Transcription
In this video, I have one point to make that can be summed up in one word: context. Now, specifically in this video, I'm going to be talking about high LDL levels and, by extension, ApoB levels in the context of different ideologies or causes of high LDL cholesterol levels and what impact that might have on coronary plaque progression. But just remember a core truth I'm trying to communicate here is context, which generalizes across medicine.
Now, in terms of organization of this video, I'm going to present to you a thought puzzle. Then, I'm going to present some data from JAMA Cardiology. After that, we're going to go back to the thought puzzle and figure out what we've learned. All right, let's [Music] go! Welcome to my channel; stay curious.
So, let's start with the thought puzzle. Imagine you have two people, two patients: Patient A and Patient B. Patient A starts at 25 years old, and somehow you can snap your fingers and genetically manipulate this person so they have a broken LDL receptor. Effectively, you're giving them familial hypercholesterolemia (monogenic 1G familial hypercholesterolemia) at age 25. What's going to happen is that because they can't properly clear their LDL particles, their LDL is going to go through the roof. Okay? And let's say that person stays with those massively elevated LDL levels from age 25 to 35, and over that time, presumably, there's some plaque progression.
Now think about that, and let's compare it to another case: Person B. Let's say Person B is basically the identical twin of Person A. For the first 25 years of life, they're genetically identical; they have the same LDL and ApoB levels, the same exposure. But at age 25, rather than snapping your fingers and breaking this person's LDL receptor, they go on a high-fat, low-carb ketogenic diet and manifest lean mass hyperphysiology, which is basically a metabolic response to carbohydrate restriction where the body increases fat fuel trafficking through the lipid system, causing LDL to go up.
So, let's say in both these people you have this massive jump in LDL at age 25, right? And let's say the ApoB goes up just the same amount—it's for the nuance ninjas listening there, right? They both have this exposure to the same level of very high LDL and very high ApoB from ages 25 to 35. So, for all intents and purposes, they're exactly the same, except for one person: Patient A, between ages 25 and 35, had a broken LDL receptor, and that was what was driving up their LDL levels. For Person B, they had a metabolic response to carbohydrate restriction, and that's what was driving up their LDL levels to the same level.
Okay, now if you assess them at age 35, will they have the same amount of plaque or different amounts of plaque? I want you to pause the video and think about that.
Now, let's go over some data that may help inform your prediction with respect to the thought puzzle. These were data published in JAMA Cardiology, and this was a case-control cohort study using participants from the UK Biobank who had elevated LDL levels but for different reasons. Some participants had elevated LDL levels because of a monogenetic cause; they had dysfunction in one gene, like the LDL receptor, ApoB gene, or PCSK9 gene. Another group had polygenetic familial hypercholesterolemia; they had elevated LDL because of contributions from many genes. Then the third group had elevated LDL but without a known genetic cause.
So, there are three different groups with similar LDL levels but different causes of elevated LDL. Now, I will just say this paper comes with limitations, caveats, and lots of nuances. I'll put some more details in the video notes below if you want to check it out. But for the sake of time, I'm just going to focus on what I really think is the takeaway, summarized in this key figure. What you're looking at is time to first cardiac event, and basically, the way to interpret this graph is: if the slope falls off more quickly, it's a steeper slope. Then what you have is a worse profile; they're getting events younger, and that probably relates to faster plaque progression and more cardiovascular events at a younger age, despite, again, similar LDL levels.
What you see is that—and this is all I really want you to take away from this graph—the groups do separate. Despite similar LDL levels, they do separate whereby those with monogenetic causes have a worse prognosis than those with a polygenetic cause, which is worse than those with no known genetic cause. The point here is ideology; cause does matter. High LDL isn't equal to high LDL; there is context, and part of this context is ideology—what the cause is.
To hammer this point home, here's a quote from the authors in their own words: "These data suggest that mechanisms underlying hypercholesterolemia (high LDL in this case) and the measured level of LDL cholesterol contribute to cardiovascular disease (CVD) risk, which underscores the importance of ascertaining the causes of hypercholesterolemia to accurately assess risk."
Okay, hopefully, that's clear. Let me try to also reframe it, come at it from different angles to really hammer the point home. One way to think about it is: imagine you have a graph of plaque progression on the y-axis versus LDL or ApoB milligrams per deciliter years exposure—how much exposure your vessels have to elevated LDL or ApoB concentrations. Now, if the rate of plaque progression were purely dependent on LDL levels, you should see the same slope, the same steepness of slope for everyone. But what they're really saying in this paper is the slope differs based on the cause of the high LDL.
Some people say those with monogenetic FH may have a very steep slope for a given amount of LDL/ApoB exposure to their vessels; they have a lot more plaque progression than other people, say those with no known genetic cause, who probably have a more shallow slope. Another way to think about it or analogize it—and this is getting really goofy and stupid, but hopefully, it'll make it stick—is that if we assume that high LDL and high ApoB levels constitute increased risk as compared to having lower LDL/ApoB levels, with everything else being constant, then there is a threat of sorts. But that threat has a magnitude, and the magnitude depends on the ideology.
So, by analogy, it's like saying lizards are a threat, but we know intuitively that Godzilla and the Geico gecko are not the same threat. It's important to determine which we're dealing with in order to assess what we need to do to terminate the threat. Make sense?
So now, let's return to our thought puzzle. Remember Patients A and B? Well, Patient A, we basically established, is monogenetic FH. Remember, we snapped our fingers and broke their LDL receptor, so we can bucket them into the monogenetic FH cause, which, remember, had the fastest drop-off, the steepest slope, and the worst prognosis.
What about the lean mass hyper responder patient? Well, upon first thought, you might think, "Oh, maybe we can bucket them with a non-genetic cause group." But this wouldn't be appropriate either because they're distinct from that group. The non-genetic cause group in the general population broadly constitutes people who generally have signs of metabolic syndrome, maybe elevated triglycerides, as was in this study, and are on a mixed diet. Whereas the lean mass hyper responders tend to be very insulin sensitive, very healthy, other than maybe their high ApoB, if you consider that an unhealthy profile. They're having this massive jump in LDL and ApoB as part of a metabolic response—an adaptive metabolic response to carbohydrate restriction to meet energy demands, the energy demands of their muscle tissue and to replenish their fat tissue.
So, we have a different system here where you're increasing fat fuel flux. Now, what is the consequence of this particular physiology on risk? The answer is we don't know. We don't know how the curve of the lean mass hyper responder or the slope of the lean mass hyper responder—the plaque progression versus LDL milligrams per deciliter year exposures—we don't know what it looks like, and it needs to be studied.
But the original question was: would these two people, Patient A and Patient B, have the same rates of plaque progression or different rates? I think the only fair answer is to assume that they would actually have different rates of plaque progression. Now, the question is: what is the rate of plaque progression in the lean mass hyper responder? We have to say we don't know. We don't know, but we need to study it because if we don't know the degree of that slope, we have no way of accurately assessing, on the spectrum of Godzilla to the gecko, what the actual threat size is. Without knowing that threat size, we have no way to properly assess the risk-benefit ratio of various interventions, especially if the ketogenic diet in the given lean mass hyper responder patient is therapeutic. To abandon that diet or adopt pharmacotherapy would come with patient-specific harms.
So, we have no way to properly size up the pros and cons, and that leaves patients in a rock-and-a-hard-place scenario. So again, I come back to that singular word: context. I'm going to leave this video here. Hopefully, it was provocative, and hopefully, you got what I was trying to communicate. I realize I assumed a little bit of background knowledge, so this is a little bit of a niche video, but I hope it was productive for you. Let me know your thoughts. [Music]