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Targeting Lipids to Improve Outcomes in Your Cath ...
Genetic Basis of Lipoprotein (a), ApoB, and Lipid ...
Genetic Basis of Lipoprotein (a), ApoB, and Lipid Analysis in Contemporary Practice
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Video Transcription
Okay, it's a real pleasure and an honor to be with you all today, and thanks for sticking around. Fortunately, this is a genetics talk, not a lifestyle talk, so feel free to have second portions. Hopefully there's some desserts. So, we'll start with the case. So this is a lady I really remember quite vividly. She came in with the, with chest pain, had VF, needed to get shocked a couple times in the ER, came up to us, had this incredible kind of scraggly right coronary, large right coronary. You know, she was 59, female. She did not have perfect lifestyle and was moderately obese. But when you do her risk calculation, it's quite low, and that's not uncommon as we will see. So, so I think we end up really addressing this question, my cholesterol, you know, or other things are good. Why did I have a heart attack? And I think it's still a difficult question to answer in many of our patients. So we'll talk a little bit about the biochemistry, some clinical implications, and then the therapeutic landscape, which has really changed dramatically since the 10 years ago that I took care of this patient. So, why should this be an interventionalist talk? So, Subhash did a great job of addressing some of that, but I think that there's a lot of reasons why this will probably be a topic that will grow on you. If you're like me, it may not be the most interesting topic right now, but, but we really have a place in this because our patients all come from the very high-risk category, and we have pictures, we can kind of, I think, better risk stratify them, and we can help patients kind of see what's going on inside of them, and sometimes that is what patients need to derive some motivation. This is also an area where you can really, I think, make good friends amongst your referrings and grow your practice, because if you show, you know, an attentiveness to what they are trying to tackle, particularly optimizing their medical therapy, then I think you gain a lot of their trust and a lot more of their patience. The other thing I'll point out is, you know, we have access to patients' families. When we come out of the room and we're talking with a son or a daughter or a spouse or a brother, many of these genetic conditions are obviously familial, and it begins a conversation that can move the needle in terms of not just a patient's health, but a family's health. I also, I think that this area is, has taken off so quickly that there is the need for scientifically minded folks to tackle this, and you don't need a research lab like mine to address many of these issues, and so it's a timely thing. And then I think what you'll see is, you know, I think we quibble about technical pieces, and certainly, you know, I think about anti-thrombotics whenever I'm thinking about patient compliance, but I think that, you know, that the compliance with anti-lipid agents is arguably a stronger correlative outcomes. So this whole field really began 50 years ago with Brown and Goldstein at UT Southwest, and they're doing work on sequencing and showing the functional qualities of the LDL receptor was awarded the Nobel Prize in 1985 in biochemistry. So they really were working on the receptor. We sometimes think more about the lipids, but the fact is that the liver controls both the production, but also the consumption of LDL and circulation, and so whenever the liver does not express the LDL receptor, patients have high cholesterol, and so they were the first then to make the link with atherosclerotic disease clinically, and that's brought forth this whole field, really. So these lipoprotein particles are arguably doing the right thing, right? You know, it's not clear to me exactly still why patients develop atherosclerosis, and it shouldn't be clear to you all, and and sometimes it's really clear to patients, but I think the scientific links are still really uncertain. But suffice to say, lipids, particularly triglycerides and cholesterol esters, the the nonpolar fatty particles need to be encapsulated by first phospholipids, and then the apolipoproteins encapsulate them. So there's a lot of different, obviously, cholesterol particles. They contain their host of apolipoproteins, and an apolipoprotein B tends to be the apolipoprotein that gets into arteries. I'll talk about why that might be. But suffice to say, these other apolipoproteins are getting a lot of attention. They're generally formed in the liver. The liver takes up siRNAs, and so unlike an endothelial cell or a vascular smooth muscle cell, these apolipoproteins are actually druggable with non-traditional methods, and these are in industry really being explored very aggressively, and so there'll be more to come on these other apolipoproteins. So the liver secretes and then reuptakes, but as I was alluding to, it's not really clear to me, it's not really clear to, I think, most people, once you get, you know, to drilling down on mechanism, why cholesterol collects in the arteries. And it doesn't collect in everyone. Some people with FH, I've seen people in their 90s who weren't on a statin, and they have never had a heart attack. So the heterogeneity of the penetrance of the genetic disease is broad. And it's also not really clear kind of why this should happen anyway, but we have therapies, and so we know that there is pathogenesis to be learned. So one clue is that, you know, the body did not evolve to form heart attacks. It didn't evolve to have atherosclerosis, but it did evolve to be able to take care of cellular injury in a very aggressive way. And so to the extent that LDL circulates, it's probably pretty inert. Immunologically, it really doesn't do anything in an in vitro context, but oxidized LDL is quite potent as an immunomodulator, and so it's probably reasonable to assume that the condition of atherosclerosis is kind of an off-target result of our evolution towards trying to control cell injury. My lab has been interested in this because the effects of oxidized LDL are really not straightforward, and they lead not just to cell activation of monocytes, but a really kind of unique phenotype that tends to have these monocytes crawl. They interact with rhombin. They produce tissue factor. They grab onto platelets in really unique ways. So the oxidized LDL is sort of, for a cardiologist, what a gram-negative bacteria might be for an infectious disease immunologist. So also kind of unique cellular immunosuppressive effects on T-cells. So there's a local response, but I think that very clearly there's a systemic response, both to oxidized LDL and other things, and it's really a two-car direct crash, not just a local subendothelial process. So apolepiprotein little a is something that I'm sure you all have heard a lot more about than I did 10 years ago or 15 years ago. And this will be interesting. So the apolipoprotein itself becomes covalently bound to apolipoprotein B100. So the same LDL particle then gets further encapsulated by this second ring. And it's not really clear kind of what it's there for. It's not clear what it does to cause potentially atherosclerosis. It's very, very interestingly heterogeneous in terms of its levels across racial distributions. So like a lot of things, there's probably some genetic drifts due to malaria or other aspects that that lead to variants in populations. Some people think that it's prothrombotic because there are kringles that look like fibrinogen. Other people think that it has a oxidative process, and so the greater expression of these apolipoproteins may be pro-oxidative. What is very clear is that it's really, really tightly associated with outcomes. And it's outcomes not just for atherosclerotic-minded people like coronary or peripheral interventionists. It's very closely related to aortic stenosis and in these particles get into the valves. So there's a lot to be interested about this because it's druggable. And it's druggable not just with siRNAs but now small molecules. And so we'll learn now in clinical outcome trials over the next couple of years whether or not it's causal or just associative like HDL. Okay, so entering a new era, you know, where there was stagnation in terms of what to do. Actually during the time, you know, this is a good topic for Subhash because we were told ten years ago to really not necessarily check a lot of LDL levels because it's sort of the primacy of statin use was all we had. Now, it's become much more difficult to know exactly who and how people will respond. The latest agent that we have is bimpedoic acid. So just a year and a half ago in the New England Journal, this agent reduces LDL and CRP. So it has anti-inflammatory effects and that then relates to long-term clinical outcomes. There's a whole host now of agents both on the market and coming down, but certainly statins, bimpedoic acid, azetamide, PCSK9 inhibitors, both monoclonals and now siRNA approaches. Fibrate still can be useful in some patients and then we'll see about apolipoprotein little a. I want to just introduce the fact that, you know, the effect size of statins, especially when uptitrated to recommended doses, is really, I mean, it's a two-fold change in people's risk. And it doesn't happen, you know, in many of these primary, secondary trials, it's after a year or two. But in post-PCI patients and in post-PAD patients and in post-TAVR patients, separation of the curve is really within months. So it's before they come back to see you. So it really should remind us, as we're thinking about how to, you know, think about antithrombotics, we should also just put a note in part of your recommendations about sort of what you would like to have happen. And many of these patients will come back to see you and you can really alter their lives, especially if they have genetic processes, not just their lives, but their family's lives. So she came in, she actually did very well. When you look back, it's clear she had undiagnosed FH. She also has a little bit of an elevated LP little a. This was ten years ago, but the only option really was for LDL efferesis. Now, of course, there are much other, much better options for her. So you're really entering this at a better time. Thanks very much. David, one quick question. For lipoprotein little a, who, when, and who and when do you routinely check that on? Yeah, so I think, you know, when talking about sort of system-wide interventions, so I would say that there's enough to be gained in terms of the knowledge base that I wouldn't necessarily do anything without being able to publish it. So whether that's having, you know, a randomized design or an observational design where you are cluster randomizing a particular subset of patients. So with regard to LP little a, I think what I would love to study is just sort of the intervention of adding on an LP little a test, just like a TSH, you know, gets, you get an add-on T4. So, so I think that that's, you know, one area where there is a huge uncertainty about how much of our patients have LP little a elevations. And even if you just do it to intensify statin while we wait for these outcomes, I think that that's, that's probably the first step and it's, it's, it's, it's doable very easily. Thank you.
Video Summary
The talk focuses on genetics, lipid metabolism, and their implications for cardiovascular health. It discusses a case of a 59-year-old woman with unexpected heart issues despite having low calculated risk. The speaker explores why people with certain genetic predispositions may still suffer heart attacks despite seemingly low risk factors like cholesterol. The liver's role in cholesterol management and the significance of lipoprotein particles, especially Apolipoprotein A, are highlighted. Recent advancements in treatment, including new agents like bimpedoic acid, are discussed, emphasizing the need for personalized medicine and genetic consideration in treatment plans.
Asset Subtitle
David Zidar, MD, PhD, FSCAI
Keywords
genetics
lipid metabolism
cardiovascular health
lipoprotein particles
personalized medicine
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