Introduction

Steve Dale:
Hello, welcome, good afternoon. Welcome to the Winn Feline Foundation Symposium. Do you all like cats? Do you all love cats? That's better. We are going to hear a whole lot about two very important topics. We have amazing speakers. The Winn Feline Foundation Symposium has been going on for several decades now, and we do get the best people in the country. Today you are about to hear two of the best in the country. I am here with one of the best in the country to my right, your left, Dr. Susan Little, who speaks all over the world. Before we start, we are going to tell you a little bit about the Winn Feline Foundation.

Before we do that, index cards like this, they are right there at your tables in front of you, at least they should be. Fill them out if you have questions. Then, at the end, what you are going to do is hand the index cards to the captain of the table. Then, this lady right here, Maureen Walsh of the Winn Feline Foundation, will walk around, pick up the index cards and give them to me, and I will read questions and we will answer as many as we have time for. For the veterinarians that are here looking for continuing education credit, you have come to the right place, but, you have to fill out the evaluation forms that are at the table right in front of you, and then where you registered, where you came in, where those two lovely ladies said "welcome", that is who you give those to. Then they can give you what you need to get your continuing education credit. When we start, please have cellphones completely turned down or on vibrate or off, because we don't want to disturb other people.

I also have another announcement to make. About this time last year, the Winn Feline Foundation Symposium was on something horrible called feline infectious peritonitis. You are going to hear about cardiomyopathy and two of Winn’s many initiatives are to some way, certainly somehow, and well within my lifetime, I'm young, we are going to solve these problems. She is looking at me like "you are really not young" that lady over there. Don’t know why that is. Today, we just got a check for $10,000 to the Bria fund for FIP research.

So we are going to tell you a little bit about the Winn Feline Foundation; Susan Little is going to do that. By the way, if you haven't checked this out and you want to know everything and I do mean everything there is to know about cats, or instead of joining a health club, because her book, which is 1400 pages long, 1400 pages, it is this big; carrying it around, you work off calories. The name of the book is The Cat: Clinical Medicine and Management. Dr. Susan Little here to tell you a little bit better about who we are.

Dr. Susan Little:
Thank you very much Steve. So it is a joy for me to get to work with Steve because I look it as beauty and the beast. I don't know about you guys, but that is the way I look at it. Of course he is the beauty; I get to be the beast.

Steve Dale:
I don't think so.

Dr. Susan Little:
After a margarita or two, yup.

Steve Dale:
No, no, no, no.

Dr. Susan Little:
Okay, so my job this afternoon is to talk to you a little bit, for those of you in the room who may not known very much about the Winn Feline Foundation yet, I will tell you a little bit about us. So, we are a non-profit organization. We have been in existence since 1968. Some of you may remember our 40th anniversary celebration a few years ago, which was a big milestone for us. So our primary focus, our only focus, is to fund feline medical research because no other organization in the world funds only Feline Medical Research and unfortunately still at this time, despite the fact that cats are the number 1 pet in North America, they receive only a tiny percentage of the research funding that is out there. The dog world gets more than we do, and you know, that just shouldn't be. Should it? It just shouldn't be. So, one of our goals of course is to provide more funding through your generous donations and through our cooperation with some our corporate partners, to enable researchers, like people you are going to hear speak tonight, to advance feline health and welfare. That helps you and I as pet owners. It helps us as veterinarians. It helps everybody who has a stake in the future of the pets that we love so much. So many of you will know about the important advancements that Winn has been able to help fund or be a part of over the years. So some things like knowing that cats have blood groups and knowing how important that is in veterinary medicine and in transfusion medicine; and for some of you with certain breeds, for breeding your cats that is important. The role that taurine played in virtually eradicating an important cardiomyopathy. You know, we should be so lucky we can eradicate hypertrophic cardiomyopathy. Well, Winn played a role in helping fund the research that eliminated, or virtually eliminated dilated cardiomyopathy. All other kinds of things you can see on that slide; measuring blood pressure, polycystic kidney disease through the work of Dr. Lyons, learning how to give oral medication safely to cats so that it does not cause esophageal disease, treating diabetes, things that touch all of us, whether you are breeder or you are just a cat owner or you are a cat lover, it touches all of us. So our role has been deep I think, and our goal is to continue this and push this into the future and continue to make the advancements that we all need. So we have still so much work to do. As proud as I am of what is on that slide, we have so much more work to do and we are going to do it with your help, I know. So thank you for being here and thank you for supporting us. Steve is going to talk to you about one of our really important funds, which is the topic of our discussion here tonight.

Steve Dale:
Thank you. So, there I was just one day sitting in my office and my wife comes up to me and says "Steve, we've got to do something about our dog, Lucy." She did animal assisted therapy. You know what that is? Where you go, in this case Lucy went to the rehab institute of Chicago, a very famous place, and both children and adults benefited by our little dog. One of the things our little dog, Lucy, did was tricks. She wanted a new one. So I thought "what am I going to teach Lucy?" I don't know why, but I thought it would be fun if Lucy could play a little kids piano. Does that sound kind of fun? What made me think of that? So I got a little kid’s piano and began the process of clicker training. So I clicked and gave Lucy the dog a treat, and click and treat, click and treat, and Lucy began, as I began to sort of mold the behavior, and the paw would lift up a little bit, and then lift a little bit more, and a little bit more and I was going through, and Lucy was learning, it was going fine. Then I closed the door to this room that we were working in. I didn’t close it all the way and in walked that cat Ricky. Ricky, who is a Devon Rex cat, looked at me, looked at the dog and then went "ping" on the piano. I thought "what I am fooling around with this dog for?"

Ricky was a very social cat anyway, and I have always wanted to demonstrate that pretty much anything you can teach a dog to do, you can teach a cat to do, except the cat may do it better, and I wanted to go out and show the world this. Now, this was before the days of You Tube. The internet was around, but you weren't showing videos, but I will tell you, Ricky did more television than I did. People would come over with the TV cameras and Ricky learned, "oh my gosh I'm going to get treats probably and I will get attention" and actually then when the camera light, the little red light you would see on a TV camera, a real TV camera, he would perform. I mean do all these things, and he did more than just play the piano. He also could jump through a hula hoop if you happened to have one, or if you had a little kid, he would jump over the kid. If you had a dog that could do a down stay, he would jump over the dog. If you had a series of dogs, he could jump over the series of dogs, and then he could do this; come when called. Ricky was amazing. Have any of you ever had a cat that just somehow, or a dog that you had this pet, that you had a relationship with that was hard to even define? And you wonder in your lifetime if you are ever going to have that again. You know what I am talking about? I mean I swear, if I fell down a well, the cat would be there to get the police and bring the police to the well to rescue me like Timmy and Lassie. He was amazing, and he knew what I was thinking, and I kind of knew what he was thinking. Training him to do another trick was easy.

Then one day I brought him to the veterinary clinic because my veterinarian complained to me that "We have never had a piano recital here at our clinic, why don’t you do it here?" So we did, and everybody you know, applauded as Ricky played the piano and all that. We would go to Pet Stores like Pet Smart and Petco, and what I should show you are the peoples' faces while this cat was playing a piano in the middle of the Pet Store. It is like they couldn’t believe it. People came up to me. I remember one lady came up to me and she said "where are the strings"? She thought it was a puppet of some kind. We would go to the bank, we would go to get a video (when there were video stores) we would go to the video stores, we would go to the dry cleaner, and Ricky would walk up on the counter they have. Other customers would come in and Ricky would give them the dry cleaning. I mean, just an amazingly social cat, amazing, and people were just so enamored and because Ricky was a Devon Rex, looked kind of unusual. Very, very quickly we went to the bank once with Ricky on my shoulder. I made the deposit or withdrawal, whatever it was. On my way out a security guard, it is true, stopped me, and I thought really I am busted, you know I didn't think. Okay, you cannot bring a cat into a bank, I'm in trouble, and he said "where did you get that?" I am thinking, like, does he want to know the name of the breeder? What does he want? He said "what store?" He thought it was from a Steven Spielberg movie. Then Ricky went "meow" right on cue.

Ricky was absolutely incredible, incredible, incredible. The bond we had I wish I could put into words. I don’t believe there are words for that. So we were at the veterinary clinic and Ricky was playing the piano, everyone applauded. We began the exam and there were still lot of people in the room, in those little veterinary rooms. No matter where you are, right, those rooms seem to be small anywhere in the world, and there were like 10 people crammed in there, but the veterinarian listened to Ricky’s heart. She kind of had a look on her face and the room cleared out. It is amazing. It was 2002 and I am still as moved today as I was then in some ways. I was determined, and this is why and how I joined the Winn Foundation’s Board of Directors. I was determined that we needed to do something about hypertrophic cardiomyopathy. There are no hard numbers on this, but it is very possible for indoor cats between the age of about 2 or 3, or 4 and the age of about 9 or 10, that this could be the number one cause of death. In any which case, it is the most common heart disease in cats, and it is really common and I was determined to do something about it.

We have raised over $100,000 in feline medicine, which I think is nice, and I thank all of you who have given to the Ricky fund, and I hope continue to do so. $100,000; we have done something with that money, and we are going to hear a little more about this. For two breeds of cats, the Maine Coon and the Ragdoll, as I suspect you know, the gene defect has been identified. So by a simple cheek swab we can determine if those cats have it. Breeders like you can respond. It is great, it is a great start. We need to do much more than that and to do that, we need your help, and maybe this symposium is a start of reinvigorating what we need to do. I don't want to forget about the cats with heart disease, as I will never forget about Ricky. Thank you.

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Beginning of Dr. Lyons Audio

Dr. Susan Little:
Thank you very much Steve. So I have the great pleasure of introducing our first speaker this evening and that is Dr. Leslie Lyons. It is a pleasure for me, because I have known Leslie both professionally and as a friend for a great many years. So, I could tell you about the stuff that is on the slide there; about her undergrad and her graduate work at the University of Pittsburgh, and I could tell you about her time at the National Cancer Institute working on the Feline genome project. As most of you know, in 1999 she moved to UC Davis and setup her feline genetics research lab and has been responsible for many of the important advancements in feline genetic research that we have seen and continues to be so. Winn has supported Leslie for many years as you know. I'm sure most people in this room are familiar with the work that Leslie has done and it has touched you in some way. But there is another side to Dr. Lyons that I wanted to tell about tonight and that is because I have a very special and important role as a board member of the Winn Feline Foundation. I am the only board member to have this role. No one has had before and probably no one will have it after. My job is to follow Dr. Lyons around the world and ensure the safety of our investment in this investigator, because she likes to do things like bungee jump. I am the one who gets to take the pictures and the video because, notice, I am the intelligent one, I am not jumping. So that video was taken in South Africa last summer and the picture I think is near Victoria Falls in Zambia. So I am happy that I brought her back alive from that event, but it is that courage, that, you know, resourcefulness, that love of a challenge that takes Leslie around the world to do things like that, that has made her an outstanding feline researcher. That has enabled her, I think, to push the boundaries forward and really to change the game for us in feline genetic research. So with pleasure, I bring you Dr. Lyons.

Dr. Leslie Lyons:
Okay. Are we good to go? Excellent!

Thank you very much Susan for the introduction. One day, I can get even. I have my own videos and things too, but at least every time I am out doing some of those things, we are collecting cat swabs wherever we are, so there are few things. I will try and speak lightly because I think this is turned up a little too high. So I am going to kind of walk us through where we have been for the past, I guess you know I realized it has been 20 years now that I have officially been involved with cat research. When I moved to the national cancer institute in February of 1992, that was beginning of my cat world, and so it has been 20 years and I am quite pleased that we have actually solved one of my 20 year projects, which we will talk about. So I am going to try to show you how things have evolved, and what we can do now with DNA projects, and we will be moving quite quickly forward. But over all these years, the Winn Foundation has been right behind me. Certainly, our biggest funding comes from the National Institute of Health. So I always do, although I know everybody wants me to work on silver, I always have to put disease projects at the top, because that is what the NIH wants you to do, but give me a moment, and I can turn any cat trait into a genetic problem that NIH would be interested in. As you know, I am at the Center for Companion Animal Health and Niels Pedersen is right there with us. He is actually the head of my cat colony, but these are the guys behind me that actually do all the work. So I want you to keep in mind when you are funding our lab, you are funding students to become geneticists, become interested in cat genetics, and hopefully their lives and their careers. So Barbara is who found a couple of these things that I will discuss today. Barbara ‘the Italian’ is what we call her, and she will be joining us tomorrow night and be speaking at the Burmese thing as well on Saturday when we talk about the craniofacial defect.

So, as we already know, cats are a wonderful pet and they are certainly taking over as far as being one of the most popular pets in the United States. One third of the households in the USA have cats, but of course most of them are not our fancy breed cats, which are the ones I tend to work on. But over the past 10 years, cats have really jumped forward in research activities. So as you know, there has been cloning of the domestic cat and everybody thought that was a big hit for a while. They were going to sell cats and then they realized, well that is not really a lucrative process, so they don’t do that anymore, but we have also made glow in the dark cats. So there are green and red fluorescent protein cats, because we are trying to work on transgenics. Now that I have found, or many people have found these genetic diseases, we can prevent them from happening by a genetic test, but what can we do about the animal that actually has the disease? Maybe we can do gene therapies, and that is why you develop a glow-in-the-dark animal, because you are trying to show that you can do a gene therapy, right? It is not just to make a glow-in-the-dark cat, but we are now learning that we have the technologies to be able to do things like that. But, so far, in the past, what generally has happened with genetic projects are things called candidate gene approaches. We have basically stolen the information from other species and used that and helped to try to translate that in the cat. So that is how we have found a lot of our genetic traits over the past, say 20 years or so, but now life is changing and I am going to show you how we work away from this.

So this is called comparative genetics, comparative medicine. It is the candidate gene approach where you actually use a gene from another species, analyze that gene in the cat, and see if you can come up with the proper mutation. So that was used in the early 80s or so to figure out the gene that causes gangliosidosis in korats, and that is one of the first genetic tests that has been available, and because you had a biomarker that was out of whack, you could kind of guess what gene would be involved. These conditions occur in other species. They have already been worked out, well gee, let’s look at the same gene in the cat and see what happens, and sure enough you find the mutation for different types of gangliosidosis. It took a lot of work back in the 80s to do that because you didn't have a lot of genetic sequence for cats but that is how we approach things. Through the same technique, when we found out the mutation that breaks this enzyme that converts these two different types of acids; so this acid here is what is on your cells when you are a type B cat and this is a type A cat. When this enzyme is broken, you are a type B. All we had to do was read the literature, and within a month, we sat down and said "Hey, it is probably this gene, lets analyze the gene in the cat" and sure enough we found the mutation. So a student came from Italy. She wanted to work on dogs. I said "Go ahead and read the dogs, but you've got to read about cats too." She read about the cats, came in and said, "You know, it has to be this enzyme in the cats, the dogs I cannot figure out yet." I said "Well do this while you are working on the dog stuff", and within a month she had the mutation for type B blood type. So it wasn't quite magical, but you are being smart enough to pay attention to what work has happened before you. This is also how a lot of our coat colors have been figured out. This is the pathway to produce colors, eumelanin is black, pheomelanin is yellow. Those are the only two colors that are in your cats. Everything else is an optical illusion. So it all starts with tyrosinase and the different enzymes along the way are the things that sometimes get broken or altered, that lead to our coat colors. So one of the things in the pathway is actually Agouti so we have found the mutations that make one mutation takes out the yellow pigment in ticked fur here, and that makes a black cat. So there is only, in what looks to be a brown cat, that is black and yellow fur, that gives you the optical illusion that it is brown, and you have a black cat.

We have also found the mutations for Siamese and for Tonkinese, Burmese, for the different brown color variants. That was all done by candidate gene approach. We knew what these genes were in mice particularly, that is really where the research was done. We looked at the same genes in cats and were able to find these mutations. Now also we sit and we wait to see what happens in other species. So other researchers have done work on a keratin gene called keratin 71. They published a paper on dogs and found the curly coat, the Portuguese water dogs, and the wire hair of a couple of other dogs, and they said "Well hey, we have curly coated cats and wired haired cats, let's take a look at those same genes." Sure enough keratin 71 is not only the mutation for the devon rex's curly coat, but, you know, people like Robinson and you guys had already kind of figured out "Well, we think hairlessness of the sphynx is in the same category as well.” So what use to be considered two different loci, devon curly and sphynx hairless, that is actually mutations at one gene, that keratin 71, that caused, that pretty much just knocked out that gene, and the sphynx is dominant to the devon rex. The devon rex has to have two copies for it to be a curly coated cat. sphynx then, of course, can carry devon. We have also, through a candidate gene approach, found the mutation for little white feet, gloving. And this was fun because, did the ragdoll steal the birman white feet? And the answer is no. They did not. There are some ragdolls in the world that look like they do have some birman cross in them, but overall the majority, whatever is causing the mutation for ragdolls to have mitted feet, it is not the gloving of the birman cat. So you can actually genetically test and prove whether your mitted ragdoll has come from breeding with a birman or not.

Then kind of finally, we have always wondered about the new mutation that has been found that is called amber, and that is found in some Norwegian forest cats. This is in a gene called extension MC1R, and the point is, everybody has always wondered, that has always been the first gene that everybody has looked at. So orange, everybody look at MC1R first and then that was wrong. So everyone has always wondered where is this mutation in cats? Because in horses, that is what causes red horses. Can anybody name this horse here? This is Secretariat. This is the one that was just going to win and then didn’t run in the Triple Crown, so he is a red horse as well. So red takes the black hair of the mane and makes it into red. Red pigs are also extension mutations. So we have known these for a long time as well as yellow labs and stuff. Red hair. So we have always wondered, "where is extension"? So when the amber cats came along, at least the researchers were like "there it is! Very cool. Alright, finally we have one" and stuff. But this has been known for a long time and was one of the first coat color traits ever known in humans, dogs, and horses. So finally we have the same gene in cats.

So a lot of our genes have already been found by what we call the candidate gene approach. We basically took a shortcut and used what we had learned from other species. Then we kind of evolved into what are called family-based studies. So that is where I was always bugging you to say "Hey, I need your cat that has FIP, but I need the parents, I need the grandparents, I need the siblings, I need all that," so that I can build up pedigrees of cats and families of cats that have interesting traits and problems. So the point is, you have to have very large extended families to do these types of studies and this has been my life for the past 18 years; it has been truly trying to build family-based studies. Genotyping, so actual genetic testing in all these families is very laborious and takes a lot of time. You tend to need to have traits that are clearly dominant or recessive, and the statistical analysis is called a linkage analysis. So we would have to have 2 to 500 polymorphic markers. Those type of markers, if you have ever heard me talk about microsatellites or STRs, those were the type of markers that we wanted, and they are little repeat units that are just found all over the genome. They are very highly polymorphic, meaning they are very informative in many different animals, in different individuals of a species. So you guys know about these because if you have ever watched CSI, this is exactly what they are doing. So when they take a little buccal swab, they are going to run a gel that looks like this. These are different genetic markers, different STRs that ends up looking like this. Sometimes you will see a printout, they will put a printout on a screen that looks like these bunches of peaks and stuff, so that is basically this gel turned sideways, and a laser is used to read the intensity of the peaks. Then, from the sizes up here, we actually figure out the sizes of the different alleles of the individual and that is how we just genetically type individuals for STRs. So this is a DNA profile. We can do these DNA profiles with cats, for humans, for pigs, for dogs, but they all use different genetic markers. We needed it in family-based studies, some 500 of these that we would have to type in all these different individuals of a family.

Here is an example of it done in a small family, this is a small family. The black circles and squares are individuals that have polycystic kidney disease. Here we have the genetic markers and their genotypes down below, and we figured out that for polycystic kidney disease, this allowed us to figure out what chromosome it was on and then what kind of gene to look at. So by figuring out what chromosome it was on, we could guess, if it was on a cat chromosome, what we call A3, we knew to look at all the information that was on human chromosome 2 because we knew how the cat chromosome matched to the human chromosome. By doing that comparative approach, we knew that on human chromosome 2, there was a gene that caused human polycystic kidney disease. So, hey! That is the gene we are going to look at. Now why wouldn’t you just do that right at the very beginning? Well, because if we look at polycystic kidney disease in the cats (never expose who your clients or patients are, right); it is a dominant trait. We could only be very certain that we knew how a cat would be affected by doing ultrasound at about eight months. That was after you wanted to make decisions on your cats and stuff. There are also liver cysts but kidney cysts are the primary presentation, but there is more than one type of this in humans. So there is more than one gene known in humans that causes polycystic kidney disease. So by doing this comparative approach and having good ultrasound, so this is ultrasound with what the cysts should like in a kidney with PKD. This is kind of what a cat can look like. So most of our cats are very mild, but some cats get very severe disease and by the age of 2 to 3, they can have a kidney like this. What is amazing is before this cat was dead, it was alive and it had a kidney that looked like this. So it was limping along for quite a while. So cats are quite amazing, that they can be pretty bad off and then suddenly go downhill, but this is very similar to the human presentation as well. The point is, one DNA mutation, one DNA nucleotide was out of whack in this huge gene, and here is just to show you; the gene has 46 axons. It is 3 pages long. We did not want to go looking for that gene unless we knew we had the right gene because that would have taken a lot of time and money, and out of 46 axons, a very large gene, one base pair is out of whack, and that is what causes polycystic kidney disease. So quite a remarkable disease. Exact same condition in humans and in fact in humans, you have heard about cystic fibrosis, you have heard about sickle cell, you have heard about Duchenne muscular dystrophy. PKD is more prevalent than all three of those combined. You never hear about it because it affects old people, and nobody cares about us old people. So by the time you are my age that is probably when you would start going into renal failure with polycystic kidney disease. Let’s save all the young little kids that have CF and stuff like that, but this is the second reason, biggest reason of why people are on kidney dialysis behind being diabetic. Usually, if you are on kidney dialysis, you last about seven years, and usually someone with polycystic kidney disease, by the time they are 60, they are on renal dialysis. So that means they generally have a 10 year shorter life span than other individuals.

So we used to do genetic tests that kind of looked like this. This is the normal allele for polycystic kidney disease. This is an affected cat, and we can see that the affected cat always has the normal allele as well. We never find cats that have two copies of the mutation for polycystic kidney disease. That means they are dying in utero. They probably get formed as an embryo, but then die very soon. Kind of like the manx trait in the tailless cats. But, from there in early 2000 to 2006, the NIH said "Okay, these cats, we are kind of noticing that they are kind of important, let's do some DNA sequencing effort." So they did what is called a light-coverage DNA sequencing effort, and we got stuck in there with the armadillo. Why would you do an armadillo? They are a great model for leprosy actually. So armadillos, guinea pigs, elephants, tree shrews and the bunny rabbit and a few bats got sequenced at the same time as the cat. But it was a very, what we call light coverage. They didn't really do a real strong job like they did for mice and humans. But, by being able to do that and do still linkage-based studies, Dr. O'Brien's group, Marilyn Menotti-Raymond working with Kristina Narfström, they were able to use that same approach to find the mutation that causes retinal degeneration in abyssinians, so a recessive mutation in the gene that is called CEP290. Now, what has been interesting is once you go out and actually you genetically type cats for CEP290, you see that abyssinian observed heterozygotes, so those are the cats that carry the mutation, certainly carry this mutation, but we can also see, look at this, some Orientals and Siamese and Singapuras are carrying that mutation as well. That was a surprise. So once you have these genetic tests, you can go out and survey your populations, and see who is at risk as well. So there are a few blind cats out there probably, that we either don’t recognize, don’t know about, but the disease can have a very slow progression as well. So by doing these genetic studies we can actually find other breeds and population that are at risk.

So, so far here are some of the diseases that we need to worry about in our fancy breed cats. We have one major form of PRA. There is a second form, but it is not as important to the fancy breed cats. Pyruvate kinase deficiency is certainly very important in abyssinians, but we have also seen it in ocicat, Bengals, some Siamese and very significant in singapuras as well. We have different types of gangliosidosis in Burmese. In the UK, hypokalemia, it is a potassium disorder that affects Burmese. We have just been able to find that mutation this year and I will tell you about those studies as well as now we also know the mutation that causes the craniofacial defect in Burmese cats as well.

So we have quite a few different genetic mutations that we have been successful to date using these old style approaches. Linkage, family-based linkage studies and candidate gene approaches. We have found a lot of the different colors and there are certainly more on the way. People are looking at inhibitor. I know the mutation for orange has been found, so that will get introduced soon this year, and also probably a mutation for one of the tabby genes as well. So one by one we are starting to knock these off. Primarily, I have been interested also in studying our fancy breeds and understanding their domestication, but I have an ulterior motive to doing that. So I will tell about the ulterior motive, but I will tell you first about the fun thing that was important for you guys.

So we did microsatellites, so those old-school markers on over 1000 different cats from up to, now we have about 29 to 30 breeds that we have done, and we have actually now done different types of markers. We went to Egypt and collected cats in Egypt. We were actually looking for, we were trying to figure out the site for cat domestication. Wild cats use to live in all these areas that are colored, but we think there were three different sites where human beings settled down and independently developed agriculture. One was in the near east in the Fertile Crescent. That starts around Baghdad, goes up into Turkey where the Tigris and Euphrates rivers are, and then down the Levant, which is where Israel is, and into Egypt. Then there is an area called the Indus Valley, which is right on the border of Pakistan and Indian, and then also the Yellow River region in China, so very distinct regions 10,000 years ago. There was not a lot of transport at that time. So we are trying to figure out if cats were domesticated more than one time. We certainly know cats were at least domesticated in the Fertile Crescent from the African wild cat, but we are still trying figure out about the South Asian cats which are very special too. So there might be second domestication site, but we have to figure out a way to prove that.

Along the way, by doing these studies, we have been able to figure out that there are 8 major races of cats in the world. So we tend to say that there are races of humans, right? So now we kind of think that there are 8 major races of cats; European, Mediterranean, Egyptian, Iraq/Iran, cats from the Arabian Sea area, cats from the Indian ocean area, South Asia, and East Asia. So if you send me a DNA swab from your cat, we can actually tell you whether it is one of these eight major races of the world, and that includes your Monty cat, your just household pet, your random bred cat. We can match it to one of these races. Most cats in North America are going to be European cats. They came with Columbus, right? They came with Magellan and Cortez and so they are European cats that came over with those great explorers and stuff, and also are migrants as migration came to the United States. But, there are still other very interesting and diverse populations of cats. We did find out that cats from Southeast Asia, for example, so this group here, the South Asian cats, have led to the development of specific breeds. So the Siamese, the Singapura, the Burmese; these cats really do come from South Asia and their nearest relatives are the street cats of South Asia. Most cats come from Western Europe, most of our breeds. Some of the breeds come from the Mediterranean such as the Turkish van and Turkish angora, and then one breed, the sokoke, looks like it is that Arabian Sea breed. I know it is not a very popular breed, but it is something that has been just developed in Europe and stuff. So one, two, three, four, four of the different races have led to the development of our cat breeds. So this will become important as we hopefully develop crossing programs for our cats. I do need to mention that we have looked at bunch of different breeds, but the breeds don’t all fall into genetically distinct categories. So if we count two breeds as Persians and exotics, if I look at them from a genetic point of view and I am not biasing myself by saying this is a Persian, this is an exotic. If I just look at them from their genetics, I cannot separate them as two different gene pools. That is because one genetic mutation does not make a breed. So, short haired Persians, there are long haired exotics, they are Persians. So that is I know a little controversial, but ……. so we can see that, for example we can see that the Havana brown is kind of mainly the same color as the Siamese. So they are just a solid chocolate point. They are basically the same thing. So we can see which breeds are genetically distinct and which ones are not. More recent studies have shown that Scottish folds, even though you had the fold mutation, they are becoming very much like British shorthairs and British shorthairs are actually becoming very much like Persian. So that is kind of very surprising as well. So a little too much crossing going on between British shorthairs and Persians. You can't fool the geneticist, so I know what you have been doing.

So our inbred cats……. You know I would like to understand, why do people keep sending me pictures of cats with bread on their head? It's like they are in the bread, they are inbred. Oh, they are inbred cats, okay. So it took me a while. Okay, I might be able to figure out your crosses, but I am not clever all the time. So we still are very much interested in inbred cats, but we want to try to make them as genetically diverse as we can while keeping the wonderful qualities. And those wonderful qualities are temperament, color, body shape, the behaviors that they have, that they are good mommas; those are all very good and important things. But by doing these genetic studies we have been able to see that some of the newer breeds, such as Siberian, the ragdoll, Turkish angoras and manx have very high genetic variation. That is good. That is what we want because at this end of the scale that is where you find random bred cats. That is where you want to be. So as we move to this end of the scale, that is where you kind of don’t want to be; you don’t want to move this direction. I don’t want to take this slide literally one by one saying "okay, Siamese are far better than ocicats." That is too close to call, alright? So what I want you to take home is try not to be at this end of the scale, alright? So, who do we see down there? The Burmese and Singapura. So the darker bar is genetic variation and we can see that genetic variation is on the lower end of the scale, but also importantly is this lighter bar. That is inbreeding. That is your inbreeding coefficient. You want this bar to be high and you want that bar to be low, alright? So when you have a combination of both being the wrong way that is telling you that you are having a genetic gene pool problem with your cats. So one of my favorites is korats, they are a wonderful example. How can they have high genetic variation, low inbreeding, and they only come in blue, and there are like five of them registered every year? How can that happen? It happens because they share, they talk with one another and they use genetic testing in a wise way. Not by getting rid of carriers, but by managing them over a slow period of time. I think now they have gotten rid of most of those cats, but it took them a while to get there. Also, they go to Thailand and bring in cats. They are not bringing 6 or 10 cats all the time. They are just bringing in a couple every once and a while, and the cats get shared and moved around. Not everybody works well together, but overall the majority of the breeders do, and so they are your hallmark. They are your benchmark. It is to figure out how to focus your cats in this regard. High genetic variation, low inbreeding and it can be done. So the korats are an example that this can be done. We need to move Burmese in that direction. I personally think Burmese are loping towards extinction if they don’t get their act together and start really trying to diversify their cats. Singapuras probably need some help as well.

Other things we have done with this work, is we did a pretty diverse Turkish van study where we first did a study just with these cats over here on the left side. Those were Turkish vans that were registered in different cat Fanciers’. So those are Turkish vans, and then people sent in other samples and said "Hey, to me this looks like a Turkish van, is it a Turkish van?" And we could say sometimes since they matched the same colors they were right, but other times they were wrong. So genetically, even though they looked like a Turkish van, it wasn't actually a Turkish van from a genetic point of view. However, if it looks like a van, maybe you should add that in to help the genetic diversity of your gene pool. So we can actually use genetics to see how diverse they are, and then decide to add them in, or decide to keep them out. That is not my decision that is yours, but you can use it in both directions. Either it is a good thing, or maybe you don’t want it.

So a lot of this work, we had a very nice day at Davis where we had maybe 100 cats downstairs in our clinic, and we had it all set up like a cat show, and people brought their cat, and this Burmese just sat there and stared into the camera for a good five minutes; so it runs the whole credits for the National Geographic special, and so this is called The Science of Cats, and every once in a while it shows up on Explorer on the Nat Geo channel. This has led to the development of this cat ancestry test. So if you have heard about the Wisdom Panel for dogs, we basically have the same thing for cats as well. It can be found only at UC Davis at the veterinary genetic lab. That is where you have been sending your stuff for PKD testing and coat color testing and stuff like that as well. Along the way we have been able, since we got to go to Egypt, we were able to get cats from the streets of Egypt, and we have been the first to sequence Egyptian cat mummies. That paper, it just got published. We sequenced 3 mummies, bones from 3 mummies, and we have been able to show that the cats, the genetic types of these mummies, are just like the genetic types of the cats that are running around the streets of Egypt today. So that means the cats of Egypt today are the descendants of the cats of the Pharaohs. So we did that by what is called mitochondrial DNA. Mitochondrial DNA is much more prevalent. We sequenced a region called the control region, and by doing that we are able to show that the mummies, here are the mummies, are of genetic types that are only found very prevalently in Egypt and the Mediterranean. Like type A is far more found in the United States, for example. So we did that just by DNA sequencing, and if you just look at the different base pairs here, you can see that you should have two black ones and a green. Two black ones and a green, there is an insertion of these four base pairs that kind of help distinguish those cats as being Egyptian mummified cats.

But there are still some things we don’t know. Of all things, one of the first things ever genetically mapped in any species, was orange because people figured out it was associated with gender. It must be on the X chromosome. So back in the days, in the early 1900s when people were just trying to figure out how genetics worked, we knew orange was on the X chromosome. It has taken us up until now, up until this year to actually find that mutation and that has been done by Dr. O'Brien's lab. So we are just now starting to figure out what the orange gene is. We still have things to look at such as, we can tell you a cat is going to have polycystic kidney disease, but how many people out there, if you have a cat that is positive, continue to take their cat to the vet. Because you won't know whether your cat is going to have mild disease, this is very mild disease. The cat will probably never die of renal failure versus how do you know if your cat has this? That cat is going to die in few years. So if you have a positive cat for PKD, it should be going to the vet to see how it is progressing with its disease. We don’t understand the genetics that causes this to happen. There are still things to look at.

Of course silver. I know we are going to find silver one day. So hopefully we will find that.

So now we have moved into a whole new era. So the whole new era has occurred in maybe the past two years. We have been trying to move this along. That is now, instead of microsatellites, instead of SDRs, you are going to always hear me talking about SNPs. SNPs, SNPs, SNPs, alright? SNPs stands for single nucleotide polymorphism. It is just a single DNA variant, like that DNA variant I showed you in polycystic kidney disease? That is a SNP. So the thing is, because we have been able to sequence the genome, we have been able to find these SNPs all over the place; so just one single based pair change is a SNP. We had first the coverage of the 2X coverage, the light coverage that was done by the NIH for sequencing the cat, then Hills Pet Food came along and secretly kind of did their own project, but still a very small project, but they did give all their data to the public database. So that was very nice of them. But they also sequenced different cats. So the key one you wanted to sequence was an abyssinian called Cinnamon. So everybody has sequenced that cat. But they also started doing different breeds. When you do the different breeds that is when you find the SNPs. That is when you find the polymorphism, the variation. If you only sequence one cat, you wouldn’t find variation, you would only find what is in that one cat, so you have to look across different breeds. So not only did they do this, but they gave a million dollars to the Morris Animal Foundation and that becomes a key thing that happens, right? But also along the way, the NIH asked Washington University to continue sequencing Cinnamon, to do a better sequence of Cinnamon. So that has been happening as well. Our lab, you know big labs do this, this guy doesn't even know what a cat is, right? So he has to put a committee together that included us and many other researchers in cat genetics to tell them what other breeds we should sequence. So all that data that we had fun with trying to figure out which breeds are similar, and which ones are different, that now becomes the key data for the cat sequencing project, because if we only have six or seven or eight breeds that we can sequence, which ones are the most diverse that we should sequence? And now we have the answer to be able to help with that. So these are the cat breeds that we chose to sequence to find the SNPs. You have got to have them to find a lot of SNPs. So in the end we found some 17 million SNPs by sequencing these different cat breeds, and so many of you guys actually submitted, this is where I asked for blood samples, so that you could actually participate in the cat sequencing project. So the cat genome is there now. It is available to me as a researcher, so it is actually out there and it is publicly available. A huge group of people did this. When you say "Oh, Lyons is in charge of the feline genome project" that is not even close. It is a consortium. It's a big group of people. I did a small part, other people did a small part, and it all added up to a big study. But, so now this is what we have this little piece of metal that is called a DNA array. A chip. And on this chip, is 63,000 SNPs, so now instead of doing 200 or 300 genetic markers that were very hard to type in the lab, now I can do 63,000, with 12 cats at a time. All I have to do is prepare a good DNA sample. And you know what? If you take a good buccal swab, that's good enough DNA to run on one of these chips, but it has to be a good buccal swab. You have to send in a good buccal swab, and we can isolate the DNA, send this off, and in three weeks the company in Nebraska will send us back the data and it will be 63,000 genetic markers on how many cats we send. We can send them 12 cats at a time, or we can send him 100 cats at a time. Within three weeks, we'll get all that data back. So it is an enormous leap with the technology that has happened in the past two years.

But, now that means we have completely changed how we do our studies. So I have always asked you "Oh I have this affected cat, I need its parents, I need its siblings, I need this, I need to extend those pedigrees," right? Not anymore. Now we are focus on what is called case control studies. So a case is a cat with a trait of interest. It can be a Bobtail or it can be a cat with hypokalemia. Whatever your interest in it is, your case has the condition. The control does not. The thing is, these have to be perfect, these diagnoses have to be perfect. So we have to work very, very closely with veterinarians to make sure that we have these cats in the right category. If you're sloppy, and you have some cats that are affected and they are in your controls and vice versa, the study is going to be terrible, and you can spend a lot of money really quickly sending off that DNA to Nebraska, and then get crap back, right? So crap in is still crap out, right? So this is now what we are focusing on. So we still ask you for a pedigree because that is what we want to figure out; how related are our cases. How related are our controls? The best scenario now is to find cats that are unrelated. So now with cases if we can still find them within a breed, but unrelated, we can use them. If they are little bit related, that's still good. We can still use that, but now that's what we do with the pedigrees, is try to figure out what that kinship might be. But we don't need to build pedigrees of related cats anymore. Just case control, very fast genotyping, and this is called a genome-wide association study; a GWA or a GWAS, genome-wide association study. One of the other things that we have to look at is when you do one of these studies, how do you know how many cats you need? How many cases do you need? We can predict that from the breed analysis that I did, but the more inbred the breed, the lower its genetic variation, actually the fewer cases I am going to need for one of these case-control studies. So in this regard, this is why Burmese worked out so well, a very inbred population. This red line is American Burmese cats and of all the breeds we looked at, they are very, very highly inbred. This is called linkage disequilibrium. Their linkage disequilibrium is high. So, that is bad for the cats. That is good for me. That helps me find a trait very quickly with only a low number of cats. So remember, our pedigree studies, when we did polycystic kidney disease, there were 600 cats in those pedigrees. When we do these studies now, he can do them with 30 or less cases for some genetic traits. So with the Burmese projects, we have been able to do them with less than 30 cats. We also, from that genetic data, we have also been able to find that Western breeds, so these are all different breeds of cats, are genetically distinct from the Eastern breeds. But, if we need to do a genetic study say on something like Cornish rex, if we wanted to try to find the curly coat for Cornish rex, your cases are Cornish rex. They are curly coated. Who is your control? There are no Cornish rex that are not curly coated. So you can cheat by figuring out what is the most genetically similar population. So all that fun we did by doing all the populations of the different breeds, we now use that information for this as well. So I think I was just having fun trying to figure out how your breeds are related, really I wanted this information for all these different studies as well.

So now we make data that looks like this. This is called a Manhattan plot because it looks like it has skyscrapers in it. So we all walk around talking about SNPs and Manhattan plots now, and what you are looking for is the highest SNP. The highest SNP is the SNP most associated with your disease. And so we did Cornish rex. All we needed was 11 cases. That was just astounding. We had 11 Cornish rex and a whole bunch of controls. The control was just a group of cats that were most genetically related, but of course did not have a curly coat. Once we looked around this SNP here, we looked to see what chromosome it was on, chromosome 1, and wow what genes are under there. Look at that. If we read the literature, there is a gene in there that causes curly coat, woolly hair syndrome in Pakistanis. And so you look at the Pakistani data, and sure enough, woolly hair in humans is Cornish rex. So give me time, I can turn any genetic trait into a human health condition. So actually the Pakistanis also have other problems, so it depends on what mutation you have in the gene. So they also have other problems other than just curly hair and stuff. So this is actually a mutation. It's a 4 base pair deletion, so we can see the curly coated cats actually don't have that.

Now also by doing this study we were able to collect, because some veterinarians in the world actually are collecting DNA samples, we were able to call up the UK, Germany, and Australia and get all their cats that hypokalemia, put them together in a pile, run 30 cases against 25 controls, and we found the mutation that causes hypokalemia in Burmese cats. This is primarily non-USA cats. So it's European cats, UK cats and Australia cats. It causes low potassium which causes seizures and muscle weakness. Their peak looks something like this. We have now called this the peak of Dubai. You know how Dubai has all the really high buildings. So we want Dubai peaks in our plots. We are also calling this a Victoria Secret plot because the Italian picks the colors of what you're going to make your chromosome, so it is Victoria Secret Dubai plot. So now you can do things very rapidly. If you have the DNA, you win. And so it still means, if you can provide the DNA from your cats, we can do the studies very rapidly. This hypokalemia study was done in three months from a point of starting the preparation of the samples, sending them off to the company, the company gives you back data in three weeks, you see a peak of Dubai; this analysis takes about a week. Then you say "Okay, there's a gene under there, let's start looking at those genes", and if you do it well, within three months you will have the mutation. So we're just about to submit the paper for this project. You still use the alleles a little bit to prove that things are inherited and stuff. So we still kind of like to collect little families, and it was just showing us that every cat that had hypokalemia had the mutations that we were worried about. In the same way, we have been able to find the craniofacial defect in the Burmese cats. So we knew what chromosome this was on. The laboratory actually convinced me to try running it on the chips. And I'm like, the chips are just going to put us in the same place. Well what the chips told us, is that the region that we were looking at wasn't small, it was actually gigantic. So when we were looking in the small region for genes that we knew caused craniofacial issues in humans, we then later found out, no, the gene is actually a very large region and there is a gene over here that is a perfect candidate. So once we looked at that gene way over here, the Italian did it. She comes into my office and its March 29 at 9:56 AM. I'm yelling at Niels Pedersen about money. We are fighting over money. Barbara comes in and she's all shaken and she is like "We got it, we got it!" And I'm like "What are you talking about?" She's like "The craniofacial defect, we have it!" And I said "You weren't even working on that." And she said "Well I did it in secret. I didn't tell you." So it's little genes they know my accounts and they will secretly go buy primers for these genes and test them, only if they are little genes. If it's a big gene, they would not be able to get away with it, I'd figure it out, right? It's interesting, because in February I said "You know I'm getting all these invitations to talk here, and in Australia, and in Portugal. I can't face these breeders anymore. We have to find this." We had the data. Barbara is one that she sat down and actually looked at it, and she is one that found the mutation. So she will be here on Saturday to talk with the Burmese breeders and stuff.

This is a very interesting mutation because one copy causes short face. So one copy of the mutation causes brachycephaly. They have been wanting to find the gene in dogs for brachycephaly for several years. Ha! We beat them to it, right? So dogs, they have genes that kind of suggest brachycephaly, but we have one. Now, it's not the best gene in the world to have, but at least we now have the gene that causes nasal facial structure. This is actually what it causes when you have two copies of it, so a very severe malformation. This does occur in humans too. You can actually look this up, see with the gene is, put hair on the human, and it'll look just like the one of these Burmese kittens.

So, again, there are still probably other genes that cause short face. This is not the gene that causes brachycephaly in a Persian cat. So we still kind of want to look for genes that are involved with facial structure. We still want to find genes that affect why cats have liver cysts with polycystic kidney disease. We want to figure out why some cats get fat and others don't. We can start to do these studies by using these DNA arrays. We are interested in looking at deafness in cats. So we have an active funded project funded by the Winn Feline Foundation. The thing is, you think your cat can hear, but are you sure they can hear in both ears? That is the question. So anybody that has a dominant white cat any breed, a deaf cat, you can pretty well figure out if they are deaf, we want them, but we need to find the controls, the cats that can hear, and we have to kind of do BAER testing to make sure they can hear in both ears. So the khao manees, the Persians, the Turkish angoras, anything that comes in all white, we are interested in. We don't understand the genes that cause variation in blue. So these are things we can do. We are still actually looking for some retinal degeneration genes as well. So with that, we will probably end there.

So we were looking for all different types of genes and mutations that are affecting our different breeds. We have new projects on amyloidosis, on lymphosarcoma. Rag dolls have this condition where they are missing one kidney and maybe also an ovary. Egyptian maus with stones. So there are lots of things that we can do if you can get the DNA samples in. Once we get up to 30 or 40 cases, we are a go. So we have a lot of strong tools to go after different genetic traits at this point. So we still need your help. We still need the help of the veterinarians that get the diagnosis right, but we have very powerful tools. We have a new era for genetics in cats, and we can make a lot of good progress by obtaining your help. Thank you.

Steve Dale:
How are you all doing? Good! Thank you very, very much Leslie Lyons again.

Is Joan Miller is sitting in the back of the room somewhere? Joan are you here? I heard she was here. One of my colleagues Wendy Christensen is here who is a wonderful cat book author. Wendy raise your hand.

Joan is where, (next door), okay, at a meeting. Well in her absence because she is usually here. We would not have the Winn feline foundation symposium if it was not for Joan Miller, a round of applause for Joan. She was once the president of the Winn Feline Foundation. This is a very special movement. We really should have secret service I think in the room because we have a president and two ex-presidents by my count. Susan Little who you met of course, standing right here next to me. Ex-president former past president is a better way to put it of the Winn feline foundation, Susan stand up. Betty White, past president of the Winn Feline Foundation; our own Betty White! This is Betty White. Our current president and boy she is wonderful, Vicki Thayer president of the Winn Feline Foundation. There is Joan Miller walking in to the room to applause and a standing O! I think. She deserves it. A lifetime, I do not know of anyone. You know I just wrote and this is true. The AVMA convention is coming to I think your house, right? Right down the street from her house and I said you have got to go to this so I wrote the person at the American Veterinary Medical association and I said I do not know who the top ten would be of people who have done for cats over the past several decades but whoever is in that top ten, I am not sure but I do know Joan Miller would be among the top three or four. Wouldn’t you think so? She has done so much.

Speaking of people who have done a lot for cats, the Winn Feline Foundation for the past several years has created the Winn Feline Foundation media appreciation award. This is for one of my colleagues, a member of the media who has done special things for cats. It depends on what time of the year we present this award, it varies. We thought we were in Boston. Well the winner this year happens to be a Bostonian, is that the right way to put it? Is that appropriate? But she cannot be here. She had surgery just a couple days ago actually and the good news is Darlene Arden the recipient of this year’s award. I will tell you the award means something but is meaning far more to me because she is a friend of mine is that she is doing very well.

Darlene has been a champion of cats for a very longtime. She is very famous in the dog world, among her books ‘Small Dogs, Big Hearts’, ‘The Angel Memorial Hospital, Book of Wellness and Preventive Care for Dogs’ and of course this book that you all have. You have got to have this in your library. It is called ‘Rover, get off Her Leg.’ Really that is the name of the book. Darlene’s current book is called, ‘The Cat’s Meow’ and I will tell you however many years ago it was I interviewed Darlene for something and Darlene said ‘You know what cats are petty loyal and people do not consider them as such and cats are not getting the due credit that they should get.’ This was about 10 years ago. I think we are all catching up with Darlene now, right. Veterinary medicine and shelters are paying attention to cats. We are at least starting to in the way that we have not done before. The name of the book is ‘The Complete Cat’s Meow,’ everything, everything you need to know about caring for your cats.

Darlene is a former actress and dancer here in the Boston area and she now is a judge for K9 Freestyle, which is dancing with your dogs. I actually have… Well there is nothing funny about that. Have you ever seen that on TV? Well you know what they thought dog agility was crazy and now there is cat agility, right? So I expect to see Feline Freestyle, dancing with your cats. That would be fun. I wonder who would leave in that case. Darlene is on the phone, so I want (she is hearing all this). How about a round of applause?

A Boston native, a friend to all animals for many decades, I am honored and privilege to present Darlene (though we could have skyped it and then she would see it) with the Winn Feline Foundation media award. Sadly I have no bungee jumping video for this. Feline cardiomyopathy, hypertrophic cardiomyopathy means a heck of a lot to me (I’m disconnecting Darlene and I think I did) because of reasons that you heard before. I hope that you consider telling your friends about it. I hope you consider giving to the Ricky fund. I hope you consider talking your veterinarian, so when a cat passes away and sadly so many do of HCM, maybe a contribution will be made to the Ricky Fund.

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Beginning of Dr. Rush's Audio

Steve Dale:

Few have contributed as much to learning about cardiomyopathy in cats. Dr. Rush obtained his DVM and Master’s degrees at the Ohio State University in 1984. He joined the Cummings School of Veterinary Medicine at Tufts in 1989. He has severed as section head of the Emergency and Critical Care Services and as a clinical cardiologist and as an associate department chair. His research interest includes cardiac biomarker, cardiovascular drugs, dietary therapy for cardiac disease, and interventional devices for cardiac disease. We are going hear a lot about that and in terns we can all understand. He has published over 115 peer-reviewed articles on cardiomyopathy, Dr. John Rush. Thank you.

Dr. John Rush:

Thanks for that introduction. It is wonderful to be here! It is just going to take me just a minute or two to switch computers around here and then we will get started.

Alright thanks again! It is wonderful to be here. It is wonderful to be invited to talk little bit about Feline heart disease. How many people have actually had a cat with heart disease at some stage? Almost half of the people here have had a cat with heart disease. As we said before it is a pretty common issue. Happily though the Winn foundation has helped to support research in heart disease and they have supported us a little bit recently so hopefully we will be able to push this along.

This is the veterinary school at Tufts University, not far from here and of course there is always the rainbow that ends at Tufts University, a never ending pot over there. It is often appropriate at least in professional forums to tell you a little bit about who has sponsored the research that we are doing as there might be conflict of interest for instance if I am going to talk about a drug that is made by a company or something like that. There are a variety of different companies that have supported some of our research activities.

Think about heart disease and I am giving you kind of the approximate frequency of heart disease that we see in cats at Tufts.

We have seen a lot of hypertrophic cardiomyopathy and a relatively small number of dilated cardiomyopathy in these heart muscle diseases. We see a fair number of these that are either restrictive or unclassified cardiomyopathies. We see a number of cats that have arterial embolism, a clot to a limb. They end up being euthanized before anybody figures out what kind of heart disease they had because it is a very difficult disease. In the spectrum of seeing diseases that are heart muscle diseases, that is the vast majority of what we are going to see for feline cardiac disease. When we think about the most common form it is going to be this hypertrophic or thick walled heart muscle disease, so this just means thick wall heart muscle disease. This is sort of what the heart should look like in cross section with that red mushroom being the size of the cavity and this brown being the thickness of the walls. I think you can appreciated this cavity is very small and the walls of the main pumping chamber, the left ventricle are very thick. That is essentially the disease that we are interested in as the most common disease. What does this disease cause? It can cause congestive heart failure, clots often to the back leg, sometimes a front leg or someplace else. It can cause fainting and it can cause sudden death which is probably one of the more common causes of sudden death in cats.

When we see cats that seem to be healthy, but they go in under anesthesia and die suddenly under anesthesia it is probably one of the common causes that the cat had underlying heart disease and nobody knew about it. Then a bad thing happened under anesthesia, so the main feature is this probably is not that critical to know but the walls of the main pumping chamber are very thick. The cavity is small. If you were to look at this on a microscope, some people find that the fibers they just are not lined up. We would like them to line up and when the muscle contracts that they contract in a uniform fashion. They work with each other. If this one contracts and it is at odds with that one and so we are not going to get effective contraction and sometimes we see this green scar tissue in there fibrosis and certainly you would not want scar tissue in your muscle if you are hoping that it is going to contract. As a result of these changes, the upper chambers of the heart, the left atrium and/or the right atrium started to get enlarged and then pressure starts to build backup. So this is not a problem with the heart pumping. This is not a contractile issue. This is a problem of the heart filling, it happens during the filling stages, diastole; that thick heart makes it hard especially for the left ventricle to fill with blood and again a lot blood the is flowing through the heart muscle is going happen in a slower heart rate during the filing phase so when the heart starts to beat really fast, it is going comprise the heart’s ability to fill. Again, we said the contractile function is usually okay, but problems in these lower chambers leads to enlargement of the upper chamber, the left atrium and the right atrium. That said, this left atrium we are going to concentrate on a little but because that tends to be the marker of whether we are getting in to trouble or not.

So what causes hypertrophic cardiomyopathy in the cat?

Well we just heard that genes are important and in the genes, this is kind of a little contractile unit, you may have heard things like actin, myosin, troponin, and tropomyosin which are all just different proteins that work together to allow the heart muscle to contract. It is the same sort of stuff that is in skeletal muscle, but they are just a little bit different in the heart. An abnormal mutation in any of these proteins can cause hypertrophic cardiomyopathy so there are abnormalities that are well defined in people and there are seven hundred different specific mutations that cause cardiomyopathy in people. In cats, we have identified two; one of them in Maine coon cats and one of them in ragdoll cats and that is it. It is likely the mutation that is in Maine coon cats is not the mutation that happens in domestic short hair cats or happens in any other breed, so we have got a long ways to go to try to identify these genetic mutations.

What is the relationship between the genetic test and development of hypertrophic cardiomyopathy?

How many people have done a genetic test on cat of any sort? A good number

So okay, one of these things that is hard to get in your mind is how do these two relate to each other? So if we just look at when do cats present with signs of this hypertrophic cardiomyopathy? Then say they start out at age 0 and we are lucky they live to 20 or longer. Well, an average cat has no signs of hypertrophic cardiomyopathy. No problems until it is middle aged. We just have it at about eight but it could be at two years of age, it could be at 12 years of age and then after that point in time if they are positive, they have clinical signs of the disease. This may not be not exactly the sphere because if they have heart failure they are only going to live six months or year after that.

So if we were to do the genetic test, the question is when the genetics test is abnormal. Well again, the genetics test is going to be positive from birth, so while they do not necessary having a clinical signs of the disease, the gene is positive at birth. The next question would be well when is the echocardiogram? We are going to talk about the ultrasound exam of the heart, that is the main test that we do to try to sort out what kind of heart muscle disease is there, when is it abnormal? Well again at birth and at maybe the first six months of age, the echocardiogram looks perfectly normal and then somewhere between six months or a year of age and 10 or 12 years of age, some of the cats start to become abnormal. Then later in life most of them that are going become abnormal are abnormal. So that echo may not look abnormal until middle age or later and the other thing that is a little challenging is some of the cats with the genetic mutation never showed an abnormal echocardiogram. They never get the disease. So that is another major challenging thing for us in trying to decide how to tie this all together.

If we talk about this myosin binding C protein mutation in Maine coon cats and this is one of the ones that Dr Lyons talked about having identified as a clear-cut mutation. It pretty reliably picks up the cats at the University of California Davis cat colony where they have a Maine coon cat colony. Although they have seen a few of their Maine coon cats that are negative for this genetic mutation that still got hypertrophic cardiomyopathy. If we look at the tests about one-third of all Maine coon cats around the world carry the abnormal gene.

In the real world, it is a little bit more challenging. Some of the Maine coon cats with the mutation get hypertrophic cardiomyopathy. Some of these cats get really severe disease and some get mild disease. It is not clear why some get it really bad. Some cats with the mutation never get hypertrophic cardiomyopathy and some Maine coon cats without the mutation get hypertrophic cardiomyopathy. So I think this tells us that genes are not the entire story. So if we kind of look at this and we say well what is the population of Maine coon cats that do not have the gene, it is like this, it is about a third of the cats that have the gene. If we consider this group that has the gene, many of them but not all of them get hypertrophic cardiomyopathy but some are not going to get hypertrophic cardiomyopathy and if we consider the ones that do not have the gene, some of those get hypertrophic cardiomyopathy, but a lot of them, the majority of them will not. So we have to kind of find a way to explain this phenomenon that is sort of difficult to explain. So there are several options. There could be more than one genetic mutation or that other genes that are inherited at the same time bring on the hypertrophic cardiomyopathy or it may be that environment influences impact the expression of genes that cause it, things like drugs, vaccines, a stressful environment, exercise, nutrition, and/or early growth patterns, those all could cause it. Certainly it is possible that genetic play a very little role, but I think very few people think of that.

So we had some interest in the nutrition end of things and that was driven a little bit by the fact that when I see cats in our neck of the woods that have hypertrophic cardiomyopathy, a lot of them are the big boned, big headed cats and we thought that there might be something there. So we started to look at cats and measured their heads, measured the size of the vertebra, measured the length of their humerus and we identified that the cats who got hypertrophic cardiomyopathy were on balance bigger. They had bigger skulls and a long humerus than the cats that did not get cardiomyopathy. There seems to be some role for genetics in this and when we look at the Maine coon cats, we actually find a closer correlation with obesity and size of the cat than we do with genetic mutation. So that is sort of very tricky in trying to sort that out. Again, I am going to skip this and move right around here.

So what do cats with cardiomyopathy, how do they get into trouble? They can get into trouble with congestive heart failure. They can get into trouble with arterial embolism, fainting, or sudden death and unfortunately in cats the main clinical manifestation of heart disease is usually a crisis even. Cats do not do as much as say dog or people with regard to chasing balls and then kind of slowing down or getting short of breath. They kind of throttle themselves down so a lot of times, cats do not tell you they have a problem until it is nearly at the last minute, which can be very challenging. So indeed it can be any breed, although there are some predisposed breeds, it can be any age. There is about 2 to 1 predisposition for male and so there is despite the fact that probably you get the same genetic material, there is something bad if you are a cat about being male. It brings on hypertrophic cardiomyopathy or at least the clinical signs. We tend not to see coughing but we do see rapid breathing, difficulty breathing, and they tend to be like cats in that they become lethargic, they hide; they just do not interact with people as much. Again if there is a clot, we see sudden onset limb weakness or paralysis. Again things that might cause a fast heart rate in a cat like recent major stress from anesthesia, surgery, et cetera that seemed to be able to bring on the shortness of breath.

On exam, there is a variety of things we look for; altered pulses, altered things on listening to the heart. That may be one of those things that – well we will see if this will go through. I do not have dog picture, we do have the cat picture. Let’s see if I can get this is to play here because, it is not going to play. Sorry it is not going to play loud enough. Well these are the heart sounds. A normal heart sounds is just lub-dub, lub-dub, lub-dub, lub-dub, and cats that have heart disease often have either a gallop, which is an extra sound so a-lub-dub, a-lub-dub, a-lub-dub, a-lub-dub or they have a murmur, lub-shhh-dub, lub-shhh-dub, lub-shhh-dub. Although they have to do it at cat heart rates which are up at 160 to 200 so it is tik, tik, tik, tika tck, instead of lub-dub, lub-dub, lub-dub, lub-dub. So those are some of the things you can pick up with stethoscope.

What is congestive heart failure?

To me congestive heart failure is fluid accumulation in or around the lungs so pulmonary edema if it is in the lungs, pleural effusion if it is around the lungs causing the lungs to collapse and that fluid accumulation causes poor oxygen exchange in the lungs which leads to rapid breathing, labored breathing and the other things we see in cats.

How do we figure out whether it is heart failure or not?

Well certainly the history and the physical exam which as we talked about can help us. Chest x-rays are important in trying to figure out is there fluid in or around the lungs. The echocardiogram and there is a new test that is called the BNP test, NT-proBNP which is cardiac biomarker which actually looks pretty promising and very interesting for trying to figure out whether there is abnormal heart disease.

These are chest x-rays and again this is a normal cat, this is a cat with actually pretty darn bad hypertrophic cardiomyopathy, one of the things I want to point out is that especially on the lateral view the heart sometimes does not look especially big on a chest x-ray, so it is not always the best test for us for looking at the heart. Although to look at the lungs – that is what I want you to pay attention to – this black area here is the lungs, that is the heart, this is the lungs around it. Keep that in mind because I am going to show you fluid in the lungs in a minute. So you have to have that picture of what the lungs look like, so normal and a cat with hypertrophic cardiomyopathy. On the other view, again it is a little bit easier to pick out that heart as big on the other view. Still the lungs are nice and black because they are full of air. So now if we take a look here at heart failure, the heart is bigger and see this whiteness in the lungs? That whiteness is going to be heart failure fluid, pulmonary edema. You can imagine the lungs are going have trouble exchanging oxygen. That is going to cause rapid breathing and shortness of breath, difficulty breathing.

In another situation here, we have a cat that has fluid around the lungs so this is the air-filled lungs and this is all fluid around the lungs. We take a needle and we tap that off and the lungs are much better shortly after that. I think those are the two we think about with congestive heart failure, fluid in or around the lungs, that tends to be what we see in cats and this is the fluid that is in the lung. I am sorry that is sort of graphic, but this pink foamy fluid is what is accumulating in the lungs and that is what causes of the shortness of breath.

So that chest x-rays, how about echo? Because you know lot of times people say we should look at an echo on your cat to figure out if it has heart disease or not.

We use an echo to try to figure out are the walls thick or not, so what we are measuring is the walls of the heart, is the main pumping chamber thicker than our little cut off 0.6 cm and an echo also allows us to look at the size of the left atrium and are capillary muscles thick and a little bit on the right heart.

What does is this echo look like and how is it helpful. This is kind of a short answer. We are going to look at the size of the cavity of the left ventricle. The blue is the right ventricle, the brown is the muscle and here is a fairly normal cat echo. You can see it has a pretty good cavity size. The walls are not that thick and the heart can contract pretty well. So that would be a fairly normal echo.

Here is for comparison a cat with hypertrophic cardiomyopathy and it still has pretty good contractile function, but I think you can see the cavity is much smaller and the walls are much thicker. That is how we are identifying or defining, hypertrophic cardiomyopathy, it is dramatically thickened walls of the heart and a small cavity and it is really hard to get that muscle to stretch and fill with blood and sometimes it is the whole pumping chamber of the heart and sometimes it is just the free wall or just the septum. Here is just the free wall, see how thick and muscle bound that is? You can image that just does not work very well.

Then in the next picture we look at, we said if the heart does not fill well with blood, the left atrium gets big. The left atrium is the upper chamber where blood is coming back from the lungs to the left atrium down to the left ventricle. This little Mercedes Benz sign is the aorta and that is the left atrium and on this view in a normal cat, we could maybe take two or two and half of the aortic dimensions and fit in this left atrium, 1, 2, 2.5, 3. So here is a normal aorta and a normal left atrium in a cat and what happens is as the blood backs up because it cannot fill that thick chamber, the left atrium starts to get big and I think you could appreciate that this aorta and this is the left atrium that is dramatically enlarged left atrium and that is going to be associated with the heart failure. The other thing that we can look at on this particular one, which is another cat with a very big left atrium is you may or may not be able to see that little blush of smoke that shows up. That little blush of smoke, oops sorry, that is my bad. That little blush of smoke that shows up is a marker of cats who are at risk of getting a clot in their heart. The clot then breaks loose, goes down stream and lodges someplace else in the body. When we see a big flotation with that smoke we worry a lot about clot formation.

On an echocardiogram again we are going to measure the thickness of the septum and the thickness of the free wall and figure out if it is normal or if it is too thick. If it is too thick then we are thinking it is probably hypertrophic cardiomyopathy. One other thing that it does here which ends up being a challenge for treatment and this may be certainly in the more than you need to know category but if anybody has ever talked about an out flow tract obstruction or systolic anterior motion of the mitral valve, it is very confusing. So if you wanted to know about that the general idea is that this is the aorta and that is the main pumping chamber. This is the wall which is too thick and there is thickening up at the top of the intraventricular septum. This should be a straight shot right down into the ventricle and this thickening is causing an obstruction. So in order to maintain an arterial blood pressure of 120 like your arterial blood pressure, the left ventricle has to work harder. It has to raise the blood pressure up to 150 and as it does that we get turbulent flow here which causes a murmur and it pulls open the mitral valve which causes mitral regurgitation. At that end point we should not see any color on that echocardiogram and all that color is abnormal flow and that abnormal flow is what causes the murmur. The lub-shhh-dub, lub-shhh-dub, lub-shh-shh-shh is the abnormal blood flow that is in the heart as a result of this problem. When this happens if we do the drug that increases the vigor of contraction in the heart which is what you might want to think about doing in some cases and then we pinch that off even more – now the blood pressure goes even higher here and that might even lead to a low blood pressure, hypotension.

That is one of the challenges we have in cats that is different than dogs and different than most people’s disease.

When think about clots in cats, this pad is nice and pink and this one is not because the cat threw a clot to that leg. Again pink and not pink because the clot went to the leg. These clots tend to go to the back legs. This is a clot that was pulled out of the main artery in a cat. It was pulled out of the aorta and you can see this vessel goes to one back leg and that vessel goes to another back leg. These are supposed to supply like the bladder et cetera. This clot problem happens in 20 to 40% of cats with cardiomyopathy and the bigger the left atrium is the more likely we are going to get a clot in the left atrium and then it breaks loose and goes down stream.

So, we can see them go anywhere but the majority of times they go to a back leg. If it goes to a front leg they are dragging their front leg. They cannot use it. If it is both back legs they cannot walk at all. It is kind of often a major crisis event because no cat has told anybody that they have a heart problem. They are just walking around being normal cats, doing what they are supposed to do and then you come home from the grocery store and they are crying and they cannot use their back legs and they are pulling themselves along with their front legs. It is kind of a catastrophe when that happens. They can go to other places in the body but this is the one we tend to see most often. So there is the aorta, there is the big left atrium. That is a clot that is floating around inside the left atrium and that is about ready to break loose and go down stream. You can also see a little bit of the smoke in there. That is a scary thing when we see that because we know this is a cat that is about ready to throw a big clot and that it might not survive that. Again as we said there are a lot of cats with arterial embolisms who that is the end of the game. They get a clot in their back legs and people say it is a bad deal, you should quit.

Let’s talk a little bit about other forms of heart muscle disease.

Dilated cardiomyopathy, the cavity is dilated and the heart does not contract well. What you have in mind is that is a big cavity, the walls are thin and it just does not squeeze down very well. The contractile function is markedly reduced with dilated cardiomyopathy. Again this is one of the ones that was previously studied. Again taurine deficiency was identified to be a cause and as a result of figuring out that the diets were a little too low on taurine in part from I think Winn Foundation funds, this disease went from equal frequency to hypertrophic cardiomyopathy to now where it is very uncommon. That is one of the ways where supporting research can help things because we basically almost wiped this disease off of the map through research activities.

Restrictive cardiomyopathy, you may or may not be able to see this kind of scar tissue in here with little clots attached to the inner surface. This is another form of cardiomyopathy which we probably do not need to spend too much time on.

We are used to getting blood tests, blood tests help us for certain things. They are really helpful for kidney disease. They are really helpful for like is there an anemia or not? So are blood tests helpful for cats that have heart disease?

Well some of the main tests that we do like a complete blood count or CBC or a chemistry profile, we tend not to see major abnormalities in cats. If fact some of the sickest cats have pretty normal blood tests. If cats are over 6 years of age we recommend getting a thyroid test because high thyroid function, hyperthyroidism can affect the heart and cause it to get a little thick. Certainly in the cats that look like they have reduced vigor of contraction we want to get blood taurine levels. If they have a really big right heart we want to check for heartworm disease. But there is this new test, this NT-proBNP test that looks kind of promising for what it might be able to do and this is one of those tests that we have been studying so I am going to talk about it just a little bit.

It turns out that if you have a cat and it has a murmur or an irregular heartbeat or somebody hears a gallop that extra third sound, but it does not have any signs yet. It is a healthy cat that is taken in to the vet and the vet says ‘Oh you cat has got a murmur.’ Then you have to try to decide, do I want to do the echo or not? The echo is like; I do not know what it is costing for you but three, four or five hundred dollars for an echo. Do you want to go ahead and do that or not? Well this test might help us because if this BNP is above 100 the chance there is significant heart disease is much more likely. Whereas, if this test is like 25, the chance you are going to get some sort of useful information from an echo is pretty low. That may be helpful there. The second spot where this test might be helpful is a lot of times when cats come in with shortness of breath it is hard to tell if have heart failure or if it has asthma or FIP or pneumonia or pyothorax or some other disease process and this test differentiates heart failure from the rest of those shortness of breath diseases. This test is available in people. If you go in to the hospital and you have shortness of breath or difficult breathing they will do this test and if it is real high they think you probably have heart failure and go down that diagnostic pathway and if it is low they will look at something else.

This test is now here and if we kind of look here and we say well how high is this level? Well in healthy cats it is pretty darn low. In those who have cardiomyopathy but they are not telling anybody about it, occult cardiomyopathy, it is kind of middle range and in those that have heart failure it is way up here. Hopefully this is going to turn into a bedside test so that people can get this answer really quickly. It is a pretty good test for trying to sort that out. It is right nine times out of ten and so it might give you a little bit of the wrong information one time out of ten but still it turns out that veterinarians, if they only have a history, physical exam and ECG (the electrocardiogram) and a chest x-ray, if they do not have an echo for shortness of breath – they are correct about 70% of the time. The test is better than the veterinarians are on their own.

So, could it be useful either in an asymptomatic cat that has a murmur or gallop and you are trying to decide should I do an echo? Then, you can do that test and try to decide whether to do an echo. In a cat with shortness of breath and you are trying to decide is it heart or lung disease, especially if the client is kind of on the fence as to whether they want to spend money or not or they do not want to do an echo. The BNP might then be helpful. That is where that new blood test might work.

We have talked about congestive heart failure, arterial embolism, syncope in the asymptomatic cat.

Let’s see what do we have loaded here next.

We have got these various diseases:
- Heart failure
- Clots (FATE)
- Fainting (syncope)
- The asymptomatic cat

Now we are going to think about what cardiac medications do we have available to try to manage these cats. So we have one FDA approved medication. From a perspective of what does the FDA say, yea the companies jump through the hoops and we are confident this works in cats. What medications do we have? We have one – furosemide also called Lasix which is a diuretic. If we take a peek at well what are the cardiac medications that we use with some frequency in cats it is actually a lot of them. I use these medications almost every month. We use furosemide, drugs called ACE inhibitors, pimobendan, nitrates and other diuretics. We use anticlotting drugs like aspirin, Plavix, clopidogrel and other heparins. We use drugs to try and control the fainting and even in asymptomatic cats we try to use some of these drugs. Then the question is well ‘How do we know to use these?’ Well as you already know there are not a lot of people that are plunking down giant amounts of money to study cats. We are kind of left on our own to figure out well what is the dose in dogs. What is the dose in people? Let’s figure out a dose that might work in cats and try and go from there. How many of these drugs have been reported in the literature to have been used in greater than 30 cats with heart disease?

Well, actually not very many of them and all that says is we gave this drug to 30 cats and this is how they tolerated it. It does not tell us anything about the effectiveness. So 30 cats are not a lot of cats, you know there are all sorts of fun reactions that can happen with drugs so we really do not know a lot about what are the best medications to treat cats. They can figure that out, you may have heard of a blinded, randomized placebo controlled trial which basically means you look at a drug versus a sugar pill and the owners are blinded and the investigators are blinded and once it is all done you get a feel for which one works better. Sometimes the drug works better and sometimes the sugar pill works better. So if we were to say well how many of these studies do we have, blinded, randomized control trials that we are confident that we know this drug works in cats with heart disease? None. There are no blinded, randomized control trials looking at cats with heart disease. That is where we are in the scheme of research and being able to answer, you know when you take your cat in to the veterinarian and they say you should give this drug or maybe this drug will work that is kind of where we are. We are not as far along as we would like.

If we get fluid in the lung, congestive heart failure; we have got a cat in the oxygen cage and we have got some chest x-rays that show a little fluid in the lungs. What might we use? We might use furosemide, Lasix which is a diuretic. We might use an ACE inhibitor like benazepril or enalapril. Everybody thinks furosemide works and a lot of people think ACE inhibitors are helpful. After that we kind of do not know which is the best way to go. So there are a couple other drugs we might use and certainly dietary modification because water, the body holds on to water by holding on to salt or sodium. We do not want to give them a high salt diet. Fish oil supplement might be helpful so you know that is kind of where we are at right now so we wanted to try to sort out well could pimobendan be useful to treat fluid accumulation in cats with cardiomyopathy. This is a drug that increases the vigor of contraction of the heart. It makes it a little bit easier for the heart to pump blood forward. We know in dogs that it improves survival time, in dogs that have heart failure and it results in improved clinical signs because somebody has paid to have these randomized blinded placebo controlled trials and/or comparative trials done. We do not really know very much about it in cats. So we went out with a couple of other places in this area, the Massachusetts Veterinary Referral Hospital and Angell Animal Medical Center and then Tufts and we put together all of the cats that we had treated with pimobendan which was 170 cats. They tended to be 11-year-old cats again mostly male, that is what we see. It is more often males that get heart failure and this is a reflection of just what we see in cats because a lot of you might be interested in a specific breeds but the majority of cats we see are domestic short hair and domestic long hair cats. They tend to be a little bigger than normal. About 40% of them had hypertrophic cardiomyopathy. A much smaller proportion had the dilated form of cardiomyopathy.

These are the medications they were already giving and then we looked at the addition of pimobendan. This is the dose we used. It seemed pretty safe. Pimobendan was only stopped by 5 of 170 owners. That actually seems pretty safe. That is not too bad. In two of those five cases the heart disease resolved and in one the owner could not afford the drug anymore, they stopped it for cost. In one they could not get the medication in to their cat so they stopped. We are all familiar with that game. It is amazing the owners deny they do it. Then one reason for stopping is they thought their cat was vocalizing and seemed agitated after getting the drug. So if we look at what is noted in the record for side effects, again only five cats had a side effect that might have been related to it. That vocalization and agitation was seen in two cats. One of them wanted to continue it because their cat felt better; then not wanting to eat, vomiting and constipation so not that many side effects so it seems promising from that. What we do not know is whether that actually translates into clinical benefit or not. We have greater comfort that this drug is safe but what we do not know is, is there a clear cut clinical benefit? Do they either live longer or do they feel better. The live longer, you can only sort that out with a randomized, blinded placebo controlled trial and the same sort of trial could also answer the question of do they have a better quality of life where there clinical signs improve.

We have one or two other studies with a couple other institutions especially the University of Pennsylvania trying to answer that question and it turns out that if you ask cat owners and dog owners the question of if you could have really good quality of life or a longer survival time, which would you pick? A lot of the owners say, like 90% say quality of life. They value quality of life over survival time. Then when we asked people, both dog and cat owners of animals with heart disease how much time would you trade, over 85% of those that would trade would trade at least six months of high quality time for improved survival time. So, this quality of life thing is another piece of the puzzle that is really hard to study but is highly valued by cat owners and so we need to be trying to sort that out.

We just published on a quality of life tool that we are hoping will be helpful to try and assess that. When we think about an active clot, you have got a cat and they walk in the door and they have a clot well potentially not a lot that we know of really works there. We can give oxygen. If they have fluid in their lungs we can treat that. We can warm them up a little bit. We want to give pain killers because these cats are often are very painful. Physical therapy might be helpful and then we can give anticlotting drugs. Drugs like heparin, Plavix, clopidogrel and aspirin. We can give drugs that try to break the clot apart although these drugs have not been proven to really result in any major benefit or we can go ahead and try and cut the clot out but these are cats with bad heart disease and they tend not to really tolerate the anesthesia. If we think about, you know a lot of people say well this sounds like a bad deal. How is this going to go?

For those that have back leg clots about 30 or 40% will walk again. So that means that over 50% of those cats are never going to walk again. It is a bad deal. For front leg clots over 90% of them will walk again and so I think a lot of veterinarians on the basis of well it is the back legs, only 30 or 40% of them walk again and we are not sure what treatment is the best thing and they are very painful when this happens and they might get another clot. A lot of people decide to quit. I am a fan of treating it at least for a couple of days. I think a lot of veterinarians would say it is time to quit when this happens. The question is a lot of cats are put to sleep in the first 24 hours, what happens to the cats that are not put to sleep in the first 24 hours. Most of the cats with a front leg clot regain function and there are three or four studies that looked at somewhere between 60 and 184 days tends to be the average survival time for the cats that are not put to sleep. Some cats may live for a very long time. We had one cat in that particular study that had three clots over a nine year period of time. Recent studies suggest that cats after they get a clot are more likely to die from fluid accumulation in the lungs than from another episode of a clot.

The more that we can get good at trying to figure out how to prevent this the more likely that we will be able to help cats. These are drugs for not when you actually have a clot but in cats that you think might be at risk of a clot that you might use it to try to prevent it. So aspirin is used, we do not know the dose, we do not know the right frequency. It is, you know there are some other issues with. There are low molecular weight heparins. We will talk about that. There is Plavix or clopidogrel which look kind of promising. Then Coumadin or warfarin which is really hard to use, I will not use it because I have made too many cats sick with it. We tend to initiate it in cats that have a pretty big left atrium or those that have a prior clot or those that have that smoke in their left atrium, that is when we tend to use it.

These low molecular weight heparins; dalteparin, Enoxaparin – they have a longer duration of action than the regular heparin formulation that we use in the clinic all the time. They are pretty safe; they do not need any monitoring. The two main down sides are they require subcutaneous injections twice a day. It is a volume that you might give that would be similar to that for diabetic cats so it is a really tiny volume but is still an injection twice a day and they are expensive to use on a long term basis. Probably 400 to 500 dollars a month for a really big cat, 300 to 350 for a small or medium sized cat so it is kind of expensive. This is though currently my preferred anticlotting drug and that is just based on anecdotal stuff.

Most people would say they like Plavix or clopidogrel which is an antiplatelet drug so platelets float around in the blood stream; they can glom together and form a clot which is different than interfering with protein which we were talking about with the previous one. Plavix is kind of expensive but in the last month we have got generics available and so the cost is going to be much lower at this point in time. The main side effects we see are foaming at the mouth in maybe 15 or 20% of cats where it tastes really bad and then sometimes you can hide it in a capsule or a liver toxicity. An increase or elevation of liver enzymes with increased bilirubin and they turn yellow. The few cats we have seen with that have had that go away when we stopped the Plavix. So this is my second choice for an anti-clotting drug.

Then there is that cat that does not have any outward clinical signs. We just do an echo and they have a really thick heart, is there anything we can do for them? Well a lot of people think if you can slow the heart rate and improve filling that would be useful and drugs like beta-blockers Atenolol or carvedilol are probably used most frequently and some people use diltiazem. Those would be drugs that would help keep the heart rate slow and might improve that outflow tract obstruction but cardiologists are highly variable in their approach to say who needs it and who does not need it. Some use those very early in disease and some do not use them at all.

How long will cats with cardiomyopathy live? The asymptomatic cats are often going to live from three to eight years from the time of diagnosis. Those that have heart failure the various studies have said somewhere between 92 days and 1½ years. I would say on balance if we can get them six months to a year that is very good. The fainting cats are much less common and flat cats again the studies are sort of showing a much shorter period of time once they have a clot.

Who should you screen for hypertrophic cardiomyopathy and how should you do it?

That would be a very interesting question to be debated. You could have 10 cardiologists up here all with a different opinion. In my mind if you have a cat with a heart murmur or a gallop they may be hiding heart disease. That would be a cat that I would try to figure out if it has significant heart disease or not because the first sign of a problem is usually going to be a crisis event where they either have heart failure or a clot so if you find it earlier you can maybe do something about it. Cats with irregular heart rhythms, cats that have unexplained respiratory difficulties or a related cat has heart disease. Probably about half of the cats we have are you know in the same household and they have the two brothers or the brother and the sister. About half of the brothers or sisters that we see have heart disease when we have diagnosed heart failure in one of their other cats. Then sometimes people just like to know, ‘My breed is disposed for cardiomyopathy, do they have it?’ That might be a good enough reason to look.

How to do it; well the dogs are checked for shortness of breath and then in cats that does not work very well. You know how do we do the screening? We do the screening with echo. Maybe that anti-proBNP will play a role. Certainly listening is helpful but you know a solid 30 or 40% of cats have no murmur or gallop when they have big time disease so just an exam by a veterinarian is not going to do it because you are going to miss a whole bunch of cats that have significant heart disease. Cat disease is hard, it is not easy and those are some of the tools of the trade and I think we are learning more every year in part from various places that support the interest in cats like the Winn Feline foundation.

I was asked to maybe mention two of the things that they are supporting and we have in fact been studying. One of the things we are looking at is that pimobendan drug that we talked about for heart failure. We have seen a couple of cats with kidney disease and heart disease that seem to do better and their kidney values actually dropped a little bit. We are trying to do a study now to see if there is anything there. What I do not want you to do is start giving pimobendan to cats with kidney disease though because we are not anywhere near that. No place close to that.

The other thing we are looking at is a treatment for cats that have active clot. It is called bosentan which is a new drug that is very expensive, like ridiculously expensive $1000 a dose or more and it seems to help in people that have high pressures in their blood vessels to their lungs and we think there might be a chance that this could be helpful for cats that have clots and so we are starting a study to try and investigate that. You know those are just examples of us trying to get a little bit more information about it so that the rest of the veterinary world can hopefully learn from that and do a slightly better job.

That is all I have.

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Beginning of Question and Answer Audio

Steve Dale:
Thank you Dr. Rush. I have heard many cardiology talks and I think that was great because it all was in language we all could understand. Thank you again, thank you!

Now I have got these cards and Maurine, Maurine wave your arm! There she is! Please give her the cards, questions you have on the talk you have just heard and I am going to call our speakers back up here to answer some questions that I have that you have asked. If you would like to add more it does not have to be on a card. If you cannot find one scribble on a piece of paper and give one to Maurine. I think the best thing is for both of you to stand to my left so people can see you and share maybe the microphone back and forth.

The first one as the dance together is Leslie Lyons. Do you have any FIP updates?

Oh yes, you know what? No matter where we go the subject could be ‘Why do cats inappropriately eliminate?’ The subject could be bungee cord jumping and people always ask about FIP.

Dr. Leslie Lyons:
Yea always a talk that starts off with silver and FIP and just be done with it.

So Dr. Peterson is very jazzed. He too has learned how to use DNA arrays so it has been very fun working back and forth. He is always trying to steal my Italian and, you know, so she has been teaching their lab how to use the DNA arrays and so he has one of those Manhattan plots too. We started with Birman and because they seemed like they had a higher frequency or so. We want any samples of cats with FIP. Alright, because if you solve it in one breed you will automatically go look in another, just like the HCMs, once you find one mutation you will check all the other breeds also. So you have to have the samples to be able to know. You need unrelated cats too so there is a question up here about ‘Do you want samples from this Birman I have?’ Well yes because they can be used as controls for these studies as well. He has a Manhattan plot, he has several peaks. What you have to keep in mind is he is working on a very complex trait. It is not going to be a single gene that causes cats to have FIP. It is probably going to be more like a susceptibility resistance type part kind of like what HCM is. So, he has several peaks and he is looking at those and although he is retiring in January, he has already negotiated to keep his lab and a technician and he is not leaving until he finds something about FIP. So we are getting there.

Steve Dale:
Yea well when you said that at last year’s symposium the expression on his wife’s face.

Dr. Rush, and then I have some questions here. But I have my own question here about HCM because of my interest in this disease in cats. How many of you have had a cat or have sold a cat with HCM? I said it was common, there you go and you mentioned domestic short hair and long hair cats. This is not only a pedigreed cat issue. We talked about Dr. Peterson not retiring. You are younger [Yea]. This is going to happen sooner I hope. Do you really see and there is a question in here about this to so it is not only my question. Is there a medication perhaps on the horizon that if not you one of your colleagues may be working on and is the answer a medication or is it in genetics?

Easy huh!

Dr. John Rush:
The answer there is just really complex. There is clearly going to be genetic underpinnings. There are probably other genes that are inherited currently that are going to impact the expression of it so that might explain why some will get it bad and some do not get it or will get a mild form of the disease. I think our hope is that we will kind of find something that may alter it. I think it is going to be a disease that is with us for a long time and we are probably going to be able to palliate it. We will get better with figuring out which medications help but I would be surprised if it went the way of dilated cardiomyopathy. I would be surprised if that happened.

Steve Dale:
But we need all of you to help and if everyone here, $20. I am just naming a number and then some of the people you know and spread the word about it. I think anyway we can really make a difference. You mentioned the proBNP test. The question is, ‘Is that widely available at veterinary offices?’

Dr. John Rush:
The anti-proBNP test is available for dogs and cats through one of the companies, one of the ones that I consulted with to try to look at this test. It is available through IDEXX which is one of the main companies that does laboratory testing. There is a dog BNP test that is available through AMTAC which is one of the other major laboratories and so those are the two that are available to my knowledge. AMTAC does not yet have a cat BNP so if you wanted to do BNPs in cats it would have to be IDEXX at this stage.

Steve Dale:
Are you sure, Leslie Lyons, that heterozygous cats with a Burmese head fault gene are asymptomatic? In American short hairs this does not seem to be the case.

Dr. Leslie Lyons:
Yea exactly, that is something that we will discuss at the breed council meeting tomorrow is that cats that have one copy of the mutation have a fairly brachiocephalic face. They still are the cats that are going to have cherry eye issues and dermoids and issues like that. So maintaining that mutation still might not necessarily be the best idea so they are not going to have the severe craniofacial defect but they still have some other problems that we kind of want to strongly consider getting rid of.

Steve Dale:
Should we as Maine coon breeders do both, and this is a great question, the genetic test, which by the way the Winn Feline Foundation supported funding for, and the echocardiogram or just the echo.

Dr. John Rush:
And/or BNP to decide if they are going to do the echo or not.

Steve Dale:
Explain what you mean by that.

Dr. John Rush:
Yea so to me that is a really hard question to know the answer to because the genetic test if it comes back positive it probably tells you that there is a much greater likelihood that cat might develop hypertrophic cardiomyopathy in the future. It does not tell you in absolute certainty. The homozygotes are probably going to get hypertrophic cardiomyopathy, but the ones that carry just one of the two genes they may or may not get hypertrophic cardiomyopathy. But, if we tell you that you need to be more vigilant than someone who has the negative test, I think that is helpful. I think probably I would have to defer to Dr. Meurs, I have heard her lecture a couple of times on breeding suggestions and that is also a nuanced thing as to who you should breed and not breed because she is very worried that if you pull 33% of the cats out of the breeding population that that is not a good plan either so you know if the test is positive and they got bad disease at an early age that is one that you want to pull out of the breeding pool but just because it tested positive maybe not. So then you have a cat that has a positive gene test, then because this disease goes from a normal echo to mildly abnormal echo to very abnormal echo during the course of the cat’s life do you test every year? Do you test every other year? Should you do that testing by an echo, should you do that testing by BNP and only do the echo if the BNP is high? Those are difficult questions to answer. Some people are advocating once a year echoing is that over kill? Well maybe but…

Steve Dale:
Yea, I have a Devon rex and I can relate to that. Where are you, you Leslie Lyons? Where are you in identifying a gene for mutating the enteric corona virus and FIP?

Dr. Leslie Lyons:
Well that is something I am personally not looking at so that is where we are with FIP is pretty much Dr. Peterson who is studying that. He is approaching it more from the particular cat point of view. So when cats get FIP they have it. Most all cats have enteric corona viruses. At some point one gets a very high proliferation of this virus and it tends to mutate and then some cats cannot deal with that and they get FIP. So you have to consider both the virus but also the genetics of the host as well. So Dr. Peterson is approaching it from the point of view of the genetics of the host trying to find a gene that might fight it off for cats in that it may either keeps their enteric corona virus levels down or when you get a mutated versions actually deals with that and the cats do not get FIP. There is probably going to be different genes along the way that will help with different aspects.

Steve Dale:
Thank you. Dr. Rush, it says here ‘When is it exactly that you are going to go bungee cord jumping?’ No that is not what it says at all. What a zapper, I am with you!

What is the role of EKG in diagnosing HCM?

Dr. John Rush:
The EKG we did not talk very much about, the EKG or an electrocardiogram measures the electrical activity of the heart. In order to get the upper chambers to contract first and prime the lower chambers that has to be done in a coordinated electrical activity and the EKG records that and some cats with heart disease have irregular heartbeats. They have premature beats or have fibrillation waves and that is one of the things that can lead to fainting. In a cat, who after listening the veterinarian identifies an irregular heart rhythm that for sure is the situation where an EKG is helpful. In a cat that has had an episode of fainting the EKG is helpful. I think from a routine diagnostic standpoint in every single cat it is not clear to me that an EKG is all that helpful.

Steve Dale:
Okay, ‘Can I help,’ it says here for Lesley Lyons, ‘with the Orange gene studies?’ There a study of renal amyloidosis?

Dr. Leslie Lyons:
Yea, you know any time samples get sent to the lab we will search through our data base and try to figure out which ones might be good controls for this or that or other various different projects. People that just give – when I walk around at cat shows and collect samples you never know they might already be in an Orange project or controls for something or things like that. So with amyloidosis, yes there is a study to start, well I have a colleague that very much wants to study amyloidosis whether it is in abyssinians or also siamese. Abyssinians tend to have more renal effects of amyloidosis whereas siamese or Orientals tend to have more hepatic involvement of amyloidosis. Yes we very much want to study those diseases. Very actively we want to try to collect those samples so if you have a cat that does not have amyloidosis please send that sample in as well. When I say a good buccal swab that means you know get the Q-tip up between and underneath the whisker pad and roll that around good. Do both ends of the Q-tip. We sometimes get people who send in something and they did not do both ends so how do you know which end they did? Right? Send in a couple buccal swabs, you know several investigators still want blood samples. That is because they do a lot of different things, they are searching a lot of different genes and so yes the buccal swabs can be good. Blood samples are still always better but I realize I am going to get more samples by taking buccal swabs. But they still have to be good ones and you know there is a lot of spit in there, keep rolling it around until something comes off.

Steve Dale:
When push comes to shove for hypertrophic cardiomyopathy does an early diagnosis really matter? I think that is a really good question I mean the cat is either going to have signs, and what you did not mention that maybe you could also talk about is cats percentage or some number of cats that are diagnosed with hypertrophic cardiomyopathy that die at 21 of something else.

Dr. John Rush:
Hypertrophic cardiomyopathy can be a really bad aggressive malignant disease or it can be relatively benign and we certainly see some cats that have murmurs and we do an echo – they have mild thickening of their heart and we echo a year later and it is about the same. We echo two years later and it is about the same and then they never have a problem with their heart. That is challenging and I think based on that the more advanced the disease is the more likely we want to try and start some treatment. The bigger the left atrium is the more likely it is that somebody is going to want to start either an anticlotting medication to try and prevent arterial embolism or something like an ACE inhibitor like benazepril or enalapril to try to delay the time until heart failure comes on and then we talk about that outflow tract obstruction and systolic anterior motion of the mitral valve, that is one of the things that often causes a really loud murmur. A lot of cardiologists feel that giving the beta blocker is helpful because if they give the beta blocker they may be able to make that outflow tract obstruction go away and in a subpopulation of cats the walls get a little bit thinner and then people think well if we have made the walls of the heart less thick we probably have helped this cat. What we do not actually know is just because the murmur is not as loud and the wall are not as thick whether that actually translates into a better survival or not. I am actually dubious, but I am probably the lone cardiologist on the planet who thinks that way. That is what the majority of cardiologist think, if there is a big time outflow tract obstruction, treat them with a beta blocker.

Yes to the degree that we are confident in any part of feline heart disease there are a lot of people that think if you have got moderate to marked disease in any symptomatic cat it is worthwhile giving some medicine.

Steve Dale:
But then could you be doing more harm than good?

Dr. John Rush:
Could it be doing more harm than good? I do not think so. My best assessment is not and I think the bigger the left atrium is the less likely it is that you are going to do any harm.

Steve Dale:
The lineage test that you were talking about: Is that available now? And, how do I find it?

Dr. Leslie Lyons:
Yes it is available now, now, now! You can go to the web site a UC Davis so it is www.vgl.ucdavis.edu. VGL stands for veterinary genetics laboratory. Any time we develop a test, we do it in a way that is very slow and expensive and then we publish a paper. Then we give all our control samples, all the genetic sequence and everything over to the service laboratory and they probably do actually a much better job than we do in the research lab of getting that through production fast with the extremely high quality of being accurate and correct. With this test, this test is more of a fun test too. Alright so we can kind of think about it that way. Only Davis is going to be able to offer it and so it is at Davis right now and it is mainly a fun test for your random breed cats but it can be useful to some of the breeds as well.

Steve Dale:
Might there be medical uses for that potentially as well?

Dr. Leslie Lyons:
Yeah. So medical uses, we would be careful with that, you know the dog test kind of gets toted that way and I want to be careful with that type of advertisement. If your cat truly is half persian or a quarter persian then I would say yes, then you might want to check that cat for polycystic kidney disease. So the genetic test with that ancestry test will first tell you race and then it will try to decipher whether you have high percentage of a breed. If you do not, you are not going to get a breed reported back. We are not going to force a breed to match because that is just incorrect. So if you force the breed to match then you are going to cause somebody have false worry about some genetic problems that might be in their breed. So we are trying to be very cautious with the advertisement for this test in that, that is not the main highlight that we want to use it for. It is a coffee table test, something fun. If you cat has come to the new world with Columbus, if you cat is you know, were they related to the Pharaohs or something like that. It is meant to be a fun test. But breeds can use it to some extent.

Steve Dale:
I think it is a lot of fun actually.

Dr. Leslie Lyons:
The website again is www.vgl.ucdavis.edu.

Steve Dale:
Do it one more time.

Dr. Leslie Lyons:
www.vgl.ucdavis.edu.

Steve Dale:
Thank you. This in my hand is the last question. How often do you see cats and this is kind of along answer that you mentioned before and I get this a ton too, which I asked cardiologists. How often do you see cats with stress murmurs, no echo abnormalities, what you tell the people?

Dr. John Rush:
Since we are given out website stuff, I’ll just give you mine as well. If you Google Tufts and heartsmart all one word, heartsmart, http://vet.tufts.edu/heartsmart/ we have some stuff. Probably there is less for cats because there is less known about cat than dogs but there is some dietary stuff there that may helpful to you as well as little bit information about the diseases. I guess the question is cats that have a murmur, especially a murmur that is more impressive when they are excited and they have a faster heart rate so you get a little release of adrenalin and that causes a murmur, some of those cats have significant heart disease and some of those cats have no significant heart disease. They just have a little bit of turbulent blood flow on the right side of their heart and that is really the whole problem and if you do an echo and the walls are not thick and there is a little bit turbulence in the heart, it is not really a big deal. The likelihood they will progress seems reasonably low but then if on exam at subsequent point in time now the murmur is more consistent, it is there all the time or it is louder or they have an irregular heartbeat or now there is a gallop then that would be cause for reevaluation. Because yes this is a disease where at 2 years of age the heart probably looked perfectly normal and by 5 years of age they got big time heart disease.

Steve Dale:
It is either, speaking of web sites, mycatsheart or yourcatsheart, http://www.yourcatsheart.com/. Do you know which one I am talking about? Okay. There is a website that is either mycatsheart or yourcatsheart.com but one of the two has tons of great information as well, which cardiologists have put together.

Isn’t this a great team we have for you today?

Steve Dale:
However, before we go.

Dr. Leslie Lyons:
Before we go, yeah. I would just like to point out on these research updates and I did not really highlight it enough in my talk. Yeah the Morris Animal Foundation donate money for these chips. That was really fantastic but the Winn Foundation and the AVMF pulled together and formed the Cat Health Network that is really what push researchers forward with doing these array studies and most of the that money really came from the Winn Foundation. So when you see on this research update, when you see fine mapping of sphinx HCM that means that Kate Meurs has a peak of Dubai alright. So that means that she has a candidate gene that she is perhaps looking at it. That still takes a while; you just have a peak so you have to look at a large region under there and maybe you have good candidate and maybe you do not so it is still going to take some time. But with the Winn Foundation funding these types projects that is really pushing these array studies over the edge and getting the results back into your hands. So we really have to appreciate the Winn Foundation for the work they have been doing.

Steve Dale:
Thank you, thank you and thank all of you. Thank you Dr. Rush. Thank you Dr. Lyons.

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