a miserable disease that we do not have to deal with.
Natural history, I will talk about in this other...
How do we best detect cardiomyopathy? We start with a stethoscope, right? Here is a little secret. The vets in this room know this because you are cat people. A lot of vets don’t. If you take a dog, the dog is just going to sit there and you can put your stethoscope at the elbow and you are in the mitral valve area. The dog doesn’t care, doesn’t know, the vet doesn’t care, doesn’t know; it’s a win-win. What do cats do? They squirm. They want to get away. They crouch down, they do all this stuff, and you need someone to help, not restrain a cat but keep it from jumping. The client wants to hold the cat and you tell them, “That’s no good. That doesn’t work.” If you scratch your nose, the cat jumps off. So, what the problem is is that if you put your stethoscope down to a cat that is kind of bread-loafed, you are over the spine, and there are no murmurs that occur over the spine. So, you see what I am doing here, you guys, lift the cat up, so with my right hand I am picking it up. It does not like it that much. It is squirming around, but it allows me to put the stethoscope underneath the chest, which is where the valve areas are. You do that on the left and right side. It takes me a couple of times because I am there and the cat took a half step up, now I have got to repeat it, so you are actually painting from the left to the right side with your stethoscope, from the elbow up to the front. If you do that, you are going to hear a lot of murmurs. That is the secret; I mean, it is not a secret, but that is the secret.
A VD is the best x-ray to take because a VD will show you a big left auricle. Here is a big left auricle in a cat with cardiomyopathy. This was one of my best clients ever from New Jersey. She was a wonderful lady and a wonderful cat. I had treated this cat until the HCM got really bad and he got a blood clot to where we picked off one bad leg and the leg ... Rarely, these cats, if they survive, they get atrophy and then the paw heals in contracture. This woman made a little peg-leggy thing. It was great. This device was so good that the cat could still get birds, so she put a bell around it, but the cat figured out how to do that and then finally, the cat embolized again and she euthanized it and she donated this so that we could teach from it. This is a big left auricle, but it is the sensitivity. If you have a good echo and the cat is not dyspneic, then I would do an echo first. So, of course, the cat has respiratory disease, you have to do an x-ray first because you have to know if there is edema or not. ECG is a lost art. Hardly anybody does these anymore. They are really useful. If a cat has wide P waves or tall R waves its got heart disease. It takes about a minute or less to figure that out. It is cheap. Everyone has an ECG machine they got from their great-grandfather. So, it is paid off and you do not have to charge the Cardiopet or whatever it is called and I guess it is IDEXX. You do not have to quadruple it so it is $400 to the owner. I fight with our administrators all the time and hide the ECG so that it’s not...you know, it’s like 40 bucks. It’s worth about 40 bucks and I do a lot of them. It is good information and it is quick and if it is normal, it doesn’t mean anything, but wouldn’t you hate to miss...like, wow, look at the width of those P waves. It is a real strong clue.
Gallop rhythms. What is a gallop rhythm? Yeah, it’s an extra heart sound. So, here is a soap-boxy thing I have. How do people know we are veterinarians? It is because of our jewelry and what is the most common thing we wear – and it is not underwear – it is a stethoscope, right? That is how they know we are veterinarians. We have it around our neck all the time, from the second we get up to whatever. How much time do people spend learning how to use it? I have never seen anyone who says, “You know, I go to the Internet every week and I look...” Nobody does that. There are some good commercial CDs. Gallop rhythm is really useful. So, if you have a cat with HCM and it has a presystolic gallop, you can make a cageside, bedside, in the booth diagnosis, largely.
Normally, your heart sounds are lub-dub, lub-dub, lub-dub. Lub is S1, dub is S2. Lub-dub, lub-dub. Now, if you have HCM, you usually have a fourth heart sound, which is presystolic, so lub-dub, it is buh-lub-dub, buh-lub-dub, buh-lub-dub. So, the buh is right before lub. Buh-lub-dub, buh-lub-dub. It is a timing thing. If you hear that, you probably have HCM. Probably. Very likely. So, a cat with a murmur and a gallop, well, the murmur is real common. A gallop is going to indicate that you probably have HCM if he has a gallop. An S4 gallop or an S3 gallop is a diastolic gallop, so lub-dub, lub-dub, lub-dub-buh, lub-dub-buh, lub-dub-buh and if you heard that in a cat, that cat has DCM; we still see that, or a doberman or dog if you do dogs. So, I would suggest to you, you have got to pay a little attention. Just go on the Internet. They are all free. Some of them are terrible and some are real good. You will train your ear. It will make a big difference. Make a big difference.
Now, what about BNP, biomarkers?
How many people use that? Okay. It is useful in a cat. IDEXX is coming out...well, I think it now has a bedside SNAP test and I was one of the people in the group that investigated that. The advantage of that is that you will have it and you hear a buh-lub-dub and you go, “Oh, I heard this talk in Louisiana. It sounds like an S4 gallop. I think I ought to do a SNAP,” whatever they are going to call it. A SNAP test, if it is abnormal, the likelihood is that the cat probably has HCM. That is how that is going to work, so just keep your ears peeled for that. They also have a blood test that you can use. It is not as convenient. It is more accurate so you have to...I don’t know how these things are priced out. I think that if you use IDEXX, if you add a BNP, it is not much money. That is probably way cheaper than the other, but the other you get it quicker. So, keep aware of that.
What are the strategies to manage heart failure? Well, this is easy. Here is a poor cat that is dyspneic. He is in an oxygen cage. Cats that are dyspneic with edema, I think, have a fairly characteristic affect and it is very different than dogs. This is as bad as you get with pulmonary edema before you are dead in a cat. These cats are almost fatigued. Their heads are generally down. They are sternal and they are panting. How many times do you ever see a cat pant? Rare, very rare or when it has got respiratory distress. Even if it got stepped on or injured, they do not pant. The other thing to do is you can look at their nostrils. Their nostrils will flare out. You have to look. They will dilate. They are sucking. They are sucking air in. That is a real dyspneic cat. Now, most of these will have crackles and we basically want to...this will be...I am not going to present this tonight. This is part of what this study will get us to is risk factor analysis because what you want to do is you want to put the highest category of risk those conditions that are markers for sudden death, increased morbidity and decreased quality of life. So, we will be in a position to significantly contribute to the literature based upon this that we have. The other thing is are there effective long-term therapies? We do not actually know that. And what about the asymptomatic cat? So, I think we want to bear in mind the fact that the potion has to be worth it in order to justify it.
So, I will spend a few minutes just showing you some of that data with this background and just hit the high points of it because there is lots of data and I don’t want to make you convulse. This is the study. Let’s see. I started this, like I said, with my best buddies at universities and once we hit a time to get the data, no one had done any of the work. It was one of these good ideas. It was like being good and going to church and loving your neighbor. Yeah, it sounds good, but no one is going to do it when it comes down to it and getting the data to Fox. I had a panic attack and I had to start to reach out to others and I started to tap some colleagues in Europe whom I had overlooked because I thought it would be easier to work with the Americans, and the Europeans are a lot easier to work with because they are Europeans. I got a 110 cases from Valérie Chetboul at Alfort in France and I got 85 cases from Gerhard Wess at Munich. The Italians were wonderful and they started to roll in and then I would use that as a lever with N-wide American colleague, got a big slug from Ohio State and it started on a roll. So, it has taken several years to get this data. We wanted to assess five-year outcome. Once you diagnose HCM in your cat, what happens in five years? That is the key. The cases we recruited were never in heart failure and they just had HCM. It’s kind of like real-life stuff. So, we called it...So, I am really delighted. Everyone’s got an acronym. I don’t have an acronym. My whole career, you know, about 100 publications I don’t have a paper with an acronym. My kid actually did this for me when he was 14. He said, “Why don’t you call it REVEAL?” and then he did it in his head and that is why he’s got A’s in physics and math. So, it is REVEAL and actually, it is pretty good. The international collaborative study to assess cardiovascular risk and evaluate long-term health in feline HCM. Bruce Keene and Dr. Motsinger-Reif for NC State. Bruce is a long-time buddy. He is a stellar cardiologist. He is head of cardio there and Dr. Motsinger-Reif is head of statistics at NC State, so these are real pros and I am delighted to have that. Again, thanks for the support.
Here is why: Science is a way of trying not to fool yourself. That is why we do this. The first principle is you must not fool yourself and you are the easiest people to fool. That is what this is about. That is what it is about for us as specialists. We think we know it. We are fooled and that is why we do these studies.
I am going to roar through this because I covered a bunch of it already.
We wanted to basically identify and risk-stratify cats that were asymptomatic at the time of entry. We wanted to differentiate whether there was increased risk between HCM and HOCM. We wanted to know what was the actual incidence of heart failure and blood clots. If your cat had HCM, wouldn’t you want to say how likely is it it’s going to get heart failure and how likely is it it’s going to get a blood clot because if it is likely, you might want to treat or monitor, and that is what it is about. This is what is cool about the study. It is a global study. I made every mistake you can in one’s career, but I do want to take a little credit for this because it is a global study, and I would tell you that there are very few global studies in veterinary medicine. I am not aware of one. There are 60 investigators in 20 countries and these boxes indicate the countries. I could not get anyone from China that I could speak to and understand. I was dealing with a guy I know pretty well in Moscow. He is like a Mafioso guy and he kept on telling me that he was going to come through. So, he could not deliver a Russian and I got no Chinese, so I feel bad about that, but I got Taiwan; it is not really China but...pretty much across the US. The green states are not Republican or Democrat or...Western Europe and Scandinavia. I was delighted to get those groups as well. There is a long list of people. These were the best people in those countries. These are not schmucko people. These are people who teach, are board certified, teach cardiology or are recognized by peers.
There are a couple of ways you could diagnose HCM. Let’s see if this shows. That’s okay. That doesn’t show. Okay, so let’s look at some of the data. We statistically evaluated and compared sites; are the French data the same as the Hungarian data are they the same as the Danish data, and you have to do that. Now, since this, we now have 1,700 cases, so it is a real study; 1,700 is a real epidemiologic study. Most veterinary studies are small, clinical studies, they can be 12 cases, single site. We have over 700 normal cats and over 1,000 HCMs. I wanted a thousand. I wanted a few more than a thousand so I could say we have more than a thousand, which sounds a lot better than if we say we have damn near a thousand. We’ve got more than a thousand cats. It is marketing. So, there is good statistical power. You can largely believe that the statistical test differences that are revealed – no pun in REVEAL – are likely true versus various...because most veterinary studies are underpowered and when you look at the limitations, they say studies are underpowered. So, these cats were an average of around five years of age when we started. They were about 5 kg of so, which is 11 pounds. That is the typical cat. HCM cats are more predominantly male, as we know. I am not going to go through these, so I am going to give you the broad brush strokes.
The first thing we found that there was no difference in anything between the obstructive and nonobstructive forms of this disease, so we combined HCM and HOCM and treated as one and compare that against normals. If you read a study that does not have a control, it does not mean it is a bad study, but it does mean that it is unsure that you can believe the conclusions because they are not compared to anything. So, the value of the study is we had 700 cats at least that did not have heart disease. These things are called survival curves. All you need to know about them. This is time. So, in the beginning, you start day zero and this is the percentage of cats alive. So, at the beginning, 100% are alive and they start to die. One wants to look at median 50% survival, so you draw a line and you see how many days, months or years and, obviously, the longer the survival, generally the better. Let’s see.
There is another thing called hazards. It is called a Cox proportional hazards ratio. You will see it in the literature. It is very useful. Here is how it is useful and we will take this, for example. This is time to event for arterial thromboembolism. Let’s see. If you were a cat that had hypertrophic or hypertrophic obstructive cardiomyopathy compared to normal, you had five and a half times greater chance of...actually, that translates to an 85% greater chance of getting a blood clot every day you wake up. So, if you are a cat that has this, every day you wake up, you have an 85% greater chance of developing that than a normal cat. So, it is useful and it is valuable to say, “Wow, the magnitude of that change is a big deal.”
So, what comes out largely is three variables that appeared to predict risk or to offer prognosis because that is what you want to know, whether it is you or your family or your dog or cat, what is the prognosis if I have X, what is the risk, and that is the thickness of the septum or free wall and the diameter of the left atrium. All these analyses, you will see these boxes turn up yellow. One of the things that we will do when the second paper that comes out of this is actually publish the risk factors that can be used by veterinarians to say, “Okay, does this cat that I’ve echoed have the parameters of thickness or atrial size within these categories that then puts it at risk?” If you remember that pyramid I showed you just a little bit ago, the high risk is where you want to focus, so you should be able to, as a veterinarian, say, “These are the top three things. You’ve got them or you don’t got them.” If you have them, what are the opportunities to manage? Basically, that is how this data will be used.
I am going to finish up with a summary. By the way, there was no breed difference in survival, even though some breeds are predisposed to HCM. It did not matter if you were a Sphynx cat or a Maine Coon cat or whatever for the numbers of cats we had. I think that there are certainly some cats that have malignant genotypes. I was working with a great Maine Coon cat breeder in New York and Mark Kittleson, who has done wonderful work at UC Davis, has this in-bred colony. If you are one of Mark’s cats or this breeder’s cats, all of this siblings, the parents would die and then the siblings would die, so that is called a malignant genotype and people have it too. That is why if we had that, you would be wearing an internal defibrillator, but it is not done in cats. But, anyway, we were not able to find a big incidence rate, so this is interesting. These numbers are not the numbers because the data has been redone and I do not have it yet with the higher number of cases; they will be proportionally the same. This really surprised me. If you are a cat that has any form of heart disease, you have a 3.4% chance per year of developing over five years, so five times three is 17%. It is a lot. It is way more than anybody thought. So, if you had 17% chance of going into heart failure in five years, I don’t know what you’d think. It would get my attention. So, that suggests that maybe we ought to be monitoring these cats in a certain way and looking for things that might actually prevent it, which there are no known things to prevent it yet, but it shows you, I think it cries out for a need to look at these affected cats differently. That is the value of this. And then for blood clots. I was shocked with this. I thought that it was 1 in 500 cats that would get a blood clot, 1 in 1,000, and what it showed was that cats with HOCM or HCM had about an eight and a half chance over five years of getting a blood clot. That is like 1 in 12. That is way higher than I thought. That is pretty high. How high do you have to...Once you get it, it is a disaster. So, I changed what I did, what I do. Now, I am more aggressive with aspirin or clopidogrel.
Here is the other interesting thing, lastly. We looked at the prevalence and cause of death of the HCM cats because they started dying, because that is what you do, and we looked at the control cats. For the first time that I am aware, this study has revealed the actual causes of deaths from the major causes of mortality. Now, these were not autopsy-performed. This is an epidemiologic study. If the vet said the cat had FIP, we said FIP. If the vet said he died of anemic or chronic kidney disease, so right there I am going to get crucified by the reviewers who are going to say, “Well, you didn’t keep him in your lab around the world for five years,” so I will have to deal with that, but this type of study has value with this number of numbers. Number one cause of death, noncardiac death, is cancer. The number two cause was chronic renal failure. Number three was what we lumped as GI disease, so if it was not cancer and you had weight loss or you had ascites or liver enzymes and it wasn’t kidneys, we lumped that as GI disease. That is the first time that has ever been revealed and how that will be used will be interesting, but instead of maybe focusing just on flea and tick control, maybe the focus ought to include in a different way but I don’t know what way that is, so a more aggressive way to monitor for cancer, which is the number one. That is how I would interpret this data.
Let’s see if there is anything else. I think we are just about...
In summary, we documented and compared the natural history and health outcomes in 1,700 cats. We found no difference if you were H or HOCM with regard to heart failure, cardiac death, blood clot formation. We found substantial hazard or risk if you have really thick ventricles or a big left atrium in terms of cardiac pathology. I have described the incidence. What is the difference between prevalence and incidence? Prevalence is a snapshot, so here I go – kachunk – and I can print it out, I can count out the number of men, number of women, so there are 68% women and the rest are men. That is the prevalence at this moment in time. If I photographed you all when you were 10 years of age and monitored your, whatever, until now, the new diseases would be the incidence. It is the development of a new disease. That data is hard to get because you have to do studies like this. This study identified the actual incidence of cancer, kidney failure, renal disease, heart failure, blood clot formation and, lastly...oops, I’m sorry; I went back to the top.
Here is the last thing: survival curve. So, what does it mean, the number of days, percentage alive. Red is heart. Well, I just said what it is. This is noncardiac. If you are a cat with heart disease, you would drop off, you start to die a lot more quickly than if you are a cat that does not have heart disease. I think that suggests that we would take this – and I don’t know the adjective – not more seriously, because we take it seriously, but we might look at it in a way not to freak out the owners but, instead, to identify the strategic monitoring opportunities that will have to be developed in order to identify hitting risk factors that might then trigger certain treatments.
Thanks again to Winn for your support.
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Beginning of Question and Answer Audio.
Maybe what I’ll do is have you stay more or less put and share the microphone with Beth. You all have sheets of paper, pads, and we are going to have some volunteers, our wonderful volunteers, go around and retrieve the questions.
I have some exciting Winn Feline Foundation news for you while I wait for the questions to come to me. We have a single web address, but soon we will reveal a new website! Woo-hoo! So, we are updating our website, making it easier for people to give us money, but also offering new and different information and we will have a new and better look, still with feline health w-i-n-n – thank you, sir – felinehealth.org.
Dr. Vicki Thayer:
Winnfelinefoundation.com. I mean, .org. So, it is winnfelinefoundation.org.
Which makes sense, right? So, winnfelinefoundation.org. So, about 15 minutes. Where’s Beth? There you are. I want you to share a microphone with Dr. Fox because we need you to answer the questions also.
So, the first question is: What do you guys think of the US soccer game this afternoon?
Audience member: Who won?
Not the US. Germany did win.
Any updates on the use of polyprenyl to treat FIP? I don’t know that you would necessarily know that. This question is about polyprenyl immunostimulant. That is the drug that Dr. Al Legendre is here talking about. Would you know if there is any update or not?
Steve and I spoke about this today. I am really not familiar with a lot of drugs that are out there to treat FIP, so I cannot answer that question for you.
I can answer a little bit. What he is doing is looking for another drug, ideally, to use in conjunction with that is what he told me.
What is your experience with adult cats, 3 years old, with dry FIP? Do you see cats like this very often? And also, do you see senior cats? What’s sort of the age range?
Most of the cats that come to us are younger animals, but certainly, especially in an outbreak situation or where catteries are having a problem, we do see older cats. I believe we do actually get a fair number of the dry FIP cases and I could go back in our records and look and maybe that would be some nice data for Winn to have and what we have in our foundation but, yeah, it is definitely something that we see and the dry cases are especially hard to diagnose, too. That is also a problem for us, so they don’t go through necropsy. Sometimes it is a little bit challenging to diagnose this.
This is an interesting question: Does the ultrasound - this is for Dr. Fox – does the ultrasound thickness of the wall of the heart vary in the size of the cat? So, would a Maine Coon cat, therefore, have a different thickness than, I suppose, a Singapura?
Dr. Phil Fox:
I do not think it varies that much. I know I have colleagues who believe more strongly that it does. You take the extremes. You take a 4-pound cat, it is going to have a smaller heart than a big Maine Coon, but I think, by and large, the numbers, they seem to be pretty close, but it is unresolved and there is some controversy about that.
If you have a cat that diagnosed with HCM, that is asymptomatic, young, is one option do nothing except watch?
Dr. Phil Fox:
Yeah, one option is absolutely nothing. I am working on a manuscript with Dr. Carson Childer, Ohio State, for a special feline issue for the Journal of Veterinary Cardiology and this article is on what do you for the asymptomatic cat. We talked back and forth a bit and in previous years, decades, people felt compelled to just review the literature, which is really human literature, and truthfully, there is no data in animals. We don’t know. I think that it is a reasonable option not to treat many cats that are not severely affected and I think that many, many people would go along with that. I think this is an emerging area that as more data comes out that indicates prognosis or risk that that will force opinions one way or the other.
I have a quick question to add onto that of my own. Does aspirin really do any good? I am talking about for cats, not people.
Dr. Phil Fox:
Dan Hogan at Purdue has done a wonderful job. You might have heard of it. It is called the FATCAT study, the feline arterial thromboembolism study. This was an issue that people had...we would curse it every day because nobody knew if aspirin worked and then when clopidogrel came out, which is better? Clopidogrel is much more expensive and it is daily versus aspirin every three days, so what Dan and his colleagues showed was that clopidogrel is superior, quite superior. So, if you had a cat that had a blood clot, it is not that aspirin is useless, but you would want the best drug if they could afford it. Now, what nobody knows is what about the cats that never had a blood clot? Well, I think if you are at high risk, with a huge left atrium, I think you are compelled to discuss with the client the options. I just had a client last week who could not afford the clopidogrel, but she could get aspirin in every three days, so I felt okay about that. I have got others who want it. So, if you say if it works better in cats that had a blood clot and survived, it is not a big stretch to say maybe that is the best drug that probably has risen to the top.
Is anyone working on doxycycline as an MMP inhibitor in FIP?
Not that I know of right now, but it’s probably something that I think we would be interesting in looking at because FIP being that it is a disease that there is really no good treatment for, I think our ability to do clinical trials in animals would be a little bit better as when you think about cancer. It is sometimes easier to get drugs into clinical trials that way. It certainly wouldn’t hurt to look at, and Gary and I are thinking about proposing a grant to do that through Cornell in collaboration with our hospital, but doxycycline is specific against MMP-1 and MMP-2 and we are looking for MMP-9, so it might not actually be something that would be ideal, but certainly, if we had a more specific MMP-9 inhibitor, it would be something to think about. I think with cats you always have to remember that; they do not really tolerate a lot of drugs as well and some of the protease inhibitors can be quite toxic, so it would be something to think about. But, yeah, for FIP with no treatment, it would be really nice to have something.
So, let’s say there is a cat with early suspected dry FIP. Is there a downside to trying doxy?
I don’t know enough about doxycycline in cats to answer that question, but there are veterinarians in the room who could certainly answer that better than I. I am not any good at these treatment questions, I will admit that right off the bat, as a young veterinarian.
I have a question for Dr. Fox, then. How can the pro-BNP test be used to weed out HCM in a breeding program or can it be used? And you might briefly – I don’t know that everyone knows what that test is – explain.
Dr. Phil Fox:
Sure. Great question. BNP is a biomarker. Biomarkers are chemicals that can be detected in tissue or fluids. It can be detected in urine, effusions, blood, serum --wise. So, if you could get an indication of a condition without doing a brain biopsy – I am making that up – wouldn’t that be better? So, BNP stands for a thing called brain natriuretic peptide. It was first discovered in pigs in the brain, so it stayed like that. That test is an IDEXX test. ANTECH has another biomarker called ANP for atrial natriuretic peptide, so there are a couple of these out there. I am not sure in a dog or cat. ANP has not been looked at that much and more information is available for BNP, so I can talk about that more intelligently. I was always looking for a way to supplement the echo, which is expensive. If you have $300 or $200, whatever, for an echo, it is a lot of money, so we looked at BNP in cats with occult cardiomyopathy, it’s published, and found that the BNP was pretty good at a certain sensitivity and specificity. I think it was 85% sensitivity, 84% specificity. So, it was not 100% but if you were a cat and you use the IDEXX BNP and the value was greater than 100, that test was, let’s say, 86% sensitive and specific, which is not bad. So, it picks up a number of cats at a reasonable cost. Then, you should then go and do the echo. This is not a replacement for echo at all. It is to help people screen and that is how I think it should be used. I have got colleagues who do not like that notion for different reasons, but I think that that is reasonable. It is how it is in the human healthcare system. It is a reasonable screening.
What if you have a Maine Coon cat or ragdoll cat or there are other breeds, too, that sometimes are associated with HCM, American shorthair and the Devon rex, etc. Are you more likely then to proactively even suggest to your veterinarian, maybe I should have the cat tested?
Dr. Phil Fox:
If we had more time, that would be a great question for the audience to see what the practice and perspectives are. I am biased, so I am not going to do a BNP ever because I have an echo machine right here and I can do an echo pretty quickly and way quicker than I can get the result back and it is more reliable than a surrogate marker, but I think that anything that gets clients to pay attention to their pet’s health when there is a reasonable – and here is the caveat and it is a good that you asked that, if you just add it to every cat you do ... like ages ago when I was moonlighting and Cardiopet was not IDEXX, it was Cardiopet. Cardiopet, which was a company then, marketed that every cat that breathes should get an ECG and it was a presurgical screen. Well, it was almost always unremarkable because if you select an unselected population, you are going to get false positives and you will not get a cost-benefit ratio that is reasonable. Same thing for biomarkers like BNP. It is best used in cats that you have an inkling, a gallop, a murmur, an irregular heart rate, a history of siblings, x-ray looks like the heart is a little big, then it is reasonable. Most people think it should not be used in complete absence of good clinical judgment or clinical database, so if you are just going to run it and add it on your profiles, you will get more false positives and you will have to describe to the owner why you ran it in the first place. So, just use your good clinical sense and select the best patients to run it on.
Two final questions. Beth, for you first. You’re young. I want to know if, in your lifetime, we are going to see an effective prevention or an effective treatment for this very mysterious disease called feline infectious peritonitis.
Maybe because I’m young, I’m also a real optimist, but I think so.
That’s a yes.
Okay, and maybe not as young but nearly as young, Dr. Fox. Same question, really, for you. HCM?
Dr. Phil Fox:
(Does not sound as optimistic so far). It depends when the horizon is. There is only a set number of drugs and they do not come along very quickly and people use them de novo without any data and then they get ingrained. I think the profession is getting very good at detecting HCM. The echo machines, by and large, except for that cheapo one I mentioned, are getting very good and any practice that wants to invest in an echo machine, you can get a pretty decent machine, way better than the high-end machines we had 15 years ago, for 50ish – I’m not trying to sell them – 40, 45, 55, you can get a really nice machine and with some training, you can make the diagnosis. So, we are better at that than knowing what drugs to treat. We know when something is effective in a multicenter clinical trial and they just do not come along very quickly. So, I think that, yes, we will not know for at least 10 years because I do not know anybody who is doing these studies and they will take at least five years to do.
So, in five years there will be no HCM?
Dr. Phil Fox:
That’s not what you said?
Dr. Phil Fox:
I think that things will emerge in dribbles and I think we will collectively get better. It is frustrating because we would all like to know right away and it is just unfortunately, it is just not that simple. I think, if anything, we will see somewhat of a trend away from treating mild-to-moderate cases because of the difficulty in getting people to jam drugs down for a benefit that is elusive.
All right. Two stellar speakers once again – we couldn’t do this without you as well – so thank you.
I just wanted to mention to everybody so that we can raise some more money for Winn, we are having the Internet Cat Video festival in New Orleans. It is an excellent time. If you have free time on Saturday, it is right down at the City Park taking the street car and three stops to have the street car to get you there and will make sure you find your way back. They have funny cat videos showing in the park. They have great food, you don’t worry about that in New Orleans I know. They will have snow cones and ice cream and great music and they are going to have fabulous feline artists. We have five different feline artists that are going to be there, some from New Orleans, some from other places. A place where you just can come and enjoy yourself and do all things cat. It is 11 am to 6 pm. The videos show at 11 o’clock, 1 o’clock and 4. It is $12 for the video screenings and the rest of the festival is free and the proceeds go to two things, one is a nonprofit called Art for Cat’s Sake, I got tired of being an older veterinarian seeing the same diseases untreated, no effective cures or treatment. FIP being one of them, squamous cell carcinoma being another one. We started a foundation, all of the proceeds that we are raising will go to Art For Cat’s Sake to share between Winn Foundation and One Shelter which will raise money for spays and neuters keeping unwanted animals out of the shelters that too many are being euthanized but also to my Foundation that raises money for research to go to Winn and Morris Animal Foundation…
Well thank you, thank you. Once again thank you all very, very much.