The Peter Attia Drive – A Deep Dive into Lp(a): What Every Doctor, and the 10-20% of the Population at Risk, Needs to Know

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Key Takeaways
  • A Lp(a) particle is just a LDL particle with an Apo(a) particle attached to to
  • 10-20% of people have elevated Lp(a) levels 
  • As a patient, demand that your Lp(a) level be know, especially if you have a family history of atherosclerotic disease
  • Lp(a) particle number is the best measurement – Peter likes to see his patients < 50 nmol/L
  • The potential dangers for people with elevated Lp(a) include enhanced atherosclerosis, enhanced venous thrombosis, and aortic stenosis
Intro
  • This is a deep dive episode into the subject of Lp(a) aka Lipoprotein(a)
  • Bob Kaplan, Peter’s colleague who is helping him record this podcast, is on his 7th coffee of the day
  • Before reading these notes, check out these other Podcast Notes from a recent Peter Attia episode, which will serve as a good introduction to everything you need to know about cholesterol
An Intro to Lipoproteins
  • Cholesterol – cargo carried by lipoproteins
  • Lipoproteins – spherical macro molecules, composed of cholesterol and other lipids (like triglycerides and phospholipids), and most importantly a variety of different proteins which form a capsule around the lipid cargo
  • When cholesterol is on an LDL (low density lipoprotein – a form of lipoprotein) particle – we call it LDL cholesterol (LDL-C)
  • Cholesterol
    • Where does cholesterol come from?
      • Every cell in the body makes cholesterol
      • Most cells in the body make enough cholesterol to meet their own needs
      • Cholesterol makes up the bulk of cell membranes
      • Organs (adrenal glands, ovaries, testes etc.) turn cholesterol into sex (and other types) of hormones – so cholesterol is important
    • Cholesterol is hydrophobic, so it repels water
      • To move cholesterol through the blood stream, you need to package it in something hydrophilic (the lipoprotein)
      • The two dominant lipoproteins found in the blood stream – LDL, and HDL (high density lipoprotein)
    • Your LDL cholesterol (LDL-C) number in your blood, is the total amount of cholesterol you have on all of your circulating LDL particles
      • Same story for HDL-C
    • LDL particles (LDL-P) are most strongly correlated to cardiovascular disease risk 
      • LDL cholesterol is just cargo on an LDL particle – the amount of cholesterol on an LDL particle can vary
      • The LDL particle causes the plaque to develop in arteries, not the cholesterol
      • So your LDL particle number is more indicative of cardiovascular disease risk than your LDL cholesterol number
    • The key protein that holds a LDL particle together – ApoB 100 (identified as ApoB)
      • ApoB is often used as a surrogate to measuring LDL particle number
        • There is only one ApoB per LDL particle
Lp(a)
  • 10-20% of people have elevated Lp(a) levels (depending on where you define the cutoff)
    • In some cultures (like South East Asians), it’s even higher
  • For a refresher from the above, and lipoprotein is a spherical particles (20 nm in diameter), with an outer structure made of lipids, cholesterol, and phospholipids
    • Inside it has a core consisting of cholesterol and the triglycerides
    • Also on the outside, one ApoB-100 particle – remember, there’s one ApoB per LDL particle
  • A subset of these LDL particles, have something else attached to the ApoB particle – something called Apo(a) – this makes the LDL particle a Lp(a) particle
    • Here’s a pic of a Lp(a) particle (Image credit: lpacare.com)
    • Apo(a) is made in the liver
    • Apo(a) has a repeating folding structure, the domains are called “Kringle Domains”
      • Kringle Domain is identified as “K”
    • Lp(a) resembles another molecule in the body called plasminogen (just a clotting factor), because Lp(a) has the exact same Kringle Domain 5 and Kringle Domain 4  as plasminogen
      • There are 5 kringle domains – KI, KII, KIII, KIV, KV
      • Apo(a) does not have Kringle Domains 1, 2, and 3 (KI, KII, and KIII) like plasminogen
      • Kringle Domain IV (K IV) of Apo(a), has 10 subsegments (Type 1 – 10)
        • For example – KIV Type 1 = Kringle Domain 4 Type 1
      • KIV Type 2 is where you see the greatest variability in fold counts (could be 4 folds, could be 40)
        • This determines the mass of Lp(a)
  • So – the big questions:
    • How many of your LDL’s have those Apo(a)’s attached to them (so what’s your Lp(a) count)?
      • This matters more than the below
    • What do those Apo(a)’s look like? (So really, what do your KIV Type 2’s look like – how many folds do they have?)
  • The ties between ApoE and Lp(a)
    • ApoE is the gene that codes for how the brain metabolizes cholesterol
      • ApoE exists in three forms (ApoE2, ApoE3, ApoE4)
        • ApoE2 and ApoE3 cause you to be less resistant to parasitic infections in the brain
        • ApoE4 protects your brain from parasite infections
      • ApoE2 people have a a genetic protection against Alzheimer’s disease and atherosclerosis
        • ApoE4 possessors are genetically predisposed to Alzheimer’s disease
    • People with the ApoE4 allele, have higher Lp(a) and ApoB, and lower triglycerides than people with the ApoE3 and ApoE2 allele
Lp(a) Measurements
  • Lp(a) Mass
    • This is the most common Lp(a) measurement
    • For Lp(a) mass, normal levels in the US are below < 30 mg/dL, and < 50 mg/dL in Europe
    • This, as mentioned, is largely, but not solely, determined by the fold count of Kringle Domain IV Type 2
    • A “good test, but not a great test”
    • For particles that carry Apo(a), it measures the mass of everything – Apo(a), ApoB, phospholipids, cholesterol, and triglycerides
      • The larger the Kringle section for KIV Type 2, the more that mass is dominated by Apo(a)
      • This can be problematic, because…
        • Two people can have the exact same Lp(a) mass, but one of them can have a long KIV Type repeat binding domain (many folds), and the other person a short KIV Type 2 (not as many folds)
        • The former will have a lower Lp(a) particle number
    • For a person with a low Lp(a) mass (around 5 mg/dL or less), the likelihood that their Lp(a) particle number is high, is very low
  • Lp(a) cholesterol
    • Analogous to measuring the cholesterol content of all LDL particles (LDL-C)
    • Here, it’s measuring the cholesterol content of all Lp(a) particles
  • Lp(a) Particle Number: Lp(a)-P
    • This is the measurement Peter prefers – it counts the Apo(a)’s attached to Apo(B)
    • Reported in nmol/L
    • Peter likes to see his patients < 50 nmol/L
      • Over 125 nmol/L is dangerous
  • To note…
    • Apo(a) has lots of the amino acid lyseine, and lyseine tends to bind to oxidized moities (like phospholipids)
    • ApoB does not contain much lyseine at all – so its not an effective oxidized moiety scavenger
    • So…
      • An oxidized phoppholipid measurement, normalized for ApoB, would give a good estimate of Lp(a)-P
Cardiovascular Disease
  • Normally, if a patient doesn’t have a family history of heart disease, doesn’t smoke, and isn’t diabetic, but has heart disease – they’ll often have an elevated Lp(a)
The Origins of Lp(a) and the Potential Evolutionary Advantages
  • Plasminogen is a clotting factor, and we know Lpa(a) is similar to it
    • People with elevated Lp(a) tend to have hypercoagulability – they have an ability to form blood clots better than someone who doesn’t
    • In today’s environment, that’s not an advantage. 50,000 years ago, it was a different story, as bleeding to death, might have been a significant concern.
    • Think about child birth long ago – elevated Lp(a) levels would provide an advantage, due to all the bleeding
  • In a low oxidative environment, Lp(a) particles are good scavengers 
    • They can scavenge more oxidized phospholipids and take them back to the liver – the place of clearance for the Lp(a)
    • This would pose an advantage (unless there’s too many oxidative phospholipids to collect) – you’d be overwhelming the systems ability to clear these things
The Potential Dangers for People with Elevated Lp(a)
  • Enhanced atherosclerosis (a disease of the arteries characterized by the deposition of plaques of fatty material on their inner walls)
    • Why?
      • The Lp(a) particles are more likely to be retained in the sub endothelial space due to all the oxidized moieties and Kringle Domains
      • The particles are more likely to kick off an inflammatory response due to all the oxidized particles they’re dragging into the sub-endothelial space
  • Aortic stenosis 
    • 2/3rds of the cases are explained by elevated Lp(a)
    • This is a blockage of the aortic valve
  • Enhanced venous thrombosis
    • Aspirin can counteract the effect for a small subset of people
    • Check out the product – Flight Tabs
      • Peter recommends people with elevated Lp(a), on long flights, take the above to reduce the risk of deep vein thrombosis
How is elevated Lp(a) treated?
  • Historically Niaicin
    • Niacin lowers ApoB, in addition to LDL-C and LDL-C
    • HDL-C goes up
    • It lowers Lp(a) by about a third
  • Statins alone don’t lower Lp(a)
    • Statins work in two ways to lower LDL-C
      • Their primary effect – they inhibit the first step of cholesterol synthesis (they inhibit HMG-CoA reductase – an enzyme that catalyzes one of the early steps of cholesterol synthesis)
      • Their indirect effect – the liver, in response to the above, upregulates the LDL receptors, and you get enhanced clearance of cholesterol
    • If Lp(a) is just an LDL particle with Apo(a), attached to it, why isn’t Lp(a) lowered as well?
      • Lp(a) will get cleared by the LDL receptors on the liver, but it’s just last in line to LDL-C, and vLDL-C
      • But you never really get there…
    • When you combine a PSCK9 inhibitor with a statin, you see a reduction in Lp(a), why?
      • One of the roles of an enzyme called PCSK9, is to degrade LDL receptors on the liver
        • Some people have a hyperfunctioning PCSK9 enzyme, thus lowering their total number of LDL receptors, and increasing circulating LDL cholesterol
        • Some people have genetic mutations in the other direction – they have a hypofunctioning PCSK9 (so the LDL receptors are upregulated) – they have lower LDL cholesterol
      • So, by inhibiting, PCSK9, you get more LDL-receptors, and Lp(a) can get cleared
  • PCSK9 inhibitors alone, will lower Lp(a) about 30%
  • One drug, currently in phase 3 clinical trials, looks promising
    • It’s an ASO – antisense oliglonucleitide
      • Note from Podcast Notes – this isn’t discussed much
    • They disrupt Apo(a) synthesis which occurs in the liver
    • Peter thinks they’ll be on the market in 5 years
How can you lower triglycerides, LDL-C and other things through diet?
  • Lp(a) probably can’t be modified much by lifestyle 
  • Certain people, when consuming high levels of saturated fat, will start making much more cholesterol (so their LDL-C goes up)
    • When you replace the saturated fat with monounsaturated fat (like olive oil and macadamia nuts), levels return to normal
    • Peter also talked about this in these Podcast Notes
    • This was not the case for Peter – when he followed a ketogenic diet, he estimates he was eating about 150 grams of saturated fat per day. His C-reactive protein (a marker of inflammation) and his triglycerides were very low. His LDL-P was normal.
Quotes and Tidbits
  • “If you are anywhere in the cross hairs of taking care of a patient, where you have some input into how they lower their risk of cardiovascular disease, and you don’t understand most of what we’re talking about on this podcast, I’m worried you’re missing an opportunity to help patients”
  • “The more you learn, the less you know” – Bob
  • The fact of the matter is, most physicians are not knowledgeable about Lp(a)
  • “If you’re listening to this as a patient, you should demand that your Lp(a) be known, it’s non negotiable, especially if you have a family history of atherosclerotic disease.”
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