The Peter Attia Drive: Ron Krauss, M.D. – A Deep Dive Into Heart Disease

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Key Takeaways
  • Your LDL particle number is more indicative of cardiovascular disease risk than your LDL cholesterol number
  • Small LDL particles are more atherogenic than large LDL particles
    • If you have high LDL cholesterol, but low to normal levels of LDL particles – you’ll have less of a risk of developing heart disease
    • If you have a high LDL particle count, but low LDL cholesterol, you’ll be at a high risk for heart disease
  • PCSK9 is an enzyme that affects how cholesterol is cleared from the liver, and thus how how high or low your LDL cholesterol number is
    • Some people have hypofunctioning PCSK9, and thus low circulating LDL cholesterol
    • Some people have hyperfunctioning PCSK9, and thus high circulating LDL cholsterol
Intro
  • Ron is currently the senior scientist and director of atherosclerosis research at Children’s Hospital in Oakland
  • He’s one of the primary lipidologists Peter reaches out to when he’s stumped on a clinical case
  • Peter has an EXCELLENT series of blog posts on cholesterol
    • Note from Podcast Notes – I highly recommend this, I feel like I know more than my own doctor when it comes to cholesterol after giving it a read.  
  • “Statins are a tool, and the most important thing about having a tool, is knowing how and when to use it”
Atherosclerosis and Heart Disease
  • “Atherosclerosis is a multifocal, smoldering, immunoinflammatory disease of medium-sized and large arteries fueled by lipids” as defined in this paper
    • Atherosclerosis is the underlying process that ultimately leads to vascular disease, heart attack and stroke
    • It starts in childhood – “heart disease is a disease that begins in infancy”
    • The build up of cholesterol on the artery wall forms what are known as fatty streaks – this is normal though, as long as it doesn’t progress to far
      • Why is it normal? – It’s a way for the arterial tissue can put cholesterol in its cells, and eventually use it
    • Artery plaque develops when the fatty streaks essentially build up, due to an accumulation of bad (atherogenic) lipoprotein particles (lipoproteins are defined below)
      • Plaque is essentially a larger fatty streak, but with a greater variety of cells – it’s much more complex
      • The plaque is encapsulated by a fibrous layer, but inflammation can cause that fibrous cap to weaken and eventually rupture
        • Here inflammation is defined as – the accumulation of cells in the artery wall that deliver various inflammatory molecules
      • When that rupture occurs – that’s the “beginning of the end”
        • Most cases of heart attack and stroke involve this sort of acute rupture, and ultimately the formation of a clot that blocks arterial blood flow
  • The most common first presentation of heart disease – sudden death
    • “Around one third of people’s first brush with the knowledge that they have atherosclerosis is death”
    • For this reason, heart disease can be a silent killer
  • Even significant plaque build up can occur in childhood
    • Risk factors for this – smoking, diabetes, hypertension
  • The greatest risk for heart disease – age
    • Like most things in life, atherosclerosis compounds
    • “It’s a cumulative process that can progress at various rates, depending on the condition”
      • If you have genetically elevated cholesterol levels, this process will be accelerated, allowing for a greater risk of heart disease showing up earlier on (it could even be in the teens)
Terms, Definitions, and the Bottom Line
  • Cholesterol – cargo carried by lipoproteins
  • Lipoproteins – spherical macro molecules, composed of cholesterol and other lipids (like triglyceride and phospholipids), and most importantly a variety of different proteins which form a capsule around the lipid cargo
    • Cholesterol is hydrophobic, so it repels water
    • To move cholesterol through the blood stream, you need to package it in something hydrophilic (the lipoprotein)
    • There are two forms of cholesterol
      • Cholesterol ester – the fatty form, this is the type that’s bound to lipoproteins
      • More waxy – not bound to lipoproteins (not discussed what happens to it if it’s not bound to lipoproteins)
  • When cholesterol is on an LDL (low density lipoprotein – a form of lipoprotein) particle – we call it LDL cholesterol (LDL-C)
    • So the LDL cholesterol number in your blood, is the amount of cholesterol you have on all of your circulating LDL particles
    • 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 particles that have less cholesterol are smaller and more dense, the ones that have more cholesterol are larger and less dense
      • The LDL particle causes the plaque to develop, not the cholesterol
        • “The particle is the agent of damage in the artery, 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 lipoprotein particle together – ApoB 100
    • ApoB 100 is  often used as a surrogate to measuring LDL particle number
      • There is only one ApoB per LDL particle
      • ApoB is found on other particles, but primarily on LDL
      • Measuring LDL cholesterol, can under represent the number of LDL particles, compared with the measurement of ApoB
  • So…
    • Smaller LDL particles (with less cholesterol) are more dangerous – they have more pathological properties
      • People with smaller LDL particles are at a greater risk for heart disease
    • Historically, measuring LDL-C, has worked reasonably well for a significant subset of the population, as a marker for LDL-P, because most individuals have LDL particles in the middle of the LDL size and density range. The cholesterol content on those particles is fairly proportional to the number of LDL particles.
      • But this is where things break down..
        • If you have high LDL cholesterol, but low to normal levels of ApoB (so LDL particle number) – you’ll have less of a risk of heart disease
          • Due to the higher amount of cholesterol on these particles, the particles are generally larger and less dense (and therefore less dangerous)
        • If you have high ApoB (so a high LDL particle count), but low LDL cholesterol, you’ll be at a high risk for heart disease
          • Due to the low amount of cholesterol on these LDL particles, they are generally smaller and more dense (and therefore more dangerous)
      • One of the greatest drivers of this discordance (the LDL particle count is higher than the LDL cholesterol) is metabolic syndrome
        • The 5 criteria for metabolic syndrome
          • Low HDL-C (high density lipoprotein cholesterol – not really discussed), high triglycerides, high fasting glucose, high blood pressure, and truncal obesity
          • The most prevalent underlying factor for the development of metabolic syndrome – the amount of abdominal fat
More on Cholesterol
  • Every cell in the body makes cholesterol
  • After being made, cholesterol gets circulated and ends up mostly back in the liver
    • The liver is the factory and the disposal plant for cholesterol
      • When the lipoprotein carrying cholesterol returns to the liver, LDL receptors (in the liver) latch on to ApoB (on the lipoprotein), then the lipoprotein and cholesterol is excreted (in bile)
      • Some of the lipoproteins/cholesterol is reabsorbed back into the blood
    • So, the LDL receptors in the liver are very crucial for clearing cholesterol 
      • Most of the drugs we use to lower cholesterol act on the LDL receptors in the liver, to increase the disposal of lipoproteins/cholesterol
      • If LDL particles are not being cleared by the LDL receptors efficiently, they will circulate longer, and have more opportunities for “mischief”, thus raising the risk for heart disease
    • The LDL clearance (and thus cholesterol clearance), via LDL receptors in the liver, can be more difficult for some people due to genetics
      • One of the roles of an enzyme called PCSK9, is to degrade LDL receptors
        • 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
          • These people will most likely never get heart disease
  • The liver makes lipoprotein particles
    • One class of lipoprotein particle that the liver makes, called VLDL (very low density lipoprotein – so they have lots of cholesterol on them) particles, act as precursors to LDL particles
      • Their half life in the blood is usually 0.5-2 hours
    • Then we have LDL particles, which we’ve been discussing,
      • The LDL particle has a half life of 12-24 hours (or longer)
        • As we know, these are smaller, and more dense (they have less cholesterol, and more phospholipids as their cargo)
        • Smaller LDL particles have a longer residence time because they’re less avidly removed by LDL receptors – this is bad, as the longer they’re circulating in the blood, the more opportunities for “mischief” they’ll have
More on LDL Particle Size and Particle Number
  • We know a small LDL particle is more atherogenic than a larger one (more likely to lead to atherosclerosis)
  • Any large or small LDL particle can enter the sub endothelial space (anything under 70 nm in diamater)
    • The smaller the particle, the more likely it is to do so
    • The longer a particle is circulating, the more likely it is to do so
  • Typically, people with larger LDL particles have higher HDL cholesterol (the good type of cholesterol), and lower triglycerides
    • It’s essentially the opposite of people with metabolic syndrome
    • They also have low insulin
  • If you have a LDL receptor defect in the liver, it results in the presence of more large LDL particles (the particle is larger because of it’s high cholesterol content, not as much cholesterol is being cleared)
    • This is bad because their residence time is longer than it should be
Can LDL-C / LDL-P / ApoB be too low?
  • Look at people with genetic mutations for low LDL-C – like people with hypofunctioning PCSK9, they seem to do just fine
    • Remember – this is an enzyme that acts to degrade the LDL receptor, thus hindering LDL-C and lipoprotein clearance
    • When it’s function is inhibited, LDL receptors in the liver are upregulated, more cholesterol is cleared, and LDL-C gets very low
  • Look at statins, they do two things
    • Their primary effect – they inhibit the first step of cholesterol synthesis
      • We haven’t found genetic variants that allow for this
    • Their indirect effect – the liver, in response to the above, upregulates the LDL receptor, and you get enhanced clearance of cholesterol 
      • This is essentially the same effect as a hypofucntioning PCSK9 – so we know it’s fine, since it’s seen genetically in some people
More on Statins
  • In a ideal world, statins would only inhibit cholesterol synthesis (meaning HMG-CoA reductase activity) in the liver, and you wouldn’t affect cholesterol synthesis in the brain, muscle etc.
    • BUT this is not the case – statins DO effect cholesterol synthesis in other parts of the body besides the liver
    • Note from Podcast Notes -they don’t really discuss HMG-CoA reductase, but it’s assumed this is involved in cholesterol synthesis in some way
  • One unexpected effect of statins – they can increase blood sugar and increase the risk for diabetes (in about 10% of people, it seems to be 30% in women for some reason)
    • Some statins are more likely to raise blood sugar (and increase the risk of diabetes) more than others 
      • For example – LIVALO (pitavastatin) seems to be less likely to do so
      • The one most commonly associated with risk – Lipitor (atorvastatin)
        • However – most of the time, you’ll be fine taking this
        • You can quickly switch to a different statin if you notice changes in blood sugar anyway
    • It seems to be dose dependent as well
    • The point is – people need to be careful and monitor their blood glucose levels on statins closely
  • “We are conducting an experiment in the global population that has never been done before – prescribing statins to millions of people as a life long treatment, without knowing what the down stream effects are, beside the limited clinical trial data we have”
    • THAT SAID – that doesn’t mean we should avoid them
    • There’s just things we don’t know yet
  • An alternative to a statin that Peter likes to prescribe to certain patients – a PCSK9 inhibitor
  • Statins also seem to be effective at reducing inflammation – lowering C-reactive protein (CRP) levels
  • Statins may have an adverse effect on muscle loss (also know as sarcopenia)
    • We know statins target cholesterol production in muscle cells
    • It’s thought that in people more prone to muscle wasting (the elder population), statins might accelerate this muscle loss
Niacin
  • Niacin lowers ApoB
    • It also lowers LDL-C, and raises HDL-C – it seems like the “dream drug”
    • It also does create some insulin resistance (this is bad), more so than statins do
  • It’s not used as commonly anymore, why?
    • The HDL-C raising effects of niacin have shown to not be protective in terms of lowering cardiovascular disease risk
      • When HDL particle counts get too high, they get hung up in blood plasma (“the toilet is plugged”) – you essentially prevent them from doing their job – you’re not delivering cholesterol back to the liver as efficiently for excretion
  • Niacin does seem to lower small LDL particle numbers
    • It seems to be that Niacin preferentially targets smaller LDL particles over larger ones
    • We’ve learned that PCSK9 inhibitors and statins tend to upregulate LDL receptors in the liver – that effect primarily lowers medium and larger size LDL particles, and has less of an effect on the smaller particles – this is the opposite of Niacin
      • This is true because smaller LDL particles are less avidly removed by LDL receptors, the receptors more readily remove larger LDL particles
  • Niacin can lower lipoprotein(a) (aka Lp(a)) by up to 25% or so
  • So, the perfect patient for Niacin:
    • A person with high Lp(a) and high small LDL particle counts 
Other
  • Ron wrote a review article on the history of lipoprotein research – Ron’s paper.
    • Peter thinks Jarrow is the best supplement maker out there
    • He commonly will test his patients’ CoQ10 levels in their blood – only Jarrow’s version shows up as having an effect at raising blood CoQ10 levels
      • It’s very readily absorbed
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