The Peter Attia Drive - Qualy #106 - Does LDL cause heart disease?

Episode Date: February 5, 2020

Today's episode of The Qualys is from podcast #03 – Ron Krauss, M.D.: a deep dive into heart disease.   The Qualys is a subscriber-exclusive podcast, released Tuesday through Friday, and published exclusively on our private, subscriber-only podcast feed. Qualys is short-hand for “qualifying round,” which are typically the fastest laps driven in a race car—done before the race to determine starting position on the grid for race day. The Qualys are short (i.e., “fast”), typically less than ten minutes, and highlight the best questions, topics, and tactics discussed on The Drive. Occasionally, we will also release an episode on the main podcast feed for non-subscribers, which is what you are listening to now. Learn more: https://peterattiamd.com/podcast/qualys/   Subscribe to receive access to all episodes of The Qualys (and other exclusive subscriber-only content): https://peterattiamd.com/subscribe/  Connect with Peter on Facebook.com/PeterAttiaMD | Twitter.com/PeterAttiaMD | Instagram.com/PeterAttiaMD

Welcome to a special bonus episode of the Peter Atia Qualies, a member exclusive podcast. The Qualies is just a shorthand slang for Qualification Round, which is something you do prior to the race, just much quicker. The Qualies highlight the best of the questions, topics, and tactics that are discussed in previous episodes of the drive. So, if you enjoy the quality, you can access dozens more of them through our membership program. Without further delay, I hope you enjoy today's quality.

Let's talk a little bit about a paper that you were an author on this year. It was the European Ethrosclerosis Society consensus statement. Now, you and I were joking about this a while ago that you almost couldn't believe this paper needed to be written, but sometimes there's a benefit in writing it. And what was the conclusion of that paper? Or more to the point consensus statement. It was more than just a paper. I mean, it was really a tour de force.

So this paper assembled a multiple lines of evidence addressing the question, does LDL cause heart disease? Is LDL a causal factor for heart disease? And just to be clear, the counter argument is sure people with high LDL are more likely to get heart disease that can't be disputed. The epidemiology is clear. Theargument is, but LDL is not a causal role. That's right. And associated with that, efforts to lower LDL cholesterol are not fully justified as a means of attacking the cause. I don't want to be responsible for having stated that incorrectly, because I still can't quite believe anybody would hold that opinion. But that was my understanding that led to the coming together to counteract that perception that lowering LDL was not beneficial.

But there are there are many people. I mean, not that I spend terrible amounts of time on Twitter, but it's a pretty commonly held view at least in the vocal minority that love to write about this and talk about this that, hey, LDL cholesterol is a myth. Like heart disease has nothing to write about this and talk about this, that, hey, LDL cholesterol's a myth. Like, heart disease has nothing to do with this. And the problem is, and it's gonna come out in the paper to some extent, but I'll tell you, there is a second component to that effort

that is still being written. It was planned and will be a two-part series. The first part is assembling all the evidence from epidemiology, clinical trials, genetics, etc. They speak to the causality. And the second one was really relating all of this information to the role of L.D.L. in the pathophysiology of atherosclerosis. And that paper is a work in progress.

But it could actually be those two papers assemble just about all the evidence when needs to support the use of L.D.L. cholesterol. And when will that second paper be out? I can't tell you. We don't even know. It has taken longer. all the evidence when needs to support the use of LDL cholesterol. And when will that second paper be out? I can't tell you. We don't even know. It has taken longer if we thought.

Well, we'll certainly link to the first one in the show notes because that was published in early 2018. Yeah, we expected the next year or so. But one thing I do want to say because there's a caveat and part of my life as a researcher, as well as a clinician, is recognizing the complexity of what we're dealing with. In discussions such as this, it's important to keep the concepts

straightforward and understandable to the best to be possible, but the flip side of that is the risk of oversimplifying a complex situation. So when I just said that the evidence is that lowering LDL cholesterol is beneficial, that's not always true. And so one can point if one is so inclined to the evidence that under certain conditions and certain populations with certain approaches, uh, low LDL cholesterol does not result in reduced heart disease risk. And to the extent that you consider that to be a fatal flaw in the argument, that can be, I think, brain misleading because it's not the fact is that LDL is causal, but there are other circumstances that modify that causality to the extent that some forms

of LDL under certain conditions, and this may not be uncommon, can be elevated without pathologic consequences. And so lowering LDL in those cases may not give uncommon can be elevated without pathologic consequences. And so lowering LDL in those cases may not give benefit in that. We know that there is heterogeneity in the clinical response when it looks at how do you ask your protection with LDL lowering treatment. So I have to absolutely extend the simple notion of LDL causality to saying that when it has to look very carefully at the arguments against LDL causality because they latch on to piece of information that are really misleading. It's just because Luring LDL cholesterol is not always beneficial.

It doesn't mean that LDL is not pathological. And the second component of that is the focus on LDL cholesterol that goes back to our initial discussion here today, as a marker for a causal mechanism, but it's the particles that are causal. And LDL cholesterol, as we just talked about, does not always mirror the number of LDL particles. Now, I don't think we should necessarily take the time

to go through the paper in incredible detail, but it did touch on eight criteria for causality, plausibility, strength, biological, gradient, the temporal sequence, the specificity, consistency, coherence, and then the relative risk reduction or risk reduction with an intervention. Among those, I found the Mendelian randomization to also be very compelling. So when I talk about this with people, I generally talk about the natural experiments,

such as the people with PCS-K9 mutations, both hypofunction or, you know, gain a function, loss a function, PCS-K9, the FH patients, the Mendelian randomization and the intervention. If you were gonna bring up three points from the paper that you think probably are most relevant, what would they be? Well, you've just touched on probably the number one strongest argument. And it's really where we, those of us who have been in the field for decades started with being impressed with the role of genetic elevations of LDL, very, very strong evidence. I would put that

probably right at the top and you talked about this condition, familiar hyperclestrolemia, when there's two doses of an abnormal gene, the LDL levels in the skyrocket, I referred to that a little while ago as the condition that can lead to heart disease early in childhood. It's unequivocal. In fact, the reason I got a little bit, I was a little bit taken aback by the need to do this more extensive review, which I think by the way, was quite a good exercise for both for those of us who did it,

and people hopefully who read it. But all you have to do is look at a eight year old child with cholesterol levels that are eight or nine times normal who's candidate for liver and heart transplant, to know that that's it, that's causal. But the genetic support is beyond that. Right. Now, in those cases, the genetic defect

is one in the LDL receptor. Correct. So closing the loop on how this works, right? The body makes cholesterol. The body, so every cell in the body makes cholesterol. Then cholesterol gets recirculated, ends up mostly back in the liver. It gets secreted, some of it in bile gets reabsorbed,

and this process continues, but it's this LDL clearance, mostly via LDL receptors in the liver, that seems to be where a lot of these genetic things go awry. That's right. Yeah, the liver really is the factory, as well as the disposal plant, if you will. Most of the cholesterol that winds up in the blood is released in lipoportines that are

synthesized by the liver, and then they come back to the liver ultimately after they've done their thing, so to speak, deliver their cargo or interacted with cells in various ways, and come back to the liver. And a large portion of that return is mediated by these receptors that latch onto April beat. It's April B that is the kind of the key that binds to the lock that snaps up the LDL in the liver and degrades it and exweats it into bile. And that's the way we dispose of cholesterol. There are other mechanisms involving HDL, but the receptors are a key determinant and

do represent a mechanism by which most of the drugs that we use to lower cholesterol act to increase LDL receptor mediated disposal of LDL particles. Hope you enjoyed today's special bonus episode of the quality. New episodes of the quality are released Tuesday through Friday each week and are published exclusively on our private member only podcast feed. If you're interested in hearing more, as well as receiving all of the other member exclusive benefits, you can visit peteratiamd.com forward slash subscribe. This podcast is for general informational purposes only and does

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