334 - Cardiovascular disease, the number one killer: development, biomarkers, apoB, and more

Tom we're obviously going to talk about cars today because that's no I'm just kidding we're here to talk about ascvd cardiovascular disease it's the leading cause of death globally so let's start off with the risk factors age is one smoking of course lipid disorders and high blood pressure give folks the little explanation on what apob is well APO is the ball game nowadays in other words is all of the risk of everything you just discuss captured in the Apo marker personally I believe the only things you need to measure in the blood are apob and

triglycerides do we have tools to really understand these early stages of disease none of this happens like you overeat a lot of cholesterol tonight and then boy next week you're you're going to have a heart attack it takes decades what role does cholesterol play in the brain cholesterol is almost certainly the most important molecule in the brain what are you most looking forward to in the next 3 to 5 years hey everyone welcome to the drive podcast I'm your host Peter [Music] AA hey Tom thank you so much for for joining me um I it's

actually probably been a while since we've done an actual podcast together though of course we speak so frequently that it uh almost feels a little strange to be talking in this way butth anyway thank you for for joining us now it's a thrill to be back on the podcast series it has been a while and uh there's always stuff to talk about in lipids as you and I know too well so Tom we're obviously going to talk about uh cars today because that's no I'm just kidding everybody knows what we're here to talk about we're

here to talk about ascvd cardiovascular disease um I think in part I'd like to do this because there there aren't many people who probably heard our first uh podcast series together I I think that was a five seven part series something of that effect I still obviously get you know many notes from people who who are just discovering that or who listen to it way back but but I I also think if I was if I could be critical of that discussion as much as you and I enjoyed speaking for what I think amounted to

eight or nine hours um it's a little bit intimidating uh for someone who's trying to understand this topic and and so the the two things I would like to accomplish today would be to to sort of bring a little bit of brevity to what we discussed then and of course also to update people on all the things that have changed since then because that's sort of the beauty of of this field is that a lot has changed in the probably six years since that discussion um but maybe we should at least start by letting you

define for people what is uh what is meant by atherogenic uh or atherosclerotic cardiovascular disease that's a very specific type type of a vascular disease and that means arteries throughout your body um acquire a pathology and that pathology is simply the deposition of cholesterol in the artery wall I always joke there's like one synanon for aerosis and that says do you have cholesterol in your artery wall or do you not if you don't you don't have aosc orotic heart disease and of course the the we have many many arteries in our body and some are

much more Afflicted than others and the ones of most concern are typically the smaller ones that are supplying our heart in our brain because those are sort of essential organs that uh need a profuse blood flow with all the nutrients and oxygen in the blood so small arteries if pathology is afflicting the artery wall can cause trouble before the big arteries you know you can get atheroslerosis in your big abdominal aorta but that takes an awful long time before it's going to basically get to the point where you have an aneurysm and explodes but the

coronary disease of the cerebral arteries uh because their Lumin is so small and you know the Lumen of a coronary artery is like the dot of a pencil that's so it doesn't take much to afflict the affect the blood flow that's going through it and over time this deposition of cholesterol has two things that can happen it can build up and the artery Lumen starts to narrow narrow which would interrupt the blood flow but all too often probably more often is the deposition of cholesterol in the artery wall and those collections are called plaque that

plaque can become very inflamed and rupture or erode and that sets off the coagulation system in the arteries which like a rapidly cause narrowing or obstruction of that coronary artery so AOS sceris is the deposition of cholesterol in the artery wall as you know and we'll get into it likely in some parts is well how did that happen the artery is not over synthesizing cholesterol it's my joke is it's a dump job somebody brought cholesterol into that artery War I just want to kind of reiterate a few things you said there which is probably the

role I'm going to try to play today is uh just just uh play the uh Play The Interpreter sometimes so we talked about how you know obviously we have arteries in all shapes and sizes uh largest artery in the body of course the aorta coming off the heart uh running up in an arch to supply the vessels of the head and then down into the abdomen where every artery of the uh body arises um and as you point out it's not that the arteries of the heart are uniquely susceptible to this process you just described

as atherosclerosis it's just that two things uh are conspiring against us the first is that they are very small arteries and therefore it does not take a significant amount of obstruction or occlusion to create aeia which is just the technical term for when oxygen is no longer able to profuse the tissue and then of course at the risk of stating the obvious the second fundamental problem is it happens to afflict an artery that is let's call it specifically sensitive to the demands of oxygen um I remember explaining this to my daughter when she was in

grade school and I came in to do a you know a little dissection for her seventh grade class and I explained that part of the reason we don't have butt attacks and we have heart attacks is that the glute muscles are not quite as sensitive to oxygen and there are many forms of collateralization and of course saying that to a group of seventh graders or fifth graders or whatever turned out to be maybe not the best judgment because that was all they remembered for the rest of the class was but attacks so head uh or

brain and Heart have this issue where tiny blood vessels not a lot of collateralization catastrophic things happen and I also want to highlight the other point you made which was look this can happen in two ways one tends to be catastrophic and one maybe not as frequently catastrophic the gradual occlusion of the arteries is probably what more often leads people to complain P of chest pain under demand you know gosh I was climbing the stairs or I was at the gym and I just felt a tightness in my chest and and you know under normal

circumstances I don't feel it or maybe I do feel it but then I take a nitroglycerin everything growes away we'll talk about while of that's happening but it's that really frightening scenario where a person in a moment has a complete occlusion of a coronary artery when a plaque ruptures and as you explained it the plotting system of the body responds in the way that it should respond when damage occurs if you for example cut your skin um but it turns out to be absolutely the worst thing the body could have done and in an ironic

way the body kills itself this clotting response is what creates a sudden occlusion and if that occurs in the wrong part of the anatomy of the heart uh that that person will be dead within a matter of minutes uh if an intervention not performed so with all that said anything anything you would add to that Tom as far as just setting the stage for what we're about to talk about no you explained things very well from my physiologic or pathologic explanations to really drive home uh why those two vascular beds are so important brain and

the heart can't go very long without the nutrients and also that was a great Point too that the obstructive part of coronary art Ary disease or even kateed disease extra cranial disease the bigger arteries that are Bing blood to the brain uh they're pretty asymptomatic until Studies have shown that the arteries have to be almost 75 80% uded before those organs are deprived of the nutrients they need so you can go a long time building a a an expansion of an artery that's going to olude your artery without knowing it or so uh and I

don't know whether that's good or bad but uh uh ultimately if you at least uh report chest pain you will get diagnosed in time to do something about it it's not like you said a plaque rupture you got four minutes for somebody to dial 911 and hopefully somebody can CPR you till the you can get and take a clock Buster y so let's talk a little bit about the the pathophysiology of this um before we get into what the non-modifiable and modifiable risks are because we have two categories of risk let's just talk a little

bit about the timeline of events uh of course I'm I'm spoon feeding you an answer here that I know is is a very important teaching point but you know when we think about atherosclerosis being the leading cause of death which it is I guess we should have stated that at the outset right this is the leading cause of death in the United States it's the leading cause of death globally it's the leading cause of death in men and it's the leading cause of death in women so it's hard to really imagine anybody listening to this

who shouldn't be concerned by it um I suppose if you're a squirrel you can probably skip this podcast so given that it's the leading cause of death it doesn't exactly show up as the leading cause of death in People Too Young right it's not like we're watching teenagers 20y olds 30y olds or many 40y olds although there are some tragically who die of this disease this is largely viewed as a disease of the elderly um does that give us any insight into the time Horizon of this disease or the pathophysiology I think it clearly does

so if the deposition of cholesterol is the problem I you don't if you ran to your doctor tomorrow and got your cholesterol checked uh uh checked and it's very high you don't have to rush out to see a cardiologist uh to check your arteries that day because it takes a long long time for this cholesterol deposition to occur remember we're talking about an very small molecules here so and even the way that it's being deposited in your artery wall are very very tiny dump trucks they don't each carry four pounds of cholesterol so if they

carriers of cholesterol are invading the artery wall it takes decades for this plaque to finally get to a point where it's noticeable and some diagnostic image certainly uh it would take even longer for symptoms to occur and everything so it's a slowo process but we know this is occurring basically from childhood on there are pediatric studies pday bugaloos heart study where young children have died of this or that and they get autopsy and they have fatty streaks in our aort at ages four 5 7 and 8 we know from autopsy studies of military personnel who

unfortunately get killed in their job that these young men many of them robust in great shape have subclinical atherosclerosis but none of them are dropping dead of heart attacks while they're serving in the military with rare exception so it takes a long long time so that's the point ultimately yes you will pay the price and most of the heart attacks are men after 40 women after 40 but the we are recognizing now the real opportunity is to sort of diagnose who might be having cholesterol deposition at a much younger age when we can just arrest

it with various modalities yeah I've told this story before but it's it's probably Bears repeating in in medical school so now this is you know maybe almost 30 years ago the pathology Professor this is first year of medical school said what is the uh most common presenting sign of myocardial infarction and uh this was true at the time I don't think it's still true today but it's close and everybody of course every medical student put up their hand and went through the Litany of uh symptoms that you might have chest pain shortness of breath uh

left shoulder pain nausea Etc and he said no it's actually sudden death um the last thing I read suggested slightly fewer than 50% of people's first Mi will be a fatal one you do you happen to know the most recent stats on that Tom no but it's still quite high it's very high yeah majority do survive and get to us but uh you know it's got to be close to 40% that just don't have that opportunity to yeah which is is is staggering and to think that only 253 years ago that number was north of

50% um the other statistic that I've that I've shared before but again it always Bears repeating is that if you take all of the men who are going to suffer a major adverse cardiac event so heart attack uh inclusive of stroke cardiac death Etc you take that whole group of men and that's a pretty big number 50% of them will experience their first event before the age of 65 and 33% of women in the same boat will experience their first event before the age of 65 now the older I get the younger 65 feels so

there was a day when 65 seemed that's that that's those are old people um I don't think of 65y olds as old people anymore I'll tell you that much and therefore to think that 50% of men and a third of women who are going to ultimately suffer a cardiac event will suffer their first one which could potentially be their only one if it's fatal prior to that age also I think puts in perspective the temporality of this condition so we've just established that this is a disease that begins at Birth this is largely established through

autopsy studies where uh children teenagers people in their 20s die for other reasons car accidents homicides war and in the process of doing an autopsy we begin to see the early stages of atherosclerosis um I think is is quite conclusive that this is this is a disease process that might be inevitable to our species if we live long enough and what might separate the people who never get it or the people who die from something else at old age uh versus the people who do simply has to do with the rate of the accelerator and

the rate of the break application Visa these modif if iable and nonmodifiable risks which I guess we should talk about now one addendum to that is just to show you how early this can start there are fetal autopsy studies in mothers who have familial hyper cholesterolemia and when they look at the little fetus's heart they actually see the beginning of plaque development in that instant instance so yeah it occurs early and this is why pediatric guidelines have now at least encouraged lipid testing in the Pediatric age group probably age eight or nine you don't wait

till you're 40 or 50 like you just implied because yes we can still help that patient but we're moving into what's called primordial prevention discover the risk factors early and whatever ones you can modify earlier rather than later is the time to do it yeah thank you for making that point and I was actually not aware of the fetal studies in FH we're going to obviously come back and talk about FH or familial hyper cholesterolemia um as it is sadly not as uncommon as one would wish so um let's talk about the risk factors here

there are a solid seven or eight really really well understood risk factors um many of these are modifiable but some are not so uh take them in any order you like Tom yeah the one thing we've been uh trying to uh uh exemplify later is the difference between risk factors and risk modifi risk markers risk factors have pretty much been shown to be causal of the disease through the ways you do that mandelian trials a ton of randomized Trials and even observational trials whereas the risk U markers are not causal per se not to say

they're not important and we should attempt to modify them all so there is that little bit of Distinction so let's start off with the risk factors things that are no doubt about it let's not argue about these and age is one now we can't modify that so fine and dandy but the things we can uh smoking of course is really at the top of the list uh and that can be modified with the the patient's cooperation uh lipid disorders are certainly in a causal risk factors and high blood pressure you can say things like diabetes

and everything but you know they bring basically the hypertension and the lipid disorders to the table so the risk Mark the risk markers would be a long list of other things and there are ones that are biomarkers but others are not like coronary calcium CTA if you see that you have atherosclerosis it's certainly a rist marker but homocysteine omega-3 issues vitamin D A lot of the biom inflammatory markers that we can look at that would be uh if you have risk factors and you have these risk markers on top of them the worst gets worth

it's like a Chinese menu the more things on there it's going to be more expensive at the end of the day so uh of course my world is lipidology that's what I focus on but I know in your practice you're super aggressive with blood pressure management for doesn't seem like there's too many smokers in your practice which is good maybe they don't want Peter as their doctor if they're puffing away um so uh you can take it from there with that little introduction yeah I like that distinction um of looking at the the causal and

the non-causal as you could almost have a 2 by two causal versus associative and modifiable versus not so I would say two of the most important um non-modifiable or really three would be obviously age um one particular Gene that we don't yet have the ability to fully modify its phenotype which is LP little a that we'll talk about and then of course there are other um very strong lines of family history that aren't necessarily transmitted through through lipids the way FH are uh the way the FH gene or sets of genes are in other words

there there seem to be other polygenic causes here um that run very strongly in families in fact I would I would argue that have some of these genes Tom as as you know my family history is riddled with cardiovascular disease and yet it doesn't come in the flavor of profound dyslipidemia right I have a normal LP little a I I never actually had a very elevated uh apob and in fact when I had that first calcium score at the age of 35 that already showed the presence of calcium it was in the context of an

LDL cholesterol at about the 50th percentile so in other words I was was about an average Joe as you could be um and yet there was clearly something else going on right I wasn't insulin resistant I wasn't uh smoker I you know I had none of the risk factors right normotensive there was something else going on we could probably spend a minute on talking about why I've had zero evolution of that disease over the past 16 years um which also speaks to the nature of interrupting causal Pathways um and now on the causal side you

know it's interesting I don't think there would be any dispute from any reasonable person on the causality of apob um hypertension uh let's talk about two other things though specifically let's talk about insulin resistance per se and chronic renal failure is do we have um do we have strong enough evidence on the causality of these which are clearly highly associated with the condition or how do you think about that well the chronic kidney disease is a of course a super Majoris factor for there but probably primarily through virtually everybody with chronic renal failure has lipid

disturbances high apob and which you just mentioned and they have a high degree of serious hypertension so you got two really causal things that are basically present in everybody with CKD so is that the only reason CKD is doing it I suspect that when you kidney is not getting rid of a lot of things there are other things floating around that are irritating your arteries for sure one other thing I might add there Tom is when we we when we do see people with even compromised kidney function we generally see homosysteine go through the roof

and while it might be a bit of a stretch as you recall we used to spend some time looking at uh markers I don't even want to get into it because it's such a mouthful but you you'll recall the days of asymmetric and symmetric dimethyl Arginine and we would see these things Skyrocket in people with high homosysteine because homosysteine impaired their clearance and of course there's at least reasonable mechanistic data to suggest that high amounts of symmetric and asymmetric dimethyl Arginine impaired the enzyme nitric oxide synthes which produces nitric oxide which leads to vasodilation so

to put that entire path together there's a very clear link between kidneys that don't work fully High homocystine and then the buildup of amino acids that prevent the body from making a vasodilator um I don't know that the causality of that has been clearly established in humans uh but it would serve as at least one additional plausible mechanism for why renal insufficiency could be leading to an increase in vascular disease yes that's sort of what I said hey there's other things floating around when you have CKD homeis would certainly be one you could throw uric

acid into that equation probably also and uh other metabolites ceramides and uh things that are beyond what we want to discuss today so uh uh multifactorial CK as far as atherosclerosis and then let's talk a little bit about hyperinsulinemia and insulin resistance again let's try to disentangle what's obvious which is as you pointed out already those that that condition tends to traffic hand inand with Hyper lipidemia and hypertension which are clearly an independently established as causal what do you make specifically of hyperinsulinemia and hyper glucosa as independent risk factors beyond the lipid and hypertensive components

I sort of don't accept that and it goes back to this incredible uh study in the '90s by Steve G when nmrs came to the table nuclear magnetic resonance an uh analysis of lipoproteins and there are distinct lipoprotein signatures associated with insulin resistance for the they can go back and listen to our original podcast but basically if you look at certain characteristics of the low density lipoprotein the very low density lipoprotein and the high density lipoprotein you will see distinct patterns that that appear in insulin resistant people you would have bigger vldls cuz they're triglyceride

carriers you would have smaller ldls because the triglycerides convert big ldls into small likewise you would not have big hdls because triglycerides enhance HDL catabolism making the HDL small so if you look at all those distinct and they're easily measurable by NMR if you have c those patterns and this would cooperated doing insulin clamp studies you so if we saw these type of lipoprotein signatures and we looked at the insulin clamp studies they're all insulin resistance and the interesting thing was these signals occur before post prandial insulin goes up certainly before fasting insulin goes up

and decades before glucose goes up so at least and I think it's just impossible to separate insulin resistance and lipoprotein abnormalities those type of lipoproteins that I uh just disc discussed are the ones that are delivering cholesterol to your artery wall so we also know not everybody who has atherosclerosis has insulin resistance so it's not there are people out there who believe boy if you have insin if you don't have insulin resistance you cannot get aerosis that's silly but it's still promulgated out there so I don't know I look and maybe it's my little sphere

of lipidology I look at everything as related to lipids maybe too much but there is that very early on before at least insulin levels start to go up now we even know before insulin levels goes up there are other cellular mechanisms that are going on in insulin resistant people so uh I don't know uh they're together if you and I don't know what purpose it serves to hey uh whether you call insulin resistant causal or non-causal it's a very serious abnormality to be taken incredibly serious yeah I mean I I think I kind of tend

to lean towards some independent causality there and I and I point to some of the diabetic research where um you know they look at studies where you take two different approaches to maintaining U glycemia right so um as as you know Tom there are obviously pharmacologic AIDs that can do that without the use of exogenous insulin and with the use of exogenous insulin so in other words you could have two different ways to bring glucose down one by increasing insulin sensitization and one by actually just giving more insulin and interestingly when you parse apart the

results of these studies you see something interesting which is that that there appears to be some vascular damage that is mediated by just the hyperinsulinemia alone even in the presence of normal glycemia of course we would understand why hyperglycemia is problematic for microscopic vessels but it's kind of these larger vessels that seem to have a negative response to hyperinsulinemia um and again it it it it it almost comes back to this idea of what's going on with uric acid and homocysteine are these things somehow inflammatory to the endothelium and therefore render the endothelium even more

susceptible to a given concentration of lipoproteins um it again it might be a moot point because I think when it comes to ascvd the goal is probably to address everything um uh and and therefore you know we might be sort of having more of an academic debate on on on this I I think the other point that I that is probably worth mentioning to people when we talk about causality and biology is distinguishing between things that are necessary and things that are sufficient um and and obviously once in a while you find something in biology

that is both necessary and sufficient but many times it's neither and it can still be causal so I'll use the example of smoking right so is there any doubt that smoking causes lung cancer there's there's no doubt in anyone's mind anybody who doubts that probably shouldn't be having a discussion at this point so smoking is causally related to lung cancer but is it necessary for lung cancer no only about 85% of people with lung cancer are smokers 15% have never smoked is it sufficient for generating lung cancer no it's not because there are many smokers

who don't go on to develop lung cancer so in that sense you can have something that is very causal meaning it's about a thousand times increasing the risk of lung cancer but it's neither necessary more sufficient this will be relevant when we pivot to our next topic which is apob right and and it'll be interesting to talk about apob through the L through the lens of necessity and sufficiency so before we do that maybe give folks the uh the little explanation on what apob is and maybe why we shouldn't think of it as synonymous with

say LDL cholesterol yes well apob is the ball game nowadays uh it's not widely tested like it should be but anyway um a cholesterol's got to get in your artery wall to cause this disease atherosclerosis we know cholesterol is an organic molecule that is in the lipid classification and there are many other lipids but what the definition of a lipid is it's a molecule it's not soluble in water and the Dilemma is our delivery system of everything in the human body is a water solution called plasma so how in the world are lipids trafficked in

plasma that's a basically a physical chemistry impossibility so uh you know you've heard me say this many times to patients Evolution had to De develop a lipid Transportation vehicle so these hydrophobic lipids could be trafficked in aquous plasma and the solution was very simple because proteins are soluble in water so if one just combines a collection of lipids to a protein carrier lipids can go whereever the human body wants them to go in plasma so the the things that traffic lipids in our body are protein and wrap lipids the proteins are called apoproteins once they

bind to lipids they're called APO lipoproteins and the whole macr molecule once it's fully developed is called the lipoprotein so lipids go nowhere in the human body unless they're a passenger inside of a lipoprotein now there are many proteins that can associate with these lipid collections but there's two that are we're going to put at the top of the list they're the structural APO proteins these proteins provide structure stability and water solubility to the lipids there are two basically categories of lipoprotein families in our body we're talking about the apob family right now so APO

B happens to be the largest of all the APO proteins that the liver uh and even the intestine can produce by the way no other cells in the human body produce apob B it's the liver and the small intestine you know very high molecular weight so particles that are en wrapped with apob and of course they're full of thousands of molecules of uh triglycerides or cholesterol phospholipids and other lipid Moes the apob family we have other ways of classifying them and that's in the cuge so the apob family consists of what everybody has probably heard

low density lipoproteins the LDL very low density lipoproteins the vldls which are our triglyceride carrying particles idls I'm going to mention them for completeness intermediate density lipoproteins they're very transient characters in between vldls and ldls they're not a consequence other than some very rare lipid Disorder so that's the apob family but the really good thing and what what makes apob so valuable is there is one molecule of apob per apob containing lipoprotein and this is great because it's a very easy assay for labs to do it's an IM imuno assay well standardized so we can

have on our patients hey go get an apob concentration and when we get that number back we know we are actually counting the number of apob containing lipoproteins and that's so critical because the particle that can leave plasma enter the artery wall and start off this atherogenic process are the apob family the other family of lipoproteins are our high density lipoproteins are hdls their structural protein is APO protein A1 except there's from one to five copies of APO A1 per HDL particle so that doesn't become a useful biomarker to get an HDL particle concentration and

the hdls until you get into the uh subd discussions of them per se are not atherogenic so don't worry about them too much it's the apob particles and to just complete this discussion on the importance of apob what what makes an apob particle decide to leave plasma and crash the artery wall rather than go back to a receptor in the liver that can bind it and pull it out of plasma in a process called clearance because if all your apob particles are being cleared in a liver there would be none to invade your artery wall

so what forces them into the artery wall and depending on other factors there are threshold concentrations above which the odds are good apob B particles are crashing your artery wall and Because unless you have horrific other risk factors that's why atherosclerosis takes decades to develop cuz it takes a long time for these tin8 tiny apob particles to keep crashing the artery wall and maybe later we can discuss what happens to an APLE B particle once it's in the artery wall but Step One is crashing the artery wall traversing the endothelial barrier the one cell lining

that's on every artery in our body and going in so it's particle number and the best and easiest way and the most tested way to get an accurate atherogenic particle number is to measure AO B so that's why and you know you'll hear even statements say APO is causal you know you hear LDL cholesterol is causal because of its very long plasma resonance time compared to the short plasma residence time of vldls about 95% of our apob particles are ldls hence ldl-p another way of checking uh particle number is really what drives total apob not

that the vldls are not important they can be but it's the ldls that are doing most of the cholesterol dumping in the artery wall so apob really gives us a good handle on LDL particle concentration so and yes apob bringing that stars into the artery wall is causal but it's really the sturs that do the Dirty Work once the APO is in the so you can't separate apob from cholesterol so I don't care whether people say cholesterol is causal or apob is cholesterol because you can't separate the two in physiologic circumstances so let's maybe go

a little bit further into that process just so folks understand it so um let's for the purpose of this discussion assume that it is indeed the most common apob bearing particle it's a low density lipoprotein so um an LDL molecule carrying its load of cholesterol maybe a little bit of triglyceride to boot um makes its way from the Lumen of the artery through the endothelial barrier between a couple of cells into a potential space called the subendothelial space What set of factors increase or decrease the probability that it is there long enough for its cholesterol

package to begin the process of oxidation do we have any sense of this idea of retention yes and it's always subject to new data coming in because this is under a long time and continuing investigation one little minor correction you call LDL a molecule it's a Macro Molecule thank you I'm stickler for terms as you know so once the apob particle traverses that endothelium and that can happen even if you have a normal endothelium it certainly can happen easily if you have a diseased endothelium and and and probably worth noting Tom that's almost assuredly where

things like smoking and high blood pressure make your odds worse those are things that are damaging the endothelium making that barrier more permeable which is simply a probabilistic game this is all probabilistic what increases the odds of an apob getting in more particles that's higher apob more por endothelium that's what happens with smoking that's what happens with um high blood pressure that's in my view probably what happens with things like high homocysteine High insulin or renal insufficiency high uric acid all of those things so anyway yeah it's all about the probability of making the gradient

such that the apob is going where it's not supposed to go yeah you mentioned at adma before that's basically a regulator of nitric oxide probably the most crucial molecule that an endothelium produce is to defend the Integrity of the artery or so and once that's out of whack the endothelium is not functioning like it should there are receptors that can get expressed there that can pull these particles in but okay the apob B particle is in the uh wall of the artery the inal layer there and I uh one of my jokes is usually it's

like a once a fly hits fly paper if there is such a thing anymore it's stuck there it then then uh what happens to it so when AN apob particle enters the aring wall it has a high Affinity to bind to Collective tissue molecules called proteoglycans sytin there's a whole sub family of them and now you have that apob particle that is just stuck there now look there are you know the number of LDL particles floating around your plasma we're sort of talking like apob you can count the number of particles and well actually are

quadrillions and quintilian of these particles so and that's how many are crashing your artery wall too so there's a lot of them in there and they're all right next to each other bound to these proteoglycans so it's now believe the next step that happens what's on the surface of all these apob containing particles it's phospholipids the cholesterol and triglycerides are inside these particles there's a little bit of UN ified cholesterol on the surface but these phospholipids are very susceptible to two things one is ultimately going to be oxidation which is a big big role in

atherogenesis but the first is there are enzymes called mutases that somehow realign the phospholipids that are on the surface of these particles and when distinct phospholipids are put next to each other these particles have a high Affinity to stick to one another and that's called LDL or apob particle aggregation and that is believed to be the first step so what you ultimately have is a lot zillions of these apob particles in a big mass of cholesterol and all the other lipids that are inside that particle and that's where the oxidation starts to occur because sterols

get exposed the phospholipids many of which have double bonds are highly susceptible to oxidation so now you have this Clump ofy cholesterol and phospholipids which are oxidized well oxidation is a major signal to the immune system the immune system is going all over the body and when things get oxidized that means it's on fire it's often an infection or some other pathology and here come the white blood cells to put out the fire so once you get this AGG ated mass of oxidized whatever you want to call it it's Way Beyond cholesterol white blood cells

start traversing that endothelium the monocytes and they come in and they transform into macres which express receptors that can start ingesting all these aggregated apob particles and the next step and this was seen by the great Russian I think in 1913 in ncof when a over said rabbits pure cholesterol and they developed atherosclerosis something rabbits normally don't get until you drown them with that type of cholesterol and under the microscope he saw all these things uh that there was some long German name I wish I had it for it's basically cells that are full of

CH lipids so this was the What We Now call the foam cell uh which is just a lot of cholesterol uh in the interior of these Mac rages and under the microscope they look very foamy so that's how they got their name foam cells and as you can imagine all these masses over the decades we've talked about now you have plaque but as this plaque is being formed that immune system is still trying to put out the darn fire so what the next thing the immune system does is once the maccrage have eaten it and

sort of organized it into a pool of cholesterol is smooth muscle cell are recruited from the external surface of the arterial wall they migrate and they start covering this G this mass of cholesterol and other lipids and now you really have a distinct plaque where you have a cap on it and the cap is simply smooth muscle cells originally but these smooth muscle cells transform into more complex cells that can start secreting calcium and that gives this uh C plaque a fibrous integrity and what is the purpose of that to prevent what Peter and I

talked about early on you don't want this plaque to rupture and if we can put it's like putting a heavy mounded dirt on a volcano I guess it's less likely to rupture if you can cover it ultimately the type of uh cyto kindes and chemokines that are being produced by these white blood cells some of them have bone forming ability and that's why much later in the disease calcium starts to get deposited in this cap plaque and that's maybe somewhat fortunate because being radio Opa that enables the type of Imaging studies we have now to

say oh my goodness there's calcium in your artery wall which there's only one cause and that's atherosclerosis so those are the several steps maybe you want to elucidate them on further Peter but none of this happens like you overeat a lot of cholesterol tonight and then boy next week you're you're going to have a heart attack it takes decades yeah well again that's uh that's a great explanation maybe maybe I'll just sort of summarize it a little bit right so so we already talked about how we get into this process where uh you know you

you have the the apob uh carrying lipoprotein let's again just simplify it and call it the the LDL in this situation although as we'll talk about I'm sure they can also be an LP little a it it's it's it's enters that subendothelial space and its presence alone uh makes it susceptible to have its contents oxidized uh it's it's cholesterol is a rich Target for oxidation and as that happens we we once again uh have this example of the immune system which is out there uh basically surveying constantly looking for things that are bad usually in

the form of monocytes and they're sensing they're seeing a chemical signal for that oxidation and as they enter that space they become this other type of cell they they they metamorphy into something called a macras and the job of the macras is to literally consume to phagocytose to eat the thing that it is concerned with and when it begins to eat that oxidized cholesterol that produces the foam cell I want to pause there for a second and talk about how way down the line when we ultimately have that calcification as you said that's actually quite

visible calcium scan is exactly looking for that phenomenon right but I often get asked the question Peter is there anything I can do today to know if there is any damage to my endothelium are there any foam cells in me are there any fatty streaks and then of course the next thing we kind of talk about is a CT angiogram which in its first phase uh when it's run without contrast which it usually is you have the opportunity to potentially see calcifications and then once the contrast is injected you get a higher resolution image uh

that shows more anatomic detail of the Lumen but in my experience Tom you have to have a reasonable amount of soft plaque non-calcified soft plaque to show that suggesting that there's probably still quite a bit of damage that could occur before you would see anything on a CTA and of course I realize there are some people listening to this saying what about newer tests like clearly that um are using uh a fat attenuation index to you know look at the changes in the character of the fatty tissue in and around the adventia and to see

if that is in of itself predictive of damage so so I'll just kind of let you take that in whatever way you see fit but you know outside of research-based tools such as uh intravascular ultrasound um what what do we do we have tools to really understand these early stages of disease if a person says look I don't want to get treatment now but I don't want to wait until I actually have calcium like is there a middle ground not definitively but there's two things certainly there are these Advanced Imaging techniques and that's one where

they're analyzing certain characteristics of the artery wall I think still not ready for Prime Time play yet and certainly because of its cost it's nothing the average person's going to run down and get tomorrow or so so we go back to then hey these macres that are sending out these signals recruiting more and more white cells to get in there and help me it's like a fire department calling for a second third fourth alarm we need more uh immune uh operators on the system is are there immune markers we can perhaps measure in the blood

and that's basically what we're doing right now so obviously these would be different types of inflammatory markers uh and they're looking at other type of biomarkers that might signal this type of pathology going on the are the ones that are readily available to most people and these are risk markers because by themselves they're not causal and they have other ideologies or other causes that might explain them why they're high the first and the one with the most evidence is the C reactive protein test that was used for years to help diagnose rheumatic fever which obviously

had a lot of inflammation down the road Paul riter was the guy who did this he discovered well the type of inflammation that goes on in the artery wall is incredibly subtle at first so you're not going to see a c reactive protein of 22 or a sedimentation rate of 55 in the blood test the oldtime markers of inflammation he says can we analyze C reactive protein at here to for trivial not even looked at levels so they started looking at extremely low C reactive protein levels and lo and behold he showed it's beyond debate

now that yes they call the test High sensitivity but it's actually the same damn aate it checks for CRP if you have rheumatoid arthritis but the high sensitivity has a different reference range that they relate to atherosclerosis and obviously much lower than you would have with some Rheumatic disease so subtle elevations of this C-reactive protein yeah you know those the rule is hey above two you're at worry above four you got some serious inflammation in your body going on it's not necessarily cardiovascular but you know could you be in an early stage of some other

inflammatory disease sure that's why it's not specific but you know we look at levels even less than two as a signal to us to start worrying so that's the first inflammatory Market I just haven't been that impressed with with hscps sensitivity uh pardon me specificity right so um there are too many people I have seen who have a normal hscp and I actually Define normal is less than one so I'm not even talking about the actual assay cut off of two so these are people that walk around with an you know hscp of 0.8 um

and yet you actually do a calcium score on them and you find they've got a calcium score of 10 which again this is not a person who's going to die anytime soon but they've already progress to a calcium score of 10 you know this is a person who might be in their 40s so this is a person who's actually on the path towards premature atherosclerosis so I I I I just think that that inflammatory markers are probably not specific enough or in the case that I just gave even sensitive enough at low low levels of

this disease in particular because I think that this disease has multiple paths you know just even though we're not going to talk about it today another topic we love talking about is as Alzheimer's disease and brain health and how there are different paths that patients will take to get Alzheimer's disease some patients come at it through almost a genetically pre-programmed path others come at it from much more of a vascular disease path and yet others come at it from a more metabolic and an inflammatory path and there all these different paths and I and I

almost wonder if there are similar paths towards atherosclerosis and there are some people who are arriving at it you know it's almost genetically programmed in them and then there are others who are showing up through this very you know lipid based path and yet there are others for whom inflammation is the dominant path and maybe those are the people where the hscrp shows up very early in the process again I'm completely making this up as an analog to what we see more common ly in in the paths to dementia but I guess what I'm saying

in a long-winded way is I find myself rather unconvinced that we have great tools to measure the phenotype of early atherosclerosis no that's so true and it's the specificity as you said I can name two or other three other inflammatory markers that would have the same weakness you could have a fatty liver in they're elevated or so or some infect subtle infectious disease somewhere so they're not specific you could say and riter would tell you in the scenario you described where but God coronary calcium is there already but their CRP is perfect that maybe that's

a stable plaque that's not going to rupture herself so you know you can get into those type of debates yeah or maybe we missed their C maybe they had a CRP blip five years earlier when that plaque was still being oxidized yeah I I I understand that for sure so I think the only way we can use these inflammatory markers is hey if apob is high or LP little a two major risk factors and these inflammatory markers coexist with them I worry about you perhaps a little more but that doesn't mean if apob is high

or LP little a is high and your inflammatory markers are perfect that we dismiss you as aha you're the one who's not going to get atherosclerosis cuz that's not a game you want to play so that is the weakness of those type of markers I don't have any other markers that I can tell you uh to check on inflammation other than there are 10 other subtle rarely tested inflammatory cyto kindes and chemokines that can be measured and um you know it's saying hey if your apob is whatever and your homoy is high we worry a

little bit more about you we have to uh maybe uh attack that cuz it's modifiable so I'm not sure what the other markers would be outside of you wait long enough you're going to get some Imaging thing that's positive or uh do we just start respecting APO B and that's basically where the lipid world is going and that's where this New Concept primordial prevention has come into play in the old days it used to be primary or secondary prevention hey you've had a heart attack thank God you've survived we're going to try and prevent the

third heart attack secondary prevention or once Imaging came along then we can say aha your CTA or your ca see is positive to me that's secondary prevention right there I wouldn't call that primary prevention so what is primary prevention you have a high apop oh you you know you have high blood pressure but we're not talking about that aspect and what we would do with that today and therefore what is primordial prevention people with physiologic parameters in the lipid and lipoprotein spear so we still going to check them because we think at a certain age

or depending what else goes on in that person's life they will enter that primary prevention and then once that is if that's defined as escalation of apob then you're going to get into the decision of what sort of Therapeutics might we want to offer this person whose apob is just slightly high we don't wait till the apob is in the 80th or 90th percentile because I think if there was a way of getting into those people and looking for this pre-imaging atherosclerosis we might find it and some we would not there are no doubt there

are some people who just as you said not every smoker gets lung cancer there are people with high apob who live long and healthy lives but I don't know what else is going on in their artery wall and I have no way of measuring that to assure them aha you're the exception to the apob rule well there's a lot you said there that I think is is a great place to go next but maybe just to finish a little bit of housekeeping we've now both brought up LP little a at least twice so I think

uh you know we've we've done many podcasts on this but what would be the three-minute explanation for the person who either needs a refresher or maybe who is new to this and hasn't heard of what LPA is yet and why should they care about it we've defined an LDL particle as a collection of cholesterol little bit of triglycerides wrapped by one peptide called APO lipoprotein B in some people who have the genetic IC Machinery their liver makes another protein called APO protein small case a the guy who discovered it thought he discovered a new antigen

a was the signal for antigen so that's where the little a came about again capital A is the APO protein a that is on an HDL particle so there are distinctions between small APO a and uh capital A all right so if your liver if your Gene tell your liver protein macking apparatus to produce this apoa within the liver it binds to the APO B that's on a primordial LDL particle that's being produced in the liver so now some of your ldls APO little a binds to it and the liver just secretes them into your

plasma so that's what an LP little a particle is it's a low density lipoprotein that is carrying another protein that should never be on an LDL article that APO protein little a has some characteristics that make it extremely atherogenic much of it ties into the oxidation that we mentioned before so if that particle enters your artery wall whatever oxidative forces are at play are going to get much worse which is not good as far as atherogenesis is concerned so if you have these LP little a particles and it's amount of concentration gradient that drives them

into your artery War that's sort of an inflamed particle carrying some oxidized phospholipid that can be pulled in by receptors that are still not defined but it can easily get into your artery wall so it's like hey we got a little fire in somebody's backyard and somebody brings a can of gasoline and throws it on the existing fire so the AOS scerotic process occurs much more rapidly earlier in life and uh it's bad news now the good news perhaps is uh 80% of people don't inherit the gene that makes you produce the sapo protein little

a but 20% do now people oh 20% no big deal look at 20% of the world population you're talking billions of people who have what's now recognized to be the number one uh lipid lipoprotein disorder associated with atherosclerosis so my goodness and this is why there's an alol for let's everybody get that checked once in your life life early on because you either have it or you don't and if you do have it then we can start looking at ways to perhaps modify some of the bad news risk that's going to occur with that process

right now we can't get rid of the apol little a particle that's perhaps coming there are drugs under investigation to do that all we can do if we discover this LP little a is look with a magnifying glass at every other risk factor or risk marker you have and do what we can to control those so LP little a is a bad news uh LDL type particle it's not atherogenic because of the amount of cholesterol it's carrying it's a what I call a minor LDL particle but it particle for particle it's seven to eight times

more atherogenic than an LDL particle so even now you have way way way more LDL particles you know an average person might have an ldl-p of 1200 nals so and you might have an LP little a of aund nanal and you would say oh that's that's a minor particle yes but if it's eight times more atherogenic than in LDL it's a bad news particle so it's like the the not everybody's a criminal in our country but it doesn't take a lot of criminals to cause a lot of Havoc so it's a terribly dangerous inherited type

of lipoprotein that's a great analogy to think about it you don't need a lot of something that has high virulence and potency to cause um a lot of difficulty um let's pivot for a minute to talk a little bit about something you also touched on briefly which was that when we're young we have what's referred to as a physiologic level of apob or LDL cholesterol um so the the concentration of LDL cholesterol in a child is low the concentration of apob is is low we don't see this very often because we're not used to checking

these things things in kids but occasionally um you know you'll even notice it as a parent if your kid gets sort of a comprehensive blood test um that you know their their total cholesterol might be you know 60 milligrams per deciliter with an LDL cholesterol of 30 milligrams per deciliter and an HDL cholesterol of 25 milligrams per deser I mean they're very very low levels of this um why does this change as we age why is it that aging seems to be associated with a monotonic increase in lipoproteins and this is absent something that we

could even get to later if we have time which is what happens during menopause for women which is more abrupt but just talk to me about ages you know 10 to 50 why does everybody seem to go the wrong way well a lot of of course is the multitude of things we sub subject our bodies to uh if you want to Encompass that with the environment or lifestyle you quote unquote whatever and you can throw probably whatever you want into that category of things that might cause your body to as apob B goes up it's

almost all related to your liver is losing the ability to clear these particles out of plasma it's not like you're overproducing 10 tons of them that's it C can happen but that's rarely a contributor to the high apob levels so scientifically we have to zero in on what regulates clearance of these particles and the simplest thing is to say well the only way these APLE B particles get cleared is our liver produces something called an LDL receptor which migrates to the surface of the liver cell that interacts with the blood flow the plasma and these

LDL receptors are Engineers to recognize any apob B peptide that floats by it so if an LDL particle containing apob floats by an LDL receptor it will get grabbed and then it gets internalized into the ldo receptor and it gets catabolized and then the liver can take whatever cholesterol triglycerides fatty acids blah blah blah is in that molecule and use it for other purposes or somehow get rid of it in the bilary system if the liver doesn't need it so it's going to come down to what are these factors that I called Hey environmental lifestyle

that affects what we call LDL receptor expression and it's a lot of things well one of the things you mentioned before insulin resistance would affect that numerous components of the diet Express are you uh regulating LDL receptors or not uh how much cholesterol your liver is being told it needs to put in the next vldl particle or more importantly the HDL particle going out so lipid balance in the liver is regulated by a bunch of things called nuclear transcription factors and they actually sense hey the liver needs some lipids or the liver's got too much

lipids and we got to get rid of it those nuclear transcription factors migrate into the nucleus and and the nucleolus of our cells and they bind to specific parts of the DNA and tell our genes produce this protein produce that protein this enzyme that enzyme this receptor that receptor that can go out and help restore sterile homeostasis to this human body so we could probably every adversarial thing you've been told in your life not to do gain weight don't eat this don't eat that are all affecting these nuclear transcription factors that are going to regulate

clearance of these aobb particles and it's a long list of things that can probably do that it is interesting that um that that on average more of the things that we do that are quote unquote less healthy he whether it be gain weight uh eat a certain way tends to result in decreased hepatic clearance um so so on that topic um one of the questions you and I get asked all the time is look hey hey Doc I uh I kind of buy I buy your thesis that apob is bad I buy your thesis that

mine is too high and I buy your thesis that I should probably lower it um I'd really like to start with my diet before um I I turn to pharmacology um you know typically there's two things I tell patients here the first is I think your two best levers nutritionally to reduce apob um are lowering triglycerides and lowering saturated fat intake now of course this assumes that you have high enough triglycerides that lowering them further will indeed lower apob and it of course assumes you're eating a high enough of saturated fat that reducing it significantly

will will lower apob so let's assume for a moment that those things are true we're talking to a patient Tom whose apob is 100 milligrams per deciliter um you know you and I have just kind of I I don't want to say read him the riot act but we've we've you know we've we've given him the the education that says look you'd be a heck of a lot better off if you were at 60 mg per deciliter um his triglycerides are sitting at about 100 62 milligrams per deciliter um and when we query his diet

we realize it's pretty high in saturated fat he's probably getting you know call it uh I don't know 40 or 50% of his calories from fat and he's probably getting you know 50 60 grams per day of saturated fat alone so in other words he seems like a really ideal candidate if he's willing to switch more of his fat calories to monounsaturated and polyunsaturated or even just reduce fat altogether and he's willing to take the dietary steps to reduce total calories uh and maybe even carbohydrates specifically um to to kind of bring down um his

his triglyceride so without getting into how he's going to do that can you explain why lowering triglycerides and lowering saturated fat intake those two things could bring this guy from 100 down to 60 sure the saturated fat is uh a little easier to explain we have plenty of studies that Show Excess saturated fat uh those genes that are regulating lip or those nuclear transcription factors that are regulating lipid balance in the liver and the liver is the master controller of lipid homeostasis in the body It Works hand inand with the intestine but the liver is

sort of the brains of the operation so uh in many many people exposure to saturated fat the nuclear transcription factors realize oh my God the fatty liver uh fatty acid toxicity is going to occur to this liver we have to uh take our defensive mechanisms on that so what they first thing they do is say my God we don't want more lipids being pulled into the liver by these LDL receptors so the nuclear transcription factors go into your DNA and say stop making these LDL receptors stop sending out the signal that will be translated into

an LDL receptor so of course if you eat saturated fat and your liver stops expressing LDL receptors your apob is going to go through the roof what is the apob particle carrying cholesterol and above the threshold concentration it's going in the artery wall typically if that person does follow your advice and restricts the saturated fat they will go back to some more increase in their LDL receptor expression all right uh the um saturated F and some people too also turn on the enzymes that induce cholesterol synthesis so now if the liver starts overproducing cholesterol then

the lipid pool is out of whack the same nuclear transcription factors go in and say stop making your retiv we don't want to pull in more cholesterol into this liver that's over synthesizing cholesterol so that's it it's another whole story as you know Peter why we don't necessarily tell people you have to restrict cholesterol in your diet that we're talking about saturated fat here and the absorption of star in your gut has nothing to do with the absorption of fatty acids in your gut totally different mechanisms that pull them in the triglyceride story gets much

more interesting and maybe much more important because it's so epidemic in this the world now this uh we know triglycerides is a poor man's biomarker of insulin resistance two things I wanted to say if you're measuring triglycerides in the blood and personally I believe the only things you need to me measure in the blood our apob and triglycerides uh there are basically two categories of hyper triglyceridemia one is it above 500 a, if it is you have some crazy genetic disorder that is uh involved with your high triglyceride and most of those are not associated

with atherosclerosis so but nonetheless they are associated with pancreatitis and other pathologies so you would want to lower what's called a very high triglyceride level but the average doc who's out there doing lipid levels is going to see a triglyceride maybe between 130 and 160 180 what you said every once in a while you'll see a 3400 but they're less common that almost is always insulin resistance as the idiology of that uh through many factors so once you have too many triglycerides and where are those triglycerides being made in your liver other cells don't produce

triglycerides other than an osy but if your liver is over producing triglycerides the liver says oh my God I got to get these out of here because if the liver retain triglycerides you know it's going to get fatty liver not a wise thing the liver wants to do so the liver then packages them into uh the triglyceride containing lipoprotein the very low density lipoprotein why do we even make vldls what purpose do they serve even if you have a physiologic vldl concentration it must be doing something once the liver mix it and secretes it and

that is very similar to the big kyom Micron particle that comes out of your intestine these are the triglyceride carrying vehicles that are bringing fatty acids in the form of triglycerides to the tissues that need to grab the triglycerides convert them to fatty acids and oxidize those fatty acids to make ATP they would be our muscle cells the heart being a very important muscle that you want to keep beating it's a big consumer of triglycerides the muscles the big Chom microns the big vldls coming out of the liver they go into beds that Express the

triglyceride dissolving enzyme lipoprotein lipase muscular beds or atpy beds the triglycerides are hydroly the fatty acids they enter those muscular beds and then they can be oxidized for ATP in an adpo site the fatty acids are pulled in reconverted to triglycerides and stored for future energy needs so that's what vldls do but if you have way more triglycerides in your liver because you're insulin resistant and your liver is over producing them the liver makes very big vldl particles earlier on I talked about hey there are certainly NMR signatures of insulin resistance the big vldl is

one a normal person with physiologic triglyceride never makes big vldl particles there's no need for them that person makes smaller vldl particles that carry just enough trigs to be sufficient for energy needs of the muscle but in an insulin resistant person with high triglycerides here come these big particles out now insulin resistance is not only associated with too much triglycerides there's another apil protein that is made in excess and it's called APO protein C3 so the vldls coming out of the liver are now carrying something they shouldn't carry very much of apoc3 make a long

story short it retards the catabolism of these triglyceride Rich vldls so it blocks their attachment to lipoprotein lipase so the plasma residence time of a vldl or kyom Micron which should be extremely short is now prolonged what is the consequence these triglyceride Rich vldls float around longer than they should number one if you measure triglycerides in the blood it's going to be higher than an ordinarily would be and that's why if you look at a certain triglyceride level you might suspect this is happening but here's the continuing bad news when these triglyceride Rich vldls are

floating around in plasma they bump into the much much much more numerous LDL and HDL particles and what happens we we carry a lipid transfer protein that actually locks ldls and hdls into vldls or ldls into hdls it's called cholesterol Ester transfer protein CP it really should be called CP cholesterol eser triglyceride transfer protein cuz what happens is when these two particles my joke is they're mating cuz they're now connected with this little Canal they exchange one molecule of triglycerides for one molecule of cholesterol in essence the vldls and chylomicrons become triglyceride poorer but more

cholesterol Rich whereas the LDL and the HDL become cholesterol poorer and triglyceride Rich any doctor who does a lot of lipid profiles knows yeah you're right Tom I notice every time triglycerides goes up LDL cholesterol doesn't necessarily goes up but almost assuredly HDL chol olol goes down and that's because hdls which should really carry almost no triglyceride molecules have now sucked in a lot of trigs but they've given up cholesterol if we were measuring HDL triglyceride levels we would see it's very high but we just see the HDL cholesterol is low the last step what

happens to any triglyceride Rich particle there are light Paces ready to dissolve it endothelial lice and hepatic light attack triglyceride Rich hdls by extracting and hydroling the trigs the HDL particles become so small they break apart apoa1 goes down to the kidney where it can be catabolized into amino acids and excrete it hence explaining why diabetics people with high trigs have such low HDL particle counts and low HDL cholesterol but basically here's what happens to the LDL now the LDL is sending cholesterol in exchange for triglycerides to the vldl or the kylo so the little

LDL particle much smaller than those monsters becomes triglyceride rich and cholesterol poor so what is the fate of that type of LDL if we could only measure LDL triglycerides it would be by far the best lipid metric we could ever measure so Tom it seems like the reason apob is going up in a high triglyceride environment is because you need more ldls to carry the same amount of cholesterol eser because so much of their carrying capacity is going towards also managing the transport of triglycerides and therefore while LDL cholesterol might remain constant it's being spread

out over more particles therefore apob which is the marker of particle Concentra is going up and of course that's the metric that matters this of course is the classic example of where we see discordance between LDL cholesterol and apob particle concentration so we were talking about the triglyceride Rich LDL particle and what happens is the liases mostly hepatic lias takes the trigs out and then the LDL particle becomes very small so you have a small LDL particle which per particle can't carry many cholesterol molecules but the major reason apob goes up is an LDL that

is small the apob assumes a different confirmation on the surface of the LDL and it is no longer recognized by the LDL receptor so you have marketly delayed clearance of the small LDL so uh yes you'll have whether your LDL cholesterol goes up or not the cholesterol is spread among more LDL particles cuz they can't be cleared anymore so that is why lifestyle can work very good CU or anything that lowers trigs can interrupt this pathologic lipolysis or catabolism of these apob particles if we could make those small ldls disappear and they would assume their

more circular shape they're they conform to the LDL receptor more so this is why if you look at the APO b or even the LDL particle count in diabetics it's through the roof or in people with high triglycerides due to mostly decreased clearance and so the ldlp goes up but what's driving the total ldlp it's the small ldlp they would have some large LDL still floating around there's never going to be anybody who has 100% small or 100 and big but the predominant species when triglycerides goes above a certain threshold is the cholesterol poor small

LLS that have decreased clearance so apob goes up and well when APO goes up where do these small particles go that's an apob particle it crashes the artery wall with relative ease uh so that's the basic explanation there and this is why other things that uh the other thing I should tie into this that what level of triglycerides can this occur and you know the silly guidelines have put hey and triglyceride of 150 above is where it's high risk and that's what the average practitioner patient believes because that's what the labs report on the lipid

profile this transformation that starts to delay the lipolysis of these particles occurs somewhere at a triglyceride 100 or above uh it you don't have to have a trig of 150 that's the 75th percentile of a population triglyceride distribution my God we don't wa for any other lipid metric to hit the 75th percentile so I'm not sure why they still do that uh other than perhaps they didn't have enough uh to tell people what to do about it but you and I know when we look at it at the lipid panel we're a little nervous when

tricks start to go much above 80 to uh never mind 100 to 120 I often use myself an example I've been a lifelong very insulin resistant guy always had a pretty decent l the L cholesterol my trig was always in the 102 105 range which I dismissed as being normal but of course once NMR came around I saw oh my God look at your LDL particle concentration look at the number of small ldls and this is why triglycerides cannot be unlined from APO B2 cu the real pathology of high trigs it's just creating too many

cholesterol carrying particles that can invade the artery wall it's not glycerides in the artery wall that are generating a atherosclerosis it's the delivery of cholesterol but as trigs go up you have a lot more apob cholesterol carrying particles even though each particle is carrying lesser numbers of cholesterol than before there's just many more of those LDL particles that are crashing your artery wall so when we do get to come up with a way to lower triglycerides nutritionally or even if we wanted to use a drug and virtually every single one of our lipid modulating drugs

is FDA approved to lower triglycerides you can't look at it and say oh I've lowered your trigs from point x to x minus whatever you have to lower APO B to see aent reduction with trigs now most of the time when you lower trigs with proper therapies lifestyle drugs you will see a drop in apob but there have been several trials that dramatically lower triglycerides with the fibrates that did not reduce mace because although they dramatically lower triglycerides they were they're not the greatest apob lowering drugs in the world so respect triglycerides at much lower

levels than You' never been taught but your goal of therapy be it lifestyle or drug is did I normalize apob yeah so I I think that's a very important point right which is um it's always worth taking a shot at modifying your nutrition to fix apob but don't forget the goal the goal is lowering apob we have these two proxies that are are quite helpful triglycerides if they're high great great way to approach usually in most people caloric reduction is the is the is the key of doing that and therefore if you have a person

who's on who's eating a lot of saturated fat a lot of carbohydrates you know lowquality carbohydrates sugars hypercaloric that that person can actually do a lot of uh apob reduction with with nutrition conversely when you see a person whose trigs are 50 migs per deser who's not mainlining saturated fat and eating in relatively normal amounts I typically advise those people against Draconian fat reduction which admittedly will indeed lower um cholesterol uh but but often comes at the consequence of something else nutritionally and so we we tend to sort of steer clear of that and and

save that for for people who who have an obvious reduction um I think this point by the way about the confirmational change um in uh in the relationship between the LDL uh uh receptor on the liver and the LDL particle is a very interesting one of course it begs the question Tom do we believe that LDL particle size should be of concern um given that you just acknowledg that these smaller cholesterol depleted LDL May linger longer or can we largely ignore that if we have a good handle on apob in other words is all of

the risk of everything you just discuss captured in the apob marker yes but uh if you were doing everything you say nutritionally or pharmacologically to doer that you would see a transformation of those small LDL you wouldn't find them anymore and you'd have a normally sized and apob composed particle but what I should introduce into this discussion is the nonsense going out there that these big ldls often called fluffy Buffy or cardioprotective but guess what happens on a big LDL the apob gets distorted on the big LDL too and those particles are far less compliant

to the LDL receptor it's one of the reasons people with FH have such cuz they have very big particles and their high apob is due to defective LDL receptors but it's also due to defective attachment to LDL receptors because the apob is no longer in the proper confirmation and the last thing I'm always going to sneak in on this triglyceride topic I did mention it's the kyos and the vldls that carry Triggs they're the big triglyceride carrying particles yes they screw up the hdls and ldls by sending trigs over there but normally those particles should

deliver the trigs to the muscle cells where they lose trigs and then they get smaller the kyos and vldls smaller kyos and vldls are called Remnant vldls or kyos but when they shrink the main reason they get cleared from the body is they carry multiple copies of APO lipoprotein e and APO e is the APO protein on vldls and kyos that binds to a very specific hepatic receptor in the LDL receptor family called lrp LDL receptor related protein but when apob B is on big vld and kyom microns it's contorted it doesn't bind to the

lrp but once the kyos and vldl shrink down the apob assumes a confirmation and that's why their plasma resonance time is so short it's all apoe mediated and each of those particles carry several copies of apoe but in insulin resistance where the vldl and kyos can't get rid of their trigs they then you these people have what is called increased remnants now they're nowhere near the particle number of remnants doesn't even come close to an LDL particle number but it's up way more than it should be and particle for particle remnants carry five to six

to seven times more cholesterol per particle then an apob LL particle so if you let these remnants float around they get pulled into the endothelium they're a very inflammatory particle in part because of the apo3 on them they get internalized easily into the artery wall which is another reason people with high trigs have so much atherosclerosis it's not only because they have too many LDL particles they got too many remnants and if they're losing hdls if hdl's perform a cardioprotective function by extracting cerol AIO they no longer have enough hdls to do that that's why

you and I get very nervous when we start to see trigs exceeding a 100 because we assume some of these pathological pathways are at play so a couple of very important points there Tom the first is yeah it's true that the remnants just like the lp little A's are captured in the apob concentration but it's almost like you have three populations for lack of a better term really four populations that are buried within apob you have the majority of them which are ldls you have vldls your garden variety vldls you have your LP little a

if you have too many of those and then you might have too many Remnant vldls and of these four it's that Remnant vldl in the lp little a that pack more of a punch than their counterparts the regular Garden vldl and the LDL and so this is where I think apob by itself can be a bit misleading in other words you could have two people that both have an apob concentration that's identical but if one of them has it in the context of basically it's all LDL cholesterol and some vldl yeah they're okay um and

then the other person might actually have a disproportionately high LP ltil a Andor Remnant concentration and you won't know that unless you're doing some of this additional analysis is that is that kind of a a fair rationale for saying why we want to look at everything yes so you measure LP little a that's easy and you see it's not a major contributor APO B but it's a terribly atherogenic particle so we get nervous with it with the uh vldl particles you measuring apob B tells you nothing about the number of vldls have because although they

can be particle for particle more a enic there's not very many of them so what's a poor doctor do here's my little Pearl so there's another metric people should look at it's called U non HDL cholesterol think of what that means that's the cholesterol that's not in your HDL particles in essence it's your apal B cholesterol so how would I know if your apob cholesterol is up I can't look at apob B but if I did that calculation non-hdl cholesterol if your apob is looking good but non-hdl cholesterol is still a little high I'm suspecting

you got some of them Remnant V the old particles floating around now it's not 100% true but it's about the only thing you can do there are no accurate Remnant tests that are available to the run-of-the-mill doctor so look at non HDL cholesterol and by the way for the listeners that's a freebie on the lipid profile it's basically total cholesterol minus HDL cholesterol so that means it's the cholesterol that is in your vldls and ldls so if your LDL cholesterol apob B is looking good but your vldl cholesterol is still high that would drive non-hdl

cholesterol to be higher than it should and that's why Peter and I also have very aggressive goals for non-hdl cholesterol also we don't always discuss it with the patient but we would if it was still elevated within the face of normal ail B all right let's talk about hdl's the most confusing of the lot now we've already done dedicated podcasts on this topic we've spoken at length about this so we're not going to be able to obviously cover this in too much detail and we'll Point people back towards the previous podcast where I've done this

but um you've already alluded to the fact that hdls can be protective this has led M many people to refer to HDL as the so-called good cholesterol and if your quote unquote good cholesterol is high yeah you don't need to worry about anything um I'm not going to ask you to debunk that because the tone of my question already suggests that that's nonsensical so let's let's have you know kind of a a modest but but brief discussion on how hdls work and why is it that when they're functioning they can be quite protective um but

at the same time maybe say a word about why unfortunately we can't figure this out or discern this from blood tests yep and it's so important and it's so unknown out there in the real world and in the Layman's world it's probably not known at all because they keep reading these idiotic missives in newspapers and magazines that boy check your good cholesterol and even if it's high you don't have to worry about your bad cholesterol LDL it's so sad it's even Saturn that some providers still believe this and tell their patients that all right so

basically what we say very quickly to any patients is uh as we're teaching them about lipoproteins and what they do and what they carry we get to a point where we say we're not going to talk about hdls anymore now don't get me wrong HDL particles are incredibly important to both your cardiovascular system and probably many other tissues in their your body and that means a hdl's perform a lot of functions that especially with the heart may be very cardioprotective we also know that some people have the type of hdls that don't perform those cardioprotective

functions they actually perform bad functions to the artery wall and plaque and the heart so and the important thing is you can understand boy so it's what hdl's do let's call that HDL functionality and to to make a long story short whether your hdls are doing those cardioprotective functions or they're doing bad things to your vasculature whatever they're doing has zero relationship to their cholesterol cargo meaning your HDL cholesterol level in the blood there are people with low HDO cholesterol often a signal for high cardiovascular risk but not every body and there are people with

very high HDL cholesterol been told they're protected and we know they are not a group of them gets aosc orotic disease a group of them have been described with breast cancer dementia so obviously you can't look at an HDL cholesterol in an individual patient and make extrapolations on what the heck the hdls are doing in that person the reason hdls have these either miraculous or disastrous properties comes down not to their lipid content certainly not their cholesterol content again but to their two things their protein content over 150 proteins have been found to be associated

with various HDL particles and they perform an immense number of likely very necessary uh actions that need to go on in certain tissues where things may be going wrong we also know that the coat of an HDL apart from its proteins is virtually all phospholipids so the exact phos phol lipid concentration of an HDL surface has tremendous amount to what to do can an HDL do wonderful things or bad things those phospholipids depend really determine what an HDL can bind to in various tissues now of course we can't measure HDL phospholipid content there are hundreds

of phospholipids you would you would get a lipidome coming back that you you couldn't even pronounce half of the phospholipids or at least the fatty acids that are in those phospholipids and same with the protein if there's 150 of them I guarantee the average doctor might be familiar with about 10 of those proteins and not with the rest of them so I don't know how to determine a patient's HDL functionality clearly the people having adverse effects with high HDL cholesterol have dysfunctional hdls probably related to that proteome or their phospholipid content and vice versa so

what we tell a person right now is in the year 2024 we didn't always believe this this bad cholesterol Had An Origin that everybody believed way back when Framingham Mr fit the earlier observational trials nobody ever adjusted for apob in those trials it wasn't even available when they were doing it so we now know that the people with low HDL cholesterol who do get atherosclerosis always have high apob B and why why do those people have low HDL cholesterol I've already told you it's the trigs that knock the HDL and the trigs may not be

400 the trigs may only be 130 which are being ignored so and what is high in them APO B so the proper treatment of low HL cholesterol in the person you believe has cardiovascular risk is just like trigs lower APO b lower non-hdl cholesterol if you can't get an apob B I don't know what to if somebody has a high HDL cholesterol I don't know what blood test to tell you I always checking apob we do that in 100% of people and if it was high we would treat apob regardless of an HDL cholesterol level

but I can't look at a man or a woman and say oh my God you're the one with high hdlc who might wind up with Dementia or some cancer or something I don't know so we'll track those other diseases with other modalities that we have at our beck and call I don't know what to tell you about your cardiovascular health if you have high hdlc but I can guarantee you it is not a declaration of cardiac morality so it's HL functionality and you recall the the we had an nice email exchange about a friend of

mine who's I've known for many years he's always had a very high HDL cholesterol and a very low LDL cholesterol um in fact his HDL has routinely been above 100 milligrams per deciliter um and his LDL cholesterol has always been below 100 milligrams per deciliter so this is this is a guy that by anybody's metric looks like he's in tiptop shape um but I did suggest to him at one point you know it would be reasonable to at least do a calcium score because you know we I've seen these case studies of individuals with high

hdlc low ldlc who still end up having arthrosclerosis and it can be quite aggressive because it could be that that high HDL cholesterol is actually a marker of of dysfunctional HDL that are having a difficult time clearing it to make a long story short he ended up having quite a high calcium score and so now he's on very aggressive treatment to to take any residual risk out of that apob so he's on you know double therapy now and he walks around with an apob in the 20 to 30 range and and hopefully that's going to

be sufficient to this um but again always a great story I remember you sharing that I remember you sharing that case with me and I my God why the heck did you do a CAC and because you've heard me spout enough you learned your lesson I don't use hdlc to make any decision yeah it it I distinctly remember reading a case study 10 years ago about a woman who looked just like that and ended up having very Advanced artherosclerosis um let's pivot and talk about the brain a little bit this is an area where your

own knowledge has grown rapidly Tom this is clearly an area of immense curiosity for you for me um because you know cherol plays an important role in the brain I think to to put it mildly um and people have many questions about the role of cholesterol lowering therapy and brain health so um what let's just start with a basic question which is what role does cholesterol play in the brain um and what do we know about the different pools of cholesterol we have cholesterol outside of the central nervous system cholesterol inside the central nervous system

can they move back and forth can lipoproteins go back and forth is LDL taking cholesterol into the brain and back to tell us about how that whole system works so important I'm glad we're going to chat about this a little bit and it's obviously so complex really I almost give you credit you're the guy who got me interested in lipids in the brain year probably 15 years ago when you introduced me to Richard Isaacson at the Cornell dementia clinic and he was very interested in lipids cuz he just knew lipids are part of what's going

on in the brain and I better learn more about lipids and you were good buddies and I got Dr pulled into that Circle so that's I like how you said dragged initially I mean uh I mean I mean pull pulled slowly yes now you're a strong Guy Peter you uh you've motived me to study a lot of things that maybe I wouldn't have tripped into and that uh I don't know I would have ever met a Richard Isaacson had it not been for you but thank God you did and so we've been trying to learn

about brain and the lipids so often the last thing I'll say you did that great podcast with Dan Raider on hdls and it's a podcast everybody should listen to but at the end you sort of turn to Dan you said where are we going with lipids Dan we've sort of solved the APLE B we're learning a lot now about HDL and Dan said it's lipids in the brain is the next Frontier and why has that not been studied very much until now because you can't stick a needle you have to go into the get cerebral

spinal fluid to analyze what's going on in the brain and uh most people are amenable to a ven in their elbow not a spinal tap so here's what's going on cholesterol is almost certainly the most important molecule in the brain the brain is by far the most cholesterol carrying organ in the body the brain actually makes more cholesterol than any other organ per se way more than the liver even so if I gave you a dumb question hey I'm a I got this body here and I want to find out where all the cholesterol is

where should I go open this skull and take out the brain that's where you're going to find the most cholesterol wow so obviously cholesterol is crucial to the brain and that's because the brain is made up of a lot of cells all of which have important functions especially those neurons that shoot off all the action potentials that make our body function and everything and what's on the surface of a neuron free cholesterol and phospholipids so Evolution I guess figured out a long time ago that the brain needs cholesterol so we're not going to make the

brain dependent on cholesterol that's floating around the plasma or what's in your liver or your intestine we're going to let the brain make all the cholesterol it needs so we're going to really drive the enzymes that uh synthesize cholesterol in the brain so the brain needs cholesterol to make a long story short every cholesterol molecule that's in the brain got there by denovo synthesis in the brain not a single molecule of cholesterol was delivered from the periphery meaning that floating around our plasma leaves the plasma and enters the brain now by the way where is

all the cholesterol in our plasma I've already told you it's got to be inside of a lipoprotein floating in plasma that's where we measure cholesterol that's where we measure lipids in the plasma but I can assure you there is no cholesterol carrying particle in the plasma be it a vldl an HDL uh or an LDL that crosses the bloodb brain barrier and says okay brain here's your cholesterol for today doesn't happen there is a rapid turnover of cholesterol in the periphery cells make it they get rid of what they don't need it's brought back to

the liver uh for to for the liver to decide what to do with it the turnover time for cholesterol in the plasma is 2 to three days all right so if a cholesterol molecule is synthesized in the brain what is it halflife 5 years now halflife if a halflife is uh a given number the total sort of brain resonance time of that cholesterol molecules you multiply that by seven so uh some cholesterol molecules last up to 30 years once they're synthesized in the brain and that's why cholesterol synthesis in the brain starts in utero early

on Mom Supply in the little fetal brain with a lot of cholesterol but very rap rapidly second third trimester those brain cells start making their own cholesterol once a child is born there's a lot of cholesterol synthesis going on by virtually every cell that exists in the brain there's only like three of them but at a certain point somewhere between the ages of 5 and 10 the brain May has made all the cholesterol it needs so then only two cells continue to make cholesterol so lesson number two what are the cells in the brain that

we're in this conversation with neurons I've mentioned in utero and in childhood neurons produce a lot of cholesterol but at a certain age the neurons got more work to do they don't want to make cholesterol why because every cholesterol molecule requires 27 molecules of ATP to produce it's a super energy gien process neurons need ATP for a lot of other functions those electrical charges they make all right so what are the other two cells in the brain oligodendrocytes make the most cholesterol and where is the cholesterol they make become myelin which coats every nerve ending

every axon and dend in your body so uh the those aliga dendrites are big time cholesterol producers but they make all their cholesterol go to myin they don't send any cholesterol over to neurons so what is the other cell and it's asites in again in infancy and childhood and utero alod dendrites asites and neurons are making cholesterol let you know tomorrow once the neuron stops making it astrocytes are the soul maker of cholesterol that supplies the neurons but how would an asite synthesize cholesterol and send it over to the neurons aha the brain has to

have a lipoprotein system just like the periphery does now between astrocytes and neuren neurons is basically its brain interstial fluid sort of a loose connective tissue it's called the matome so if asites synthesize cholesterol they obviously have to package it inside of a brain lipoprotein secrete that lipoprotein which swims through the matome and goes over and guess what the neuron expresses LDL receptors LDL receptor related protein or something called the scavenger receptor all of which can bind to the type of lipoprotein that an asy produces so the brain also has a lipoprotein delivery system but

here's the difference what is the main structural protein in the periphery APO b or APO A1 what is the main structural protein in the brain APO e so when an asy makes an lipoprotein it's an APO e containing lipo protein and by the way they're smaller much smaller than the particles the bra that we find in the periphery if we put them in a cuge they have the density of a high density lipoprotein that would floats around the periphery so they're often called brain hdls but don't confuse brain hdls with peripheral hdls cuz most of

the brain hdl's have APO e as their structural protein in the periphery they have a A1 here's where the story gets a little more complicated as always what is the smallest ail protein the body can make it's actually APO protein A1 which is why an HDL needs four or five of them so if APO A1 can dissociate from an HDL and we do have free HDL in the plasma that's measurable it is small enough that it can cross the bloodb brain barrier and once it joins the bloodb brain barrier what is the small APO A1

looking for an HDL buoyancy particle so it joins with the apoe particles so the brain lipoproteins are all apoe or they're all apoe plus apoa1 and you can have multiple copies of each of those on those particles so wow so now as long as the APO A1 by the way which can bind to an LDL receptor or the scavenger receptor same with the AP OE the neuron can grab them and either internalize them or delipidated particles can go right back and fill up at the asite again so that's brain cholesterol transformation but Peter I know

you CH you check apoe genotype on your patients and you do worry when certain apoe genotypes come back especially those carrying the E4 a cuz we know that's associated with ad and we have enough knowledge to know that God those brain apal proteins the brain hdl's carrying apoe4 are guess what dysfunctional hdls just like we've discussed you can have dysfunctional hdls in the plasma so if your brain makes apoe4 instead of apoe3 or apoe2 you are not going to have the best brain HDL particles and not only do brain HDL particles carry cholesterol back and

forth they also can if ameloid or TOA is being produced in a neuron they can grab it and transfer it over to U microa which are brain immune cells which can get it and take it down and get rid of it in the brain lymphatics so your apoe genotype certainly affects the our vldls and kylo in the plasma that's a lecture for another day cuz that's not that common but in the brain ape4 you only have apoe containing lipoprotein so you don't want to have it Tom let me just interject for one sec I just

want to make sure people aren't uh confused on that point so uh definitely people listening to us are familiar with the apoe4 gene but just to reiterate you you you're going to have two copies of these genes just as you do for every Gene this is a gene that exists in three isoforms so none of these are considered mutations uh meaning there are three types that occur in nature the E2 the E3 and the E4 um isopor so you have six combinations of these and therefore three of these combinations include at least one copy of

an E4 so there's the 24 the 34 and the 44 so we know epidemiologically that there's a clear increase in the risk of Alzheimer's disease As you move from 24 to 34 to 44 and I just want to make sure people understand that we're kind of going back and forth between the Gene and the protein if you have an E4 gene or a e3 gene or a two or whichever combinations you have you still make an APO e protein what is different is what the protein looks like in response to the Gene and what's very

interesting is if my memory serves me correctly I believe it's only a single amino acid substance ition between each of these in other words one amino acid difference between the one made by the three isopor and the for isopor results in what you just said which is individuals who have the apoe4 gene have an apoe4 protein that wraps their brain lipoproteins that gives it less affinity for doing this job of transferring cholesterol from astrocytes to neurons so this is is a very important explanation of why it is that people with an apoe4 Gene are at

an increased risk this is not to say it is a a causitive gene it's not a deterministic gene it's not a gene that if you have the if you have a copy or two copies of the apoe4 gene you're going to get Alzheimer's disease this just explains why there's a greater susceptibility and why an individual who has one or two apoe4 genes needs to work that much harder on all of the other variables that factor into ad um and again to your point why does this not really play as much of a role in the

periphery we could save that for another day but it sort of does in the edge cases and that's why we see a higher incidence of ascvd and apoe4 carriers you did already allude to it but only the astute listener will remember it when you talked about the apoe and the confirmational change of lipoprotein I'm not going to go back to it because I want to stay on the brain um but anyway I just wanted to interject that point so people knew the relationship between the genotype and the phenotype of the structural protein very but and

even that single amino acid change just affects the shape of the protein so it no longer binds where it should and it screws up its so-called functionality of the particle one amino acid in a peptide you wouldn't think but it's true now there's one other part to the brain lipid story and it gets deeper and remember in the brain we're on our infancy so much of what I'm going to tell you now it's not carved in stone and the discussion but it's how we understand it in September October November of 2024 so it's the cholesterol

story in we know brains that have if the brain can't get rid of cholesterol that is associated one of the characteristics of people with Dementia or Alzheimer's disease so there comes a point where too much cholesterol in the brain can be bad news but we also know and I'll discuss it in a moment but because cholesterol synthesis is so crucial to the brain you would never want to restrict uh cholesterol synthesis to a severe degree that wouldn't of just suggesting that you would say yeah that doesn't sound too bright so let's get into cholesterol homeostasis

in the brain so now the neuron is an interesting little cell there because it gets its cholesterol in adulthood from these apoe containing particles but if the neuron wound up with too much cholesterol uh just like too much cholesterol in any peripheral cell the liers it's lipotoxic it by itself would kill the cell so the neuron is the one cell in the brain that was given an enzyme that it can transform cholesterol molecule into a metabolite that's called an oxy stero and do we have another name for oxysterols and this will make you scratch your

head yeah they're bile acids the liver by the way can change cholesterol to an oxysterol which me sends it right down the bile acid synthesis pathway and the liver dumps it in the bile and we excrete it fecally so if the neuron can change cholesterol to an oxysterol is it possible for that oxysterol to leave the neuron and enter the plasma and that would be a way of the central nervous system to get rid of cholesterol now wait a minute that's a lipid lipids can't pass through that bloodb brain barrier so the neuron makes an

these oxysterols that's basically a stero with extra oxygen molecules attached so the neuron makes something called 24s hydroxy cholesterol for those of you who've listened to our first podcast you know cholesterol at one end has a hydroxy group that's what makes it somewhat water soluble but the other end of the cholesterol molecule has no hydroxy or it's all lipids but if we could stick another hydroxy group on the taale of the cholesterol molecule that has a hydroxy group at both ends it actually becomes a rare hydrophilic lipid it's a lipid that's soluble in water and

it has no trouble passing through the bloodb brain barrier once it enters the bloodb brain barrier it's in plasma and it either rapidly binds to albumin or to any lipoprotein that's passing by and both the albumin or the lipoprotein brings that oxysterol to the liver which converts it to a bile acid and excretes it so the brain can actually get rid of sterols in a ferous way by sending it down to the liver which makes a bol from it so 24s hydroxy cholesterol or hydroxy is the enzy only neurons have all right but so there

is people think if we measure 24s hydroxy cholesterol in the bloodstream and it's high we know the brain's trying to get rid of cholesterol and it's a marker of brain cholesterol health because you really should have trivial amounts of that in the bloodstream and it is with mass spectrometry easily measurable all right but let's get back to the asite and the neuron making cholesterol our cells Peter has talked about this many times there's a bunch of original steps that go to a linear molecule called squalene and then it starts to form a cyclic molecule that

are called sterols and the ultimate stero is cholesterol but there's many steps of the stero one stero becomes another one becomes another one becomes another one the penultimate next to last sterols that ultimately will transform into cholesterol are either lathosterol or dmol as it turns out and it's lucky for us uh lathosterol is the major pathway of peripheral cell cholesterol synthesis when your liver makes cholesterol it goes through the lathosterol pathway same with most of the cells in your body who uses the desol pathway why did Evolution give us two cholesterol synthesis Pathways because cholesterol

is essential for human life God forbid you had some genetic defect where you knocked out one synthesis pathway you've still got another so you're still survivable all right so the desmal pathway although it could be used by any cell is primarily used by the brain asites also in the periphery by the steroidogenic tissue so very interesting so in your brain can we measure serum desmal would it reflect what's going on in the brain actually we know it does cuz people have done the studies where they've done spinal taps analyze CSF desol and it correlates incredibly

well with serum desmo so Serum desol is a biomarker reflective of the desol synthesis pathway by the way for the Nerds that's called The Block pathway the lostal pathway is called the canand dut Russell pathway asites predominantly use the block to desmal pathway and in adults asites are the supplier of cholesterol to the neurons if for some reason the asy fails and the neuron and an emergency how to make cholesterol it actually uses the lathosterol canand dut Russell pathway but in adults that pathway is for the most part not at play it's inactive so again

that's why we don't measure lathosterol lathosterol is telling us anything going on in the brain because it's all coming from peripheral cells it would be a minuscule amount that might be brain by the way Tom do you think it's uh my speculation has been that the reason that the place we see desol in the periphery in the steroidal tissue is that that's the tissue that has the highest demand for cholesterol production maybe suggesting that the dmol pathway is more suited to a high demand pathway Visa the asites and the steroidal tissue again we're so far

in the nerdy stuff on this now that I don't think that's that's just a just a speculative comment no but listen it's the AA brain that thinks of stuff like that's why I love that I known you for 15 years cuz many of the things you tell me I got to go look up and say God that sounded logical let me check if there any truth to and I think you're absolutely right with that statement so uh before I get more into that anybody who's ever prescribed the Statin to people knows there's a very small

amount and it's even in the package insert that comes back and tell doc since you started this I'm not right I'm not thinking right I'm not calculating right my brain is in a fog and we use the word brain fog again an extreme minority of people given statins have that we had no clue what caused that invariably would stop the Statin try another one it usually occurred or if it didn't fine but if not then we'd have to figure out other ways to lower LDL cholesterol which was not easy years ago but anyway my hypothesis

nowadays is these small number of people who get brain fog I wish I had disero levels on them could some people be very sensitive to the effects of a Statin we know in the periphery hyp synthesizers of cholesterol respond incredibly well as that and so excuse me over synthesizers do hypos synthesizers do not so who knows but that if that being said now here comes the next part of that epidemiologic study where they correlated low desol with serum desol people who had low serum desmal had a much higher incidence of cognitive impairment and Alzheimer's disease

which would lead simply to the hypothesis that Serum desmo is a usable biomarker to say is somebody at risk for Alzheimer's disease and this goes back to when uh I met Richard is and with Peter we started throwing these hypotheses around and we've watched that ever since where would it come into play so if we're and you know until recently statins were our only game in town so if we write a Staten especially if used it higher dose if desol was dropping low and we'd use an arbitrary cut off point the 20th percentile would that

be maybe you don't want to inhibit cholesterol synthesis in the brain to that degree might we want to attack APO be with another agent all hypothetical uh Reasons I'm putting on the table here right now and I think right now we look at that especially in who who are the people that we know are likely prone to uh demension cognitive impairment the E4 carriers people maybe with strong family histories people that have other identifiable trits that may traits that make us think they're prone to ad we would watch desm rol incredibly closely in that population

so now the last thing I'll tell you if the astroy is not making cholesterol because of its being overs supressed by a Statin the neuron would be getting less cholesterol the neuron would convert none of that cholesterol to 24s hydroxy cholesterol because it's trying to conserve every cholesterol molecule it can so I think if you were somebody who could measure 24s hydroxy cholesterol in the serum you would not see it in somebody who had cholesterol synthesis suppression in the brain this all has to be worked out in future clinical trials but there there are looking

at this in some clinical trials right now so one day we'll be a lot smarter on this right now if you want you could measure dis mool and perhaps use that as a cautionary marker number one if they're not on a drug and it's low you if you haven't done an apoe4 genotype you might look at it uh but if it is somebody who has a propensity does mool and you have to use a Statin maybe you want to watch that the good news is and I think it's why our Mantra is if we have

to use a Statin we start with lowd do statins we have very little use for the high do Statin in the year 2024 because none of the other apob lowering drugs be it bidic acid a ZM certainly pcsk9 Inhibitors get into the brain and suppress cholesterol synthesis so we have many ways of lowering apob if we a little fearful of low desmo in a patient prone to a or so so that's about as much as we want to get into probably with brain lipids right now and understand apoe is a big player up there and

there are different types of the apoe protein but understand cholesterol homeostasis has a lot to do with what is in the peripheral cells we can look at markers of synthesis the markers of cholesterol absorption that we use big time when evaluating peripher cholesterol homeostasis obviously is not at play in the brain the brain is not absorbing cholesterol from your gut before we leave that Tom um what is our hypothesis around the hydrophobicity um of various Statin and do we think that certain statins are more likely to cross the bloodb brain barrier are there certain statins

that should be ignored in patients with margin desol great question and the thoughts have changed on this too cuz early on if you go back probably maybe even listen to the podcast you and I did in 2018 I believe we were talking about hydrophilic and lipophilic statins and the lipophilic ones can pass right through the barrier a little easier than the hydrophilic one which need receptors to pull them in but uh subsequent analyses is shown all statins get into the brain ultimately once you have a steady state Statin level in the blood they all will

get into your brain and they all have the ability to suppress cholesterol synthesis in the brain now the last thing I want to say about statins before everybody says oh my God I'm stopping my Statin tomorrow I can't get a desmo level well they're available if you look for but in general if you analyze all of the stat and data the many trials be they observational or randomized control there is no signal whatsoever that in a population statens uh worsen or cause cognitive impairment or Alzheimer's disease there's a few studies that even suggest perhaps some

lowering maybe that's through a scerotic cerebral vascular disease who knows but don't worry that Statin in the overwhelming vast majority people are not hurting the brain but I think we've introduced perhaps a biomarker that you might know with a little more certainty if you have to write a Statin in somebody subject to dementia yeah um we actually covered this at length in one of the previous uh amas and I went through every meta analysis on this topic it's important for people to understand that at least at the time and I don't think this has changed

there has been not been any Statin trial where the primary outcome was dementia uh the primary trial is always cardiovascular disease but there have been more than a dozen such trials where the secondary outcomes are dementia it's worth noting that in every one of those trials regardless of Statin used there has either been no change in the risk of Dementia or a reduction in the risk of dementia now it's interesting these studies were almost all done in the setting of trying to determine if lipophilic versus hydrophilic statins were more less or better and the answer

always emerged it didn't seem to matter which of course makes sense if you understand now that they probably all cross the bloodb brain barrier so the question remains will there ever be a study done that tests this question specifically as the primary outcome in other words where the study is powered to ask the question does the use of a Statin increase decrease or have no effect on the risk of Alzheimer's disease and Dementia or will we instead be forced to rely on these secondary outcomes which are always subject to some potential misinterpretation again I take

much more comfort in knowing that they are all either neutral or favorable that would certainly be better than the opposite U but again that remains uh a bit of an unknown and and you might be right Tom it might be that on average it's having no effect on the brain on average it's having a beneficial effect through the vascular system but then there might be edge cases that are not being captured in large clinical trials based on hundreds of thousands of people correct and it might in fact be those patients in whom a little extra

knowledge goes a long way Visa cholesterol synthesis in the brain and the final point I'll make here is what a privilege it is to be practicing medicine in 2024 when we don't have only statins but we have aetam we have bidic acid we have short pcsk9 Inhibitors we now have long acting pcsk9 Inhibitors uh we have a Asos around the corner uh there really is no need for a patient to ever endure a side effect of lipid lowering medication today we can we can lower everybody's lipids without side effects uh and and so that's that's

you know that's and that's only going to become more and more true in the next decade couldn't argue with anything you said there it's brilliant what you said and also this is is not a reason not to use statins you individual we're not evaluating populations we treat people one at a time so in somebody we're worried about dementia we have a biomarker that's probably usable and if God you can't take the stattin so what we can get your apob B go pretty easily with the other things that we know are not affecting the brain what

Peter said wouldn't it be nice to have a randomized blinded trial to answer this question statins are generic I don't know of any Pharma company that's going to spend a billion dollars to prove or disprove what statin do to a cognitive functions of the brain so it's not going to happen so if it's not we can use in individual patients these Oddball biomarkers that is what I think is part of medicine 3.0 where we maybe use a little smarter uh knowledge to try and do a better job the last thing I'm going to Peter is

harp this enough too we can I maybe I bad mouth high do statins we don't use them we're not treating acute coronary syndrome patients where maybe you want to be out a h High those Statin for x amount of time you can get most of the apob B lowering with a Statin with the baby dose this has been proven in trial after trial most of the LDL receptor upregulation occurs with the lowest dose that inhibits cholesterol synthesis you start doubling tripling quadruple you might get another 6 7% not the original 30% lowering or so so

in today's world why do you ever have to double triple or quadruple the dose of a Statin uh when we have all these other additive drugs that you take a baby Statin my sort of acronym for a lowd do Statin and you combine it with a zmi bidic acid or P ps9 inhibitor you've got a uh a military machine that can destroy AO B so that should be the thought processes about attacking April B nowadays we have so many options which we didn't have in the hey day I always say one last thing because I'm

old enough to remember where did all this hydrophilic lipophilic stuff come from the first two competitive statins on the market were Simba Statin which was MC's most potent Statin more potent than their Lattin or meore so everybody jumped on zelor or simvastatin but Bristol Meer squid made pristan hydrophilic and there was a lot of thought looking at other biomarkers that the and even catabolism that the hydrophilic statins were safer than the others was there a little more brain fog with mevacor zore than there was with pricol anecdotally people said that I never saw a trial

it looked at that so but that's where it all came from pharmac competitiveness hydrophilic versus a lipophilic sta well Tom my final question I guess um really comes down to what are you most looking forward to in the next three to five years I mean I I have an answer for what I'm most excited about but but I'm obviously more interested in hearing what you're most excited about in the entire field of cardiovascular medicine is it is it something on the drug side is it something on the diagnostic side uh is something else what what

has you most excited well most excited is I hope I'm still here in five years and I hope I'm still capable of having these discussions with you Peter's working hard to make that happen with me so I highfive him on that but if I do make it that long look I think we've got apob B solved right now I mean there are they're looking at even other types of pcsk9 coming down the pipe a little more potent on ldlc than the current ones there's an oral pcsk9 that they're working on would you rather swallow a

pill and take an in but you're still just chasing apob B and we can pretty much with rare exception get that to goal now so I'd be more exced exced about for the people with the rare genetic disorders that are driving their Li lipids and lipoproteins out of whack there are drugs coming that attack other apal proteins that are there so but again that's going to be a minority of of patients on that uh diagnostically I would hope I can't ever see it coming but you know I couldn't see a lot of things coming that

there might be some usable HDL functionality tests which would make us a little smarter perhaps on giving a patient some insight to uh their HDL markers or so and uh uh would there be other types of uh earlier markers I don't know that we're going to get an earlier Imaging marker than a a CTA right now that uh without being invasive or maybe they you know optimal tomography and stuff is showing us stuff within the vessel wall so who knows what Imaging is going to bring today table but that probably won't be in widespread use

when it first comes out would there be other the inflammatory markers we have now fine you can use them you can look at them I hope I didn't say it before but does everybody understand that whatever inflammatory marker you're looking at that is not the goal of therapy apob is the goal of therapy the thought being if you make apob low enough the AOS scerotic process in the artery wall would dry up scar up and there'd be no more inflammation in the ayol but there are other things going on as Peter alluded to so there

are other biomarkers coming that might certain amino acid biomarkers are being looked at or so that might give us other types of insight looks at the arterial wall pathology that might be going on I would love to see some of these um synthesis and cholesterol markers perhaps even uh LDL andh triglyceride levels the latter two are just simple assays being made of available to the general public uh and I would like to see more widespread availability of the sterile biomarkers and you know you need some education on how to use them but that would be

all uh great and the last thing two things that I guess about two weeks ago the nla published their first statement on April B and we've given you a lot of info why we use it but you want to get down into the weeds that's a statement to read and they do mention it good as it is it can't happen tomorrow no guideline is going to tell you to make a B for the simple reason is the overwhelming majorities of practitioners really don't know what apob B is including those in the Cardiology Community for goodness

Sak so we you can't get a guideline declar and everybody stop doing lipid profiles just get apob B because nobody would know what you're talking about sadly today the nla put out a secondary expert person statement on LP little a and they get into the same thing yeah everybody should get an LP little a once in your life but we right now in 2024 there are several drugs coming to lower it we have no idea whether they're going to reduce mace or not so stay tuned we're going to get the readout on one next year

what if it failed then LPA just becomes a wrist marker like CRP or something it's not a goal of therapy so stay tuned for that but they also get into it a lot of labs just are not doing the right type of LP little a testing uh LP littlea testing I was shocked to hear it because it's kind of a cheap test but apparently there are third party payers given doctors grief for ordering it for God's sakes and again the overwhelming majority of pcps and a heck of a lot of cardiologists have no idea what

LP little a is so uh what good does it tell you to get it tested and you show up in your doctor's office he goes who that's nothing don't worry about it so I'm hoping for better education among doctors in the lipid World God knows Peter you've done your part and I just always like to Pat you on the back you know last year Peter was made an honorary lifetime member of the nla and I would suggest you go to their website and see who else has ever achieved that title it's the Giants of the

field who invented to Cen auge or that type of serious analysis why did Peter give it Peter has probably brought more lipid education to more people than any of those gigantic thought leaders ever did so I high-fi my buddy for doing these type of things and giving lipid its due presence on his missives his Instagrams and his podcast for sure so like always Peter we're going to know a lot more some of the stuff we said today is probably going to sound like idy idiocy in five or 10 years but I think a lot of

it's going to be right if I look back at my life and I prognosticate about a lot of stuff I've been a lot more right than wrong so I'll Pat my own back well Tom it was uh it was a huge honor last year to receive that award from the nla and I uh in no in no small part at all that's that's obviously due to your mentorship and the mentorship of others um so so thank you very much thank you obviously for your continued education both for me personally and and also for everybody listening

you're um an absolutely tireless educator your your Zeal for for teaching your generosity of of knowledge is uh is really unparalleled and you and I joke all the time about that first time we met uh way back in in Reno total chance coincidence and you know uh certainly one of the more fortuitous things that's happened to us both so thank you again I think this was a a great discussion um and I and I I I know that at times it got a bit technical but I I would uh encourage people to maybe go back

and listen to this again really go through the show notes on this one uh all the stuff we talked about you'll you'll find you know summarized there and links to other studies if you if you want to be able to go into some of the details so so thank you once again Tom for for everything you've taught me and and obviously everything you've you've taught the listeners vice versa my dear friend [Music]