Lp(a) - My Viewpoint

foreign [Music] let me give you just a real quick little uh story here so when I first started my career for about three years I had NIH funding and I would um create couch potatoes for about a month mainly have college students we pay them not to do anything and then we would eat pizza and do these super carbohydrate diets and then we would exercise them for a month and then turn them back into couch potatoes again and we would draw blood and some of the markers we were looking at is oxidation of el pillay and all these other things seeing if exercise influenced it it did change a lot of things but it did nothing to help you a little late so that's all I'm done no anyway so but anyway so I do have some interest in some history with this and so let me um just sort of this will be I hope fast and a little bit of fun how many folks have checked in lpla in the last year wow okay it I was gonna ask how many people have ever checked in opioid I'll show you our colleagues here in a second um and I guess uh Dr Marshall is mainly interested because of aortic stenosis but we're going to cover we're going to cover the the guy with some of the basics the uh Mass versus concentration which I think creates more confusion than anything guidelines I was careful because there's really not great guidelines but more consensus and then we'll talk about emerging therapies and you so we did this uh study this is back in 2012 2011 at Piedmont called the family heart study so uh you know it's it's triggered here there's more to the story but I found I went back and pulled some a couple of patient profiles and uh these are two 38 year old females and obviously they have a family history otherwise it wouldn't be in the trial and and we would and both of them were on the fathers and by definition they had to have fathers had infarcts under the age of 45. now this is 2012. now I you know we were so I said in 2000 I was looking at LP LA but let's just say in America it wasn't commonplace right now would anybody do any further risk stratification on these two individuals and and you'll say why'd you do a calcium score on a 38 year old and I say I'll tell you that was part of the trial but um anyway um you'll notice that the one on the left my left she had an opioid of 190 milligrams per deciliter now this is going to confuse you because we're going to jump all around between mass and content I mean mass and concentration so let's start off with the basics lpla was first discovered by um a Norwegian physician in the 60s and it is exclusively made in your liver you inherit codominantly from your parents the genes to create LP little a and it starts going up around the age of Two And it Peaks at about age five and then it's set for pretty much your entire life some things can affect it um in 2012 I would have said the same thing I'm gonna say now it is a risk factor but it's also a causal agent and we understand a lot more about that part now um and Carol probably knows a lot more than me but where I was going to go with this is you know it has two components so we've known about for a long time and then it has all these different isoforms and I'm not going to get into that but you know really it causes plaque and it causes clot and if you can think about it as simple as that it is the perfect molecule um so and and let me make sure oh sorry okay there's the ledge point so not to not to bore you with a lot of cholesterol pictures but really it is made up of two pieces one is a APO B molecule which is really very similar to LDL cholesterol and then it has this apoa moiety attachment and you'll see right here this is plasminogen right here this is the first part of this APO a moiety and and the similarities of that with plasminogen are what causes some of the downstream trouble and we'll we'll show some pictures of that in a second but when we start talking about the different isoforms the as we've learned more about LP little a it has more and more of these little what we call crinkle repeats and the size and the um and what we're learning about it is is changed by these different repeats and I don't want to get into the discussion too deeply on that but keep it a higher level so Arthur um studied this very carefully I I'm gonna keep this real simple for you this is where the balloon goes but um but but but as we move forward lpla is a wonderful signaling molecule it actually sort of crosses the endothelial barrier and screams for other macrophages and molecules to come to it and this is one of the things we saw it did it didn't our exercising didn't protect you from its ability to recruit all these other Bad actors to start causing the clot that Catherine has to come in at 2AM and fix but at the other part of this plus it what it does is it has the ability to bind fibrin and inhibits plasminogen's ability to turn into TPA which lysis clot so that's where the little crinkle repeat that looks like plasminogen causes the other half of the problem so it's an incredible oxidizer it recruits and then it it helps prevent cause plaque the other interesting thing about LP La we saw some of this when we looked at it a long time ago was and this is data out of the consensus paper in case anyone wants it this was published both in Jack and the journal anybody in LA and you know and what you'll see is you know it's a it's a huge risk factor genetic risk factor but one of the things you'll see is that areas of turbulence and and bending of vessels as well as valves is where a lot of the oxidation um and activity happens so it's found in very like in twists and turns or turbulent conditions um activates and causes more oxidation of um LP delay and so you know obviously there's a lot of interest especially among this group about aortic stenosis so you'll see it there I'm not going to dive deep into it there are two papers about you know or well actually there are a lot of papers and different isoforms and isotypes that can cause aortic stenosis and the real simple take-home messages the higher the lp little a value the the more progression you have that's uh velocity by the way I'm sorry it doesn't carry forward very well but the progression about the of aortic stenosis it correlates with the degree or the level of LP level a um so what changes these because I don't typically repeat measure these until we have a reason to do so with Therapies I will tell you that sometimes they do change and you can see that renal disease or it's really nephrotic syndrome can change it by 60 they change a little bit in pregnancy it it can cause an increase I'm sorry it causes an increase and I did put alcohol consumption because we are in Napa can lower LP little a but you got to drink it chronically to make it happen and the biggest star is down here is this table really doesn't mean anything clinically so anyway um so here we are our nice Georgia native um so here's the confusing part Mass versus concentration Arthur this is gonna be hard for you so it goes we'll go slow um and I think that's one of the most confusing things because we have a different set of numbers and it's created confusion about where does risk start and how do we think about treating it and and what we understand is with the isoforms it's really the concentration that matters and so we've we've done both within the past we've measured and reported milligrams per deciliter or in animals per liter and the numbers obviously are very different and finally we have a who standard and recommendation that we really report in terms of concentration and it's these Kringle repeats that determine that concentration determine the size and and the different isoforms are correlated with different diseases um 50 milligrams per deciliter or a hundred in animals so 50 and 100 is kind of like our LDL goals you you can remember that is roughly 80 percent of the US is the sort of the 80th percentile in the U.S population um you know the cut points because of Prior standardization of where risk starts we're actually getting a better handle on now than we did in the past and um ACC aha 2018 consensus really said okay at 125 nanomoles per liter we should probably Elevate risk or or intensify therapy so what do the guidelines consensus sort of say so I'm going to say this is what I thought in 2012 and we can see if I've changed my thought in 2012 the same same with that patient I thought it was a causal agent uh you know niacin I uh when I was at Vanderbilt and Dr Marin was my attending we didn't use a lot of nice and I came to Emory as a fellow we'd use tons of nice and so it's interesting how communities are different um we'll cover that in a second um I would always think about checking it and folks with family histories early onset atheroscleros especially also with low HDL patients so it's the most common inherited pattern with low HDL um and then I always considered Cascade screening and that was in 2012. and um at that in the old days we used to sort of take the old LDL Target and subtract 30 from it and that was sort of our best what we thought or what I thought at the time was the best way to offset the risk of higher LP Lele so that was 2012 what do we have now well this is this 2019 consensus again and it looked roughly the same obviously screening uh and and both people with early disease and also family history and FH patients uh ischemic Strokes especially younger individuals with ischemic Strokes um use it to intensify therapy and I think nowadays as we've become as we can lower LDL into the 30s and 20s or and people have repeated events I often think about reach about repeat checking LP level a and those individuals and luckily the consensus writers believe that as well and then recently we're talking more and more about aortic stenosis with LP lilay is you can stain the actual valve and you see LP Lele molecules deposited so this is I started off with a vote this is our colleagues here and this was uh ACC 2021 on the website it was just a survey asking about LP Lilly and the reason they did this was because the European Society of Cardiology recommended checking LP lalay and they were wondering about the takeoff in the United States and about 30 percent of cardiologists in the United States have never checked in LPA little a or wouldn't think about it and you'll see about 25 percent had this uh this audience obviously maybe were jaded and biased um you know and how did people treat it well luckily not many people use uh niacin very much um and you know statins were the primary go-to so what about other countries what do they say now remember it's genetically inherited so when you talk about Europe it's a big area and and the genetics within Europe very greatly so their their definition and concentration is 430 nanomoles per liter for being higher risk um but it's a bigger pot it's a bigger mixing or Melting Pot the nla and um and um heart UK recommendations really sort of recommend the same thing we have talked about and they you know and suggest screening their definitions are higher risk look very much like the United States this is just the European paper I'm sensitive to time so issues today really are that we don't have a defined Target to treat there's no standardization of treatment but uh exciting stuff on the way so this is sort of the nuts and bolts by the way this is a this is got presented just about two weeks ago at the European atheroscler atherosclerosis society meeting and it it actually just reconfirmed about what we were doing in 2000 and 2012 was was not bad and roughly they looked about 500 450 000 people and as as LDL went down and LP little a went up you would offset the risk roughly by L'Oreal LDL by about 30 points so in the higher risk individuals then this was at 250 nanomoles per liter um I just thought that was interesting data that added to what we used to do so these are the these are the therapies for LP little a you can see that the pcsq9 Inhibitors lower moderately now the offset is moderate reduction and LP little a probably has no benefit you really got to reduce it 80 to 90 percent just offset the risk if you're just targeting opioid and so that and and obviously we you know ldla for recess which we used to do a fair amount of occasionally I mean back in before 2010 um you can see that in the states it really doesn't lower LP little a that that much once it hits a plateau now the new therapies they're all small Inhibitors of mRNA at one point or another and I'm just going to cover them briefly just so you're aware and new options are are not going to be that far away so this is an exciting topic for those of us that enjoy cholesterol um or creating exercising couch potatoes what I was going to say is you know the Horizon trials can be completed hopefully by 2024 it's fully enrolled we participated um once again it is a Nevada sponsor trial and it also is a small messenger inhibit RNA inhibitor um Amgen also has a compound that is is finished phase two lowers about 90 percent and starting phase three we're participating site in that and then finally this is the um I believe it's science Therapeutics but this got presented at ACC just another um phase one very similar injectable subcutaneous um that shows promise and and this is the paper that's associated with it I have I went over 38 seconds all right um thank you that was LP lily in a summary in a nutshell um in a whirlwind was it too fast all right thank you guys foreign

Channel: Piedmont Heart Institute

Views: 3,415

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Id: lYC9_XiFq7o

Length: 14min 41sec (881 seconds)

Published: Thu May 25 2023