Qualy #106 - Does LDL cause heart disease？
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Summary
In this bonus episode, Dr. Peter A. Atiyah and I discuss a recent paper from the European Society for Atherosclerosis (ESAS) on the role of LDL cholesterol in the pathogenesis of heart disease, and the counter-argument that lowering LDL cholesterol is not a causal factor in heart disease risk.
Transcript
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Welcome to a special bonus episode of the Peter Atiyah Qualies, a member exclusive podcast.
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The Qualies is just a shorthand slang for qualification round, which is something you
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do prior to the race, just much quicker. The Qualies highlight the best of the questions,
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topics, and tactics that are discussed in previous episodes of The Drive.
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So if you enjoy the Qualies, you can access dozens more of them through our membership
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program. Without further delay, I hope you enjoy today's Qualies.
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Let's talk a little bit about a paper that you were an author on this year. It was the
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European Atherosclerosis Society consensus statement. Now, you and I were joking about
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this a while ago that you almost couldn't believe this paper needed to be written, but sometimes
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there's a benefit in writing it. And what was the conclusion of that paper? Or more to the
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point consensus statement. It was more than just a paper. I mean, it was really a tour
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So this paper assembled multiple lines of evidence addressing the question, does LDL cause heart
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disease? Is LDL a causal factor for heart disease?
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And just to be clear, the counter-argument is, sure, people with high LDL are more likely to
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get heart disease. That can't be disputed. The epidemiology is clear. The counter-argument
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is, but LDL is not a causal role. That's right. And it's associated with that. Efforts
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to lower LDL cholesterol are not fully justified as a means of attacking the cause. I don't want
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to be responsible for having stated that incorrectly because I still can't quite believe anybody would
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hold that opinion. But that was my understanding that led to the group coming together to counteract
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that perception that lowering LDL was not beneficial.
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But there are many people. I mean, not that I spend terrible amounts of time on Twitter, but
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it's a pretty commonly held view, at least in the vocal minority that love to write about this and
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talk about this, that, hey, LDL cholesterol is a myth. Like heart disease has nothing to do with this.
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And the problem is, and it did come out in the paper to some extent, but I'll tell you, there is a
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second component to that effort that is still being written. It was planned and will be a two-part
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series. The first part is assembling all the evidence from epidemiology, clinical trials,
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genetics, et cetera, that speak to the causality. And the second one was really relating all of
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this information to the role of LDL in the pathophysiology of atherosclerosis. And that paper
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is a work in progress, but it collectively, those two papers assemble just about all the evidence one
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Well, we'll certainly link to the first one in the show notes because that was published in
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Yeah, yeah. We expect it in the next year or so. But one thing I do want to say, because
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there's a caveat and part of my life as a researcher, as well as a clinician, is recognizing
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the complexity of what we're dealing with. In discussions such as this, it's important to
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keep the concepts straightforward and understandable to the best degree possible. But the flip side
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of that is the risk of oversimplifying a complex situation. So when I just said that the evidence
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is that lowering LDL cholesterol is beneficial, that's not always true. And so one can point,
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if one is so inclined, to the evidence that under certain conditions in certain populations,
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with certain approaches, lowering LDL cholesterol does not result in reduced heart disease risk.
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And to the extent that you consider that to be a fatal flaw in the argument, that can be,
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I think, very misleading because it's not. The fact is that LDL is causal, but there are other
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circumstances that modify that causality to the extent that some forms of LDL under certain
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conditions, and this may not be uncommon, can be elevated without pathologic consequences.
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And so lowering LDL in those cases may not give benefit in that. We know there is heterogeneity
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in the clinical response when one looks at cardiovascular protection with LDL-lowering
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treatment. So I have to absolutely extend the simple notion of LDL causality to saying that
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one has to look very carefully at the arguments against LDL causality because they latch on to
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pieces of information that are really misleading. Just because lowering LDL cholesterol is not always
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beneficial doesn't mean that LDL is not pathological. And the second component of that is the focus on
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LDL cholesterol that goes back to our initial discussion here today as a marker for a causal
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mechanism. But it's the particles that are causal. And LDL cholesterol, as we just talked about, does not
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always mirror the number of LDL particles. Now, I don't think we should necessarily take the time to go
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through the paper in incredible detail, but it did touch on eight criteria for causality. Plausibility,
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strength, biological gradient, the temporal sequence, the specificity, consistency, coherence, and then the
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relative risk reduction or risk reduction with an intervention. Among those, I found the Mendelian
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randomization to also be very compelling. So, you know, when I talk about this with people, I generally talk
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about the natural experiments, such as the people with PCSK9 mutations, both hypofunction or, you know,
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gain of function, loss of function, PCSK9, the FH patients, the Mendelian randomization, and the
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intervention. If you were going to bring up three points from the paper that you think probably are
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most relevant, what would they be? Well, you've just touched on probably the number one strongest
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argument. And it's really where we, those of us who have been in the field for decades, started with
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being impressed with the role of genetic elevations of LDL. Very, very strong evidence. I would put that
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probably right at the top. And you talked about this condition, familial hypercholesterolemia, when
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there's two doses of an abnormal gene, the LDL levels can skyrocket. I referred to that a little
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while ago as the condition that can lead to heart disease early in childhood. It's unequivocal.
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In fact, the reason I got a little bit, I was a little bit taken aback by the need to do this
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more extensive review, which I think, by the way, was quite a good exercise, both for those of us who
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did it and people hopefully who read it. But all you have to do is look at an eight-year-old child
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with cholesterol levels that are eight or nine times normal, who's a candidate for liver and heart
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transplant, to know that that's it. That's causal. But the genetics support it beyond that.
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Right. Now, in those cases, the genetic defect is one in the LDL receptor, correct?
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So closing the loop on how this works, right? The body makes cholesterol. The body, you know,
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so every cell in the body makes cholesterol. Then cholesterol gets recirculated, ends up mostly
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back in the liver. It gets secreted. Some of it in bile gets reabsorbed, and this process continues.
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But it's this LDL clearance, mostly via LDL receptors in the liver, that seems to be where a lot of these
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That's right. Yeah, the liver really is the factory as well as the disposal plant, if you will. Most of
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the cholesterol that winds up in the blood is released in terms of lipoproteins that are
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synthesized by the liver. And then they come back to the liver ultimately after they've done their
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thing, so to speak, delivered their cargo or interacted with cells in various ways and come
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back to the liver. And a large portion of that return is mediated by these receptors that latch
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on to ApoB. It's ApoB that is kind of the key that binds to the lock that snaps up the LDL in the
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liver and degrades it and excretes it into bile. And that's one of the ways we dispose of cholesterol.
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There are other mechanisms involving HDL, but the receptors are a key determinant and do represent
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a mechanism by which most of the drugs that we use to lower cholesterol act to increase
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LDL receptor-mediated disposal of LDL particles.
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