Dr. Calvin Yeang discusses the connection between lipoprotein(a) levels and the increased risk for cardiovascular disease in various patient populations.
Back to Symposium Page » Our next speaker is Dr Calvin Yang. Dr Yang is a board certified cardiologist who specializes in general cardiology and heart disease management, as well as preventive cardiology, echocardiography, lipid disorders including lipoprotein. A In addition to teaching medical students and fellows at UCSD School of Medicine, Dr Yang is a physician scientist with an active translational research laboratory with the aim of improving prevention and treatment of atherosclerosis and aortic valve disease. Specifically, Dr Yang's research focuses on understanding nontraditional but common risk factors such as lipoprotein. A And we'll be speaking to us today about that. This research has been funded by the American Heart Association and the NIH. He has authored co authored, excuse me, I authored several peer reviewed articles. His work has appeared in Nature, Journal of American College of Cardiology, speculation, european heart journal Jama Cardiology, among others. Dr Yang completed his Internal medicine residency and cardiovascular disease fellowships at UcsD School of Medicine here in his medical degree and doctorate from Sunni Downstate Health Sciences University in Brooklyn new york. He's board certified in cardio, vascular diseases and Internal medicine. He's a member of the American Heart Association and the American College of Cardiology. So please join me in welcoming Dr Yang, who's going to speak to us about lipoprotein A. And cardiovascular disease Calvin. Thank you Dr Rogers for that kind introduction and thank you the thanks for the organizers for the invitation to discuss L. P. A. Or like protein A. As we call it and its role in cardiovascular disease. Over the next 20 to 30 minutes or so, I'd like to discuss the concepts regarding which patients should be tested for like a protein aid and how to manage those with high protein a given that elevated like the protein, it is very common in the general population as we'll discuss. And even more enriching our patient population is cardiologist. I hope that you'll find what we discussed this morning useful to your practice. Here are my disclosures lipoprotein A. Or L. P. A. As I'll just say for short is a risk factor relevant to many aspects of our practices. Cardiologists specifically the strong supportive evidence for its role as a causal risk factor for atherosclerotic disease including coronary disease, broke for artery disease and stroke as well as calcification, aortic valve disease including the aortic stenosis. I felt I had to find a slide that incorporated heart failure and opulently for this conference. Uh but before you all get too excited. The risk for incident heart failure due to L. P. A. Has largely been attributed secondarily to schematic heart disease and aortic valve disease. This is a patient I shared with eric Adler and Sam Sam Marquez at U. C. S. D. A few years ago when I was a fellow. And in this picture he's holding his ex planted heart in my research laboratory. He had a large antichrist Emmy at the age of 36, resulting in an ischemic cardiomyopathy and ultimately requiring for transplant. His only identified this factor was actually L. P. L. O. A. Which was elevated at 116 mg for Dust Leader. I showed this picture because it illustrates how many of us whether we're general cardiologists interventional heart failure will take care of patients with high. Okay. Yes now elevated L. P. A. Levels associated with cardiovascular disease is very common. The population On the left hand side of the slide. I'm showing a meta analysis of over 120,000 patients in about 36 prospective studies with over 9000 coronary events And what this figure is showing is that L. P. levels below 30 mg for dust leader are associated with quite negligible risk. But beyond 30-50 mg for death. Leader. The risk for M. I. Or death related to coronary disease rises literally. This is why most clinical laboratories reported LP a threshold between 30 to 50 mg per desk to address what's considered normal On the right of the slide. I'm showing you an analysis of a us outpatient laboratory database with more than half a million individuals with LP measurements showing that the prevalence of LP above 30 mg protest leader is 30 in the population and those with L. P. Levels about 50 to 60 mg with this leader The prevalence of that is 20%. So very very common levels at risk are very common in our population because L. PEE levels are largely genetically determined, meaning that high levels and associated risk for president at the time of earth. It's a common risk factor for premature am I. As well? And when I'm showing you here is a study in uh in a large center from Australia with 162 consecutive patients presenting with A. C. S. And about a quarter of them at high L. D. A. And a third had high opa in combination with familial hypercholesterolemia or F. H. Many of us tend to think of FH as a prominent risk factor for premature Stevie, Which it is. But in this study only 15 of patients with premature in my f. H. And this is in line with the prevalence of that region. The general population At around 1-300 compared to a much higher prevalence of L. P. A. In the population. Next I'd like to discuss the biology and the genetics about the which I believe are important to interpreting the preclinical and clinical data to understand how okay mediates cardiovascular disease risk. First L. P. A. Is composed of an LDL like particle. Has shown in this dramatic with a covertly bound protein called Apple A. Shown to the bottom and to the right of the figure people A. Is what gives LP its identity. And this is an important concept will keep coming back to now a bow A. Arose through duplication of its neighboring plasminogen gene and therefore it's highly from all of their supplies managing Specifically a poet inherited Kringle for working of five and produce domains from Plasminogen. But over evolutionary time the kringle for domain was replicated into 10 different sub domains. And as they're depicted in this figure, they're called subtypes one through 10. The number of copies of print afford to freedom for type two. There is very greatly between individuals And they can range from one coffee for a boy leo To over 40 copies per a boy leo and different people. The clinical implications here is that individuals with very small ice it forms meaning that they have very low number of trained for type two repeats. These are both ways are much more efficiently produced and secreted by the liver. So individuals with these low people a or small equally ice. It forms tend to have very high levels and those with large apply ice, it forms with high number of printer for two repeats tend to have very low levels. And through studies comparing L. P. A. Levels between mono psychotic and dies. I got twins. We know that L. P. A. Levels are almost exclusively genetically determined With the Heritability Index of 0.9 Maybe that 90 of the variation and api levels in the population are determined genetically both april a ice to form size as well as single nucleotide polymorphisms or snips and the LPG are genetic determinants of LP levels. Therefore those who inherit a very small people. The ice a form sized and or an okay snip from their dad and another small a boy ISIS form and or another L. P. A snap from their mom. We'll end up with two leos and inco for very high aPI levels and have very five plasma aPI levels so well. LPS structure and function has really informed us on how it mediates disease. It's LDL Morigi confers all the pathogenic properties of L. V. O. In addition, because it also has a play this morning, he confers additional properties. For example, due to its apology with plasminogen, LP. A combined fibre in denuded or injured artery and the thallium as well as the aortic valve epithelium and the oxidized foster lipids on L. P. A. Are recognized by endothelial cells and monitor sites as dangerous danger associated molecular patterns and activate these cells using the same pathways that bacterial pathogens to. But online bacterial pathogens, L. P. A. Is constantly made by the liver and constantly sent out into the circulation. This sets up the process of chronic vascular information promoting atherosclerosis separately. A. P. H. R. E. Several pro cal civic cargo, including oxidized foster lipids myself, a specific acid and auto tax and which ends up promoting valvular calcification and pre clinical models and is a likely explanation for why LP it contributes to aortic stenosis. Human genetic studies have really complemented both the pre clinical evidence and the epidemiological studies which altogether strongly suggest that Oprah is a cause of risk factor for atherosclerotic disease and eric stenosis because human genetic studies have been so critical in our understanding of healthy A. I like to take some time to review the concepts here. Uh There are many large perspective studies associating O. P. A. With atherosclerotic disease and calcification valve disease. These involved in white reviewed quite extensively in the literature. However, epidemiology alone can't distinguish between causality and reverse reverse causality and can founders. Uh as depicted by the red arrow in this figure, because L. PEE levels are largely genetically determined and lends itself very well to type of analysis we call dandelion randomization that actually does suggest causality and this type of analysis. The genetic determinants about P. A. Such as the boy ISIS form or the okay snips were associated with risk because once jeans are not altered by cardiovascular disease nor its can founders. This association between the genes and disease outcomes can be considered causing because L. PEE levels are highly genetically determined and causally associated with the way I see from size or a business. This three way association between high LP levels, genotype encoding such levels and cardiovascular disease risk strongly suggest a causal relationship between O. P. A. And cardiovascular risk. The medallion randomization studies and several large prospective cohorts, including Copenhagen, the UK bio bank, Epic no Fork and Kaiser and complemented G. Wasps and other non observational, non genetic observational studies, consistently supporting the cause. A rule for LP and arthur historic disease and aortic valve stenosis. And this is summarised in the table from the recent National Lipid Association Scientific Statement in 2019. Uh The only thing missing to definitively we consider L. P. A. As a cause a risk factor is a randomized trial which is currently ongoing and we'll discuss later in the sock. Next, I'll review how L. K. Might be clinically useful. First. LP A. Re classifies atherosclerotic cardiovascular disease risk. And in this study of more than 16,000. Perspectively followed patients and epic Norfolk in the afternoon for Colbert, which is a european Colbert Follow for 10 years. But the accumulated 1500 events L. P. A. Attributable risk reclassified about 16% of patients that were otherwise assigned to an intermediate risk group based on the H. A. A. C. C. Cool covert equation calculator. So it can help you refine risk of patients who otherwise have not had to know with regards to aortic stenosis elevated okay levels predicted faster progression of disease. And what I'm showing you here is an analysis of 200 patients who had a baseline, mild to moderate aortic stenosis in the astronomer trial or followed for 3.5 years and both LP levels and oxidized foster lipids which carries in the upper court in the upper turtle with L. P. A. Clear them 58.5 mg. Protest leader predicted faster human dynamic progression of aortic stenosis As well as a 2-fold increased risk for DVR about replacement over the time period. Mhm. The major national and international guidelines. Now all support measuring Okay at least in select Ations. Here's a list of all the guidelines and the specific recommendations. But as a summary, most guidelines agree that L. P. A. Should be checked in patients with a family history of premature cardiovascular sees more personal history. That's not explained by other risk factors. The european society of cardiology goes as far as to make the recommendation of checking okay at least once in each adults person's lifetime. Which is all it would take to identify a person with very high levels due to the levels being strongly genetically determined and not very much affected by lifestyle or other confounding factors related to the topic of chopping checking A. P. A. I like to spend some time on okay measurements which can be somewhat confusing to many different essays that are out there that are not on all standardized with each other. Unfortunately most clinical laboratories measure LP. A. Using antibodies that recognize april as depicted in this figure here. Most laboratories in the US calibrate their essays against standards that were signed milligram for guest leader values and this was done for historic regions. So therefore most of the L. K. Values we're used to seeing are reported in milligrams protest leader. However some laboratories use calibrate is assigned an animal units and there are others that measure the cholesterol content on L. P. A. And they also report their values in milligram protest leader. But of cholesterol which is an important distinction Now we could probably spend a whole 30 minutes discussing all the nuances of Okay measurements but I want to focus on the most practical issues. So if you're like me, some patients will bring you all three different types of LK measurements that they've accumulated through the years and it's important to know how to interpret them. So first the currently available LP A. Cholesterol essays have not been validated for clinical risk prediction and cannot be converted or compared to the other two types of acids. So really the LP cholesterol stays in its current form have limited clinical use. And the immuno essays whether reporting and milligrams for just leader foreign animals. They they for the most part reflect LP. A. Particle numbers and they were the type of assays used in epidemiological and genetic studies that attributed to cardiovascular disease risk. Therefore both of these types of acids are clinically useful for assessing LP immediate risk. However, about a year ago and N. H. L. B. I. Working group and more recently an H. A. Scientific statement that will come out later this year have recommended that clinical laboratories used athletes that report LP levels in animals. So I'm including the mayo clinic, have already begun transitioning their whole system. Come to to measure and report at P. M. Animals and I said, I suspect lots of other labs will follow. So therefore we all have to be a bit more comfortable with interpreting LP eating animals. And I'm showing you here that there is a back of a napkin conversion factor between RP eight mass and particle numbers, Which is 2.4. For example, if you have a patient with an okay Animals of 120 If you take down and divided by 2.4 you roughly get 50 mg for dust leader. It's a very rough way to convert. However, it is important to keep in mind that do the differences in both the types of antibodies that are used in these essays and the different calibrations using these different key essays, conversion factor is very rough. It can be very often, levels are very low, very high and shown in this direct comparison study in the table. Next, I'd like to discuss a couple of emerging concepts even though these are not covered by current guidelines, they nonetheless might be useful for us in the art of taking care of patients with high M. P. A. First is this issue of which therapies for patients are, which therapies for patients with elevated up to appropriate And while no randomized clinical trials proving L. P. L. O. In therapy and has improved outcomes, although they are in progress, there is evidence on what may or may not be effective at attenuating risk attributed to appear. So let's review these therapies and I've summarized them for you in this figure, you can see that most lipid lowering therapies available model, like mildly or moderately reduced out here, whether it's nice and PCSK nine inhibitors, CTP inhibitors, Mr Emerson and some of these are not available in the market anymore. Uh There's also statins which happens to increase the levels as I'll show you. Uh and then there's lipoprotein apheresis, which can decrease the LP and the time average faces of about 35%. Uh some patients are on estrogen for post menopausal symptoms and that tends to have the added benefit of reducing the LP about 20%. But really the only effective, so strongly effective therapy for lowering our P. A. Is RNA therapeutics, which can lower by 80%. And we'll discuss that later. So first I want to come back to this concept that's quite under recognized that statins do not lower OPM and what I'm showing you here is a meta analysis of changes in L. P levels. This time trials consisting of more than 5000 patients You can see here, LP levels can increase by 10-20 of statins in a seemingly class effect that's consistent between tristan, resume withstanding and Travis town. There is one small trial for Tajikistan of 21 patients that did not meet statistical significance to otherwise. It seems to be pretty clear in class effect and uh you know, this is not to say students don't have a role in cardiovascular disease, but it may not address the risk attributed to L. P. A. And this was further Uh explored in human analysis of six landmark stand files Including more than 26,000 patients with more than 5000 cardiovascular events. And the residual risk in patients treated with statins were described while statins reduce cardiovascular disease events compared to placebo, comparing the absolute numbers shown in the slide. Those with elevated up to about 50 mg per guest leader remained at higher risk compared to those with L. P. A. Below 50 mg protest leader. And this finding was actually more pronounced in the statin treated group With patients in the statutory group of the hazard ratio of 1.47 And those in the placebo treated group of the hazard ratio of 1.26. Now, I want to be clear on the interpretation of this data. This does not indicate that statins increased cardiovascular disease risk or by other that those with low mp. A benefit more from statins and those with high A. P. A. As the authors of the paper state, when L on LDL tribunal risk is reduced with statin treatment, LP associated risk becomes an even stronger predictor of cardiovascular each person groups. All right, we'll go back here unlike statins alone, PCSK nine inhibitors and combinations with statins do appear to reduce risk in patients with elevated Okay, Here are secondary Nazis from the Fury, a trial where 25,000 patients were treated with level. Okay, Matt and 70 of those were on concurrent stein therapy And on the right is the odyssey outcomes trial with about 20,000 patients with recent a CS Treaty with L. A. commode And about 85 of greater. We're understanding that child A PCSK nine inhibitors very potently lower LDL cholesterol down to the 30 to 40 mg per desolate arranging these trials, But they also lower l. p. a by about 10 to 30 in both trials. Those with high LP A above 50 to 60 million Grand protest leader ended up deriving the most benefit With the number needed to treat of 41 in the most stable in the mostly stable cd population inferior And the number needed to treat of 29 in the higher risk population in Odyssey. So quite highly effective. And you know, to put this in context, the number needed to treat in the overall trial for both was about 1-61-70. Yes, I do want to also briefly mention lipoprotein apheresis as another treatment for secondary prevention of those with high L. P. A. Because it is an FDA approved option for those with L. P. Levels over 60 and LDL levels above 100. Unlike medical therapies, Avery's is involves extraterritorial removal of L. P. A. And LDL using a dialysis like set up and the column that binds these lipoproteins and removes them from the blood. Apheresis is typically performed either weekly or biweekly and while a phrases can acutely lower L. P. A by 60 to 80% acutely with each session Because the liver continues to make LK in between sessions time average reduction is about 35%. Nonetheless, it is useful in combination with PCSK nine inhibitors and select very high risk patients that may otherwise not get to their goals for treatment goals. And the most effective of yellow in therapies are currently being evaluated in clinical trials. These are RNA therapeutics using either anti sense or S. I. R. N. A. That specifically target the L. P. A. M. R. N. A. Causing degradation of this MRNA. And preventing LP from being made by the liver. Paula. Carson is an anti sense oligarch, nucleotide and Harold Wolpe is an S. I. R. Name and both can achieve more than 80% reduction in L. P levels that talk to Madison Public. Carson is already in Phase three trials With anticipated read out in 2025. An arrow L. P. A. Has wrapped up his face to travel. So there's more to come with RNA therapeutics for Okay, Another important concept that we deal with clinically quite often is that when we measure LDL as part of our lipid panel, we're actually measuring the cholesterol content of LDL but also the cholesterol content of LPS along with it. And the reason for this is that the gold standard reference method for measuring of the cholesterol separates LDL from other lipoproteins by density due to overlapping densities between L. D. L. And L. P. A. Particles. The cholesterol content on both L. D. L. And L. P. A. Are measured and reported as the cholesterol by all clinical laboratories. Because this method is a reference method by all clinical laboratories measure and are judged on their accuracy for LDS cluster measurements, all measurements for all their cholesterol that we're used to seeing clinically whether it's freedom. All calculation of martin Parkins, director of the cholesterol athletes also include okay cholesterol in the readout as illustrated on the slide. Therefore what we know is LDL cholesterol should be more accurately termed all the cholesterol plus Apia cholesterol. So, and because L. P. A. And LDL are distinct type of proteins that mediate risk through different mechanisms and respond differently delivered lowering therapies. As we've shown, they shouldn't really be lumped together as LDL cholesterol. The clinical implication here is that healthy out cholesterol doesn't allow us to fully understand how the risk stratify or manage our patients because L. K. Levels can vary more than 1000 fold in the population. When the clinical laboratory tells us that our patients of the ancestral 70 we aren't able to understand whether this patient is the one on the left shown in this picture, for example with very low opa and negligible opiate cholesterol And therefore has the correct of the cholesterol, approximating 70 mg, protest leader Or if it's the patient on the right with very high Okay levels and okay of 70 and no correct of the cholesterol at all. So the spectrum of patients here depicted here All with a measured reported of the ancestor of 70. You can have very different risk profiles in actuality determined, returning on what the L. P. A. Component is. And I'll just wrap up here with some food for thought uh to understand the real world implications of inaccuracies of laboratory measure of their cholesterol. We looked at the predictive value of clinically clinical laboratory measured of the cholesterol compared to that um Compared to that of correct LDL cholesterol meaning LDL cholesterol. Without the opiate component In a patient level meta analysis of 18,000 stand trial participants With more than 5000 events. We show that estimated LK cholesterol because L. K. Cholesterol direct measurements were not available in this cohort uh Attenuated the risk that was attributed to LV access for. We found that higher levels of clinically clinical laboratory measure of the cholesterol levels in cartels predicted insulin cardiovascular receives as expected. However, when it's okay component was removed, the resulting correct ideal classroom no longer predicted risk. And this suggests that a significant part of all the all cholesterol, medium risk might be derived from L. P. A. However, this observation will obviously need to be confirmed using direct measurements for okay cholesterol and correct LDL cholesterol. So more to come on this story to hopefully. And uh with that I'd like to end my talk and thank you all for your attention and take questions at this time. Thank you Calvin. That was excellent. We do have a couple of minutes, just about two minutes. So we do have a question. Should we be checking lipoprotein a in our patients who have coronary artery disease before initiating statins? If LDL is elevated. Should we be checking LP Little A. As well? Yeah, that's a great question. And you know, you can um as I've shown LP low is very common the population, but even more enriched in those with coronary disease. So it absolutely does make sense to check whether your patients with coronary emergencies have high opa. And that can give you a sense of how to treat them, meaning uh even if their LDL cholesterol levels or a goal, there's this residual risk attributed to the L. P. A. Which may make you want to rethink your LDL cholesterol goals. And that's kind of the way I approach it in my clinical practice for my patients with LDL cholesterol that maybe 70 but very elevated F. B. A. I might rethink my LDL cholesterol goal and want to make that 50 and maybe try to get there with the PCSK nine inhibitor. That does help address some of this residual risk attributes. L. P. A. Great, thank you very much Calvin, appreciate it. Learned quite a bit again, took lots of notes for myself. So thank you