Welcome to Dr. Warrick's podcast channel. Warrick is a practicing cardiologist and author with a passion for improving care by helping patients understand their heart health through education. Warrick believes educated patients get the best health care. Discover and understand the latest approaches and technology in heart care and how this might apply to you or someone you love. Welcome to my podcast and videocast station. Today, I'm very excited to be able to share some time with Dr. Karam Kostner, a colleague and close friend who's an expert in cholesterol management. That's Lipids. He's based in Queensland, and today we're going to be talking about lipoprotein little A. But first of all, welcome, Karam, and thank you for joining me. Thank you, Warrick. Thank you for having me. So for those who are listening who don't know too much about cholesterol and lipids, what does lipoprotein mean? A lipoprotein is a protein that carries fat in our blood, and this fat can be carried for various purposes, to transport fat-soluble vitamins, but also to make fat. cholesterol, triglycerides, and phospholipids available to various tissues in our body. It consists of a protein-type structure, which is either apolipoprotein B, A1, or another apolipoprotein, to which fats are attached very closely. So they're an important component of getting fats around the bloodstream, and often in a very simple way I think of it as a bit like... cream in milk and if we didn't have these special proteins and we stood around for too long all the cream would float up to our heads and we'd be in a lot of trouble so tell us the specific lipoprotein little a that we're going to talk about how how is that different why do why have we got a special name for it current That's a good question, Warrick. So lipoprotein A is a lipoprotein that looks very similar to LDL, which is often referred to as the bad cholesterol because it ends up in our arteries and causes heart disease and strokes. Lipoprotein A contains an LDL particle, which is the bad cholesterol as mentioned, to which a second small protein called apolipoprotein A is attached by a small disulfide bridge. So it basically consists of an apoB. and an apple small a and this apple small a shares homology with some of the clotting factors in our blood system especially with plasminogen and that's how it was discovered people discovered a plasminogen like protein that was attached to another lipoprotein and they called it lipoprotein small a the reason they called it lipoprotein small a is that lipoprotein big a was already Another lipoprotein that is mainly found in good cholesterol, HDL. And so really what you're saying is it's a cholesterol carrier with some stuff hanging off it that can cause problems of its own, like increased clotting. Is that what I'm understanding? That's exactly right. That's exactly right. It basically is a bridge between atherosclerosis and thrombosis. So why on earth have we ended up with this, Karam? Why would we have evolved to have this nasty thing? Almost, this troublemaker floating around in our bloodstream. Look, it's a very good question, Warrick, and to be honest, nobody knows the exact answer. It may just be a residue of evolution, or it may have been developed by our body for a specific purpose that we are not 100% aware of, such as sepsis. It may play a role in sepsis. It may play a role in wound healing. But one thing is clear, it ends up in our arteries in people who have atherosclerosis and increased risk of heart attack and stroke. It is probably the most significant genetic risk marker for heart disease and stroke. This has been shown in large epidemiologic studies, Mendelian randomization studies, and in humans as well, in vivo studies. Okay, so what you're saying is that when they look at communities and look at outcomes, people with elevated lipoprotein delay have a greater risk. That's epidemiological research. But you also spoke about Mendelian randomisation, and that really means if you find people with that genetic predisposition, you can compare those to the average population. Is that right? That's absolutely correct. It's almost like a way of doing a mini-trial. Yeah. So it's pretty clear that this lipoprotein little A, which carries cholesterol around, looks a bit like the so-called bad cholesterol, is like bad cholesterol with extra nausea bits on it, causes possible thrombosis and gets in the arteries a bit more. Is that what we're sort of understanding from account? Absolutely correct. That's absolutely correct. It can also oxidise similar to LDL and oxidise LP little A and also LDL ends up in your arteries even quicker. So my understanding, and you would know more about this, is that we can see this particular cholesterol carrier within families who have an early onset of coronary disease and sometimes also in people who have problems with their... aortic valve, that's the main valve coming out of the heart. Would you like to speak to those two things a little bit, Kyra? Absolutely. Aortic calcification in young people is common in familial hypercholesterolemia, where LDL, the bad cholesterol, is very high, but it's also more common in people who have elevated lipoprotein A levels. And in fact, the genetic locus for some aortic problems is in the same area as the genetic locus for elevated leg. And that basically predisposes this connection to some degree. Now, LPDLA, as I mentioned before, and as you mentioned, the genetic market runs in families. So people who have a heart attack or a stroke at an early age without other identifiable risk factors very often will have very high LPDLA levels. So one of the things that I know from my own experience in imaging the heart And I know from the association with calcium building up in the aortic valve is a predisposition to people with LP little a seeming to have more calcium in the tissues, whether it's the valve or the arteries. And I know that there's all sorts of talk about vitamin D and vitamin K. Is there any clear information on that at the moment, Karen? Where do we, do we have a guide? Yes, there is some interesting initial small sort of observational studies and some animal and experimental studies that seem to link calcium, vitamin K, possibly vitamin D, and LP little A, but the conclusive evidence is missing, similar to what we say about oxidized lipids, homocysteine, and LP little A. If all three of them are present, atherosclerosis seems to be accelerated. So it's an interesting observation, but we have to wait for larger studies to know exactly what's going on. Sure. So perhaps some stuff on the horizon. We don't have any strong indication. It's quite possible it may not do any harm, but we wouldn't be telling people to go and do it. Exactly. So if someone does have problems with their arteries or their valve and their lipoprotein little a is elevated, how can they deal with that, Karam? What sort of mechanisms are available for them? good question as well. So the most important thing is to realize initially that it's a very significant risk factor. And people who have elevated lipoprotein A should have all their other risk factors addressed by cardiologists like yourself or myself or a GP as well as possible. And that includes nicotine, smoking, diabetes, and especially bad cholesterol. So something that we always recommend is to get LDL to very low levels in people with elevated cardiovascular risk and high LKD levels. That's the first thing. The second thing is that certain drugs, like nicotinic acid, do have an effect on lipoprotein A, and we described that mechanism several years ago. But these drugs are not widely available and only leads to a 30% to 40% reduction in lipoprotein A. There is newer experimental drugs that are now approved that you and I use frequently, TTSK9 inhibitors, that have a small effect on LKa. But they cannot be recommended because they're very expensive unless you have a very high LDL cholesterol and you need to take them anyway. And then there are clinical trials with anti-sense technology, which is a genetic way to decrease the production of LpbA, that also are very promising, but that we do not have widely available yet. The strongest therapy to reduce LpbA is aparesis, which is like a dialysis-type procedure to filter it out of the blood. And that's available in some very select centers in Australia, but again, not widely unfortunate. So just for those who may be listening and not fully understand, an antisense therapy is one that literally throws a spanner in the works of the body's generation or production of that particular protein by blocking those protein sequences. So it creates a confusion. at the manufacturing level of that protein. Very interesting and amazing technology. And the apheresis is literally hooking someone up to a machine, running that person's blood through a filter and sucking lipoprotein to lay out, which is remarkably drastic, but I imagine remarkably effective and really for special cases only. Correct, yeah. So I'm going to wind back just a bit because one of the things I meant to ask you right at the very beginning was the discovery of this particular protein because I understand you may have some close connection to that. Would you like to share that story with me? Look, of course. I mean, the original discovery of the lipoprotein A itself was by a Norwegian scientist called Kalle Berg. And he basically looked at cosminogen and other proteins in the blood and found this additional lipoprotein when he did electrophoresis. And he named it lipoprotein small A. But a lot of the research after that happened in my father's lab in Austria. I'm from Austria, you know, originally. And my father did some of the pioneering work on lipoprotein A and was one of the first people to discover that it is very arthrogenic. and that is elevated in people with heart attack and stroke. So I basically grew up with lipoprotein A research and did a PhD myself many years later. Well, that's a fairly impressive lipoprotein A pedigree you have there, Cara. So we've covered a fair bit. We're coming towards the end of our time. I guess what I'd like to do is wrap up and your advice. If there's someone listening to this, who would you advise to get their lipoprotein little A checked? And if, so I'll let you answer that bit first, and if it's high, then what would you advise those people do about it? First part first, who would you suggest get their lipoprotein little A checked? Well, anybody who has an early family history of cardiovascular disease that is not explained by other risk factors such as type 1 diabetes or familial hypochloroquine, number one. Number two, people who have a heart attack or a stroke at a young age and want to know why did I develop this at such a young age. Also in people who have one or two risk factors and do not have access to imaging, which you're an expert in. And we want to know, should I treat these other risk factors more aggressively or not? And if your lipoprotein A is elevated, you would treat them certainly more aggressively, similar to elevated calcium on CT that you often talk about. So they're the people where I would recommend measuring lipoprotein A. And then there is groups of people who have other genetic lipid disorders, where we would also recommend to measure it, again, to know how aggressive we should treat these other disorders. Now, when it comes to therapy, addressing other risk factors is very important in people who have elevated lipoprotein A. Identifying high LDL cholesterol and treating it appropriately with statins and ezotrol and some newer therapies to a very low level removes some of the risks associated with LpA. And considering novel therapies in centers where this is available like mine and yours and others around Australia. Because some novel products are very effective and have to be tested before they have full finna spread. Well, I think we've probably covered a lot on lipoprotein little A. We've certainly got to over 12 minutes, and I think it's a great time to wrap up. I know I've learned from you today, particularly some of the genetic association between the loci between lipoprotein little A and the aortic valve abnormalities. These are the things that I didn't. didn't know about previously. So thank you for sharing. For those who are listening, I hope they've learned something. I'd really like to thank you for joining me today, Karim. No, an actual pleasure to talk to you about that. Thank you for inviting me. I look forward to the chance to speak again. For anyone who's listening, I hope you got as much from this as I did. If you've got any queries or questions, please drop us a note at members at drWarrickbishop.online. As always, I wish you the very best and thank you for sharing today's podcast. All the very best. Until next time, please don't die from a heart attack. Goodbye. You have been listening to another podcast from Dr. Warrick. Visit his website at drWarrickbishop.com for the latest news on heart disease. 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