Penn Presbyterian Medical Center’s Grand Rounds program welcomed George Thanassoulis, MD, the Director of Preventive and Genomic Cardiology at MUHC and an Assistant Professor of Medicine at McGill University. Dr. Thanassoulis discussed the evidence for clinical utility of ApoB testing in primary and secondary prevention, the evidence behind Lp(a), and the implications for cardiovascular specialists with relevant cases.Â
George. If you're okay we'll give folks a few minutes to to log on and then just get started here. Yeah. All right. Good morning. We'll give everyone another moment here to log in. But at least read off the CMI code in the meantime. Today. CmI code for those of you on the phone is 78 1 to 8. Again. 7 8128. All right. Why don't we get started? Um You know, there's a lot that we'd love to cover with you George today. So again today's CMI code is 78128 and it's my pleasure to announce our speaker. Dr George. Diana solis George is the director of preventive and genomic cardiology and an associate professor of medicine at McGill University in Canada. You know this is really one of the most prestigious institutions in Canada and has done a phenomenal amount of work and research in the cardiovascular space. George received his MD. From the University of Toronto before completing his medicine residency at Montreal General Hospital and then his fellowship at McGill University George has really been one of the leaders in genomics research and aortic stenosis and cholesterol. He's had multiple grants to study this and has really helped our really helped advance our understanding of lipid particles. It seems that we've become so focused on LDL recently and it's what really piqued my interest Years ago was a patient Of mine who I still care for but an avid runner by no means obese ate healthy and yet at a very young age in his early 40s had severe atherosclerosis requiring the bypass surgery. And this guy looked like the poster of health. A young distance runner ate healthy educated person and and even the LDL wasn't that bad kind of. That is some of the sub particles like LP little a We're just through the roof and so since then and it's an exciting time because I think there are some new treatments and some new options that will be in the pipeline here um to hopefully further reduce cardiovascular risk and a lot of our patients. So I'm really excited to have George speak today. I think this is a very exciting topic that I know I'm very interested in. And with that I will turn it over to you. Thank you very much for coming and joining us today. Thanks so much Samir both for that wonderful introduction and for the invitation to speak today. And you know I think we all have those patients that you're describing. And during this talk I'll actually share 2-2 or three cases um that hopefully highlights some of the the the importance of why a probie and LP testing can be so key in the management of patients with cardiovascular disease. So without further ado I'll be talking a lot about a probie and L. P. A. And their role in and um of these biomarkers in the evaluation and treatment of cardiovascular risk. Um These are my disclosures. It's going to minimize the camera here. So. Perfect. I also have I guess a bit of an intellectual disclosure or copy of interest. I've been trained by and collaborated with Professor Alan Snyderman for over 20 years. And Dr Sneiderman has been a fervent Proponent of a probie for over 40 years and has contributed immensely to the biology and epidemiology of other proteins and their role in atherosclerosis. So the objective of the talk this morning um is to review the evidence for clinical utility of april be testing in primary and secondary prevention um to the to evaluate the evidence behind L. P. L. A. What is it? Why should I measure it? And what do I do about it? And then and finally to discuss the implications for cardiovascular specialist like you with some relevant cases and I have three cases. I hope to get through at least two. Maybe we'll get to the third as well. So the first the first case starts with Mrs smith. She's a 60 year old woman who comes in to see you for a routine cardiovascular risk assessment and preventative cardiologist as a severe mentioned. So I see a lot of um this type of patient. She has a blood pressure that's a reasonably well controlled 1 35/80. She's on no medications for blood pressure. Her body mass index is 26 to the normal blood glucose glucose of normal hemoglobin. A one C her total cholesterol is 205. Her HDL cholesterol is 46 triglycerides are 2 21 LDL cholesterol are 116. And her Framingham risk and I apologize in Canada we still use the Framingham risk. I know you've moved on to the pooled cohorts equation. Her friend addresses 10%. I guess her food courts equation Would be about approximately between five and 6%. Um So you know there's a few things with it with this patient that are important to consider when you look at her lipid profile and I think I want to highlight the first thing which is really to keep always in mind that when the triglycerides are elevated, the other parameters in the lipid profile can be misleading. So when we look at a lipid profile I think it's important that we that we start trying to think about. What does that actually mean. What kind of phenotype does this patient actually have in terms of the lipoprotein profile. So in this case we could say that she has a normal profile um like on the on the left um she can have the middle profile. So high triglyceride um with a normal particle number or she can have the situation on the right which is a high triglyceride with a high particle number. Um So let's talk a little bit about april less protein be and how this biomarker can help us distinguish between those three different phenotype sis and how that can impact on her cardiovascular risk and the way we decide to manage her. So I think the first and most important concept today is that all April B. lipoproteins are a pathogenic. Um and that's I guess 97% true because the only one that's probably not anthropogenic are the kyla microns. And as you know kyla microns are rapidly cleared in circulation after a meal and therefore they make up a very very minute amount of the total A probie concentration. All other of these april be labeled proteins are are considered a pathogenic. Now I think it's important to just take a step back and really go back to the basics and think about what exactly are we measuring when we measure an LDL cholesterol and and like smear mentioned this has really been the focus for probably over 2030 years. Um In our assessment of cardiovascular risk with respect to lipoprotein risk. And when we measure the LDL cholesterol that C. Is really important because what it tells us is that we're actually measuring the cholesterol mass. So are a component of the particle um in the LDL particles. And this and the cholesterol mass as you all know can vary significantly within individuals and within different particles including even within different LDL particles. Um In contrast the april be actually measures the total number of these particles. Okay so the V. L. D. L. The I. D. L. The LDL and even the color micron remnants come up when we measure the april B. And unlike cholesterol which varies as a component of these particles a probie has a very clear relationship to the number of particles. There's actually one april B molecule per particle and therefore a measure of the concentration of april B. Is actually a measure of the total concentration of afro genic particles. The other measure that we can use and is now favored in the most recent american guidelines is non HDL cholesterol. But once again here we are focusing on the cholesterol content and the cholesterol mass in all of the different pathogenic particles. So it's a step above LDL cholesterol because we're no longer focusing solely on LDL particles but it still relies on a component of these particles that varies substantially between individuals and between different particles. When we're trying to address the total um particle number. So as I mentioned we really have been focusing all our attention on this one single particle, we hear it all the time. What's the LDL cholesterol? What's the LDL cholesterol? What's the LDL cholesterol? But as I mentioned we actually have five pathogenic particles that circulate in blood and therefore in order to get a better measure of the total pathogenic burden of particles in plasma we really need to consider all of these different particles. Now as I mentioned the simplest way to do that is to use a non HDL cholesterol because that of course will go beyond LDL cholesterol. It includes the cholesterol on all of these pathogenic particles from that we subtract from the total cholesterol. The HDL cholesterol, as we all know, HDL cholesterol is a non pathogenic particle and therefore we get a better measure of this total anthropogenic burden. Now of course that's a bit of a circuitous route to get to this total anthropogenic burden. And it's also not as precise because you are again using a cholesterol measure. Um and that is a component of the particle which vary significantly from particle to particle to address the number of particles. A much more direct and simple method to do this is to use the a probie concentration. And as I mentioned, each of these particles has one of these a probie molecules and therefore measurement of a probie gives us the total particle concentration and actually is the best measure of cardiovascular risk related to the lack of protein particles. So I always like to show this. Um figure as as an example. So here we have two individuals that both have the same LDL cholesterol on the left, we have a patient who has an LDL cholesterol 135. And on the right we have a patient who has an LDL cholesterol 135. But as you can see these patients have very very different particle phenotype since the patient on the left has five large cholesterol rich particles. The patient on the right has nine very dense cholesterol deplete particles we know now that the patient on the right regardless of the fact that their LDL is the same as the patient on the left. This patient on the right has a higher cardiovascular wrist. And why is that? That's because the probability of one of these particles entering the vessel wall and initiating the atherosclerotic process is entirely dependent on the concentration of these particles in plasma and not their composition. This is a data that we produced in collaboration with the Framingham heart investigators and dr Snyderman. And here we really wanted to look at this exact question. Um When we examine patients who have a low april beat. That is a low particle concentration regardless of their LDL cholesterol, we see that these patients had a relative relatively low event rate. In contrast when april B is high again, regardless of LDL cholesterol, the event rate is much much higher and these patients are at high cardiovascular risk. The other important point to note is that april B is actually also the best measure of the benefit from a lipid lowering therapy on the left. This is a meta analysis that um that we uh performed with again with dr Snyderman and we really compared the different randomized trials um and and looked at the different biomarkers and their change with respect to the the cardiovascular risk reduction and what we were able to show was that april B was the barker that best um followed cardiovascular risk. So the more you lowered a probie, the more cardiovascular benefit you achieved. And this was this was a better marker than either non HDL cholesterol or LDL cholesterol. I won't get into the details with Jillian randomization. Um But just I wanted to say that these analyses have now been done and they show that people who have a genetic predisposition to hire a probie even if their LDL cholesterol is not particularly high. These patients have a much higher risk of cardiovascular events. And I think it's an important clinical point because when I want to treat someone for a younger person, for example, for a very long time, I not only want to see an elevation in LDL cholesterol, but I also want to confirm that the april B particle number is high as well because those are actually patients who have the highest cardiovascular risk. I think the other really interesting analysis that was published a few years ago by brian ference in Jama looked at this point about how good a probie is as a marker of the different um cardiovascular benefit from different therapies. And we all know that there are a number of different lipid lowering therapy and they all have very varied effects on cardiovascular risk. But what was actually particularly interesting here is when you normalize the cardiovascular benefit by the change in april be the relationship was actually very, very consistent. What that means is that the major driver for the differences between therapies is not that there's something special so much about those therapies, but it's really that it's how much they're able to clear a probie from circulation and that's mainly through the LDL receptor. So whether we're examining a statin, whether we're examining is that um I or even a pc S. K nine inhibitor, what differentiates those different therapies is not anything special about the drug itself, but really how much clearance of a probie is achieved. And this point actually, you know, is slowly permeating the clinical community. But I can tell you that I often work with a different uh industry um uh and different companies. And they really bought into this this notion that if they're trying to develop a lipid lowering therapy, it needs to have some impact on april be lowering. For it to be effective introducing cardiovascular risk. More recent data from the uh the timmy group. Um looking at both primary prevention and secondary prevention. Um and you can see clearly that the the parameter that was most associated with clinical events was a probie and this was superior to both non HDL cholesterol and triglycerides. And even when these were compared head to head all put into the same model april B was always um the marker that remained significant as a marker of cardiovascular risk. These are the time investigators also did a very interesting analysis in the UK bio bank, these are patients and crime prevention where they asked the question once we have normalized for particle number does the composition of the particle actually have an impact? So are for example, triglyceride rich particles more anthropogenic than cholesterol rich particles. And this here is being done by looking at the triglyceride LDL cholesterol ratio. And as you can see um this this line doesn't really suggest any significant difference in composition. Perhaps a tendency that triglyceride rich particles are minutely more pathogenic um and more risky than cholesterol rich particles. But really these results did not reach statistical significance. And again, I think that drives home the point that once we once we have considered the number of particles and circulation their composition really has little effect on cardiovascular risk. I want to show you one final recent paper that looked at the the use of april B and non HDL cholesterol in statin treated patients. These are obviously very clinically relevant um study because these are the kind of patients that we see and it really speaks to, you know, which markers should we use to ensure that our patients are getting adequate treatment. And um just to show you here that if the if you're patient has a high a probie um and a high LDL cholesterol, these patients clearly have high risk. But what's important to look at is where these two markers are discord. So when april B is high um if LDL cholesterol has been normalized, these patients remain at high party vascular risk. And the converse is also true if a probie has been normalized, but LDL cholesterol remains high, these patients are not at increased risk and the exact same thing can be done, A lot of people say, well can I just replace a probie with non HDL cholesterol is non HDL cholesterol good enough as a marker because it's free on the lipid profile. And it's a simple subtraction of HDL cholesterol from total cholesterol and what they did here when they did this head to head comparison again of course when both a probie and non HDL cholesterol were high risk was clearly elevated. But um when we look at that again in these discordant groups, when april B is high but non HDL cholesterol has been controlled, the risk is still elevated. And when april B is low and non HDL cholesterol is high risk again tracks april B and is low. So I think that's really um underlines the importance of a probie as a measure of the adequacy of treatment in statin treated patients. Now I think it's important to note that a probie can be measured very rapidly and inexpensively um Using standardized automated methods um There is some concern um at least that I've heard from a number of clinicians that this is an expensive test, of course there's also always the issue of how much Do these these labs, you know, add profit to the to the these tests. But I can tell you that um in in in my center this test can be um obtained for about $10 Canadian which is about $7 us. I think the other important thing, especially in this in this era of ultra low LDL cholesterol levels um in in with with PCSK nine inhibitors now available is that actually at these very low levels it's much more difficult um at a at a biochemical level to accurately quantify LDL cholesterol and a coby is a much more accurate at those very low levels than LDL cholesterol. So um I actually had the opportunity to share the 2021 Canadian academia guidelines and based on the data that I just described, we made the recommendation that for any patient with triglycerides more equal to 1.5 million moles that the non HDL cholesterol or a probie should be used instead of LDL cholesterol. And we really preferred a probie if it was available locally at a clinician's constitution. Now I think it's important as we start moving away from LDL cholesterol to non HDL cholesterol and a probie that we actually have a good idea of what are these thresholds. So I think everyone's very comfortable with the 1 90 mg protest leaders to start to think about a very high level of LDL cholesterol where Um you could be even in the range of a genetic dislike epidemiology to the equivalent. There is about 220 for non-HDL cholesterol and 1.45 for a probie. Um on the other side for a patient who has had a cardiovascular event. The appropriate level of LDL cholesterol that a patient should be below is 70 mg per deciliter. Um That's 93 mg per deciliter in non HDL cholesterol and 930.7 g per liter for a probie. So going back to this patient, Mrs smith, she's clearly at this sort of low intermediate risk of cardiovascular event. And I think it's important to note here that because her tribe blisters are elevated. This tends to lead to more cholesterol depleted particles and that's why her LDL cholesterol is misleadingly low. Um When we actually look at her profile, this lady actually has a profile that's more in keeping with a high particle number which we confirmed by doing an april B value which came back at 1.3 which is actually quite hi um in this sort of what I call concerning range and therefore she does have this profile. That likely suggests both a high Vis LDL number which leads those enriched triglyceride particles and also a high LDL particle. She may actually have familial combined. Hi Pearl epidemiologists and she has no other environmental causes for this. And this is actually one of the most common genetic dis liberty mia's that lead to increased cardiovascular risk because of the increased um particle number. So I'm just going to move on now that onto the second case this is a case of mr Trent. Again a 53 year old gentleman who comes in for a routine cardiovascular risk assessment. He has no known family history. His blood pressure is 130 over 80 And his b. m. I. is 27. He has a normal blood glucose. His total cholesterol is 230. HDL cholesterol is 39. Triglycerides are 100 and 20 for LDL cholesterol 154. And he has a Framingham risk of 8% over 10 years PC approximately four or 5. So for all intensive purposes this gentleman is at a low 10 year cardiovascular risk. Um um And and and despite the fact that of course he has an LDL cholesterol that's um in the higher range. Now this is a typical patient that I see in my prevention clinic. And we um as a as a routine will get a probie to assess the particle concentration and will also get an L. P. A. And in this case is april B. Comes back moderately elevated and his L. P. A. Comes back At 140 animals per liter which is actually um in the high range probably in the 90th%ile of LPA. Um distribution. So let's talk a little bit about LP little A. C. L. P. L. A. Is an LDL like particles. It actually looks very much like LDL. It does have that a probie component. So therefore it also is an afro genic particle. But attached that a probie is this other um interesting um protein which is the A. P. A. Um molecule. And the addition of this april be this april A molecule to this LDL like particle. Makes this an Lp little A particle. And it's believed that this april A. May make this particle a little bit more um pathogenic, a little more sticky to the vessel wall and perhaps even a bit more thrombin attic. Now I think it's important. I think everyone now is aware that L. P. A. Levels are almost entirely explained by our genetics. This is a fully hereditary condition. Um And what that means is that there is very little environmental influence on LP levels. So unlike LDL um um lifestyle changes exercise and most of our lipid lowering therapies have no impact on L. P. A. Levels. Now it's important to realize that about 20% of the population has an L. P. A. That is considered elevated and that increased cardiovascular risk. And we know from these large meta analysis that increased LP and is associated with myocardial infarction and frequently premature myocardial infarction esteem. IQ stroke aortic valve stenosis which is a more recent finding and also cardiovascular mortality. And as you can see from these curves the risks associated to L. P. A. Starts to increase at about 30 mg per liter But becomes clinically significant above 50 mg per deciliter or around 100 animals per liter. Um there are two units. There is a mass unit and also a moller unit and the Mueller unit now is preferred. But a lot of the older data has been done with the mass unit. Um I think one of the important findings that have come out in the last few years about L. P. A. R. There are some individuals who have very extreme levels of LP. A. More than 180 mg per deciliter. Or more than 350 animals who have a prognosis that's similar to heterosexuals. FH and since we really go out of our way to screen for FH and perform that cascade screening through families, it's now becoming more accepted that we should also be doing screening for L. P. A. And similar family screening when these, when this biomarker is elevated. I think for the cardiovascular community. One of the most important things to know about LP Little A. And I often speak to our fellows about this is that LP Little A. Is a risk factor for recurrent cardiovascular events. And this is not a minor issue if you have a Level more than 100 mg per desk leader. These patients are at a two fold increased risk of coming back with a recurrent event. And I'm sure you all have these patients who leave the CCU and they look optimally treated and then within a year or two they come back and they need either another angioplasty or they have another small A. CS. And you look at their risk factor profile and it's not really clear why they're having this recurrent risk. And then one of the most important things to consider of course is high L. P. A. Because as I mentioned, you know these patients come in with high L. P. A. If you don't measure it um they get treated for a number of different things but then their LP remains high because most of those therapies don't affect the L. P. A. And therefore it's no surprise that the atherosclerotic process continues. I just want to say a few words about the role of L. P. A. And the aortic valve calcium. Um And aortic stenosis. This is the work. Um uh We did many years ago in collaboration with Framingham mesa and ages investigators and we were able to show that I'm just looking at at C. T. Scans of aortic valve calcium. Were you able to link those early flecks of of of valvular calcification to the presence of a of of this genetic variant in the LP. A. Gene. And then we were able to then go on and show that individuals who had these variants and who had high LP levels Actually went on to develop clinical aortic stenosis um at a relatively high rate. So there's a 70% increase in the risk of aortic stenosis and a 50% increase in the risk of a heart valve replacement. Over a median follow up of 14 years in adults who have these genetic variants in L. P. A. And our colleagues in Quebec city led by Philippe Ibarbo have now looked at this in the echo lab and this is the data from the astronomer trial. As a sub analysis of that trial of the trial of mild to moderate A. S. Or statins were used to try to slow a s progression and of course that was ineffective. But what they did show in this um uh chancellor analysis was that individuals who had high L. P. A. Had a greater progression of atherosclerosis. If we look at the V. Max across the aortic valve. And also when we looked at cardiovascular events including a VR over time, those individuals had the highest risk of those types of events. And this has now been looked at also by the fourier investigators. Um This was a fascinating study, especially since it it builds on that early um discovery linking L. P. A. To um aortic valve stenosis. And as you know, Pcs canine inhibitors are one of the only agents that actually have a um you know, moderate effect on L. P. A. Levels you get about a 20 to 30% reduction in L. P. A. So the 40 investigators asked the question um in uh in individuals who received PCSK nine inhibitors compared to controls. What happened to the incidents of aortic stenosis. Now it's important to note that this was not a predefined endpoint of the study. Um and therefore the overall effect tended to protection of aortic stenosis as would be expected based on both L. P. A. And LDL lowering. But what was interesting was after the first year where I think we can all agree that we wouldn't expect a very large effect on the incidence of aortic stenosis over such a small amount of time. But after the first year these curves actually diverged quite significantly. And when you just look at that time point after the first year, there was actually statistically a significant effect of galaxy mob in protecting from the development of aortic stenosis. Again, this is a post talk analysis using a non predetermined outcome. But it is, you know, very intriguing food for thought to say that perhaps um lowering of L. P. A. And the aggressive lowering of april be particles may have some impact on slowing aortic stenosis and potentially providing a first medical therapy for this condition. And of course this now this whole concept is now being considered for some of the new LP A lowering agents that are in development right now going back to the prevention of part um screening for L. P. A. Can also help to predict cardiovascular risk when we look at patients who get reclassified either correctly or incorrectly, we see that once you stratify someone to low intermediate or high risk if they also have a high L. P. A. You will be you should up classify their risk based on that finding and you'll be correct uh much more often in that classification of risk um when you have a high L. P. A. So this says that really if you find an intermediate or low risk patient and you find high L. P. A. Then usually should be considering them at higher cardiovascular risk. Who should be screened for high L. P. A. Well I used to have a very complicated slide with a lot of different criteria for who we should screen. I think it's becoming increasingly increasingly clear that this needs to be done um In everyone at least once. Probably at the first screening lipid profile in Canada that's recommended At 40 years of age unless there are other risk factors for cardiovascular disease. Um And really it should only need to be done once. This is a genetic marker. It's extremely stable over time and therefore it varies very little with with time. So therefore it's important to make the measurement, Make a note in the chart this patient has or doesn't have hi L. P. A. And then manage the patient in consideration of their L. P. A. Levels. Um We like the european guidelines have now made a formal recommendation to measure L. P. A. At least once in a person's lifetime as part of the initial screening and also in order to help make this more actionable because as I mentioned there aren't a lot of therapies targeted L. P. A. We said that these patients should have optimal control of all their other risk factors to try to mitigate cardiovascular risk. So I think one of the biggest um um impediments and part of the clinical inertia to LP A measurement is this question that I often get from a lot of clinicians. Well even if I find L. P. A. What am I going to do about it? There's no therapy um today to give this patient and although it's true there is no targeted therapy. I don't think it's true to say that there's nothing to do for that patient. Um First of all uh this this should be addressed with very aggressive lifestyle changes. Obviously we're going to encourage that for all patients but I'm much more um prescriptive with lifestyle changes in these patients. Um They'll be referred to smoking cessation clinics or other types of programs to try to optimize their lifestyle. I treat LDL cholesterol much more intensely in these patients. I think you have to consider that these patients have an additional source of pathogenic proteins that 80% of the population doesn't have. And therefore that adds to their cardiovascular risk when their LP is high And therefore although I can't treat the LP itself, I can treat the other academic particles and lower them as much as possible. Um Aspirin as you all know is currently falling out of favor in primary prevention. Um I don't currently recommend aspirin in patients who have high LP. A. Except in a in a patient that idea is at extremely high cardiovascular risk and in whom I believe the bleeding risk is very very low. Now with respect to lowering L. P. A. The only agent that I'm currently using and that's really in secondary prevention are the PCSK nine inhibitors. If of course the patient can get coverage um in patients who have very severe cardiovascular disease. Um you can consider lipid apheresis and that has been used um Certainly in Germany it's it's actually covered by the government for this specific indication. And there are certain places in the U. S. That do this routinely as well. And we're really hoping the whole field really is hoping for these new agents. There are two agents that are pretty far along in development paella Carson is Novartis agent and El paso Iran is an agent. These are both RNA based molecules that are injectable. Um uh and that do lead to very very prominent lowering of L. P. A. On the order of 80 to 90%. Um Now of course the question which is now being addressed in the horizon trial which just completed recruitment um a few weeks ago um is to now look to see in a secondary prevention population who has very high levels of L. P. A. Does um Khalid Carson reduce cardiovascular events and actually will provide that final piece. Um In L. P. A. Management I think historically. Um Nice and has been used and yes it does lead to about a 20 to 30% reduction in L. P. A. I've I used to use it early on in my career. I have stopped using it probably for the last five years because of varied um bad tolerance to the medication by patients. Um Had many many reactions patients don't like the feeling of taking it. Um And because the evidence is not particularly strong, I've started I've stopped using it except in very very particular situations. Just some evidence regarding the management of people who have high L. P. A. This is a observational study which again just drives home. The point that if you have high L. P. A. And then people would characterize here by having an unhealthy lifestyle, a sort of intermediate lifestyle and a healthy lifestyle. And as you can see although we're not affecting LP. A. Level. These patients still have high LP. A. Um were significantly mitigating risk. And of course the same as seen in patients who who don't have high L. P. A. As expected. Um And I think it's the most important point here. It's just to show that patients are you know doomed by their genetics and there's really nothing they can do to improve their cardiovascular risk lifestyle does still have a major role to play in patients who have high L. P. A. Um Just one word about aspirin and L. P. A. This is old data from the Women's Health Initiative um with the doctor Jasmine and Riker. And I think this data was interesting because it suggested that aspirin had the largest benefit in patients who had high el paso if you compare this group. This is a patient who had high L. P. A. Who didn't receive aspirin. And this is the line of patients with high LP who did receive aspirin. And as you can see there's a with a large decrease in risk in these patients. These results have never really been replicated in a in a in a very reliable way. I think it's really um it's shocking to me that you know, we're in the in the year 2022 there's really never been large randomized controlled trials. Um Looking at different therapies. Even some of the common therapies for patients with high LP. A. Um this of course was a sub analysis. Um but again no designated trials looking at any of these therapies in this specific population. Um This is data from the Framingham heart study that we performed with one of our cardio cardiology fellows. And we really entering the question of you know um does the combination of high L. P. A. And high LDL cholesterol, we've also done it with with high a probie does that really make an impact? And as you can see when both of these are elevated in primary prevention, these patients have a very very high risk. And I think it's important to note just how early these lines diverge. So this is why you see so much premature. Am I in patients who have this common elevation of L. P. A. And LDL cholesterol? And it's interesting when you compare patients whose cholesterol LDL cholesterol is not elevated. You clearly see that there is a quite a large difference in the cardiovascular risk. So again, this is again our observational data but I extrapolate this to say that patients who have high LP. A really need to have their uh their other pathogenic proteins very very well controlled in secondary prevention. Again, no specific data on this, but this is a sub analysis of the fourier trial which showed some interesting results um in patients who have um uh hi L. P. A. There seems to be a greater the benefit of being on a pc. S. K. Nine inhibitor than in patients who don't have high L. P. A. And again PCSK nine inhibitors were clearly beneficial in both groups. You could see a decrease in cardiovascular events even in the group with low LP levels. But really in that group with high LP levels, the hazard ratio was much larger. The absolute risk reduction was larger and the number needed to treat was a much smaller. And again I think this speaks to this this this point that if L. P. A. Is truly an aftra genic particle um then when we get someone to PCSK nine inhibitor we lower all the the sort of typical a probie particles and we get cardiovascular benefit from that. But then we might go and and capture an additional cardiovascular benefit from the extra 20% help the lowering which we've seen people with high L. P. A. So that might explain some of this increase cardiovascular risk. Um In in in this this increased cardiovascular benefit in these patients. So going back to mr Trent. Um He has this profile. He's sort of low intermediate risk but definitely has a moderate a probie and A L. P. A. With an LDL cholesterol of nearly 100 and 60. Um So really he's in this in this range and this sort of concerning range. She's not certainly in the saboteur raising the concerning range for a probie. But then when you go and add high L. P. A. I really think you're his his total risk from his afro genic particles is high. And even though he's at this sort of low intermediate risk I think his lifelong risk is much higher and I tend to recommend therapy for these patients. So I hope I've been able to show you that it's important to screen for L. P. A. To help diagnosis. Um It can be helped identify the ideology of an A. S. T. V. Event especially in a young person um to identify individuals who have an F. H. Farmall hypercholesterolemia equivalent when the LP levels are very very high to help council patients and families. Because often patients are really you know the story that Samir mentioned where you have a very healthy patient who's running who's very active who lives a very healthy lifestyle and is found to have a premature event. Um Sometimes you know finding that that that abnormality provides closure to the family because they now understand why this happened to them. Um I think I've shown you that it can improve cardiovascular risk risk assessment in most individuals at low and intermediate risk. Um And also it should really move you to manage your patients much more aggressively both with lifestyle and therapy. Now I'm I know we're almost out of time but this is actually just a case that just two slides. And really I want to just show this case to highlight the importance of looking for these additional um lipoprotein particles in your patients. This is a patient that I saw and I never actually discussed the case with with dr Snyderman after because I was really Um interested by it and he is a 63 year old man who I saw in our secondary prevention post in my clinic. He had P. C. I. To the L. A. B. And the R. C. A. Um He had a prior non stem E. In 2000 and 17 he had A. T. I. A. Two years ago thankfully he had no sick. Well his blood pressure is very well controlled. B. M. I. Is reasonable. His total cholesterol was 140 HL classroom was 39. Triglycerides were 266. So definitely elevated. And his LDL cholesterol was 46 um on a tour about 80. And has said um I've 10 and he had been on this therapy now since his first event in 2017. But despite that had had A. T. I. A. In 2020. And that was coming back with a with an M. I. Requiring a two vessel pc. I. Um and you know as I mentioned um we normally get april B. And L. P. A. And I think you know people have a tendency, especially now after the reduce the trial they see the triglycerides are high in L. A. Well maybe this patient needs cost of ethel and I have certainly nothing against using a constant ethel in this uh in this Patient. But I think we have to go back to the principles and the best therapy preventing atherosclerotic complications is lowering April be particles. We have over 40 years of evidence to suggest that's an effective therapy and therefore the first and in my view the mainstay of therapy is to first address the a probie particle risk And this patient, despite that ridiculously low LDL cholesterol. His a probie remained at 0.85. So he was actually in a in a range of of having moderate levels of of of of pathogenic particles. He had a non HDL cholesterol that was also high 2.6. We didn't even need the april b measurement to realize that he had a high pathogenic particle burden Even on current therapy. And his LP actually came back at 120 animals per liter. This patient clearly has a very, very persistent cardiovascular risk based on this um very abnormal lipid profile. And you know, this patient would typically maybe be missed if you didn't look at all this, look at the lipids and say everything has been done. We should think about other therapy. We chose to treat the patient with the PCSK nine inhibitor and actually um we got the april be down 2.6 and again, it's only been about a year now, hasn't had any further past events and is tolerating it very very well. So I'm gonna just stop there. Um I just want to again highlight that. I think it's important that we focus on academic lipoprotein concentrations, both as the best marker of risk and the need for for treatment intensification. Um and we should be now measuring LP and all our patients once and then consider this additional source of anthropogenic lipoprotein. So I will stop there. I'm happy to take questions. I think I'm happy I've been able to leave a couple of minutes for that. Um So please by all means and I know there's a lot of questions in the chat. Um Samir how do we do this George? That was fantastic. Uh One of the best talks I've heard on this topic and thank you very much for that. There's a lot we've got to dive into. Um I'll start with one question and turn it over to harvey if that's okay with with you. Um Can you talk a little bit about gender and racial differences in april B. And lipoprotein. Little A. Especially in the asian community, hispanic community um And how to interpret numbers in that setting. Very good question. So for for april be um really no major either ethnic or um sex differences. Um For L. P. A. However that's where things can get a little bit complicated. So as we mentioned as I mentioned, L. P. A. Is a genetic marker and therefore um ethnic differences have a major impact on L. P. A. So we know that LP A tends to be higher in african americans, Southeast asians and it actually tends to be lower in um in east asians. So we don't change really the threshold for what we consider high in those in those groups. And we still don't know if high levels of LP A mean the same thing in those different ethnic groups because the population means seems to be a little bit higher. But for the time being the threshold of 50 mg per deciliter or 100 and animals per leader is still considered a single threshold across all ethnicities. I'll say one point about sex. The things in front of 11 of the only reasons to consider repeating an L. P. A. Is in a postmenopausal women because we know that estrogen actually suppresses L. P. A. Levels and therefore as a transition into post menopausal, the LP has a tendency to go up. This only seems to affect or lead to about a 10 to 20% increase in L. P. A. So not all women have to have a repeat measurement, but if you're in that sort of borderline range you're near the sort of 50 mg per deciliter threshold. Um And a woman does transition. It might be worth re checking to see if she's entered into that higher risk range. Right George. Thank you. I can't agree more with some of your thoughts. What an excellent lecture. I certainly learned a lot myself and thank you. There's a couple of questions in the chat and I had one question actually You mentioned that your recommendations start screening at age 40. Is that a little late. I mean there's a lot of water under the bridge for genetic genetic abnormalities. Should we be looking earlier and treating earlier. So um you know, Alan Snyderman and I have written extensively about that notion as you know, um uh guideline groups are you know highly inert group that doesn't like to make a lot of bold changes. But I can say that from my opinion, definitely earlier identification and earlier therapy um is definitely the way to go. I'm you know, particularly aggressive in my prevention clinic when I see individuals who have um elevated levels of april be even um you know in there uh mid to late thirties and we definitely will start therapy um starting at that age. And I think the genetic data really supports that when we see that patients who are genetically predisposed, low LDL cholesterol have extremely low risk of cardiovascular disease. And I think that just speaks to the the exposure time that these patients really don't have and therefore we can perhaps recapitulate that by starting therapy much much earlier in life before thee. This process gets ingrained in the artery. Excellent. Thank you. Um The question in the in the chat here, you mentioned using a fairy sis and people with very high lipoprotein little A. Levels. And the question was, was there was there a benefit for a freezes in those patients with outcomes? Very hard question to answer. So there has been a number of studies done in Germany where I mentioned it's been covered again, these studies are often done um randomized but sort of the time. So events pre starting Apheresis and then events post apheresis they have shown benefit. It's hard to attribute the benefit only to L. P. A. But as you know other a probie particles are also cleared the way for a basis. Um So the the the evidence is compelling but perhaps doesn't meet the grade for a sort of slam dunk benefit. So yes there is some benefit but hopefully we'll get the real answer that question with these trials using very targeted therapy. Excellent. Another question that chad is what is the effect of E. P. A fish oil on lipoprotein? Little A. And Appleby levels. Do we know that? Yeah so very little actually if anything if anything you know surprisingly if you dig through the the appendix of the you reduce the trial a probie didn't really change much. If anything you might have gone up a little bit um in the in the in in in in one of the groups. Um Overall no no major effect on on lipoproteins. We don't believe that I. P. Is working through a a life of protein lowering a mechanism interesting thank you. And I just have one practical question more. So getting pcs canine inhibitors approved for these sort of nontraditional but clearly beneficial reasons. Have you had issues with that? I mean particularly some of the groups you mentioned. Yeah you know it's it's obviously we're we're we're we're working in in in in different jurisdictions in different countries. Um I can tell you that I have had some success with getting patients treated, especially the group where I think I've had the most success are vascular patients um Like very very significant polyp vascular disease, both coronary and peripheral. Where I've been able to show that the april B is controlled actually. I'll be honest here, the LDL cholesterol is what the players want to see um Although um probably not totally accurate. Um And I've been shown that the you know, the LDL cholesterol is controlled and the patients are having returned events and I've been able to get coverage um for a PCSK nine inhibitor. In patients who have very very high L. P. A. I probably have a handful, maybe two handful patients like that, but I have been successful. It's quite a laborious and it requires lots of back and forth. Um But yes, I have been successful again, I can't speak for the US landscape at all though, fascinating. Thank you. Can we do one more here? One more quick question And it's an interesting question that goes back to coagulation therapy in any any information on the effects of coagulation therapy on LP Little A levels. Yeah. So I'm not I'm not familiar with anything about LP specifically about population, so I'm not sure I can I can answer that. Um Yeah. So I I don't know, I know there's been some interesting population um in the past but not sure if there's any specific effects on L. P. A. Thanks George Samir. You wanna you wanna wrap up? Yeah if you don't mind if I could ask you one last question and we'll wrap things up here just because we've got you. And and I feel like there's so much we're learning from you right now. Um What are your thoughts on HDL? How protective really is it? How important is it? And where does that factor into your risk assessment? Yeah. So that's that's a great question severe And and obviously you can take a little bit of time to fully address it. But I guess I'll say that right now clinically I don't particularly look at HDL as a measure of individuals cardiovascular risk directly. Um And that's for two reasons. I think the data now is quite convincing that HDL cholesterol as a concentration is not um There is not a it's not a causal part of the pathogenic pathway. This is this is not to say that HDL function and it's reverse cholesterol transport function isn't an important part of the pathway. But we don't have measures clinically to address HDL function yet. And and and to do that we would you know we might be able to better predict cardiovascular risk if we did. So where where I use HDL cholesterol is when I see a patient has a high or low HDL cholesterol that actually tells you a lot about their lifestyle. Um So so if I see someone's HDL slip, I can tell them that they're not exercising as much and their and their and their diet has probably gone down because I think probably a large proportion of the variance in HDL cholesterol and and the reason why it has been shown to be productive is because it really marks those healthy behaviors that patients have. And therefore you can kind of use that to use the HDL cholesterol to kind of go back to patients say are you sure you're maintaining um all those lifestyles you were at the beginning because your HDL is dropping again. It's not a perfect tool. But that's the way I use it. But I certainly don't use it to say that if the HDL is high the patient is that all protected from cardiovascular disease based on HDL itself. Alright, well once again George thank you so much for joining us. We really appreciate you taking the time. That was a phenomenal grand rounds. And I think we all truly learned quite a bit. Um still a long ways to go. But very exciting to see that the future preventive cardiology is going to be even brighter. So fantastic job. And thank you again very much. Thanks again for your time this morning. Thanks again for the invitation has really been a pleasure. Thank you. Thank you George take care. Thank you. Bye. Right
