Hello, Anthony Chadwick from the webinar vet here. Welcoming you to our 3rd lecture, live lecture on association state. Amazing how many associations we've got involved, this time, at this conference, WVA WSAVA, BCVA, NZVA, BVA, AVS, BVDA, IVSA, RWAF, Abravec, ABCR, TTVA, SBS, ICVA, CVSS, Avazu, A L V E FAS, BVRA.

HKVA. Acom V and MC VMA. So, so pleased to have all of those associations working with us today, and I do hope that everybody's enjoying the session so far.

Do go and have a little look in the vet exhibition. We're really proud of what we've put together there to make it a more interactive experience for you. We do have some stands and and various goody bag.

Competitions that you can go into. I, I noticed there were some really nice prizes like Lipman stethoscopes. So do go in and have a little look at that.

And then at 4 o'clock when this finishes today, we will be inviting you to come to the networking, the vet or the nurse networking room, you can go into whichever room you want to. And we've got some really cool. Video software so you can actually video chat with each other as well.

So if you've got some friends you want to see, you can invite them in, and of course the rest of the conference continues tomorrow. We've recorded a lot of pre-record hours, so if you do want to have the whole experience of the conference and you haven't bought a ticket yet, there's still opportunities to do that via the website, so do go in and have a nose around the websites as well. So that is that we're very fortunate today to have Kieran Borgia, who's gonna be speaking about a rational approach to using cardiac therapeutics.

Kieran has worked in first opinion and emergency. And then he decides to undertake a residency in cardiology. He's an American and European diplomat.

He's got a particular interest in interventional surgery and feline cardiomyopathy, of which he's already spoken about at the conference. He's spoken internationally on feline cardiology, but he still finds tabletting his own geriatric cat a challenge, and don't we all? So Kieran, it's over to you.

Thanks very much, Anthony, and thank you to all the associations and all the sponsors who've been involved in in getting today to go ahead and and the whole congress. It's it's a real honour to be a part of things. So we're gonna talk about a rational approach to.

Prescribing cardiac therapeutics, when to treat, why we're treating, what we're treating. We're gonna cover a lot of basics, and I don't mean to come across in a sort of patronising manner here. Many of you are gonna be familiar with or at least have come across the things we're talking about before, but what my aim is, is to try and update you on what we consider the best practise to be, and, how to kind of prioritise some of your decisions that you'll need to make along the way.

Cardiology and treating heart failure is not just an exercise in polypharmacy in that we just don't prescribe everything in one poly pill, if you like, and there are times when we give things and times when we don't. So, things that we're gonna cover today, we're gonna consider pathophysiology of heart failure, and we're gonna focus on mitral valve disease, and the reason we're gonna focus on that is it makes up 85% of all the heart disease that you're gonna see in primary care practise, wherever you are in the world. It seems to be the commonest disease.

If you're located in Asia, especially Southeast Asia, there is a huge amount of mitral valve disease, because many of the dogs that are owned in that area of the world are smaller breed dogs, and smaller breed dogs are predisposed. . We're gonna identify at which point treatment benefits dogs with mitral valve disease.

I'm gonna just mention DCM. I don't even think I've put it in the slides, but we're gonna talk a little bit about it as a comparator cos it's very different and actually it's much more challenging to identify disease early. And then we're gonna take the mitral valve disease situation and we're gonna contrast that with cats, and then how to treat cardiomyopathy in cats because they are very different and our approach is very different, and we're gonna think a little bit about why that might be the case.

Things we will not cover. I, I'm hoping I don't see numbers of participants drop massively on this slide, because anyone who's here to to talk about refractory heart failure cases, I'm happy to take some questions on it, either here or via social media is absolutely fine. But I, I haven't put it in the lecture because we, we've got 45, 50 minutes, and if we want to cover a fracturey heart failure, we're gonna have to have another 30 minutes on top of that.

If we want to cover antiarrhythmics, give me your afternoon, and I can help you with that. Pulmonary hyper. Attention will take us up to tea time tonight.

And if we want to talk about congenital heart disease as well, that's a whole another thing. And actually, we have got a pre-recorded session, as part of the congress on congenital heart disease, and interventional cardiac surgery. So any of you who are interested in congenital heart disease, how we might make decisions about that and what surgeries we can do, there is a separate webinar for that, that, I would encourage you to watch, because, not that I'm especially brilliant presenting it, but just that there's some really pretty pictures to look at along the way.

So a lot of this stuff is witchcraft, especially antiarrhythmics, and refractory heart failure cases. There's a bit of science, but there's not much science, OK? So it's quite important with with these more advanced cases, if you're not confident with them or not very experienced with them, or the dog's just doing something that.

It doesn't normally do when you manage these cases. Speak to a cardiologist. Most cardiologists are happy to give telephone or email advice about cases.

And this witchcraft, you know, is where really the science drops away, and we have experience and, and, and, people's own, opinions coming into the matter. So we're gonna think initially about congestive heart failure. I'm highlighting the word congestive here.

I will say heart failure as a term throughout, but what I mean is congestive heart failure. So what are clinical signs of congestive heart failure? Well, it's fluid accumulation.

That's how we define heart failure in docs. If you are a human, and I am a human, then we would define CHF as chronic heart failure. And the problem with this is it's not always fluid accumulation that's present when a human is diagnosed with CHF.

So chronic heart failure is a sign of exertion or fatigue. So if, humans with, say, a cardiomyopathy, develop a little bit of, a little bit of tightening in the chest when they exercise, and when they go upstairs, they feel a bit short of breath, they'll be called CHF, chronic heart failure. They may not have pulmonary edoema or ascites or pleural fluid or whatever but these, these are the typical signs that we see in our patients when they've got fluid accumulation.

So pulmonary edoema is caused by left-sided heart failure where predominantly we have left-sided heart disease. That's the vast majority of our patients, mitral bowel disease, DCM HCM and other feline cardiomyopathies. We see tachynia, we see dyspnea, so difficulty breathing, fast breathing in, patients with pulmonary edoema.

These are the cardinal signs. Coughing is still a little controversial. Luca Ferriston is a cardiologist who's done a lot of discussion and sort of publicity around cough, and he really has, has taught us, by, you know, some research that he's undertaken, but also by teaching us about human literature, Luca has has shown us that cough is not a cardinal sign of pulmon edoema.

There are the occasional dog that we see where on radiographs they have pulmonary edoema and they're coughing, and we say, oh well, they must have respiratory disease causing a cough and pulmonary edoema caused by heart failure. And we treat the pulmonary edoema and the cough improves or goes away. So sometimes we see coughing in patients where we may not expect it, where they, the, the cardiac problem may be the only issue.

Certainly cardiomegaly can compress airways and trigger cough receptors, and certainly increases in in a. Pressure and pulmonary venous pressure may also trigger cough receptors. So some patients we see coughing, the point of this really is for me to say, don't increase diuretics in a patient who is coughing but has a normal respiratory rate.

OK. So cough is not the cardinal sign, respirate should trump that every time. On physical examination, we might find loud adventitious sounds or pulmonary crackles suggestive of pulmonary edoema.

It's worth mentioning hand in hand with pulmonary edoema, that most cats who develop left sided heart failure will also have some degree of pleural effusion. Now in cats we've got a slightly different anatomic situation, we've also got the the fact that cats will often develop bilateral heart failure right. And left-sided heart failure, because of the way their pulmonary vessels react to having increased pressure in them.

So dogs will often do left-sided heart failure, and then some months or, or, or years later may even go into right-sided heart failure because of changes to the pulmonary blood vessels. Cats will do it after hours or days. So cats will often present with, with pulmonary edoema and pleural fluid.

And if you have a pleural diffusion, we'll have du dull lung sounds ventrally and also maybe dullness on percussion of the thorax as well. Of course, the true, the same is true in dogs with pleurofusion, but the pleural effusion won't be caused by left cellular heart disease in a dog. Ascites is the cardinal sign of right-sided failure, so here we've got abdominal distension and a fluid thrill, on abdominal belotment of the abdomen.

That often will again go hand in hand with pleural effusion in the worst cases. Now, another thing to look out for in patients with right-sided heart failure who have ascites is something called the the the positive hepatojugular reflux or jugular distention. And this is something that I used to forget all the time and I, I would kick myself out, you know, my, my supervisors during my residency would say, have you looked at the jugular?

It's like, oh. I've forgotten to look at the jugulars again, I'll look now. So try and get yourself into the habit of looking at the jugular veins.

It's super useful because if we have got ascites caused by the heart, so we've got right sided heart failure causing peritoneal effusion, what happens is you may have distension of the jugular veins because the pressure in the right atrium which is driving that ascites will also cause pressure waves or or pressure distension of the jugular veins. It's not always the case that they're distended at rest, if you like, but have a look at them, and they should be, they should not be easily visible in a dog who's standing up. If they're lying on their side, you will see them because they'll be the same height as the heart.

But if they're standing up, you shouldn't see them much beyond the thoracic inlet. So I tend to try and raise them, let them down to see them, and you may be able to do that without clipping, but obviously in some dogs you may need to clip the hair to identify that. So I raise the vein, drop the vein, so I can see where it is, and then I, I let it be, and I see if it looks distended, and if there's any pressure waves, any pulsation in that jugular vein, when you're not raising it.

Now, if the jugular looks normal, you need to then get an assistant. So here I have a lot of students around who can help me, but also, another clinician who can help or a nurse. If they can just put some pressure on the abdomen.

So by that, what we're doing is we're lifting up the abdomen and causing an increased pressure in the liver, which increases pressure in the corral in the cava. The pressure wave then in a normal heart would go into the atrium and the heart has got such good compliance it can just take that increase in pressure by squeezing the liver and get rid of it. You won't see that pressure wave come from the caudal vena cava into the cranial vena cava and jugular veins.

If someone palpates the abdomen, pushes on the liver, and you see the jugular vein distend, that is patinnemonic for right-sided heart failure. It's true also in pericardial effusions, so I think they can be quite difficult to diagnose. I sometimes see dogs who've been diagnosed with heart failure after an ex lap, or diagnosed with pericardial effusion, during the middle of an abdominal ultrasound scan.

And actually if you do a good physical exam with the jugular inclusion there, you can differentiate whether the ascites is caused by heart disease or non-cardiac causes, such as, hepatic disorders or pre-hepatic disorders. So how do we define congestive heart failure? Well, I've said it's clinical signs caused by fluid accumulation, pulmonary edoema, and pleural effusion, ascites.

You know, we've all seen cavaliers with pulmonary edoema. We've all seen cats with pleural fluid, and, and pulmonary edoema. We know what these patients look like when they come into the clinic.

How do we confirm our diagnosis, that we've had on clinical exam and history? Well, radiography is the best way of looking at the lung fields. An echo is OK.

It's pretty good in cats for looking at the lungs, but ultrasound is not that accurate in dogs to detect cardiogenic pulmonary edoema. So radiographs are an incredibly useful tool for us. So we can look for the sort of holy trinity, if you like, the key three things on a radiograph to diagnose left sided heart failure, which is cardiomegaly, particularly left atrial dilation, pulmonary venous distention, particularly, you know, cranial and caudal lobar vessels, and also interstitial or alveolar infiltrates.

Bronchial patterns may cause respiratory signs, but they show airway disease. Bronchial patterns do not indicate pulmonary edoema. But sometimes we get this kind of zebra that walks along, not the common horses we see every day, but the zebra, which is the peribronchial alveola infiltrates.

And I've been fooled by those before, where you see the alveoli infiltrates around really obvious bronchi in the middle. And I thought, hm, looks a bit like respiratory disease to me. But it's a Doberman with tachypnia, dyspnea, a little bit of cough and a big heart.

So we treat what's most likely based on the clinical picture and those infiltrates go away. So we can get perironchial patterns, and they can be quite hard to know if they're respiratory or cardiac. So in that scenario, put it into context with the rest of your patients, your physical exam, your history, your other imaging findings.

Let's look at some radiographs. This is a normal dog. This is a Labrador, I think.

The reason I say that is the breed is quite important because that tells you a bit about thoracic conformation. And we all know that dogs who've got a short, wide chest like the bulldog breeds, they have a heart that looks big. They have a large vertebra heart scale, and they are dogs we.

Very easy to diagnose cardiomegaly. Spaniels are similar actually. Cocker spaniels are similar.

If we have a tall, thin chest like a Weimaraner or a Dalmatian or a Doberman, their heart should measure quite small on things like vertebral heart scale. So the Labrador is somewhere in the middle. This is kind of an average dog, and the upper limit of normal, for the tebral heart scale should be somewhere around about 10.5 or 11.

Here we can see, I'm just gonna put my laser pointer on, so you should be able to see that clearly. We've got the cardiac silt in the centre here, we've got the coralvena cava there, we've got the aorta coming arching up out of the heart. We've got the trachea here bifurcating into mainstone bronchi, and here we've got cranial lobar vessels.

So we've got the artery and the vein, in the middle we've got the bronchus. And we can see in the lung fields, we can see nice clear thready vessels, we can clearly see the crawa of the diaphragm separated, that means this is the left lateral, if they're overlying it's the right lateral. And we can see also around the bony structures here, we've got a little bit of change to the bone, which suggests this is an aged dog.

This is not a young dog. So this is a normal looking Labrador. This is not a normal dog.

This is a Doberman, actually, who has pulmonary edoema. So, can we see Cardiomegaly? Well, if we were to measure this heart, which we're gonna do in just a moment, this is a big heart for a Doberman.

If you look at the DV, that's a really useful view for identifying cardiogaly in a quick and easy way. So the He should be no wider than 2/3 the thoracic width at its widest point, at the widest point of the cardiac celerate. And here we can see it's maybe 3/4 of the thoracic width at this point.

So we can clearly see this is a big heart. In this view here in the lateral view, we can see in the position of the left atrium, which is the sort of cordo dorsal aspect of the cardiac silhouette. We can see a bump here, so this drug has a big left atrium.

If you draw a line between the carina, so the bifurcation of the trachea, and the margin of the, the, the dorsal margin of the corral vena cava where it touches the heart, so from here. To here, there should be none of the cardiac silhouette above that line. And we can see there is.

So this dog has a big atrium, the only structure that will be is the left atrium. I think we can see that the lungs look fluffy, don't they? They look sort of like there's an alveolar pattern here.

There are some bronchogras. And amongst you may spot that we've got the artery, the bronchus, the vein, and the vein here is wider than the artery, and also the caudal lobar vessels over here, the vein is wider than the arteries. So that tells us we've got cardiomegaly, increased venous pressures which link the left atriumum to the lungs, and in the lungs we have got some alveolar edoema.

So this is typical for congestive heart failure. This is a normal cat. So cats have a different thoracic shape.

You can see it's like a funnel, isn't it? And we've got these longer vertebrae in the spine which tell us it's a cat, and the bone density is a little bit different as well. Here we can see the cardiac so that in the middle, we can see the cordal vena cava, coming in a bit, bit longer than in dogs coming back up to the diaphragm, a bit more of a gap between the heart and the diaphragmatic cora.

We can see the aorta arching out and up along the spine here in the cat. We can see this nice pattern. Of blood vessels over the lungs in the cao dorsal area of the lung fields.

I often think this looks like a leaf, sort of the veins on a leaf going back up here. And I want to see though that leaf nice and clearly. If I can't see it clearly, or if I can't see the coral vena cava clearly, it suggests there's some pulmonary infiltrates, so there's some fluid in the lungs.

If we want to look for the cranial lobar vessels, we can see them here. We've got artery, bronchus in the middle, and vein. And in cats, they're smaller than the ribs, they're very thready looking and normal cats.

This is not a normal cat. This is a cat with heart failure. So here we can see in the lateral and the dorsoventral projections we've got cardiomegaly.

Again, that 2/3 width of the thorax rule applies. You can see that the margins of the cardiacilt here are quite challenging to identify on the right side because we've got a very dense lung pattern, which is much denser looking than maybe in the lateral we we might appreciate. Although cordo dorsal in the lateral, that's quite dense lung pattern here, and this is a mix of interstitial and alveolar pattern.

How do I know it's alveola? Well, I can't see the blood vessels. I can't see the leaf, I can't see the cordal vena cava, so it has to be fluid in the alveoli, facing the blood vessels, by which I mean the fluid in the alveoli, makes the the normal contrast you see between the wall of a blood vessel which contains fluid and the alveoli, which contain air, there's normally a big contrast boundary.

So you very clearly see a vessel. Here we've got fluid that effaces that border. So if you lose the vessels, that's an alveolar pattern.

Here we can see the cardiac cell and I think we can probably reliably trace it around here in the DV. So this heart looks quite rounded looking, but also it occupies more than 2/3 the thoracic width, which is typical for cardiogaly. Look at the, the stomach, there's air in the stomach this cat's definitely dyspneic.

This is a radiograph that I didn't take, and there's a couple of things that tell you that. First of all, I wouldn't take a radiograph of a cat who's this dyspneic. I would always use ultrasound to make that assessment in cats.

The second thing is this cat is anaesthetized and intubated, so you can see there's a tube here, an endotracheal tube. I, I think we can make this diagnosis without having to anaesthetize these patients. I, I'm, I'm not wishing to appear critical.

The decisions are made, they made a diagnosis, they treated the cat, catdiff very well. But it's not how I would approach it. And I'm just clarifying that, because if any of you have seen me speak before, you will know that I, I really am not very keen on taking lateral radiographs of dyspneic patients, if it can possibly be avoided.

I, I can't remember the specifics of this case, but maybe this cat was, was just too stressed and too aggressive, or they were just too worried and they said, you know, we just have to intubate it and ventilate the cat while we're doing that, we'll get some radiographs. So that's possibly why we have these images here. So we've got radiographic diagnoses of left-sided heart failure.

Ultrasonographic diagnoses are important, and I think in the acute patient, more useful in cats than radiographs are. So if we do a thoracic ultrasound in a in a tachyne called dyspneic patient, we may see pleural fluid, that will give us a diagnosis of of why there's respiratory compromise and allow us to proceed by draining some of that, either for diagnostic purposes or most commonly for therapeutic purposes to stabilise the patient. If we've got beelines on lung ultrasound, and I'm not going to go down the road of talking much about thoracic ultrasound.

There's lots of good resources out there. Look for review articles by Greg Leandro, and also, some research by Jess Ward, because that, that they're the group at North Carolina State who have done a lot of this, this work in lung ultrasound in dogs and in cats, and they're producing a very beautiful body of work on lung ultrasound to identify heart failure in dogs and cats, and ident Fight other diseases as well. And if you have bilateral beelines, on lung ultrasound, in cats with dyspnea, that's got a very high level of accuracy for suggesting cardiogenic edoema.

In dogs, it's probably about 50/50, maybe 60% of them have, cardiogenic edoema. In cats, it's more like 95% have cardiogenic edoema, so it's a very strong test in a cat and can be used in lieu of radiographs in an unstable patient. So, we're here to talk about treatment, not diagnosis, and I wanted to clarify a few things just so we're all on the same page and also just to get our head into gear thinking about heart failure.

So. Why do we get heart failure? This is a very fundamental thing to understand why we bother with treatment and where the treatment is acting.

Well, the trigger for congestive heart failure in all cases of heart failure is a reduction in cardiac output. OK, there's very rare. Things that cause a situation called high output heart failure, and we might see that with a PDA or some sort of AV malfunction, but that's very, very rare.

And, in most cases in practise, we've got a reduction in cardiac output triggering various processes which lead to the end result of heart failure. So, I've put the three common pathophysiologies here. We've got to the left mitral regurgitation.

This is mitral valve disease. You know, if you're into cardiology particularly, you might think about congenital disease like mitral dysplasia. It's the same pathophysiology as mitral valve disease.

Reduced contractility is in the centre there. This is what we see in dogs with dilated cardiomyopathy. It's also what we see in dogs with tachycardia induced cardiomyopathy.

So again with arrhythmias that are chronic, we can get changes to the heart which reduce contractility. We may see the same thing in patients with infarction, we may see the same thing in particular inflammatory diseases or toxicities. OK, so I'm not just talking about mitral bial disease and DCM and HCM here, I'm talking about.

Pretty much everything we see can come down to these 3 pathophysiologies. So reduced contractility is the second, reduced filling is the 3rd. If you imagine we reduce how much the heart can fill.

Well of course, what goes in is what comes out. So if we reduce the filling, we reduce the output, and that has a reduction in output in the same way as reduced contractility might, but the cause of it is different. So that would be typical for a cat with hypertrophic cardiomyopathy, or potentially it may contribute to the situation in, a dog with subbiotic stenosis that's bad enough to cause severe hypertrophy.

These 3 pathophysiologies are crucial because they all reduce forward flow. That is the starting point for heart failure. So actually, secret.

Cardiology is really easy. Because actually cardiology boils down to what happens when you get a reduction in cardiac output, and then you work backwards from that reduction to work out what's going on with the different diseases. So we would get a reduced forward flow.

How does the body sense that? What does the body do? Why, why do we end up in a situation with heart failure?

Well, there are various systems that are in place to help you live long enough to reproduce and pass on your genes. So evolution has created some systems that will keep you alive if you bleed or if you get so dehydrated that you've got a reduction in circulating volume. So.

We are not evolved to deal with acquired heart diseases that occur in middle age to old age. That's not why there's been evolutionary pressure to cause these things. And I know this sounds like I'm going off on a tangent.

But when I first came across these, I used to think, well, why, if these are such good mechanisms, why do they end up causing heart failure? And the answer is they're supposed to be switched off once your circulating volume is restored. So after you've replaced your blood volume that you've bled out after your fight with a bear, or once you've replaced your.

Fluid volume and your blood volume has normalised after your severe dehydration and gastroenteritis has resolved, these mechanisms will be switched off. In heart failure, the inciting cause is never switched off unless you undergo something like mitral valve repair or a heart transplant. Those are the only ways to turn these things off completely.

So we get a reduction in cardiac output within microseconds, the barrow reflex is triggered. The barrow receptors are located in the aortic bodies, the carotid bodies, and they sense a reduction in the stretch of the vessels, so a reduction in blood volume or or blood pressure. The response is to increase heart rate, increase contractility and vasoconstrict, because that's a vasovagal loop that occurs.

It happens in microseconds. This is what happens when you're standing up from tying your shoes. If you did not have this, you would fall over, perhaps die after tying your shoes, because you're a biped, and as a biped gravity is our enemy.

So, this reflex is used all the time in humans, so it's not meant for long term activation. The secondary reflex, in the sort of medium term in hours to days, is activation of the renin angiotensin aldosterone system, the RAS, and the RAS is something that again is meant to replace your blood volume, replace your circulating volume and be switched off, in, in, you know, days, if not a couple of weeks. The problem is that with longer term activation of the RAS, weeks, months, years, as happens in heart disease, we get significant changes to the heart, to the blood vessels, which contribute to a downward spiral of function in the heart, and this is called maladaptive neurohormonal remodelling, if you like, or or changes to the rash.

Let's walk it through. So we're thinking about the second by second basis here. This is the barrow reflex.

We've got a reduction in cardiac output. You get an unloading of the barrow receptors. These are stretch receptors, so they are stretched less and they fire less frequently.

So then this reduces the vagal tone that's going back up into your medulla oblong arter, and your medulla says, oh, bad news, chaps, there must be something dropping blood pressure. We've got to maintain the fusion of the brain. So what do we do?

OK, we'll increase the sympathetic drive. And what that does is increases heart rate, increases contractility and vasoconstricts. This is solely meant to preserve cerebral blood flow so that you don't faint and fall over an inconvenient time.

So vasoconstriction tachycardia and positive inotropy occurs. This maintains normal blood pressure, which keeps you alive, which is fantastic, and we're all a big fan of the barrier reflex. But it does increase myocardial work.

So even that push to increase heart rate and increased contractility and work against the, the, the increase in resistance to the blood vessels when they vasoconstrict, that increases myocardial work. In the short term, that is probably coped with OK. But in the long term, increasing myocardial work is not good if you have heart disease.

So now we're thinking about over the hours to weeks, so this is the, the RAS activation, this is a little more complicated, the renal angiotensin aldosterone system. So it's sensed, we have a drop in blood flow to the kidney. And this is sensed by the kidney actually via a slightly circuitous route, and the kidney monitors the sodium concentration of the distal convoluted tubule.

So the macular denser is is monitoring the composition of that filtrate which eventually becomes urine all the time. And it says, ho ho, we've got a drop in sodium concentration. Well, of course, the reason for that would be that we've got a drop in GFR which of course means we have a drop in blood pressure.

So here, the kidneys are saying, right, the brain's being perfused, but we're not being perfused, great. We need to help ourselves. So the kidneys.

Trigger the beginning of the renin angiotensin aldosterone system. So the renin is a hormone that's secreted by the juxttoglomerular cells, so next to the macular densa, and that converts angiotensinogen, which is an inert compound to angiotensin one. Angiotensin one, it does a little bit via some secondary receptors, but not very much of import.

Angiotensin 2, however, which is created by the conversion of angiotensin 1 to Angiotensin 2 by angiotensin converting enzyme, or ACE, Angiotensin 2 is one of the bad guys. If this was a cowboy film, this would be one of the black hat wearing bad dudes who's holding the the the bank to ransom, because Angiotensin 2 causes a lot of negative consequences. So, what do we do?

We want to preserve renal perfusion, so of course one of the first things that happens is vasoconstriction. So we get vasoconstriction, and particularly constriction of particular vessels within the region of the nephron to increase filtration pressure, at the glomerulus. But also generalised body wide vasoconstriction.

That will increase myocardial work, as we said a moment ago. We get sympathetic nervous system activation, so we get an increase in noradrenaline, norepinephrine, if you like, and this will increase contractility, increase heart rate, and remember, just like the barrow reflex, but being sustained more long term. It also causes release of ADH or vasopressin.

And ADH antidiuretic hormone, if you're British, will increase free water reabsorption in the collecting ducts, by the insertion of aquapo into two channels. All these. Words probably, you know, if you're not familiar with them day to day, they ring bells from vet school, don't they?

We always talk to our funnier students about this, and they're like, wow, I remember the words, from sometime in the past. And ADH is an important thing that increases free water reabsorption. Angiotensin 2 does something else, it causes aldosterone release.

And aldosterone will increase sodium and water reabsorption. And longer term will cause cardiac remodelling and fibrosis of blood vessels. So aldosterin is supposed to be a short term thing and by increasing sodium and water reabsorption, it will increase circulating volume, which maintains renal perfusion, and cerebral perfusion.

But also by causing fibrosis of blood vessels, it helps to maintain blood pressure without this sort of active vasoconstriction. So you can see how these things may be detrimental. So on the one hand, we increase our circulating volume, and therefore we maintain normal blood pressure, but on the other hand we increase cardiac work because we've got more blood to handle and more pressure in the blood vessels to act against.

And more chronically, this RAS activation is very detrimental. So the increases in angiotensin 2 and aldosterone cause ventricular fibrosis, a cardiac fibrosis and rigidity. He doesn't feel as well, heart doesn't pump as well.

We get an increase in cardiac chamber size. The barrow receptors are actually reset so that instead of working at a normal set point to maintain a normal blood pressure, what they do is they're reset higher, which is more efficient for the body long term, but it's not good because it means your blood pressure baseline rises. And alongside ventricular and cardiac fibrosis, we get vascular fibrosis which can cause changes to the pulmonary and the systemic blood vessels.

So again, it maintains normal blood pressure. It's OK, minute to minute, day to day, but long term it is detrimental to cardiac patients. So the RAS is not evolved for this, it's not meant for long term activation, nor the bar receptors.

So they, they deal with it as best they can, but they don't deal with it very well. So, where do the drugs fit in to all this pathophysiology? So let's think about the mechanism of action of the common cardiac drugs and see how we can slot them in to this diagram, this, this RAS diagram especially.

So here's the rash diagram again, I've taken the colours off to make it a little bit less confusing and imposing. So furosemide is the cardiac drug we all know and love the best and you love it if you're like me, because furosemide is the thing that improves your patient's welfare today. So I have a patient comes in with new onset heart failure, they feel breathless, they feel a bit like they're drowning, you know, it's not very nice, and potentially they require hospitalisation for that.

We give frozamide. That patient can be looking much better within 1 hour to 2 hours, you know, of the first dose of frozamide, so we can see a significant improvement in those cases. So frozamide will reduce your circulating volume.

So it counteracts the sodium water reabsorption of aldostera and of angiotensin2 of ADH by increasing your sodium excretion, or sorry, reducing your sodium reabsorption in the loop of. Henley. So this causes the urine to become less concentrated because wherever sodium goes, if you put more sodium into urine, more water will follow.

So we dilute the urine and pee out the circulating volume. Frizmide also has some beneficial effects on pulmonary fluid uptake. It also can help reduce any inequalities in ventilation perfusion in the lungs.

So it does some other stuff as well that helps. If you give it intravenously, it's quite a big veodilator. So that can help to reduce atrial pressure in the acute patient.

So if you give risemide IV you can get a vena dilation in about 20 minutes, and that will help stabilise the patient quite early on before it even has a diuretic effect. So rosemide IV is really good for the acute patients. Orally you don't get that same vena dilation, but it's less important because you're giving it orally, they're by definition more stable patients.

Pimerendin is another drug we use frequently in cardiac patients, especially dogs, and pierendin helps to just increase cardiac output. It's a positive inotrope, it's also an arterio dilator, so it reduces some of the vasoconstriction over here, which angiotensin 2 may be inducing, but it will help to increase cardiac output without increasing myocardial work. That's important because the heart's already failing, the last thing we want to do is make it work harder.

We've got the ACE inhibitors, it's pretty obvious where they act. They act on ACE angiotensin converting enzyme which lives in the pulmonary endothelium, and the ACE inhibitors will reduce the activity of ACE and therefore lead to more angiotensin 1, which doesn't do so much and less angiotensin 2, because the angiotensin 1 is not converted to angiotensin 2, and that's the big vasoactive compound. And finally we've got Spranolactone, which is a competitive antagonist at the receptor site to aldosterone.

So Spranolactone inhibits the effects of aldosterone, it does have a mild diuretic effect because it reduces that water reabsorption, but longer term it seems to be very beneficial in reducing cardiac remodelling and potentially fibrosis. So again, just to, to reiterate, in the chronic rash activation, we can see Pimabendin helps reduce chronic rash activation. ACE inhibitors fit in here, as do spronolactone, or as does spronolactone.

So when do we treat, what's the rationale behind the decision making in terms of timing? This is where we're gonna specify about mitral valve disease, because this is the best studied disease in dogs. It's the most common heart disease.

There's a huge amount of data out there in numerous studies, and there's also consensus amongst experts on how to treat it. You probably know as well as I do, if you get two specialists into the same room, you often don't get a straight answer. But here we've got a panel of experts who have come to a consensus on recommendations.

So this is a real rarity and something that I think should be, paid attention to. The other thing with natural bi disease is easy to identify because all these dogs have heart murmurs. So this is an echo of a dog with mitral valve disease, we can see we have the left atrium here, mitral valve in the middle, left ventricle, and the mitral valve looks sort of thickened and gnarled.

If we put the colour flow on, we see the green mosaic of turbulent flow. This is the jet of mitral regurgitation. And this is the left atrium.

Compared to the aorta. Many of you will know that the left atrium should not be more than 1.5 times the aortic size in dogs, and here we have a huge left atrium compared to the aorta.

It's probably 3, 3.5 times the aortic root size. So this is definitely a big left atrium, and we see the big left atrium occur before the onset of heart failure signs.

Cavalier King Charles spaniels are really affected by this disease. We see other breeds too, but Cavalier King Charles spaniels, just to give you an idea, have a 47 times increased risk of mitral valve disease compared to a non-pedigree dog. That's a shocker, isn't it?

Other breeds are at risk. The most at risk of the breed in the UK is the Chihuahua, which has got 6 times, risk compared to non-pedigree, and a whippet, which is almost 5 times the risk of non-pedigree. So mitral valve disease in cavaliers really, you know, is a big deal.

It's got a prevalence of 100% on pathology studies in dogs over 10. So not all dogs over 10 have a murmur, I acknowledge that, but the prevalence on path studies is about 100%. That's, that's madness.

It can be diagnosed in 1 or 2 year old dogs. I sometimes see it in in dogs who are who are 18 months or 2 years old. And the males get the disease younger or potentially more aggressively.

It seems more rapidly progressive in cavaliers and other breeds, and it's certainly much more prevalent. And we know that in cavaliers, but also other breeds, sudden death is relatively common. In one study by Melanie Hazell, one of my colleagues, about half of dogs with microbial disease drop dead, .

And that's something that may not be appreciated by most vets, because maybe they never hear the outcome of these individual cases. And probably this is caused by a full thickness endocardial tear, actually a rupture of the atrium caused by the severity of the mitral valve disease, or a ruptured cai tendon, causing a huge worsening in mitral regurgitation. Broader categories to define which drugs are at risk, 7 years old or greater, less than 20 kg in body weight, and they have an audible left apical systolic murmur.

This is based on large epidemiologic data. This is the consensus statement I talked about. It's from the end of 2019, and it's available freely online through the Journal of Veterinary Internal Medicine.

And this is a panel of experts on mitral valve disease. Between them there is little they don't know, that anyone else does. And they stage mitral valve disease on a four stage system, A, B, C, D.

OK, so A is at risk, B is where we have mitral valve disease and a mitral murmur, but no clinical signs. C is where we have overt clinical signs of congestive heart failure. And D is where we have refractory congestive heart failure defined by increasing diuretic dose.

Importantly, stage B is split up into the low risk and the high risk stage. So stage B1 and B2, and stage B2 is defined by particular parameters of cardiomegaly. It's the consensus recommendation, Stage A is monitor.

Stage A is just a cavalier that's been born and is walking down the street. You monitor for a moment, you don't start imaging all those dogs unless they're for breeding purposes. Stage B1, if we find we've got a dog with a mitral murmur and a normal heart size, we can just image them annually.

We don't need to worry about anything more intensive. Stage B2, we know these dogs benefit from pre-clinical treatment. Stage C, we've got clinical signs of heart failure and therefore diuretic treatment plus more is indicated to control these clinical signs and improve welfare.

And in stage D we intensify diuresis, we do slightly more complicated voodoo, to, to improve the quality of life in these patients that often involves intensifying the medication regime. What's the evidence behind the pre-clinical treatment? You probably have all heard of this.

There was a large multi-center trial called the EPIC trial, and my kids refer to everything as EPI. So I find it funny that, this is the EPIC trial. It was published back in 2016 now, so it's positively geriatric.

There were 360 dogs enrolled over 10 centres on three continents, that's a pretty good for a veterinary trial. And this is the largest study of pre-clinical disease ever. Including in humans.

So that's quite a big statement to make. It changed how we view mitral valve disease. So the epic study, which this is the reference for here again 2016 by.

The in the Journal of Internal Medicine, it's own access to read if you haven't read it, and they followed dogs to the onset of congestive heart failure. So this graph here looks at the two groups of dogs given Pimmoendin or placebo, and remember these dogs are all asymptomatic, but they do have cardiomegaly. You can see that over time there's steps down on this graph, and each step down is a dog either dying or going into heart failure, mostly was going into heart failure.

So you can see here that if you're in the blue group, you go into heart failure over less time than if you're in the green group. And that diverges pretty early on, and that difference between the groups lasts long term. Such that if these dogs were given immobendin, they lived on average 15 months longer than if they were given placebo.

That's quite difficult because average is, you know, half of dogs. Do better half of dogs do worse. So one way to think about it is that if a dog in stage B2 micro bowel disease is given Pimbendin, their risk of going into heart failure is 30% that of a dog who's not given Pimmoendin.

OK, so it's 1/3 of the risk, so that's quite an important statistic. The Epic trial is such a big trial that they've published 3 papers, so I, I call this the epic series, not that kind of epic series, nor that kind of epic series. But the 3 papers that came out of Epic, are quite important.

They're published every 2 years, and you know, it's almost like the authors have thought about this and plan. In advance. The first study was the one that we've talked about showing longer survival before the onset of heart failure, with Pimabundan.

The second was actually a validated quality of life score, was proven to be better in dogs on immo. So not only did they lived for longer before showing signs, they had a better quality of life and their hearts got smaller. And the third one wasn't really looking at emo versus placebo, it was looking at what predicted going to heart failure best, and they found the best predictor was something the owner can do for free at home, which is just wonderful, and that's monitor respiratory rate.

So we know from this series of papers that actually treating the pimabendan in stage B2 benefits quality of life and outcome. So identifying stage B2 is very important. We know that this improves survival, it improves quality of life, and it improves owner awareness, so they can monitor early and start diuretics earlier when they can when they need to.

So how do we identify stage B2? Well, radiographs. They are insensitive to early changes, but they're pretty good.

Vertebra heart score, greater than 11.5, is likely to indicate B2. And a vertebral left atrial size, a Vlas greater than or equal to 3 is likely to indicate B2.

So what do those things mean? Well, let's take this dog, this dog has got heart failure. Let's look at the vertebral heart size, we measure the long axis and the short axis of the heart like this, and we here we're getting a vertebral heart size of 11.5.

So that is indicative, or suggestive, strongly suggestive this dog is in B2, it's got a left atrial dilation. The problem with vertebra heart size is there's some compound error, taking two measurements, adding them together, if you get them both a bit wrong, you can end up being quite a big difference. But you can measure one measurement of vertebral left atrial size, which is measured from the bifurcation of the trachea here from the carina, to the dorsal margin of the corral vena cava where it intersects the heart.

I said anything above that line is the left atrium, there should be nothing above it, but if you measure the width, that quantifies it. And 3. Here we've got 2.8, cos I'm very honest, I'm telling you what I genuinely measured, but 3 suggests stage B2, so you know what, I'm, I'm gonna go with this dog being in B2 based on both the vertebral heart size and the VLAS.

So if we're using echo, we need left atrial dilation and left ventricular dilation. So the left atrium to aortic ratio should be 1.6 or greater, and the left ventricular internal diameter in diastole normalised for body weight cos obviously a big dog is different to a small dog, that should be greater than 1.7.

Looking at another study, this is a really useful thing. This is looking at murmur grade and which dogs with different grades of murmur would benefit from treatment. And actually if you look at the graph here, dogs with a low grade murmur grade 1 to 2, only 10% or less would benefit from treatment, so 10% or less were in stage B2 or C.

Grade 3 murmurs, it's more than half. Grade 4 is about 80%, and grade 5 or 6 murmurs is 95% would benefit from treatment. Now I'm not saying you just treat them based on the murmur, what I'm saying is if you've got a grade 3 murmur, that's very different to a grade 2 murmur.

So that means we're going to be much more likely to help a dog with a grade 3 murmur. So if you've got an asymptomatic murmur, if it's an older small breed dog, it's probably mitral valve disease, grade the murmur. If it's grade 3 or louder, recommend imaging.

If it is cardiomegaly, treat the pyabendant based on results of those epic trials or the epic series of papers. If there's no cardiogaly we just. Monitor them and monitor the imaging and if you do have a radiograph that can act as a baseline.

In stage C we treat with frozen mind. We can treat controlled dyspnea. So in the acute patient we can give it IV or IM.

IV has that advantage of renal dilation. And once they're chronic or or they're stable, if they come in and they're stable, we can just treat with oral stabilisation at home. And there's some nice data out there suggesting that a dose of 1 mg per gig twice a day in dogs has good diuretic effect.

We start somewhere between 1 and 2, and often we'll titrate that to the lowest effective dose based on owner monitored respiratory rate. What else do we do in stage C? Well, if they're not already on piendin, they should receive it.

We know that it causes big benefits in stage C mitral valve disease. We know from some invasive studies that actually reduces left atrial pressure. And we can use RAS inhibition.

So ACE inhibitors, papers from back in the 1990s show a benefit of an ACE inhibitor in canine heart failure, in addition to furosemide. And a paper from 2010 suggests that spronolactone may have a survival benefit. It's not an amazing paper, which is why I've not gone into.

On it, but it suggests that there is some benefit there from using spronolactone. So the consensus recommendation is that immobendin, ACE inhibitors, spronolactone, and frozamide should be first line therapy for dogs with stage C mitral valve disease. The same is true for DCM with overt clinical signs, and in DCM we also know that dogs benefit from pre-clinical pimaendin treatment.

It's just harder to identify the disease in those patients early on because less than half of them have a heart murmur. So they're much more challenging and therefore they're much, less comprehensively studied than dogs with mitral valve disease. But the same general rules are true if you identify the disease.

So just to summarise, this is where our drugs are working in heart failure. So when do we treat mitral biopsies? Well, in stage B2 we give himendin.

In stage C we give frozamide and immobendin. And if they can afford it or they tolerate the tabs, the tablets, spranolactone and an ACE inhibitor. We're going to quickly talk about kitty cats, cats versus dogs.

They are different. This guy that I saw just yesterday does not want you to consider him along with dogs. He is a separate species, and he will remind you of that as often as possible.

And for that reason, Virginia Lewis Fuentes and a bunch of other amazing feline cardiologists published a consensus statement at the beginning of 2020, looking at, classifying, diagnosing and managing cardiomyopathy in cats. Very similar to the mitral biel disease progression, we have an ABCD system and we have stage B divided into B1 and B2. So B2 is where we have left atrial dilation, therefore these are at risk.

The other main difference is that they can have clinical signs of heart failure or arterial thromboembolism to be classified as stage C. So what are the differences? Well, in cats, HCM is the most common myocardial disease, and that's a disease of filling, we know that.

Mitral valve disease or DCM in dogs is a disease of volume overload or output. So the end result is the same, but the pathophysiology is a little bit different. And cats also have a greater risk of thrombobolic complications than .

Dogs do. I, I think I've once seen a dog with an intra-attrial thrombus, and that dog didn't have mitral valve disease. It did have DCM and atrial fibrillation, and it was a huge dog to Bordeaux.

So I have seen those before in, in, in dogs, but they are super rare compared to cats, where we believe that probably 10% of cats with heart failure caused by HCM develop a thrombus. So in terms of response to drugs, there's some interesting data out there. Maybe 3 years ago I would have said to you there's a bit of an evidence vacuum in cats, but that's not the case anymore.

We know that most cats do not benefit from ACE inhibitors when they're in heart failure. We also know that spronolactone can be helpful, but there's not a strong proof of benefit. We know it's safe, but there's not a strong proof of survival benefit.

And Pima Bendon, based on a paper published just last week or the week before, is not useful for most cats with HCM. These are really important, research studies. So, this is a paper from a couple of years back now looking at Benazepril in cats with heart disease, and this is a prospective randomised, blinded, placebo controlled trial.

Wow, why wasn't there more made of this, I heard you say, because this is a rarity in veterinary medicine. Well, the answer is it's not a great trial. The inclusion criteria were slightly loose, so not all these cats were in heart failure.

It was a bit of a difficult paper to interpret. What we can say. This curve on the right here is slightly different to that survival curve.

Before in the previous curve, they dropped down when they died or or or or went into heart failure. Here, it steps up. This is like a mortality curve, if you like.

And you can see here that actually the two lines, the Benazapril and the placebo group, are very similar to one another. OK, so there's no significant difference in i.e.

Intensifying treatment, going into heart failure, dying. There may be a subpopulation of cats with cardiomyopathy who benefit from ACE inhibitors, but we don't know who those are based on this data, and what we can say is that most cats don't benefit. The size of cat study was looking at spronolactone in cats with heart failure.

Again, there were some problems here, the groups were not evenly matched, and it turned out the cats who were in the placebo group actually had much worse heart disease than the cats who were in spronolactone. So the study said, oh well, spronolactone actually improves survival. You can't say that because the spronolactone group had less bad heart disease and therefore they might have just lived longer anyway.

So there's some problems here, but it appears to be safe and well tolerated, and we don't know if it helps survival or not. Per Bend in this paper, as I say, is very recent, and we can see from the study curve here, there's no difference in the time to endpoint, in these cats. It's much smaller than the Pyendan studies in dogs, but we can see there's no difference in time to endpoint, and that suggests that pimerendin is not useful for the average cat with cardiomyopathy, with HCM, I should say.

However, look at this curve, the immin is the red line, and they seem to live longer and do better. This is a subpopulation of cats who don't have outflow tract obstruction. So probably there are a number of cats who do benefit from Pimabundan, but we need to echo them and make an assessment of their function before we know if that's gonna be a valuable treatment option or not.

Is the drug safe? It appears to be safe, yes. This is looking at clopidogrel.

Now we talked about thromboembolic embolic consequation consequences, excuse me, and clopidogrel is an antiplatelet drug which reduces the risk of thrombus formation in cats with cardiomyopathy. And here, again from the survival curve, we see one curve, the red curve, live longer before dying or getting another thrombus than cats who are on the blue curve, and the blue curve is aspirin and the red curve is clopidogrel. So we know clopidogrel is effective and it's better than aspirin in preventing ATE.

How does this come back to our cats? Well, we know that cats with a big atrium are at risk of thrombus formation, even without having had an ATE before and without having clinical signs of heart failure. So this is the B2 group, this is the pre-clinical group.

So we don't treat them the same as dogs with mitral valve disease, but we do treat them, we treat them with clopidogrel. Once they display clinical signs of heart failure, or ATE, we treat them with frozamide and clopidogrel. Frozamide only if it's heart failure, OK?

Now we may choose to treat the pumabendin, we may choose to treat the spronolactone depending on various factors, and that's where I think the expertise of someone with experience in feline cardiology comes in. We don't treat with ACE inhibitors, they're not beneficial to this group of cats. So, wrapping up key points, well, first of all, frozamide should only be prescribed in heart failure, it's not gonna help your asymptomatic patients, it might actually worsen the situation.

So it's important to be able to identify heart failure confidently using different imaging modalities. Staging mitral valve disease and feline cardiomyopathy is absolutely vital because you have to stage it to make a decision about what to do to help your patient. And that's reliant on combining our clinical findings, history, physical exam with cardiac imaging findings.

And the treatment for stage B2 and stage C is underpinned by good evidence now in both cats and dogs. Heendin is useful in stage B2 mitral valve disease and in stage C. It's not beneficial to all feline cardiomyopathy, maybe a subset.

ACE inhibitors are beneficial in stage C mitral valve disease, they're clinical signs of heart failure, and they don't seem to have the same benefit in cats, so they're a waste of a pill in a patient who may not be very compliant. Spronolactone is beneficial in dogs with stage C heart disease and the consensus panel recommends using it as part of first line treatment. We don't tend to use it first line in cats, again to minimise the number of pills that they are receiving.

And finally, clopidogrel is useful in cats with stage B2, cardiomyopathy and stage C, but there's no requirement for using clopidogrel therapy in dogs just because of species differences and differences in pathophysiology of disease. So thanks very much. I ran slightly longer than I intended, which may cut our time for questions a bit, and I apologise for that.

But I'm more than happy to take some questions now if we do have time or via social media, I'm available to to take questions on my Instagram account, which is at vet_cardo. There's no conflict of interest there because I don't make any money out of that at all. It's purely to share some fun pictures and some education.

So thank you very much for tuning in. And a great picture of John Lennon at the end as well, so yeah, I thought you'd like that. All good, all good.

Yeah, no, that's fine. So we've also got the Hoover app, Kieran, which I don't know if you have downloaded. But, people can go there.

But obviously vet cardio is also, it's well worth following, so do, do follow that as well. I've, I've just been, found my one of my editions of In practise, which was a whole edition on cardiology, in practise focus, sponsored by Siva. And of course, first article.

By somebody that we we all know quite well. Doctor, Doctor Borge, yes. If anybody er doesn't get in practise and would like this copy, just message me on LinkedIn with an address and I'll get it over to you so you can enjoy it as well.

I think we are tight on, on time, but if somebody's got one question, let's do one question, then we'll have to take that offline because we have, you'll have coming up just after, just on 12 o'clock to talk about dairy sheep, which I'm looking forward to as well. I'll be tuning in for that one. It's a, yeah, I think it's, it's very interesting.

It's a, it's a growth industry, so it'll be interesting to see what he has to say. Richard is saying, what about blood test for enlarged heart pro BMP? Yeah, that's a super good question.

So antiro BMP is, is a molecule which is released to counteract the RAS. So we talked about the RAS, and there's a natural braking system like there is often in biology, which is the pro BMP system. The problem with Pro BMP is he's not very good at stopping the rash, so we use it as a biomarker rather than as, say, a treatment.

We can't give it to, to reduce RAS activation. And it is elevated in dogs and cats with heart failure, and also it's elevated more in dogs and cats with worse heart disease compared to early heart disease. So theoretically, it sounds like it's going to be a really good discriminatory tool.

The the problem with it is there's a huge overlap between groups. So between, say B1 and B2, there's a massive overlap on the box plots there of of, the pro BMP. So it's not a very good, decision maker in terms of when to start treatment.

It may be useful in those patients who are asymptomatic with a murmur, where an owner says, ah, I'm not really sure what to do, and we check on antiro BMP and it's very high, we say, OK, you know what, actually it would be worthwhile imaging, but we would never recommend treatment based on a Pro BMP. That's great. Kieran, that's fantastic.

Do, do ask questions on the Hoover app or but do also follow Kieran on at Vett Cardio. I will check in with the Hoover app this afternoon and over the weekend. Yeah, that's brilliant.

Thank you so much, Kieran. Just, people were asking, it, it was, it was a focus edition, so it was, I think it was part of June 2020, so I, I think there was probably a, a full in practise magazine, but this was just looking at cardiology, congestive heart failure in dogs and cats. So if you want more reading, this might be a nice little magazine to follow.

So June 2020, but I'm happy to send this off to somebody of you. Go onto my LinkedIn profile and send me your address. I'll post it out to you.

Kieran, thank you so much, thank you so much for supporting the conference. Always great to listen to you and I hope you have a great weekend. Take care, bye bye.