The Peter Attia Drive - #247 ‒ Preventing cardiovascular disease: the latest in diagnostic imaging, blood pressure, metabolic health, and more | Ethan Weiss, M.D.

Episode Date: March 20, 2023

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Ethan Weiss is a preventative cardiologist at UCSF, an entrepreneur-in-residence at Third Rock Ventures, where he is working on a project related to cardiometabolic disease, and a previous guest on The Drive. In this episode, Ethan compares and contrasts the diagnostic imaging tools, CAC (coronary artery calcium score) and CTA (CT angiography), used to image plaque—including the latest in CTA software—and how these tools inform our understanding of ASCVD risk and guide clinical decision-making. Ethan discusses the types of plaque that cause events and the data that make a case for optimal medical therapy over stenting outside of particular cases. He explains why high blood pressure is problematic and walks through the data from clinical trials testing aggressive treatment. He talks about the best way to actually measure blood pressure, why we shouldn’t simply accept that blood pressure rises with age, and how he uses different pharmaceutical agents to treat hypertension. Additionally, Ethan explains our current, but limited, understanding of the role of metabolic health in ASCVD. He discusses the impact of fat storage capacity and the location of fat storage and explains how and why there is still a residual risk, even in people who have seemingly normal lipids, don't smoke, and have normal blood pressure. We discuss: Ethan’s entrepreneurial work in the cardiometabolic disease space [4:30]; Calcium scans (CAC scores) and CT angiography (CTA), and how it informs us about ASCVD risk [6:00]; Peter’s historical CAC scores, CTA results, and how one can be misled [10:45]; How Peter’s CTA results prompted him to lower his apoB [14:45]; Calcium scans vs. CT angiogram (CTA) [21:15]; How Ethan makes clinical decisions based on CTA results and plaque burden, and the importance of starting treatment early to prevent ASCVD [28:15]; Improved methods of CTA to grade plaque lesions and how it’s shaped medical decisions such as stenting [33:45]; Why Ethan favors optimal medical therapy over stenting outside of particular situations [41:45]; The need for FFR CTA, and the potential for medical therapy to eliminate ASCVD [54:00]; The fat attenuation index (FAI) and other ways to measure inflammation in a plaque [57:30]; Statins and exercise may increase the risk of calcification, but what does this mean for risk? [59:45]; The root cause of statin hesitation despite evidence that statins are a profoundly important intervention [1:05:30]; Importance of keeping blood pressure in check, defining what’s normal, and whether we should just accept higher blood pressure with age [1:10:45]; Blood pressure variability, how to best measure it, and data suggesting the enormous impact of keeping blood pressure down [1:21:00]; Drugs for treating high blood pressure recommended by the ALLHAT trial [1:35:15]; What the SPRINT trial says about the aggressive treatment of hypertension, and the risks of such treatment [1:38:15]; Confirmatory results in the STEP trial for blood pressure, and how Ethan uses the various pharmacological agents to lower blood pressure in patients [1:43:15]; The role metabolic health in ASCVD: what we do and don’t know [1:51:00]; The impact of fat storage capacity and the location of fat storage on metabolic health and coronary artery disease [1:56:15]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain

what those benefits are, or if you want to learn more now, head over to peteratia MD dot com forward slash subscribe. Now, without further delay, here's today's episode. I guess this week is Ethan Weiss. Ethan was a previous guest on episode number 52 way back in May of 2019. At the time, Ethan was a professor of cardiology at UCSF. Now he still holds a position at UCSF where he focuses on preventative cardiology. But his main job is as an entrepreneur in residence at third rock ventures, where he is working on a project related to cardiometabolic disease,

something that we touch on in this episode. He continues to have a small clinical practice in preventative cardiology. And a lot of our discussion really focuses on that. I want to have Ethan back on to pick things up where we left off. Over the past couple of years, Ethan and I always stay in touch and exchange emails. And at some point, those emails reach a critical mass where we decided, hey, probably time to bring this discussion to a bunch of listeners, namely you.

In this episode, we focus a lot on ASCBD, of course. And we talk about the diagnostic tools available to understand risk. Because I realized that many listeners weren't necessarily listeners back three or four years ago, we go through a pretty good overview of the difference between a CAC and a CTA as diagnostic tools that give us enormous insight into someone's existing and future risk of AS, CBD, across various different risk factors. We speak about some of the newer versions of the CTAs, which really aren't so much about the CTAs, but are about some of the software overlays

that are used to at least theoretically make the CTA more valuable. Talk a little bit about how extreme endurance athletes may or may not be at higher risk for calcification, and we talk about potentially the role of statins in that. We then move on to a discussion about blood pressure, and in reality, I think this is such an important point that this will not be the final word on blood pressure. But it is important to keep in mind that we do pay a lot of attention to lipids on this

podcast, and lipids, of course, form part of the holy triad of risk for cardiovascular disease. But the other two things, smoking and blood pressure are obviously worth mentioning. Now, smoking seems so obvious that it really warrants little attention on a podcast like this, mostly people tuning into this are quite health conscious. They're generally not smoking.

And we have done at least one podcast on smoking cessation. But I think in some ways the discussion on blood pressure has been a little bit lacking, and that's why I really wanted to have that discussion today. So, we talk about the importance of knowing your blood pressure, how to actually check your blood pressure, why high blood pressure is problematic, beyond just the heart, and spoiler alert, if you think it's bad for your heart, wait till you see what it does to your kidney, and then we talk about the different pharmaceutical agents out there and the trials that have taught us how these things work and when they should be instituted. Finally, we have the conversation

looking at what we know and don't know about how metabolic health plays a role in ASCVD. Because if earlier I mentioned the holy triad of hyperbeta-lipoprotenemia, which is just a fancy word for elevated APOB, smoking and blood pressure, there is still residual risk in people who have perfectly low and normal lipids who don't smoke and have normal blood pressure. That doesn't mean your risk of ACVD goes to zero. In fact, we know it does not. And in fact, we talk about what that X factor is. What is it about metabolic ill health that drives residual risk in ASCVD? Anyway, this is a fascinating discussion, and I suspect it's only the thin end of the

wedge into more exploration, into blood pressure, and some of the more nuanced cellular metabolic ill effects towards ASCVD. So without further delay, please enjoy my follow up conversation with Ethan Weiss. I think it was 2019, but it might have been 2018, right? I think it was 2018, which is just a function of the fact that neither of us can remember, it tells us how long ago it was. Yeah. Well, that time we spoke in person,

and we sat in your office at UCSF, that you're sitting in a new office today, and we're not in person, but more importantly, where are you sitting today? And there's been a bit of a change in your life in the past year, huh? I'd spend an evolutionary change over the past couple of years, but I did have sort of a midlife crisis decided

that I've been envision myself doing the same thing I'd been doing for the prior 25 years for the next 25 years. If I should be lucky enough to be around in 25 years, and I was given the opportunity to get involved with the local group of investors who create biotech companies, and they asked me to help them conceive and eventually they started a new biotech companies, and they ask me to help them conceive and eventually they start a new biotech company. So I closed my lab and have become a volunteer,

clinical faculty at UCSF and see patients infrequently and it's been most of my time over here working to build this new company that I can at least tell you a little bit about later on. I know we're gonna talk about some of the science that the company is interested in because it factors in I know we're going to talk about some of the science that the company is interested in, because it factors in directly to what we wanted to talk about today. So there will be a chance to talk about that for sure.

But in some ways, this podcast is really just a compilation of our email exchanges over the past couple of years. And so I think at some point, we said, we should just do another podcast, because we keep emailing each other about these things. And I suspect as is often the case, there's value in sharing what it is that we talk about with others.

So let's just start with a quick recap of what a calcium score is and then we'll follow that up by what a CT angiogram is because I think those two need to be understood to understand much of what we'll talk about in the next God knows how long. We talked about this the last time. I think I do remember that we spend a lot of time talking about the distinction between calcium scanning and CT and geography. As we discussed the last time, I think, you've

used the analogy before the calcium scan that sort of demonstrates a side of a prior injury. What we know is that quantitatively, the amount of calcium that is in the distribution of the coronary arteries is correlated significantly with adverse outcomes. So the more calcium you have in your arteries, the worse you do, the higher the risk of both cardiovascular and all-cause problems. And the reason we suspect is that that calcium represents a healed plaque. And that's the amount of calcium you have in your arteries is strongly related to the amount of plaque you have in your arteries. We know that the amount of calcium you have in your arteries is strongly related to the amount of plaque they have in your arteries.

We know that the amount of plaque you have in your arteries is related to the risk of having heart attacks and dying from heart attacks. So calcium scans are great ways to kind of analogy. I use for my patients is that it's a, you know, sort of a satellite image of your heart and gives you a sense of has there been damage there over your lifetime.

And then also gives you a nice adjunct indicator of your overall risk of dying for architect, which people like to know. And one of the nice things about a calcium score is it's very, very low in radiation. I mean, it's really even CTAs are now low. We'll talk about that. But the calcium scan is a really low radiation and a very inexpensive tool as well. There are places that are doing these scans for a couple hundred dollars nowadays. Not all places. No, that speaks to the problem in US healthcare where you'll still find some places charging 2000 while some will do the

exact same scan for literally 200. But it needn't be an expensive procedure. It's a low risk procedure. It doesn't require die. It's effectively a zero risk low cost procedure that, at least at the population level, as you say, has really great insight, especially the first time it's done, right? Absolutely. I think we talked about this the last time, but I'll just say it again for those who were in a round back then. I did a full 180 on these. When I first started practicing as an independent cardiologist back in the early 2000s, I would

get patients showing up with these calcium scans. And I really sort of wanted to make them go away. I thought they were annoying and I didn't know what to do with them. And it really has been a full 180. I do find value. Obviously, there's epidemiologic value and understanding the risk of different populations, but I do find that there is value in many contexts and even in individual patients. And we can talk about which contexts I think are most valuable. Certainly not everybody. I think a calcium scan in a 25 year old is probably not worth anything. It's just not worth doing. So yeah, I've come around now to seeing the value of counseling scanning as a tool that I use regularly.

And I know we did talk about this, but again, I learned that one of the things that makes podcasting difficult is it's very difficult for people to go back and listen to them. There's just too much volume. So we should never apologize for repeating stuff that we talked about more than four years ago. And the way that I kind of explain it to patients as well is that if you have a two by two of, you know, young versus old and zero versus non-zero as the calcification, you know, there are two areas where the scan provides insight and there are two areas where the scan doesn't really

provide insight. And so one of them, as you said, for 40-year-old shows up, has a calcium scan of zero, haven't really learned a lot. And if a calcium scan of zero in a 40-year-old is accompanied by other risk factors, I would not be dissuaded from aggressively treating those risk factors. And similarly, when an 80-year-old, with lots of risk factors, shows up and has a zero calcium scan, we'll talk about the false negative right there. All things equal, you might be less inclined to push for aggressive measures. Would you agree with that? I do. I think there's a group of very committed, whatever you want to call them, calcium

scionographers who believe in the power of zero and believe that a calcium score of zero is meaningful no matter where it comes, but I just think that defies larger. If you shouldn't have any calcium when you're 25, I'm not sure what you learn there. There may be edge cases where you know, one and several million people will have some calcium, but I just think mostly the two cases you described are where I find the most value. Well, this gets to something that I think I've learned a little bit more about both through personal experience and also just kind of spending more time in the literature on this

is that a calcium scan is a relatively in-precise measure. So the thickness of the slices that are used in that scan are significantly greater than the slices that are used in the CT and geography. I'll give you a stark example of how I learned this in my own life. And I think I shared at least part of this story last time, although clearly not all of it, because I just learned more recently. So in 2008 or 2009, when I was in my mid-30s, I had my first calcium scan.

Now, the time my doctor thought this was a crazy idea. I was 35. I was exercising at least 24 hours a week. It was no seemingly relevant reason for me to waste insurance money and do this, but I had a horrible family history. And it didn't seem to make sense. It wasn't like everyone in my family

was smoking or anything like that. So anyway, have the calcium scan and it showed that I had a score of six. So I had a single foci of calcium in the, uh, maximal LAD. And interestingly, despite being in my mid 30s with that calcium score of six, nobody really seemed to care either. That was viewed as well. I mean, look, your lipids are really not that bad. My LDL cholesterol was about 120, 110 to 120 milligrams per desolate. So nobody took that terribly.

Seriously, of course, it changed my life and it changed my interest in this field forever. Fast forward to 2016, all it's six, seven years later, I went and had a CT angiogram and a calcium scan. And the calcium scan had a score of zero. The CT angiogram, which now is at much finer resolution, indeed found a tiny speck of calcium in the proximal LED. No other finding. Bob Peters, who is the remarkable radiologist that now sees a lot of our patients, explained to me, not uncommon at all.

That little speck that you had six years ago can easily be missed if you had five calcium scans, half of them would miss it, because it's just too small. But now in the CTA, we can see it. So we repeated the CTA. Now I'm just kind of partially interested in progression, more of soft plaque.

I had it repeated very recently, so call it 2022. This time the calcium score came out as two. And the CTA and Geogram was identical to what it was in 2016, six years earlier. So you could certainly believe that if I had a CTA in 2008 or 2009, it would have looked similar. And you would argue that for basically the same lesion, the score was 6 and 2 and 0. Sorry, 6 and 0 and 2 in that order. Have you seen this yourself in patients where you've had the luxury of both longitudinal assessment and simultaneous CAC and CTA.

Off the top of my head, I can't think of anybody, but I would ask you, and this may be a leading question, but what were the percentiles of those? I mean, I would imagine that's calcium score of six when you were 35 was 99 percentile. It was 75th to 90th percentile at that age. That's right. But there's a big difference, even between six and two and a huge difference between six and zero. Yes. Exactly. I haven't seen it, but it doesn't surprise me. I guess is at a low-enough calcium score. That's not uncommon. Of course, that then got me into the literature and I realized that 15% of people who have a zero

calcium score have a finding on CTA that is either, as mine was, meaning a calcification that was not picked up or a soft plaque. Furthermore, 2% or maybe it's 1.5% of those people who are deemed with a negative CAQ have an unstable plaque on CTA. So it's not just the 15% that have something, but 10% of those people have something that's would be deemed relevant if we saw it on the CTA.

And just back to our prior discussion on age and utility of the scan, not really familiar with the day but I would imagine that that 15% is largely represented in younger people or is that not the case? I'd have to go back and look. That's a great question. I'd have to go back and look. That's a great question.

I'd have to go back and look at the study because it's been probably about six months since I looked at it. We'll find it and we'll link to it in the show notes so that it's unambiguous and we'll include the table that summarizes all this, which will hopefully include age. And if not, it'll be in the fine print.

And then the other question I have for you, Peter, is over the course of the whatever it was, 15, 16, 17 years since your first calcium scan. What's your average APOB been? Yeah. So that's the point. It's been lower and lower and lower. So I immediately, that's about the time I met Tom Despring and began to learn.

I didn't know what APOB was at the time. At first, I was just sort of bombarding LDLC and then that turned into really now targeting APOB. And so my target APOB is between 30 and 40 milligrams per desolate. That's sort of where I aim to be day in and day out. And obviously that requires pharmacological intervention. Now again, I never really had a particular high ApoB. But in some ways that actually gave me more concern, Ethan, because I didn't have the obvious risk factors, right? I'm norm intensive. I don't smoke. right? I'm norm intensive. I don't smoke. And my ApoB at the time was probably about 85 to 90 milligrams per deciliter. I mean, very few doctors would get phosphorylated over

that ApoB in someone in their late 30s or mid 30s at the time. But again, I'd watched countless men in my family die. Some of them as young as in their late 40s from heart attacks, and you start to realize, A, this is probably quite polygenic, and B, there's something going on here that's not just standard plug and play risk factor stuff. Which of course, is your practice, right? I mean, you get these really tough cases

where it's not just, oh, you know, the LDL is too high. It is my practice, and unfortunately, at least for now, the only set of tools that we have are aimed at, well, it's independent of blood pressure, which is different conversation. We'll have later, but the tools we have now are focused really on lowering the APOB through any number of different means. I think we all expect that there's something else there. There was clearly something else there in you. It's hard to make the argument that you were sort of a ticking time bomb with a widowmaker

that you were going to drop dead of a heart attack. You had a tiny, a minuscule lesion. The question would have been what happened to you over the next 15 or 20 years had you not ticking the intervention that you did pharmacologically. Yeah. As I approach 50 now, I do find it interesting to play the thought experiment of had I been on a different path in life,

had I never looked at that 15 years ago, had I never cared what would it look like today? What would that CTA look like today? How significant would that lesion be? Would there be others? And my belief is, we should obviously talk about this. I think that the epidemiology, the clinical trial data, and the Mendelian randomization to my reading of this literature,

and I don't think there's anything I pay closer attention to truthfully, is that APOB is a necessary, but not sufficient criteria for atherosclerosis. And as such, removing it removes atherosclerosis. And so my best guess as to why there has likely been no progression of this disease in 15 years, at least to the level that it can be detected by a CT angiogram, is that we've basically taken away the causal agent. Yeah, I think I mostly agree with you.

I think it's absolutely necessary. I think the data really do suggest that if it's bottomed out, absent some really bizarre, probably monogenic things that we don't see very often, that you can't get atherosclerosis. I think that's demonstrated not just in humans, but across many other animal species. The one place where I might quibble a little bit

is that I do think it's probably sufficient in some cases that in FH, for example, it's probably sufficient. Now, in other words, I don't think you have to have something else to get out through in cases where the ABOB is sky high. The sufficiency is complicated. I mean, I suppose there are people with FH that don't go on to develop AACVD. I mean, that's sort of the argument that, and I don't know if we're going to get into

this or if I ever want to talk about this ever again, but this lean mass hyper nonsense, that's the argument that they make that having a high Epopubia is not sufficient. And it's definitely true that there are some people with FH who don't go on to have ASCVD. It's interesting. I mean, obviously, suggests some other genetic modifier or something else that protects them. So I think that one could argue that apoby is not sufficient but is necessary, which is how I feel, and still take it very seriously, because let's look at another obvious example, which is smoking. And again, smoking even, I would argue smoking is even weaker. Smoking is neither necessary,

nor sufficient for the development of, let's just pick lung cancer. Let's just pick the most smoking associated cancer. So small cell lung cancer. Smoking is neither necessary nor sufficient, but there's nobody in their right mind that would argue that not smoking in our analogy, that's the equivalent to reducing ApoB does not improve risk. Absolutely. So I just think that to point to people with elevated APOB as an example of why it is safe, has never made sense to me. And I'll tell you another reason it's never made sense.

I know I'm not going to get an argument out of you, but I'm hoping we can try to formulate some argument here is there are other ways to treat APOB besides diet. And so I feel like if part of the argument for I need ways to treat APOB besides diet. And so I feel like if part of the argument for I need to have this APOB high is because the diet that's making it high is producing other benefits. That's sort of not necessary. One can consume a diet that if it needs to be in a certain way and produce a high APOB, you could still continue to consume that diet and just pharmacologically address the APOB problem. Yeah, it's the sort of mind-numbing in congruity of this whole discussion and again it makes my skin sort of want to fall off. I think you made a great point about smoking and frankly any

other risk factor for any other disease. We're placed smoking for a corner, disease with smoking for cancer. We all have lots of stories of people who smoke four packs of cigarettes a day or even at the scene where the toxicity is much more direct. It's part of the nature of the heterogeneative response that this penetrance in this case of a environmental factor is not 100%. I guess there are some that are, right? Sinite probably is, but most of the things that we encounter in our environment don't have that level of penetrance in terms of causing risk.

It's certainly not the ones that we encounter frequently. So yeah, cyanide's a great example, 100% penetrance, carbon monoxide at a certain concentration, 100% penetrance. Okay, so let's go back to our discussion and now contrast the calcium scan with the CTA. And then especially we'll use this to now explain these other variations of CTAs that have shown up where they're more like software additions to CTA. What I tell patients is that what you get from a CTA is clarity and more information, which in most cases is really, really good. And that comes at a small cost in terms of increased radiation. And I guess, you know, some potential risk of the contrast, although it's relatively small. The biggest cost and the biggest reason that I don't use it in all of my patients in whom I'm thinking about these kinds of things is it's hard to get a paid for.

So it is actually, in this case, more expensive if you paid for it yourself out of pocket, which almost all of the calcium scans that I order end up getting paid for out of pocket, almost none of them as of today at least are reimbursed by insurance. But as you said, you can get them. That's calcium scans and CTAs. They're both just out of pocket these days. No, no, calcium scans are almost exclusively out of pocket. I would say 90 plus percent of them are paid for by patients themselves, but again, as you said earlier, but it's so inexperienced.

It's a couple hundred bucks. And almost everybody can make that leap and convince themselves it is worth, you know, whatever it is, 10 Starbucks. But for CT&G grams, the cost is much higher. You know, and again, I don't know, and this is one of the problems with their health care system. I don't want to get distracted in that, but it's transparent to me what the

cost is to my patients unless they go and do some digging. What's really annoying is that it's often not clear to them what they're going to pay for until after they already have it. The cost of a CT&GG is much higher. It depends on the insurance that you have. Even if you pay out of pocket, so even if it's not covered, the negotiated rate is going to be different based on whatever carrier you have. So I would say much fewer than 50% of my patients have coverage. And we can talk about what would justify coverage for a CT-angogram. And I've sort of gotten a little bit more sophisticated in trying to be able to get

around some of what I think are these are these absurd blockers for coverage. But then obviously depending on the patient spending anywhere from let's just say $700 to $2 or $3,000 on a scan may be more or less of an issue. And in some patients it's enough of an issue that they don't get it. So I think that's just worth pointing out. World in which they were covered universally, and we could have access to the data, that in my opinion, at least, it provides so much more information than a calcium scan that I'd probably just go straight there. And especially because in a lot of these cases, we're talking about like you and your 35 year old self, these are cases where we just don't have a lot of data and the calcium

itself is just not going to add that much. Yeah, I agree. And we kind of have that discussion with our patients as well, which is that look, the IV contrast is virtually a non-risk outside of a handful of settings, which are clearly well understood and can be, we know how to handle those pretty well. The radiation these days is so low. It's really in the neighborhood of two milliseavers for a person, our size. You know, that's 4% of your annual allotment of radiation. But you're right, the cost, I mean, we sort of assume 2,000 to 2,500 is pretty standard for that test. Yeah, when it's paid for out of pocket, I would say that's probably average, but there are some, for whatever reason, and I don't understand insurance in this country at all,

but for whatever reason, some insurance carriers are able to negotiate a lower rate for their members And so I've seen some people get and it's very different institution to institution right so you could go to UCS 7 It would be $700 you might go to Stanford would be 1500 or the other way around and so I do advise people when it comes to these decisions if The money's an issue which it is for almost everybody because it's a significant amount of money to shop around a little bit. And then the question of, all right, well, what do I get for my money? And we know that right there are different scanners in different places, and those different scanners provide different information in terms of resolution, but they also provide differences in terms of how much radiation exposure.

So that's another comparable that we kind of have begun to address a little bit. And those are the two things we always sort of say. I mean, we have places we send people because we know the answers to those questions. But if it's not convenient for them, we're sort of saying, you've got to ask what the radiation is. And it's actually, it can be a 10x difference. I've seen scanners out there that are at 20 millisieverts. So now you're up to 40% of your annual

allotment of radiation for one screening scan, which personally I think is too much. I just don't think it's worth it, even if you're saving a bit of money. It's just another layer of complexity and sort of how you think about applying these different tests and getting this information. It's just really important to make sure not to forget about it. So every time I've had these CTA scans, we get these beautiful images and they're 3D reconstructed

and then they're 2D sectioned and we're looking at the lumen, the tube of the artery. In both cases, that little speck of calcium shows up in the wall of the artery and then we're also looking for sort of soft plaque as well. Unfortunately, there hasn't been any, but that's soft plaque doesn't show up anywhere in the calcium score.

So you can have a significant burden of cardiovascular disease without any calcium. I think that's the thing that maybe gets missed a lot. And that shows up in that 15% of people who have a zero calcium score. A lot of them still have a significant burden of disease. As you mentioned earlier, I mean, it could be that that calcification, where it's actually placed, is not problematic.

It's just that it's a harbinger of whatever it took to get there. Do you look at patients with high burden of soft plaque and no calcification is even higher risk? I don't really just because I don't think I buy the data suggests that I think a hybrid and a plaque period is a problem. Do I believe that a hybrid and a calisthenic plaque might be less risky because it's more stable, I guess, in theory, but I get really nervous about sort of trying to impute plausibility and things like that to drive clinical decision making.

I think the reality is a lot of plaque is bad. I mean, we know that people who have a calcium score of 4,000, which by definition means they've got a shitload of calcium, that that's a high risk. And even if they don't have any soft plaque, the risk is still high. So I don't pay too much attention. It's part of the reason why I actually, if, again, if everything else is equal, I prefer that information I get of a CTA. Of course, I'm greedy. I want more. And I feel like we just get so much more information and don't have to make that distinction between soft and hard plaque.

And frankly, I'm not sure we're at a point in this field yet where we can make a compelling argument about plaque characteristics. It's been a field that I think has evolved now since the early days, right? Since the 70s, probably when the pathologists were doing all topics on people who died of sudden cardiac death. And, you know, we've been trying to understand the vulnerable plaque and different plaque

characteristics and what confers risk of rupture and ultimately an event. I just don't think at least in my estimation, I'm certainly no expert. It's not we're not there yet. I don't use it anything other than as a sort of how much plaque is there tool. Yeah, it's really interesting that we don't yet have a better tool to explain what vulnerability means or to predict what vulnerability is. Do you think that in the research setting, things like intravenous ultrasound or intervascular ultrasound where they can actually look and measure the thickness

of the cap on the atheroma. Do you think that in a theoretical sense, those things are any better, even if they're impractical from a clinical perspective? I guess, but ultimately, as a lot of things in biology, this is just so stochastic. I think we might convince ourselves that it means something that it doesn't. So I think, you know, we've learned a lot that, again, from the early days of even understanding that ruptured plaque leads to a thrombosis

over the surface of the ruptured plaque, and that's what causes a heart attack. That was at debate until 1979, or even maybe even a few years after that. It really wasn't settled until ISIS too was published in the late 1980s that showed that if you gave Strip to Kindness or Aspen, then you could reduce the risk.

I think we'd learned early on that it wasn't necessarily that 75 or 80% or even 90% plaque that led to the big one, that oftentimes the plaques that were upshared and led to sudden cardiac death were the smaller plaques, the 30% plaques, which kind of makes sense in the context of how we think about, we'll all hear these stories and I'm sure you get patients coming to you after After somebody prominent dies,

I'll mention the name just because I think this is an example and I don't know Cheryl, but when Cheryl Sanford's husband died on a treadmill a few years ago, and I had probably 25 people call me that week to wanna come in and get a risk assessment, that happens a lot. I don't know anything about his case, and I don't know anything about the pathology,

but my guess is, in younger people who die of heart attack, suddenly that oftentimes it's a relatively mild plaque that wouldn't trigger any discussion of re-rascalization and wouldn't make anybody nervous at all that those are the plaques that end up causing problems. And we can begin to weave together reasons why that might be right that maybe in a person who's got more plaque burden, that there's more chance for a Scheme pre-conditioning, and therefore the chance of an malignant aridmic response to the Aschemia is lessen because of that. But the my point is, I don't think we have an understanding of, to me, at least that satisfactorily would allow me to change the way I practice clinically based on the characteristics of the plaque, even the volume of the plaque. And so for that reason, I treat people with plaques, any plaque, 30% plaque, pretty much the same way that I treat people with extensive

plaque, and I treat them maximally with sort of the best optimal medical therapy I can offer. We feel so similarly about this, Ethan, that we're going to have a hard time coming up with something to really clash about here because this is basically the same discussion we have with our patients, which is I'm treating the causative risks, not the end stage problems. Like if the goal is, I need to wait until you have a 30% stenosis or a calcium score of 200 to start acting, that's insane. It goes back to the smoking analogy. stenosis or a calcium score of 200 to start acting, that's insane. It goes back to the smoking analogy.

I want to tell someone the second they pick up a cigarette to put it down, not until I see that the pulmonary function tests are problematic or they've been smoking for 20 years and their risk is significant. And this is the sort of eye-believing experience that I have with insurance companies talking about adding PCSK9 inhibitors to statins and whatever else they're on. And often they'll say, well, they need to have an event first. I'm thinking, you know, I sound so backwards. You're going to ask me to let my patient have a heart attack so that I can prescribe the drug that's going to prevent them from having a heart attack.

I mean, it's really incredible. Hopefully we won't practice that way down the line. The problem, of course, is that I don't want to get distracted, but all of these trials are so incredibly expensive to do that the information that we're going to get from the most rigorous randomized clinical trials is going to be limited just because we're not going to be able to, you know, all the questions that I want to ask and answer, I'm sure that all the ones you want to ask and answer are just not going to be feasible to do because they're going to be overwhelmingly expensive. So

we have to find a way to make decisions to treat patients independent of this gold standard level of evidence. And hopefully the insurance companies come around. I've kind of accepted the fact that Ethan, we're never going to have the gold standard evidence that we need in the most important demographic, which is the demographic for whom we have the most runway to affect change. So in other words, there will never be the study done in 40 year olds that says, what is the 30 year risk of AACVD in a cohort of 40 year olds? One group whose

APOB is reduced to 30 because we've used a PCSK9 inhibitor plus or minus whatever other agent we need versus the group that's managed with standard of care or some placebo or something else. And I feel more convinced of the outcome of that theoretical trial than I do virtually any other theoretical trial I could ever muster up in my brain. And yet it'll never be done. And therefore, there will never be an evidence-based case for true prevention of ASEVD. I say something very bold in my upcoming book, which is that ASCBD should basically be an orphan disease. There's actually no reason it needs to be

the leading cause of death. It really doesn't even need to be in the top 10. It's that preventable if you start early enough and if you're maximally aggressive. And really, at that point, I think it just becomes a question of working through the challenges of tolerating side effects in patients who are sensitive. And I think there are gonna be patients

who are gonna be challenging. But with a long enough runway, this disease is sort of irrelevant. Let's talk a little bit about these flavors of CTAs that keep showing up. So, I guess we'll start with the CTA-FFR, because we did speak about it briefly. We don't have to go back into all of the detail of, and I'm blanking on the name of the trial. There were two trials

that looked at FFR in angiography. Fame and fame too, I think. That's right. Yeah, fame and fame too. I guess give the, give the, the short version of what those trials looked at, what the technology was, and then we can talk about the CT side of it. Well, I mean, the original FFR was performed that is still now performed in a cath lab is is it a way to detect a pressure gradient across us to know this is the simplest thing I used to

explain to patients is if you take a garden hose and squeeze it, that there's a gradient of pressure right, that there's going to be pressure proximal of this, your finger squeezing the garden hose and the pressure on the other end is going to be lower. And what they effectively do is to put a wire with a pressure sensor on one end of the wire on the other end of the blockage and they put one on the near end of the blockage and they can measure the delta and that using a mathematical formula you'll know the ammeter I'm blanking on it. You can impute the diameter of the artery relative to the diameter of the unobstructed artery or the garden hose in this case.

And so that kind of gives you a way to get at the severity of the blockage. And I guess what this stems from is the 40-year odyssey to try to take a very qualitative measure, which happens in a catheterization laboratory, which is measured the percent stenosis, which is done if you've ever seen it. It's done very much by of by like a gestalt. And the people who are good at it are pretty good at it. But if you watch it, you understand that the difference between 30 and 50 is probably not that meaningful.

When there are severe blockages or stenosis, you can sort of all agree that it's really high-grade. So, I think of things in high-grade modest and low. So this has been one of a number of tools that have been developed to try to supplement the information you get from that sort of very qualitative assessment of visually how bad does that lesion look. And many of these things have happened over the year. You know, I've as you mentioned earlier is one of them. There have been a quantitative cornea, angiography where they actually try and take cursor and electronically draw around the diameter of the vessel.

My Gibson, you know, back in the old days used to do this blush thing. I can't even remember what it was called, but basically it would count the number of frames it takes for the contrast dye to leave the myocardium. And that was another indication of how severe the lesions were. FFR evolved as a human dynamic way to be able to impute the severity of this denosis.

And so I think fame was the first of these studies, and it showed that if you had a significant pressure drop, if the ratio of the pressure and the sort of upstream sensor was higher than the downstream sensor that that conveyed that there was a bad lesion and that it conveyed worse outcomes in people who didn't get stended. I can't remember the design of the trials, but basically it was a way to kind of think the idea was basically look at there's no ambiguity in two subsets of people who should be stended, right? So somebody who's actively having an MI, they show up in the ED with chest pain enzymes are leaking. I mean, we just go to the cath lab. There's no need to

put surround. I mean, what's the algorithm on a clot versus stent in the active MI in the ER? Oh, in the modern era, if there's a cath lab within whatever it is, I think I don't know what the exact number is in the latest guidelines, but it might be like 90 miles. It's really the amount of time you have to calculate the amount of time it takes to get transported to a place where there's a Catholic that does stinting. Primary PCI. So primary PCI is the standard of care. I think thrombolytics are used sparingly in this country and only in remote places where there's no access.

Where they can't get to the Catholic. Yeah. So in an ST elevation in my, it's primary PCI is the standard of care class one, the whole deal. And as quickly as you can get there. And then the other indication in the non-MI setting is symptomatic, right? If you have a person who is, if someone has a stress test on the stress test, you see ST changes.

Is that an indication for a PCI as well? So we'll back up. Stem, he's the ST elevation MI is where there's a complete physiology where there's a complete physiology, a complete obstruction of blood flow. SD segments go up, you go in, there's no blood beyond the blockage. That's clear and everyone understands. What we're now calling ACS, which we used to call unstable engine or non-STLvation MIs, which is same pathophysiology, right? Rupchard plaque, a thrombus sitting on the plaque, but it doesn't completely obstruct blood flow. I think there's general consensus, even among some

of the more conservative groups out there that those people benefit from going to the cath lab early and having a stent to fix that blockage. I would say it's generally accepted on the org if I had to guess of 85 or 90% of people who'd practiced that way. And what I mean early, I mean within the first 24 hours. So it's not a sort of code level emergency.

Now most hospitals have these STEMI teams where they'll automatically the emergency department will page the page or everybody comes in from the technicians in the cath lab to the interventional cardiologist, to the fellows and everybody else. They'll just assemble there to get there as quickly as possible. That doesn't happen. There's no stemmy activation for a non-stemmy or ACS event, but I think there's still general consensus that disease is treated best with early intervention. And the only distinction between those people is the

ST change on the EKG when they present? That's right. That is the distinction. And of course, that is sensitive, but not 100% sensitive. There are certain lesions that are obscure, right? Where you would, for example, a posterior MI, you'd have to do posterior leads to be able to see that. But mostly, STEMI is an emergency go straight

to the cath lab, don't pass go. Non-STEMI or ACS is urgent, and generally people end up in the cath lab. And it wouldn't be a bad thing to have them go there relatively quickly depending on how unstable they are. Obviously if anybody has unstable symptoms no matter what they have, in other words if their blood pressure was labial or if they had heart failure or an ongoing chest pain that was refractory to medical management then that would also become a sort of don't pass, go straight to the cath lab.

So I would say those things generally end up getting stented. This is my opinion, my read of the literature, but over the past 15 years, what has changed is people with plaque, but without symptoms generally don't get stented. Even the most aggressive in original cardiologists, I won't mention names, would probably agree that people who have a lot of plaque, maybe with the exception of proximal idea of left main, there might be still some people who would think, gosh, even without symptoms, I'm gonna put up a stent on this person.

But generally people with plaque, no matter how bad the plaque looks, angiographically, those people are treated medically if they don't have symptoms. Where things have gotten interesting is in these cases for symptoms, right? Because I think most of us have... And sorry, when you say symptoms, Ethan, you mean symptoms in day-to-day life, or do you mean under stress and provocation?

Good question. Yeah, so no. So rest symptoms is unstable symptoms, and that falls into that first category. And those people should be hospitalized when they would go in that first 24-hour window. So any symptoms that rest without doing anything, we can debate about what happens if you have an argument with your wife and you get chest pain. Is that unstable or stable? But mostly it's the sort of non-classic exertional angina where you're walking up a hill and you

get chest pressure, get chest tightness, rarely pain. You stop, it gets better, you take a nitric glycerine, it gets better, classic stable angina. People have plaque but do not have stable or unstable symptoms at all. In general, these days are treated medically with some exceptions. It's the people who have this classic stable angina stable symptom. So they go out and walk up a hill, they get chest

tightness, feels like somebody's tightening a belt around their chest, they stop, it gets better. It's those people who I think are kind of the most interesting today in the contemporary practice setting. And those are the people I think they require the most thought. And I think we hadn't put it on our list of things to discuss. I don't remember if we discussed these trials the last time around, but I was the courage was the trial that sort of taught us that it's okay to have a lot of plaque and not necessarily Intermean on it. There have now been several other trials to get at that question of is and this is where part of the reason why fame is To me like not that interesting because we've kind of already answered the question in all comers

that Stenting people without symptoms Even if they have some significant lesions doesn't offer a benefit over optimal medical therapy There's now I think think, some discussion around even patients with symptoms. The range of opinion, I think, goes from anybody with symptoms should be stented or re-bascularized,

in edge cases with bypass. Some people think medical therapy, in all cases, and then I think there's sort of this new on-stand between people who think, give a trial medical therapy and see if you can get the symptoms better. It's not an automatic take to the cath lab, but try to optimize medical therapy. And if you can make the symptoms go away, then there's no need to go and stint that artery.

And that's probably where I land right now is I still use interventional cardiology. I certainly don't use it as much as I did in the past, but I do use it for people who do have what I would consider to be refractory symptoms. And then obviously for the unstable emergency acute settings, that's a different story. And if you had a patient with a really high calcium burden, so they're north of a thousand and they never experience symptoms and they're young in their fifties or something like that, would you put them on a treadmill and push them as hard as you could possibly go and assume that like, hey, they're not necessarily exercising that hard every day.

I want to really see if they have any ST changes or wall motion abnormality when I make them go to 15 mets. I don't because like I said, I sort of land in that camp of even if you had symptoms. You'd still medically... I'd still probably treat you medically. I would still try to optimize medicines. Now, if somebody came in and was on great medicines and was still having symptoms, then obviously it's a different story.

But yeah, I don't routinely do anything to people who have high calcium. In fact, if you have a high calcium score, whatever it is, a thousand, to me, it triggers a response, it's the same. I don't think you need a CTA, in that case, in the fact a CTA might not be very useful because there may be so much calcium that it kind of obscures the ability to be able to see into and beneath the vessel.

So to me, I don't automatically do stress testing in somebody like that. I often will see patients who've been completely freaked out by the result, and they'll have had a big workup, including potentially stress testing and CT angiogram. But I don't do that. And I likewise, don't do any routine stress testing anymore as a way to follow coronary disease, right? That was something we used to do in the old days when somebody had a lesion, you knew they had a lesion, you'd kind of exercise them over, you know, once a year or something to see how they progress. I don't do that anymore either.

So in light of that, fame, if I recall, basically said, we're sought to answer the question, if you took a bunch of asymptomatic people, and you did this FFR on them, you measured the fractional flow reserve. If you took the people who had a pressure drop of, I think it was either 30% or more. I think it was a .7, P2 to P1, but maybe it was .8 or .7 something like that. It was either a 20 or 30% drop. If those people automatically got stented and the others did not, and these are both asymptomatic, would we see better outcomes in the more aggressive stenting strategy? Isn't that effectively what the trial? That was the design and that was the result.

And so therefore that became standard of care in a cath lab. And most cath labs that we were doing at the FFR on a lot of patients were initially up up. I was there for these end cases where you weren't sure is this significant or not should we stent it should we not stent it. I think it went through a period and I think it's now come back but I think it went through a period where it was being used a lot based on fame with the sort of assumption that you're impacting people's outcome, hard outcomes based on your decision making and that there were certain groups of people who benefited

tremendously from getting stented and our job was just to identify who they work. On the surface, that's not an absurdity. It's definitely a possibility, but I think after however many years now of understanding the data, I think the consensus is it's just not necessary. I think really mostly it comes from the sort of line of evidence that we've had through courage, ischemia, orbita, all these different trials showing really that the take home is that optimal medical therapy, even in a mildly symptomatic patient is quite effective. So all of this basically is prelude to a CT-based version of this study, which of course can't do the intervention, but it can identify people who are getting CTAs, which are far more than the people who are getting traditional angiography, to say, hey, maybe you do need an intervention.

So again, in theory, the idea here is, well, you've got a CTA. I see a stenosis there. It's a 50% stenosis. Is it significant or not? I can't tell. I don't have a pressure transducer in there that I can measure, but I can run this algorithm on it and the algorithm will tell me what the pressure drop is. So of course, question one is how successful is that algorithm? I don't know myself. I assume that there was a head

to head that was done where you had a whole bunch of people that actually had calf, that actually had pressure transduction, and then concurrently had CTA and then they could actually see how predictive they were I have to believe that was done, right? Yeah, there was a trial. I don't remember the details of it. I guess the questions are in my mind So does the physics and I don't understand the physics, but does it make sense? Can you actually Really make this calculation in a meaningful and reproducible way and these people? I imagine back in the day when the method was being valid that there were some comparisons, they have to have required

some comparison to be able to say, just as they probably required something to clear the catheters themselves, they probably required something. It probably was close enough. I don't have any knowledge that the thing is a random number generator. To me, that's a distraction. I think there are plenty of people who go down that path.

To me, the question a distraction. I think there are plenty of people who go down that path. To me, the question remains, what are we doing and really, in the way I practice, do we need to identify asymptomatic people who are at higher risk? Is there a group of these people who are special and might show something that no other group patients has ever shown in the history

of an initial cardiology, which is a benefit from stenting? I know that my international cardiology colleagues which is a benefit from stenting. I know that my interracial cardiology colleagues are gonna hate what I just said, but we've been doing this for a long time now, and we've been looking for any group of people who would benefit from outside of the TDIMI setting, which we talked about, any group of people who would benefit

from a stent being placed in their artery, and we've had a hard time doing that. It's not for lack of track. It's been, I mean, again, courage would sort of was the beginning of the end of this in their artery, and we've had a hard time doing that. It's not for lack of track. It's been, I mean, again, courage, which sort of was the beginning of the end of this, in some way, since that was a trial that was conceived of and executed by a group of interventional archaeologists who wanted to demonstrate the superiority of stenting over medical therapy. It was designed that way, and all the bias was weighted towards getting that outcome. It did not get that outcome. And frankly,

there have been however many dozens of studies since then. And at least from my point of view, there's nothing that screams at me that, hey, look, our job as preventive cardiologists or thoughtful internists should be to go looking for people who might benefit from a stand in the absence of symptoms. And that's where I'm left today is that I don't see any evidence yet that there's something magical about some group of people where they derive that much more benefit from a stand beyond truly optimal medical therapy. And I think, as you said earlier, if everybody got truly optimal medical therapy, like if we could didn't have barriers to using all these tools and everybody, I think this disease would largely be controlled.

Now, I do believe there's something else going on that's residual. And you're an example, I think, potentially. But yes, I think the quality of medical therapy we have today is so good that it's going to be really hard to demonstrate the value of stenting people. That assumes that stenting doesn't do something harmful. And again, I think that's an open question. Why, if you have a very high grade lesion, even before there was great PCSkin I knew it was right,

they were just zo-core or something, why wouldn't opening that artery lead to improved outcomes outside of the Ak amy setting? That's a question that always plagued me, even as a cardiology fellow, I was like, this doesn't make any sense. It should. You're opening up an artery that severely blocked and restoring blood flow back to the heart. And there are lots of explanations for why that might be. I don't think we have a good one, but you could imagine that going in there and blowing up a balloon inside that artery and deploying a stint that you're elaborating the contents of that plaque downstream and much like what happens when you break up a

beaver dam in a stream, it's just going downstream and causing its own set of problems. That's just me speculating and making it up. But to me, it's an interesting question why it wouldn't be or why there were these. Has the study been done, for example, where they take a group of individuals who were asymptomatic at the time of being stented, or they weren't being stented in an acute stemmy, who then go on to have subsequent events, what the location is of the plaque. In other words, when a person gets stented in the mid-LED and they go and have another event, is that other event, can we identify a pattern. So for example, is it distal in the LAD? Is it in a part of the heart where you could say, you know, maybe there

was some mechanical change that took place as a result of that stent? Or maybe it was, hey, you know what? The reason it doesn't work is you're playing whack-a-mole. And this person had lots of disease. You just happened to pick the one that had the most stenosis, although stenosis by itself is actually a really crappy predictor of future events. So you weren't more likely to do anything here. Maybe if you, you know, stented the entire vasculature you would have, but of course you can't do that. So it really comes down to how lousy is

plain up stenosis as a predictor of subsequent events. It's a good predictor that as we discussed earlier, these plaques that end up leading to bad things often are not the plaques that we would be get stented anyway. So I think there's that, which is sort of the... And that's my point. Because another explanation, which I think you had a good one, is, if you have a 90% stenosis, and you haven't experienced symptoms as a result of that yet,

that's probably telling that if you throw a clot there, you're going to survive. That's right, because there's collateralization. And we know that, right, from seeing these, you know, you can see that. And that's probably the mechanism, right? That this Schemic Preconditioning leads to this growth of cladderals. And basically it's like, if there's an accident on the freeway, it's still like a telepatients that you get off

on the side streets and you wind your way through. It takes a lot longer and it's not great when there's like a lot of traffic, but if there's no traffic and it's relatively light flow, you do find. Right, but that's 30% lesion hasn't been tested yet. No, it hasn't. So you don't really know how it's going to respond.

It can't be tested because you would never stand at 30% lesion. Yeah. So there's that. And then the other thing I think is that if you look at and now with the advent of sort of high sensitivity, triponins and other more sensitive measures, if you look at say, triponin or CK elevations after a long intervention, they most certainly go out, not in all cases, but they do go up. And so the question is, are you basically creating a little MI in the process of putting

the stint in? And does that then cause downstream risk in the form of Rhythmias or other issues later on in life? And that, to me, is sort of an interesting thing to think about. Obviously, no great data at this point. But I think there are data, at least observational data, looking at the area under the curve of the Treponin elevations post PCI as a predictor of outcomes. I think, obviously, the more Treponin you have the worse you do as you'd expect.

Okay. So there was this study that I don't think is published yet, but I think you and I saw it and emailed each other about, was it the precise trial that we saw the abstract for? Remind me. This is the one that did the, I think, this is the one that did the FFR, and it found no difference in all cosmortality, no difference in mace, but a reduction in the need for catheterization. Right. So this has now become the sort of value ad of doing these non-invasive adjuncts to CT and Geography. And the reason that we use this now, do CTFFR on not all, but most of the CTAs that we do is that in theory, you reduce the number

of people who go to the lab. You only reduce the number of people who go to lab if you send people to the lab. If you're not sending people to the lab, you're not reducing the number of people. So again, to me, it comes back to the primary issue, which is that people with plaque probably, in the absence of symptoms, people with plaque should probably be optimally treated and left alone, and that taking into the cath lab is a very little value. And obviously, if you get to the cath lab, the chance of them getting stented goes up, astronomically, once they're there.

So yes, you do theoretically prevent unnecessary stints with CTFFR, but you can do that without the FFR. You don't need the FFR. Yeah, I think that's really well said because to me, I don't get hung up when a study like that doesn't find a difference in ACM because I think that's a short time horizon. But I do get a bit alarmed when there's absolutely no difference in MACE. Right, when you see no difference in anything related to cardiac pathology, and the only difference is an algorithmic difference that to your point,

you can make on your own. Again, I think we should maybe reserve judgment until the final study is published. So we'll wait for that. I don't know when that's coming out, but I found myself very underwhelmed by this and it didn't change my thinking, which is that at this time, I'm struggling for the use case of FFR. And as such, we really don't employ it with our

patients. I think that the issue is sort of, you have all these levers you can pull. And so your job is to kind of figure out which levers am I going to pull? And I think sometimes people over complicated, right, that there are going to be relatively low risk people. You could get away with statin, or maybe statin and a very low dose of Zedia. I mean, you know, in my opinion, if you have plaque, significant A plaque, they say a 30% plaque greater in an artery, in your corner of asculture, I'm pulling all the levers. I don't need any other information, like I don't need more, and that's a pretty good

intervention pulling all those levers. By the way, to your point earlier, let's just assume there's something in me that's off. I think the fact that the moment I had a six-score ditzel, every lever got pulled, is probably why 15 years later it looks like a ditzel still, nothing's changed, which means if we just pulled all the levers all the time, we could kind of take this disease off the table for virtually entire population. This is the mission statement of my friend's say, Catherine reason's company, Virg,

they want to crisper out PCSK 9. Not necessarily initially and everybody, but he believes that if you can do that, you'd eradicate this disease. I don't totally agree with him actually. We disagree a little bit on sort of some of these things, but in general, I think he's probably right. The question is, do you need to go to that extreme to solve for this problem? And could you apply that solution to everybody

feasibly and worldwide? That's his problem to think about, not mine. I'd love to have Seth on to talk about many of these things. Okay, so let's talk about two other things before we leave CTA. There's the fat attanuation index, F-A-I. What is that exactly? I'm going to be totally honest. I have no idea. Okay. You've seen it, I assume. It's been presented to you. Maybe I sort of have learned in now doing this for as long as I have. So I graduated from medical school in 1996 and did my residency for two years and then started my cardiology fellowship here 25 years ago

So I've sort of learned to tune out like put blinders on and to some of this stuff just because it's something new every few weeks It's been that way like consistently So I'm sorry. I'm not like completely up to speed on this latest you greatest fat attenuation index I imagine it's some CT-based way to look at the characteristics of the plaque and the sea of it's potentially vulnerable. Is that the idea? No, it looks, and I'm not an expert in this. I was hoping you were. So it is a CTA bolt-on, just like the FFR is, but it looks at the characteristics of the fat around the plaque. So it's not trying to predict vulnerability per se. It's actually trying to predict how much inflammation is,

I hope I'm getting this right, but I think it's looking for how much inflammation is around the plaque. I see, I don't know if I'm familiar. I am familiar with PETCT, the amount of, you can measure using FDG PET, you can measure the amount of inflammation in a plaque that can be done quantitatively.

There's a group of people who've been doing that for years. And I think certain pharmaceutical and biotech companies have used that as a way to kind of gauge efficacy in evaluating new molecules to see if they can have an impact there. That I don't think is being used now clinically, at least to my knowledge and routinely. I'm not familiar with the fat attenuation index. It kind of makes sense. So, it's Epicordial fat. That's right.

Okay. I mean, it's an interesting idea, right. So it's Epicardial fat. That's right. Okay. I mean, it's an interesting idea, right? I mean, Epicardial fat is visceral fat and it probably does impact risk in some way. Again, what are you gonna do with that information? You're already pulling all the levers. I guess maybe you'd focus a little bit more

on metabolic stuff, I guess. Which we'll come back to. Okay, let's pivot to another topic that seems to come up from time to time online, I guess, which is, are there subsets of people in whom an elevated CAC is not a predictor of risk? So there's been some confusion about this. I think it's maybe worth clarifying this for folks.

So James O'Keefe has commented on the fact that certain athletes who exercise a lot, so very high degrees of cardiovascular fitness, might have a higher frequency of coronary calcification. So let's first talk about that, how robust are those data, and more importantly, what does it mean? Well, I think it's plausible. We know that increasing sheer forces across endothelial service can certainly lead to damage, and that would potentially increase calcification. We know that in say patients with a bicuspid aortic valve that people who exercise at extreme

levels do appear to have an increased rate of calcification of that valve. And I say appear to you because at night studies are controlled. But it does seem that that's the case, and it makes sense and is plausible, as dangerous as that word is. I think the same thing could be true in a coronary artery, fast-cure bed, that increasing shear, as you would expect to, by increasing flow, as you would,

during extreme exercise, could potentially lead to some damage and therefore calcification. So I do think it's plausible. And sorry, I do think there is this one example where there is a disconnect between the amount of calcification and the artery, the amount of risk and that is within people taking statins.

And that's a very difficult concept for people to grasp. And frankly, it's a difficult concept for me to explain. I do find myself getting tied up and trying to explain it. And I can make up explanations like, you know, what you're doing is healing the plaque and stabilizing the plaque, which we think steds are doing and that that's a good thing and not a bad thing. But I think it's incontrovertible that steds probably do increase the risk of calcification despite lowering the risk of events. So there is this one example. So is it possible

that exercise could be similar to that? Maybe. But we don't have the flip side, right? We don't have the 40 years of really rigorous randomized trials, showing that some exercise versus some version of placebo does that. Would I say don't exercise? Absolutely not. Would I tell some patients not to exercise to that extreme level?

I don't know, I'm on the fence there. And the question is, let's just assume that it is the case that high, high amounts of cardio respiratory fitness come at the expense of some endothelial damage. I don't know if it's true, but I agree with you. There's certainly mechanistic plausibility there. The question is, the ability there. The question is, if a person goes from call it, I don't know, 50 met hours per week of exercise to 100 met hours per week of exercise, and let's assume that doing that increases their calcification. A, is that with or without more risk. Let's assume it is with more risk. But is that risk more or less than the benefit that they gain going from the 25 or 50 to the 100 met hours a week of exercise? In other words, this is what makes

exercise a bit more complicated here, which is most of the other things that are increasing the burden of calcification are net negative. Smoking more, having higher blood pressure, having worse lipids, but the correction of that moves in the same direction, works in the same direction as the improvement of the risk modifier. We've decided it's not the same. What's I think unambiguous, though, and we were talking about this earlier, more exercise is better than less, and more calcium is worse than less. I've yet to see an exception to that rule in terms of cardiovascular health. That's right. And that discordance, I think, is only mimicked by the statin story, right? Where we know more statins are better and also have laid to more calcium.

Look, here's the thing. If you put it back into the terms in the context of a patient comes to me and says, hey, I've got this calcium score, whatever it was called, eight hundred, I don't know, whatever you want to call it, 500, 300, 200, 100. I don't think it means anything because I exercise a lot. That's the question that gets presented to us at an individual level. And I guess what I'm saying is that I'm not yet comfortable

saying, oh, don't worry about that. Whereas I am comfortable saying, don't worry about that, if it's because they're on a statin. So what I would say to that patient is we have to assume that that calcium is representative of plaques in the arteries and that having plaques in the arteries is a bad thing that we should treat you accordingly, even though you exercise a lot. And if you want to be sure, then we can do a CT&G gram to kind of see how much plaque you actually have because I don't know any evidence that this calcification is not plaque-related

that it's somehow extravascular calcification or it's beyond the, it's in the intima or something, or media, I guess. But that's how I would approach it today. I just can't tell you, I can't give you a free pass on the calcium because you exercise a lot. Exercise is great, keep exercising. Don't stop exercising, but I think the burden of proof is on us to show that that is not risky. And if we did a CT-AngerGramon that showed you didn't have any plaque in it, all the calcium

is sort of extra vascular somewhere else, then sure I'd be okay with that. But that if we do it and we see plaque, I'm not aware of any data that would say, let's not treat you. Which is sort of the subtle but important difference between the statin star because the people on statin are already by definition on the risk-reducing therapy

that's been shown to save lives. It's not like what are you gonna do to that person because their calcium score is higher, which would be more aggressive, I guess, is one of one question people might ask, but that's the difference is that there's that leverage still to pull and the exercise person who's stat 90.

What percentage of your patients take statins? I mean, it's a completely biased group of people because it's all self-selected, but there are. Of course, of course. 90, I'm guessing, 90, 95 maybe. And is the implication that the 5 to 10% who don't have some side effect that they are unable to tolerate? There's those for sure, although I think

that's less frequent now because, would you say statin or any other or PCS can I in here? Because I do have a few patients who can't tolerate. I would just say statin to start. What I want to sort of explore for a moment is, what are the real world implications of the use of these drugs? What are the real world side effects? What are the real world implications of the use of these drugs? What are the real world side effects?

What are the real world conditions that prevent people from being maximally medically treated? Small number of patients who don't take them because of true side effects. Equally, maybe even slightly larger patients who don't take them because they're afraid of them. And I don't mean that to be pejorative. I think there's been a tremendous campaign, a propaganda campaign to demonize statins that's been going on for a long time, 25 or 30 years.

And it's been very successful. And people are terrified of statins. You know, I mean, there have been documentaries made on how statins are poisoned and they're killing people. And while not everybody, or even maybe most people, are aware of that, plenty of people who spend a minute of time online are. I do spend a lot of time with patients who come to see me

because I have some openness to at least having that conversation with them, and I'm not gonna force them. I have a patient of mine who came to see me with a tremendous amount of skepticism, had every risk factor, and was probably having angina when he first came to see me. And I recommended that he start taking a statin that first day and he was afraid to because of stuff that he'd read about how dangerous they were.

He ended up needless to say a few months later in the ER with an AQMI. And fortunately the outcome was good. He ended up with a statin. He stayed on a statin ever since then. So that sort of was enough of an experience for him to change his mind. But I have a number of people who just flat out either won't or it takes me years to convince them to years. Some people I've seen for years, I've had the same conversation year after year after year after year and some people never change their mind, some people change their minds because of other things happening

like this patient having an MI. And some people change change their mind. Some people change their minds because of other things happening like this patient having an MI. And some people change their minds because finally they are convinced. But I never force it. What's the core belief that's at the root of the fear you think? Again, and I say this just acknowledging that, yeah, probably about 5% of patients

are going to experience muscle side effects that are going to warrant not taking a statin because it's going to impede in their quality of life. So if you just acknowledge unemotionally that there are side effects, you're going to see trans-MNA celebrations that are just too much, especially if mixed with Zedia. If you acknowledge all of those things, there's obviously some deeper seeded fear in something that can't be seen or measured or quantified.

Where do you think that comes from? And why don't we see that with other classes of drugs to the same extent? I think we do. I just think this happens to be one of the most prescribed classes of drugs in the history of humankind. And so it's just the denominator is bigger. I think this is sort of the same thing

that gets at a lot of skepticism around science and big pharma. And there's a whole world of people out there with these vast conspiracy theories about the development of stadons and about how Rory Collins is an evil person. He's engineered this whole conspiracy to try to get the whole world on these poisons. And there are people out there who really believe that.

And you hear something enough and you aren't an expert and don't have access to all the data that we have access to, it can be compelling. And I've watched some of these documentaries they're terrifying. Just as I'm sure, you know, the documentaries we were made after the Wakefield experience in the late 90s were terrifying to young mothers who were worried about giving their kids MMR vaccines or whatever. It's very easy to convince people to be scared of something. It's a lot harder to make people unscored of something. This is just an example.

I think where there's a group of people out there who just don't believe in this whole enterprise for whatever reason, very skeptical of big science and big farm. Don't let get me wrong. Obviously, there are plenty of things that big farm has done wrong and we can go through science and big farm. And don't let get me wrong. Obviously, there are plenty of things that big farm has done wrong. And we can go through the examples of that. This happens not to be one of them. The sad thing about how demonized stands have been

is that it's one of the most profoundly important interventions that we have in modern medicine. And it's astonishing to me that like, this is being compared effectively to smoking, to cigarette companies. I haven't heard that comparison, but certainly people will quickly point to Purdue and the opioid crisis has proved positive that the pharma entities are evil. And there's no question that Purdue pharma is indeed evil.

And again, I've said this before on the podcast. I think it's really difficult for us as a species to think dialectically and to hold seemingly contradictory truths simultaneously that pharma companies can do good things and bad things. And that seems to be true across the board. That seems to be true of every person as well, right? Any given individual can do something good and something bad. The exceptions would be those that are universally good or universally bad as people. Yeah, there are people out there who are clearly bad. And there are people who are probably clearly always good

and I'm not either of those. I'd like to meet them. Let's talk about blood pressure. I think this is one of those areas that I've personally become more and more interested in over the past year. And it's actually become more of a concern to me, maybe over the past two years, through the lens of the kidney. So we have this organ that just

doesn't get much attention. I'm trying to think outside of my podcast with Chris on and day where we talked about kidney and liver transplantation. I don't think I've got a single podcast that deals with the kidney. And it's a really special organ. And I sort of explained to my patients that in our bootstrapping approach to living an extra few years on this planet, a lot of it requires a phase shift in time. Right? So if you're 50 years old, you really need to be held to the standard of a healthy 40-year old. If you want to live an extra 10 years, that's the to be held to the standard of a healthy 40 year old.

If you want to live an extra 10 years, that's the way you want to think about it. You want to think about that in terms of your mind. You want to think about that in terms of your body. You want to think about that in terms of your coronary arteries. You want to think about it in terms of your bone density, but you kind of think about it in terms of your kidneys. And so when we look at a person and estimate their glomerular filtration rate, which we use, you know, cystatin C to measure that, we've largely abandoned preatinin, it's really

tempting to say, well, you know, this guy's 55 years old, his EGFR is 70 miles per minute. That's good enough, but in reality, it's not actually. It's far from good enough. And the kidney is not uniquely, but exquisitely sensitive to high blood pressure. I'm not a nephrologist, and I never really, I don't think I remember much from nephrology, but I certainly remember that something about its vasculature is incredibly sensitive, right? It probably has to do with the fact that it's such a tiny organ that takes such a high amount of our cardiac output. And I suspect just like the heart and the brain that it's such a tiny organ that takes such a high amount of our cardiac output. And I suspect just like the heart and the brain, it's very sensitive to pressure.

And so that really is the lens through which I think about this first and foremost, meaning even the slightest amount of elevation in blood pressure is going to interfere with long-term kidney health and also with heart and brain health. So there's a win across the board if we just normalize blood pressure. So I'll pause at that and have you just kind of explain from the AACBD perspective, the importance of blood pressure and how it stacks up with smoking APOB and some of the other heavy hitting risk factors. I just want to acknowledge how strongly I agree with you about how much we neglect the kidney

as an organ and an effrology as a subspecialty of medicine. I actually used to give a lecture on hypertension in the first year of medical students at UCSF and I did that in conjunction with a kidney pathologist who interestingly was, had been in Hopkins when I was a medical student, was my advisor, very interesting woman who's now retired, Gene Olson and she co-gave the lecture, she gave the pathology part and I gave the clinical part. And I learned so much about the importance of the kidney and regulating blood pressure and giving that lecture with her for however many years it was, 10 years.

So it's both an important cause of blood pressure. And in fact, I think if you go back and look at Rick Lifton, who's sort of one of the premier human geneticists in history, member of the National Academy, had some probably should win a Nobel Prize. He characterized all of the single gene mutations that lead to extreme increases of decreases in blood pressure. I think at the time, this is 20 years ago, there were 10 single gene mutations that led to people who had really, really low blood pressure, had a constantly supplement solved and

do things like that, and then tend to lead to extremely high blood pressure. And I think like nine or whatever, just 19 out of 20 of these things were located in the same location in the proximal collecting doctor in the tubule. It was like you couldn't have picked a place that was more important evolutionarily for how we handle volume and salt and solute. So it's a incredibly important organ, both as a cause of high blood pressure and also as a consequence.

And those experiments in a gene showed these beautiful slides that I'll send along sometime, pictures of what happened to your kidney after it's exposed to increased levels of blood pressure over time. It was interesting because I was giving this lecture as a cardiologist during the kidney block. I thought I'd be pleased. So most people kind of know that when they go to their doctor and they get their blood pressure checked, normal is about 120 over 80 millimeters of mercury. What do we know about how much that changes in a healthy person across

the course of the day? So when they're sleeping, when they're ambulatory and walking around, but not under stress, i.e. not exercising, when they are exercising vigorously, when they're under stress, physiologic stress, psychological stress. All of these different things that we do every single day, surely our blood pressure must change, and yet most of us, myself included, have virtually no idea of how our blood pressure is changing under those situations, even if under perfect optimal conditions, i.e. sitting down, legs on cross for five minutes, it reads 120 over 80. So what do we know about the rest of the time?

I don't want to get too distracted, but I think it's fascinating. I thought about this a lot. And the question of what's normal is, we all assume 120 over 80 is normal. If you look at blood pressures across different animal species, it's mostly in that range. There are some that are outliers.

Obviously a giraffe is the best example of an outlier species with much higher blood pressure. It needs to have to be able to pump blood up to that head that's sitting way up high. It is weird to me, from evolutionary perspective, why we would have the same blood pressure as a mouse. It's a little tiny creature who blocks around four legs. Why should we have the same blood pressure? a mouse. It's a little tiny creature who blocks around four legs. Why should we have the same blood pressure?

It speaks, I think, to the conservation of this sort of vascular system that we have. I think most people, and I was a medical student, I'm sure you were the same, we're taught that 120 over 80 is normal, but that's just normal, whether you're 7, 17 or 75. I don't think we have a good understanding of, well, we have an understanding of what is epidemiologically normal as we age. And so we know that blood pressure does go up with each

decade of life. If I had access to that lecture, I used to give, I could show you what happened, but certainly with each decade of life your blood pressure goes up on average, if you're looking at a population of people, is that normal? Is that part of normal healthy aging, or is that just a function of pathology? Is it a function of something going wrong over time to your point? Is it something about decreased kidney function, or maybe is it increased vascular stiffness over time? I think all those things are possible and probable. So for a long time, it was assumed that a blood pressure

that was normal for somebody in their 20s and 30s was probably too low and not normal for somebody who was in their 60s, 70s and 80s. And so we sort of had this permissive hypertension in elderly people because we thought, well, gosh, they required it's just part of the aging process. And it really hasn't been until the past really 10 plus years that we've begun to ask

specifically in really well-designed clinical trials, is that the case? And is it the case when it comes to looking at important clinical outcomes? And I think my take on this now is different than it was 15 years ago. And that is that 120 over 80 is normal, no matter where you are in life, and that anything above that is abnormal. And just to kind of get to the punchline, what I tell patients is that my aspiration is that we can get you as close to 120 over 80 as we can without harming you. Because there are certainly potential harms that are associated with treating people to these low numbers, they can be in the form of side effects or impacts on lifestyle,

they can be in the form of real toxicity, hypercalemia, risk of death. I mean, there's all kinds of potential issues. It's not just a simple intervention, like treating LDL or APOV lower and lower and lower, but there's really no consequence at all. There is a consequence of lower blood pressure too low in this case. So that's my overall philosophy of how to think about blood pressure. I do think there's now evidence from good clinical trials that 120 over 80 is normal and that we should try to get there as best we can without making a mess. So, through that lens, basically, we're saying that the amount of float that we see in

blood pressure, again, we're talking about blood pressure in a very narrow instance, which is seated, resting, et cetera. We'll come back to the other point, but just to build off that, that when that drifts up to 125, 131, 35, 140 in an aging population, we're actually calling that pathologic in the same way that I think we would all agree that the reduction in glimular filtration rate, the reduction in ejection fraction, the reduction in pulmonary function. Okay, yes, that occurs with aging, but that doesn't mean that it's

not part of an aging process and therefore part of something we want to minimize, correct? That's right. We lose muscle mass as we age. Is that something we want to accept? And that's normal, or do we want to try to do it? We can't preserve the muscle mass that we had at younger and life. And again, I think here the crutch that we fall back on and is good high quality, well done clinical trials. And in this case, we now have them. And it's not just sort of an opinion-based thing that says, oh, we'll really get closer to 120 or 80.

We actually have evidence that being closer to 120 or 80 impacts mortality and that permitting people to run higher to a level that we used to consider to be just basically pre-hypertension or just normal even in older person, 140 over 90, that that leads to a significant increase in risk of dying. So to me, I think we've learned a lot, and I don't consider it to be a normal function of aging. I think there may be a process, there's obviously a process that goes along with aging, that there's a decrease in function of a lot of different things that combines the lead to this increase in blood pressure, but I don't leave it alone. I think that makes sense to me as well. Let's ask the second question now, which is the one that

vexes me the most. How much of a given day? It's assumed I sit down three times a day for five minutes, relax, don't look at my phone, don't drink coffee, don't cross my legs, I'm perfectly zen, I put the cuff on my arm, I measure the blood pressure, it's 120 over 80. Let's assume I do that three times a day and I get that number. How reflective is that of what my blood pressure is when I'm sleeping, let's say I'm sleeping eight hours, when I'm exercising, let's say I'm exercising for an hour, 90 minutes a day. And when I'm sitting at my desk, stressing out over email, how much variation am I getting? Tons. So the first time I ever was in the cath lab, it was really amazing to me to see the variation in blood pressure just in a patient lying on a table based on before they were sedated and after they were sedated. You know, there are all kinds of things. So there's no doubt that

there's a huge amount of variation from second to second minute to minute hour to hour day to day and beyond in blood pressure. And I think it's very easy to get distracted by that. And I do all the time. And obviously when I'm sitting in traffic, my blood pressure is not 120 over 80. When my kid spills coffee all over the computer,

it's not 120 or 80, right? When I'm exercising, it's not 128. There's physiology and there's pathophysiology. Physiologically, our blood pressure does go up, and it's meant to go up during some of these cases. It's a function of increased cardiac output, which is one of the components of blood pressure. So, it's understandable.

The question then is, what do you do about that? And sort of how best do you measure blood pressure? And so again, and this is a broken record, I'll just keep doing this, but I fall back on the clinical trials. And just as, you know, we try to practice as best we can with some sort of fidelity to the way the trials are done, I go back to sort of how are they measuring blood pressure in these trials, and therefore are the decisions made to adjust medications and how did that influence the practice of the trial and therefore how should that influence our practice because those are the outcomes that we look at. So this got a lot of attention. When sprint was first published, which was I think 2014 or 2015, I can't remember the exact date, but it got a huge amount of attention. There was all kinds of pushback from almost every angle you could think of. There

were a lot of people out there who felt like this is just yet another example of medicine trying to do too much. The less this borrower out hated it, this is just over medicalizing normal aging. There was a significant amount of attention paid on how they actually measured the blood pressure. Because it wasn't the way that we typically measure blood pressure. And it was the way that we probably ought to measure blood pressure, but it certainly wasn't the way that we typically measure blood pressure. So if you go back and you look at the methods, what they did was they had people in a quiet room, then automated cuff, one of the sort of standard best in class at that time, automated

cuff, they put the cuff on the person, they had them seated and relaxed in a quiet room by themselves, and they had the blood pressure measured three times, five minutes in between. So, total of once, five minute break, one more, five minute break, and once more. And they took the average of those blood pressures. And that's obviously much different than having somebody rush in after parking their car and run into the office in a sweat and show up and somebody slaps a cup on them and measures the blood pressure. But my point is that that optimal way of measuring blood pressure, even if it ends up yielding numbers that are lower than what we typically get, that led to the result and

that trial, which was so spectacular that the trial was stopped early. And this is not to all the conspiracy theorists out there. This was not a farmer sponsored trial. This is an NIH sponsored trial. The government sponsored trial and was agnostic to different agents. It was not about the physicians who enrolled patients in the trial had access to almost any therapy during that trial. So this was not about sort of proving the benefit of one drug over another. This is purely about testing the hypothesis that getting as close to 120 over 80, rather than letting people sort of float up to 140 over 90 was better or not. And it turned out

that it was with caveats. Let's talk about that methodology and then let's talk about the algorithm agents and then the potential downside. So I have started testing my blood pressure six months ago. And the reason for it, so I shouldn't say that. I have always checked my blood pressure because both my parents have hypertension. I was like, well, look, I'd always attributed to the fact that I had low blood pressure to the fact

that I was super healthy and did all these other things, but I realized, look, there's genetics to this as well. So I'm just gonna start checking my blood pressure every couple of days. And I did. And so for a couple of years, I just take my blood pressure three, four times a week, just when I'm sitting at the desk working,

never attempting to relax or rest or do anything. And it was pretty low. Probably averaged one, 10 over 70, was sort of a typical reading of while I was sitting there working. And then something happened in August. It was consistently a little bit higher than that. Not a lot higher, but it was 125 to 130.

And it was more or less 80 in the denominator. This made me get a little more serious. I got another cuff. And now I started doing the full sit protocol three times a day with both the Omron cuff and the withings cuff. And what I realized were two things. The first is I can always breathe my blood pressure down to normal. In other words, there's never been a five minute window when if I don't sit there and really focus on breathing, I can't get that blood pressure to come to normal. But most often than not, that first reading, the second I sit down, especially in August, it got better

in October and September was kind of a transition month. It's kind of normalized now, but it was not uncommon for that first one to be as high as 140 over 90. If I just, you know, was literally doing something, not exercising, but if I was doing something active and then I went and sat down like the equivalent of the guy who shows up from the parking garage, just parked the car, had to walk up one flight of stairs, sits down 140 over 90, five minutes later, it's 117 over 74. And, you know, I've been in sort of a back and forth discussion with my doctor and with my colleagues

about, is this something I need to care about? Because now, if you look at my spreadsheet and all of my phone data, my blood pressure alerts perfectly normal. For the last six months, I've averaged below 120 over 80, but I kind of feel like I'm cheating, Ethan, because to guarantee that it's low, I have to take five minutes of being calm, which then makes me wonder. I know that that's in line with how the sprint study was done. And you can argue, well, Peter, you're simply, you're actually doing

something that's less extreme than what they did because they did three measurements over 10 minutes. But deep down, I know my blood pressure is not 120 over 80 when I'm sitting in my computer writing because when I check that blood pressure straight away, it's above that. So what I think I'm hearing you say is based on the way the trial was done, we have to assume that the other people when they first sat down might have been higher as well. Here's what I would say. Sounds like something changed in you. Yeah, a book deadline is definitely what changed in August. So there's no question that was a change.

Well, so if that's the case, then that's understandable and that's okay. I think in your case, it sounds like what I was gonna say was if it was truly a change and there was no explanation for it, like a lot of things in medicine, then I probably would have paid more attention to it, even though it was going from what was normal to normal. Sounded like something did change, but in this case, it sounds like there is an explanation in that you had this dress in your life

from the book. So I guess the cheating thing reminds me of my daughter, I think I told you before, is my younger daughter is legally blind and plays basketball. We were discussing a potential, this is such a crazy little aside, but I thought I'd tell the store kids of KanaQa. We were discussing a potential procedure she could have to improve her vision as part of her decrement of visual acuities that she has pretty bad bladder on the stagmus.

And the authorologist was saying that if you can sort of make that better, understandably, you'll improve her visual acuity, and that somebody stumbled onto the idea that if you cut the extracurricular muscles and just reattach them, don't do anything else, but just sever them and reattach them, that Nostagmas can go away, and that people as visual acuity can improve a lot. So we thought, well, gosh, that sounds really interesting.

We should do that. It's fascinating how that might happen, but she said she didn't want to do it, because she was like, that's cheating. This is a kid who runs around with that visual acuity of 20 over do it because she was like, that's cheating. This is a kid who runs around with that visual of Q220 over 200 and she was like, that's cheating. So we haven't been able to convince her to do it yet. We'll see if she changes her mind someday, but I don't think you're cheating. What you're doing is optimizing the measurement.

I think what you could do, if you want to, and maybe you've already done it, if you really want to get a sense, and it would be great to have this over time, serially, is to do a 24 hour ambulatory blood pressure monitor, to really get a sense of what is the average blood pressure you're seeing over a 24 hour period, because there is a difference when you're sleeping your blood pressure should be low,

right, that's physiology. When you're out and about and doing these, it's gonna be higher. So what is the route? And they can quantify all the spikes. And it's actually a really nice tool that I'll use and people, especially in people who have some degree of what's commonly termed

white coat hypertension, which is kind of what, I mean, white coat hypertension is real life. White coat hypertension is living in the real world. How does an ambulatory BP cuff work? It's presumably a cuff that sits on the arm and then it straps to a device like a halter would. It's funny, I don't think I've ever seen a device. I've ordered a bunch. It's presumably a cuff that sits on the arm and then it straps to a device like a halter wood. It's funny. I don't think I've ever seen a device. I've ordered a bunch. It's a cuff. So it's really old school, right? It's not like this is new technology where they can measure

blood pressure without doing the old stink of monometer. So it's a cuff. It's, I think, got a self, I would imagine it's got some hardware attached to it that tells it the inflate and measure blood pressure just as you would with one that you have in your office. And it does that once a minute or whatever it is over the course of 24 hours. So it's constantly inflating, deflating over the course of the day. Patients who have mind who've worn them say that after a while you get used to it and just can ignore it.

It seems to me like it would be really annoying to add this thing like inflating and deflating all the time, but that's what it is. What it does though is it buys you sort of a distraction from real life. It buys you sort of when you're not thinking about things, when you're clearly not stressed or you shouldn't be stressed, I you when you're sleeping, what is your blood pressure? And we know that blood pressure that hypertension during sleep is abnormal. It should really be a time when your blood pressure is below us. So it's just another tool that we have to kind of get at that question. It is always interesting to me that we measure blood pressure

not just once, 10 or 30 second interval in a 24 hour day, but then we do that on average once or twice a year and then we assume that this very variable number is actually meaningful. And it's a remarkable to me that it has been even meaningful the way that we've been measuring it, because it is such a poor sample. In our patients, we'll ask them to do twice a day checks

at home, same method that I'm using for at least two weeks once a year. And if we have reason to believe that that suspect will do it more, so even though that's much more than they would be asked to do normally, it still feels woefully inadequate. And I've tried a bunch of devices that supposed to measure, supposedly measuring blood pressure, like little wrist-based devices. I've never found them to work. Is there anything on the horizon that's closing the gap on that?

You'd think so. There was a period of time where people were using a cell phone camera, and you could press your finger on the camera, and that it could basically detect the pulsation. It could almost calculate a pulse wave, and it could give you a sort of imputed systolic and diastolic blood pressure that never made it. We're not seeing this around. We're not seeing any other devices that people can wear that can accurately measure blood pressure. So I do think it's an interesting question.

You'd have to think that at some point, even if it's an intravascular device that you could put a miniature device, much like we're now using, I don't know how much to use them, and I use them a lot. These implantable event monitors, these looper quarters, we use them to detect arrhythmias.

It sounds bad. Wait, when you think about it, but it's really not that big of a deal. There has to be a way to get a pressure transducer into an artery safely that you could leave there for some period of time. Feels like that's gonna come, but I haven't seen it, and then not invasively would be amazing, but I just, again, haven't seen it.

As you know, I find CGM to be kind of a remarkable tool. I would think this is even more important, because glucose, in many ways, is less variable than blood pressure, or at least its variability is more predictable. In other words, you could, I think, much more easily get by with just spot checks of glucose, then you can with just spot texts of blood pressure. To have a true continuous ambulatory BP monitor, that would really be a game changer in medicine. Again, when you think about the heart, when you think about the brain, when you think about the kidneys, it's such an important thing.

I agree with you. I think that said, the intervention that was used in Sprint still showed a remarkable benefit. So we can't exist with the tools we have, and while they're not optimal, they're probably adequate. And they're definitely better. If you go back and look, and this is part of this lecture, I used to give, if you look at sort of the percentage of people that have either diagnosed blood pressure, how many people are known to have hypertension who actually do have it, how many people are treated at all on any medicine, and how many

people are controlled. If you look back in time, when this was first done in the first NN survey in the, whatever 1975, 76, whatever that was, only 50% of people who had hypertension were even aware of it. Only 30% were actually ever treated, and only 10% were controlled. And I don't know what the most current numbers are, but awareness has gone up, it must be north of 80% now.

Treatment is probably 75 or 80%. And control is probably somewhere around 50%. So we're still missing the opportunity to treat 50% of people with this disease. Let's go back to Sprint. This trial was drug-agnostic, right? Is this the one that basically said, start with a thigh as I moved to a calcium channel blocker

and then an A-survice versa? Actually, I don't remember the algorithm for Sprint, but I think it was relatively agnostic to it. All hat was the first NIH sponsored blood pressure trial. That was in early 2000s, like 2002, 2003. And that tested five different classes of medications, two of which were discontinued. So I believe it was calcium channel blockers, ACE inhibitors, and the calcium channel blocker

at the time was in blood-apane, ACE inhibitors, diuretics, thioside diuretics, or cortelodone, beta blockers, and alpha agonist, because at the time they were being used for blood pressure, and both the alpha and the beta were stopped early, because they were harmful. And so what the result of that trial was that using any of the other three classes was first line and treatment of primary hypertension. So calcium channel blockers. And that was lysiniprol, amlota peen, and a thiozide. Yes.

I believe the thiozide they used was clorthaladone. And we can talk a little bit about the difference between clorthaladone and hydrochlorothiozide, but in general, clorthaladone is more potent. And that's the one that was, I think, used in the LHTRI, but at F and double check. If I recall, the amlota peen, lysinipinopril and the thizide all ended up having similar outcomes, which were all better.

Yeah, no real differences. Yeah. I think there were maybe some stroke, if I, it's been like so long since I reviewed it, but I think there might have been like a minor difference in stroke risk and the emelotapene. But the take home of that and what became contemporary practice was use any of these three agents as first line in primary hypertension. And the target was 120 over 80. Well, that was... Yeah, I mean, it was the target. It certainly wasn't the emphasis was not. The definitions definitely changed, right? Because there was this sort of category in, I think it was JNC 6 or something, there was,

there was a category for normal, ah, that's right. So it was normal was actually 120 to 130 over 80, 85. Borderline was 130 to 140 over 85 to 90, and it was only then hypertension if you're a grader than 140 over 90, and then they called it stage 1, 2, and 3 was only then hypertension if you're a greater than 140 over 90 and then they called it stage one two and three. So then when they redid it and JNC7 it was normal, was less than 120 over 80. Pre hypertension was then at 120 to 140 and hypertension was then above 140 over 90. That was the difference between JN7 and JNC6. JNC8, I believe, gosh, I can't remember what happened. There was some controversy and then they stopped after that. NHLBI said we can't do this anymore because there was too much controversy over these. What was the impetus for sprint? The impetus was to test a new hypothesis that was, should we be more aggressive in the management of hypertension?

So the impetus was that there were epidemiological observational studies, and I can send you one or two, that showed that it appeared that the risk of bad outcomes, mostly coronary cardiovascular disease, was lower, step function lower in patient to had optimal blood pressure. This is according to the old classification. People whose blood pressure was 120 over 80 or less optimal.

And then a small step increase in people who had what was then classified normal. And then a large step increase in people who were considered high normal or even early stage hypertension. And so, but this was all observational. It was on a prospective study. So the NIH designed a study to prospectively evaluate

whether treating people to these two different goals, and these were aspirational goals, if whether that resulted in a change in outcomes. And so they randomized these people. Again, the doctors were given leeways to which agents to use, and you can look through the supplemental tables and see which ones were used. But there was really nothing, at least to my recollection, there was nothing about the different agents that was that meaningful. Clearly, people got to the two goals that they were assigned to randomly.

It was obviously not blinded because you couldn't be blind to your blood pressure. But they got to the two goals. So the people assigned to the more aggressive 120, where you got to like 123 or whatever it was 82. And the people into that 140 over 90 were more like 137. You can look at the curves and the new journal paper and they separated beautifully. And then they yeah, it was 121 versus 136.

Yeah, it was something like that, but it was a significant difference. And obviously the amount of medication usage was a much higher in the people who were assigned to that more aggressive arm. There are some questions there as well. Was it a benefit of the medicines or was it a benefit of the blood pressure? Look, I mean, we can ask all these questions forever and ever, but the reality is this was a really striking difference such that the NIH stopped the trial early because of benefit in that lower group.

I think it was one of the most important and practice changing trials that we've had. I don't think that it came without some cost risk. It would be so needed to just completely dismiss this. There were real issues, right? There was a greater increase in the risk of falls and syncopy. And I think even in the risk of significant kidney dysfunction, it was all reversible, but it was all there. And so what we took away, or what I took away from that trial, was it looks like you get a mortality benefit for getting closer to 120 over 80. So let's get there if we can without creating one of these problems. So obviously if you're falling all over the place because you're dizzy, or if your kidney function deteriorates because your kidneys aren't getting a blood flow,

or whatever, something else bad happens, and we're not going to do that but we're going to get you as low as we can as close to that target as we can without making a mess. That's sort of why my doc has been relatively unexcited about doing anything in me is he still remembers a year and a half ago or less than that just over a year ago when under my normal set of relatively low blood pressure, I stood up in the morning, too quickly, fell, face planted, split my head on the table. And that was an occurrence, like once, maybe twice a week, I'd get up and need to sit back down again in the mornings. Understandably, his appetite for trying to correct an average blood pressure of 120 over 78 is pretty low and I'm not keen to take any medication either clearly.

There is no doubt in blood pressure unlike in cholesterol. There is a u-shape, right? But too low is definitely bad and I think your body was telling you that your blood pressure is probably right about where it ought to be and maybe even a tad too. Maybe you're just like a little dehydrated in the morning or it sounds like your doctor made the right decision. I don't think there's any evidence that I'm aware of that treating you to below 120 over 80 is advantageous. No, it was more just my question was, should we treat such that I never have a reading above 120 over 80? And again, I think that's probably too aggressive based on these side effects. Well, I don't think it's even feasible. I mean, the way you exercise, there's just no way. I would imagine if you were a 24 hour, any belly-toyed blood pressure, when you're exercising, especially

doing, you know, isometric resistant to change, your blood pressure is going to go way out. I think that's a great idea. I've wasted a little bit of time in the last two years looking for new technology to measure blood pressure in a continuous ambulatory way. And every device I've tried has failed. So I think I just need to bite the bullet and do the old school low tech way. If some smart engineer out there wants to figure out

a great important thing to work on. This is definitely I would agree. I'd agree. That or near the top of my list in terms of things that haven't been solved. So go for it. It would be great. As you say that there isn't really anything now. There's a little fashion single manometer just attached to your arm. So what about the step trial last year? Did that sharpener thinking at all? I think it just swaged any fears that people had that there was something unusual that Spray. And of course, there was this concern over the trial being stopped early, which

does risk, you know, stuff that I do. But it does risk the possibility that the result was spurious. So I think step is a nice confirmation. Because I think that Brent was stopped at three and a quarter or something, three and a half years, something like that. It was definitely stopped early. And again, it was pre-specified. And there was a DSMB and the whole deal. And again, it wasn't industry that stopped. It was the government that stopped it because of overwhelming benefit. You know, you could have made the argument to keep going. A lot of people did. They felt like this was an important, you could calculate the number of people who were under-treated and that they could calculate the impact on mortality even here in the United States for every day that you didn't get this result out there.

And so they made the decision to go ahead and stop the trial and report the results. And like I said, there were a lot of reasons people didn't like the trial lots. And that's fine. There are lots of reasons that we can all find fault with a lot of different things we do. Anyone who's done a scientific experiment knows that there's plenty of people out there to find fault with all of the things that you did or didn't do correctly. So what I took away from step was that it was a nice confirmation that sprint was probably not spurious, that the result of the sprint was real and robust and repeatable. I think the other thing, step, had going for it over sprint is it included patients with type 2 diabetes, which I believe were excluded.

You had a longer trial, you had a more representative population. So I'll tell you, and we can leave this after we're done with this because I want to make sure you have some time to talk about the metabolic stuff. But do you have any thoughts on the specifics of various agents? So you have these two really good trials that were largely drug agnostic. And yet I still, when I'm hanging out at the bars at night, talking to, no, I'm kidding, this is not hard to say that.

You hear this little bit of R versus ACE, versus Calcium Channel blocker. And basically the question is independent of the effect on blood pressure. So if you have two agents, an ACE inhibitor or an endotensin receptor blocker, for example, or throw in the calcium channel blocker, that can equally lower blood pressure.

They can get everybody down to 120 over 80 and they can, the symptoms and side effects become non-issue. And each of those will have a slightly different set of symptoms we know. Do we have one reason to prefer one over the other, for example, when it comes to renal protection? My first answer is because of the conversation we had earlier about the lack of awareness and lack of treatment and lack of control. Blood pressure, my first advice to people is get the blood pressure control.

And that's why I tell patients, right, that let's just get the blood pressure, my first advice to people is get the blood pressure control. And that's why I tell patients, right, that let's just get the blood pressure control. And then if we want to try to optimize and find out what the right combination of things is for you given your other circumstances, and I used to use this term, extenuating our special circumstances. You know, for example, if somebody had an angina,

even the beta blockers were no longer first line for true primary hypertension. If you had an angina, you'd include the use in a beta blocker in that hypertensive regimen. It was really an anti-anginal that it will always blood pressure. So I think the first step is just get to goal. I do tend to do things differently in some context. So age to me has a big deal in both directions. Young people don't like taking diuretics.

And in old people, diuretics can be a little bit more challenging, right? So there are more electrolyte abnormalities. I see a much greater incidence of hyponatremia and other electrolyte problems. And of course, the kidney issue is there too. So while I think, if I had to pick my avid agent that I think, probably among the three classes is the best at managing sort of all the covers of high blood pressure. It would be chlorothalodin or thyside diuretic.

I don't use it as much just because it's harder to use. I think emlotapine is a great drug because it's easiest to use. It doesn't require any monitoring, right? You don't have to monitor electrolytes, you don't have to monitor kidney function. It's a benign drug, super easy, very few side effects, other than a not super infrequent amount of what's considered to be swelling in the ankles. It's not really a Dima, but it's the sort of non-adema ankle swelling that people just don't like,

especially women don't like having. So aside from that, it's a very easy drug for ACE inhibitors or ARBs, and I mostly don't make the distinction between the two. I probably should, but I don't. There are data, I think, that do suggest that those drugs may be more indicated in certain subpopulation. So for example, there was the hope trial, right, which was, I think, mid-2000s. And so it suggested there may be a benefit in people that have a throstor out of coronary disease to have an ACE inhibitor on board.

So maybe in people with ACVD or ACVD risk, I'll use that one over the others as a first line. It's also, you know, there's the whole ARB and ARC, the ammeter thing, right? So people who may have a little increase, whether you want to call it an aneurysm, but just an increase in ARC size that there may be a benefit to ARBs. You can start begin to weave together

all these little things. I like ACE inhibitors and ARBs probably the best. They do require monitoring, right? So they do require that you get electrolytes because there can be, in some patients, there can be issues, especially with potassium, and that can impact kidney function. So it's this weird thing where the benefit to people with kidney diseases is high, but then kidney doctors are also very nervous about the potential toxicity, kidney toxicity of ACE inhibitors and ARBs.

So it's this weird thing. To answer your question, I think in people with existing kidney disease, that that's probably the drug. The other place that I use ACE inhibitors, ARB first line is in patients with diabetes because that's been shown, they've been shown to reduce the progression to diabetic nephoropathy, again and again.

So I think- So some what renal protective again? Renal protective, yeah. I think they are probably the most renal protective again. Renal protective, yeah. I think they are probably the most renal protective beyond just getting the blood pressure lower, which is still to me primary, the most important thing. So really what you're saying is, look,

the first, second, third order term is take that 50% up to 100% in terms of effectively lowering blood pressure. And when everybody's at 120 over 80, we can, and we're doing it without causing ancillary side effects. So that's the third, fourth, fifth order term. The tail end of this polynomial

is the nuance around actual class of drug inside. Yeah, I think that makes a lot of sense. And tolerability, because I do think, you know, we probably don't pay enough attention to that. It's probably the biggest reason for noncompliance. And I hate that term. Yeah, I kind of include that in the second bucket, right? Is anything, whether it be ankle swelling or a dry cough that obviously tends to occur in some people with ACE inhibitors, those things, I have to do. Older people who tend to get more orthostatic, right? I'd stay away right away from direct to them because falls in older people. I mean, you're not old and you're obviously not

at risk for having a significant injury from falling, but it's a huge source of injury in older people. Did you see my face after I fell? You had a great story about the bar you were in the back of. Look, I think falling is a enormous risk for an elderly population and it's between the head bleed and the femur fracture. I mean, these are devastating consequences for someone in their eighth decade and beyond. I mean, absolutely life changing and sadly, often life ending. Yeah, and I say that with a 81, almost 82 year old father who has unfortunately fallen now several times, it's a bad thing.

So let's spend a minute, Ethan talking about one other thing, kind of bringing it all the way back full circle in the athyristlerosis world. I generally tell my patients that there are four big pillars of risk in ASCVD. Smoking, hypertension, APOB, and metabolic health. And that last one is kind of squarely because I can't point to one number that tells me like I can point your apobie, I can point your blood pressure, you're either smoking

or you're not smoking. But here I talk about the sources of fat that exist outside of your subcutaneous depots of fat. And I typically talk about five of them, but I know you tend to focus on a couple, so I want to double click on those. But just for folks listening, right? I think the generally accepted principle of this is we as a species, one of our remarkable advantages and evolution was our ability to store energy, you know, without this capacity, we wouldn't exist. And so we have this vast network of subcutaneous adipose tissue, white adipose tissue, that is incredibly adept at storing triusil glycerides. And I think what appears very clear is that different people

have a different genetic capacity for how much they can store. So I kind of liken this to a bathtub. Everybody has a different size bathtub. And the water coming in the bathtub is how much you're eating and the water leaving through the drain is how much energy you're expending. And if you're accumulating fat, you are obviously consuming more than you're expending. But at some point, you could fill that bathtub up and water can escape the bathtub. And that's when really bad stuff happens, right?

That's when it gets into the floorboards, the electrical stuff, and that's a disaster. And you don't need to get a lot of water out of the tub for really bad things to happen. Ask anybody who's gone through a leak in their house. You might have 100 gallons in the bathtub if two gallons escape in the wrong place, it can be a disaster. And so talk about the places where it escapes. So around the viscera, within the muscle itself, in the pancreas, specifically, which we can talk about maybe why that's so problematic, pericardial fat. Tell

us a little bit about why this is so problematic. Well, first of all, I'm so incredibly impressed at how you tell that story because it's exactly how we tell the story and we learned it from Steve O'Reilly who I think is the sort of godfather of this concept. I think we've all appreciated for some time that there's a relationship in terms of risk and weight that that's imperfect and BMI, right, that there BMI is not a great measure of risk. It is in epidemiology, it is a large population. We also know that how much fat you carry. So overall, adiposity is important, but what we've learned really in the past 20 years is that as you've said, that it's not so much even how much fat you have. It's where you carry it. And that we are evolutionary, like program of store energy in these places around our

hips and our butt and our legs. And not as much up here in our bellies. And definitely not in our organ. That's a bad thing. And that has been shown to be a very potent predictor of risk, and that there are a number of genetic alleles that predispose to both these differences in body composition, but also to differences in risk of developing diseases like cornage season and diabetes. So, super fascinating area that I'm going to devote the rest of my life to understanding and trying to fix. The question you ask, which is why is it that if you overrun the bathtub and leaks out and gets into the floorboard, why is that so bad?

The answer is not one I can give you, but we started our sort of process and thinking about this problem and thinking about the extremes of biology, in particular, these rare genetic diseases that are called lipodistrophies, where people are born with the inability to store fat at all in generalized lipodistrophy,

or with just an isolated inability to store fat in the Cludio femoral and subcutaneous regions in the legs, they have a selective loss of adipose tissue in their butt and their legs and therefore a huge overabundance of fat in the abdomen and the viscera in the liver and the pancreas in the heart as we talked about. And those people have tremendous metabolic disease and extraordinary levels of risk, right? I mean, there's small numbers of people, there are rare diseases, and all of these studies are observational, but there's a beautiful paper from Canada from 20 years ago showing that people born with these sort of congenital forms of severe insulin resistance, be it either lipid

dystrophy or type A insulin resistance, have astronomical coronary artery disease risk. They're women who are having bypass operations in their 30s and 40s, which is basically unheard of in women. So I think the question of why that is remains unanswered. I think there are lots of different potential hypotheses. You know, I think the role of insulin and its impact on different organs and tissues

and cell is interesting. We don't have an answer yet. What we do know is that there's this very strong now association between these different shapes, body shapes, the apple pair thing, and risk of developing these diseases. I think if you look at the epidemiology curves of say coronary disease over the past 30 years, we've done an amazing job of reducing the risk of coronary artery disease events using all the tools we have at our disposal, whether that's blood pressure smoking cessation, lipid management, et cetera, et cetera. Yet, as you mentioned at the very beginning, it's still the number one cause of death in the world. And even in the COVID era. And so it's still a huge problem.

The question then to all of us is, what is that? Is that just that we're not adequately using the tools we already have? Or is it that we're missing something else or is it a combination? And I guess I would sort of probably bet that it's some combination of sort of, we're just not doing a good enough job with what we have. And there's probably something else there. And so that's the focus of sort of what I want to spend, like I said, the rest of my life, thinking about.

I would agree with you. I think it's really a combination. I think we start too late and don't go low enough on lipids. We fail to recognize and don't get enough traction on blood pressure. I still think nearly 20% of people still smoke. So it's not like we've taken that one out of the gate. And then I do think that this pillar of poor metabolic health is so improperly understood. And I don't think we're identifying people at risk because I think

about how little I know about my own state here. Have a pretty good sense from any blood test you can do. I can do a dexoscan. It tells me how much fat I have. My transaminases are adequate, so I'm going to assume and based on last test, no liver fat, but other than that, it's a real blind spot. I mean, I don't have the clarity that I would have about my apobete, for example, or my blood pressure.

And that's, I think, or my blood pressure. And that's I think because we're sort of increasing our very poor resolution of this problem, starting with like the most blunt tool of all, which is a BMI and then moving to other things. And even what you just said, I think it still represents probably a very low resolution image into this, just focusing on that. We know that's bad, but here's a question right now, just a thought experiment is the problem with that, is that a defect in the ability to store fat where it should be stored in the Guiduio Femeral Depot, and is that just a manifestation of that?

Is there something different about that? Is there truly a benefit to having more fat and Guiduio Femeral, so in other words, to your bath of analogy, if you could make a bigger bath, that would you be more metabolic, we healthy? Well, certainly there's one experiment that Gerald Schumann did that obviously it's a contrived experiment, but it would certainly suggest in the model. So he looked at a mouse model where the mice had profound insulin resistance and he would just put more and more subcutaneous fat into those mice and they got fatter and they got less

insulin resistance. They actually got paradoxically fatter and they got less insulin resistance. They actually got paradoxically fatter and healthier. So in at least that intervention, allowing them to get fatter, making them have a bigger bathtub improved them. But it's not clear that that's the same thing, right? In other words, that doesn't answer the question is that bad simply because it's not in the subcutaneous space or is it doing something fundamentally different? And I think that's where we want to sort of eventually understand, right? Is are there cytokines that are coming out of those cells that are different from the cytokines

coming out of the other cells? And how does that factor into it? There are all kinds of things that we're learning about the difference in basalipolytic ray between the two deep os. And again, we're just describing these deep os based on what we can see and how we can describe them based on our dexas. Right. So just some low resolution compared to what we care about. It's very low resolution at this time. I think what we can say is that in a patient, well, bipodistry is an extreme who has normal lipids, right?

Not normal triglycerides. So it may be a modest elevation in apoby, but APOB drug vistoryids, that those people have extreme increases in risk, independent of their traditional risk factors. We think that there's a group of people, and I've now, as I've been thinking about this, begun to see these people all over, and once you see them, you can't not see them, but we think there are group people here who represent probably some polygenic version of this, where there's a relative decrease in fat in the legs. Like, I can think of patients now who come to my practice who may have a tiny little pot belly,

but their lipids were sort of not that bad and their legs are super skinny and they had a bypass at 38 or 40 or 41. And the number of people I can think of like that keeps getting bigger and bigger. And I think what we're going to learn is that gluteoemoral storage capacity is gonna be an important driver of risk in this context. And finding ways to change that if it's possible would be of great benefit. I think it remains to be seen if it can be changed. There is some, you know, very poor evidence, right?

If you've talked to the plastic surgeons, they've begun to understand that there are metabolic consequences to taking fat out of places like the legs and the hips that are very different from taking fat out of the belly. It's like Jerry's experiment of putting in more subcutaneous fat. It's just helping to guide us towards this idea that there's something there. I think it's really going to be interesting. Ethan is when you start to look at this in the much larger and less extreme

population of those without lipidistrophy. So the cases you're describing are profound. And but the question is, this is probably also playing a very big role in people who aren't the ones showing up for bypass at 38 years old, who don't have the complete lipidistrophy where they have no ability to store fat on their legs and hips. And so the question is, are there targeted and directed therapies that can be aimed at the metabolic tip of that spear? That's what we're doing. So my answer to you is we think so. We need to do the experiment to demonstrate that. But using hemogenetics as a guide,

there are a large number of alleles that seem to confer this concordance of changes that in both directions. So for example, people who have alleles that confer more gluteoephamerozo So really what's important is not so much the amount of visceral fat you have in an absolute sensory-demonial glute ephemeral fat. It's really the ratio in dexaterms, and they may be on your dex report called fat mass ratio. And there are different levels that are normal or abnormal for women and men, but having a high fat

mass ratio, meaning having more fat up here and less fat down here is bad. And there are alleles that confer that and that they do also confer a bunch of changes and other things that we know are bad, including, you know, lipid-based biomarkers and then diseases, like coronary disease. How can cordon to these alleles? So if you, do you have enough data to look at identical twins and say that the genes are completely concord between them and the

phenotype? I don't know of any twin data, but I do know that there are certain of these that are common enough that you can find heterozygates and homozygates, and it looks like there's a dose response. And again, it's not just one. It's not like there's just one of these things. So I do think there will be targeted therapies and we'll test one sooner than later. We'll probably begin by testing it in patients with lipid dystrophy, but the hope and expectations

that will move beyond that and to eventually try and target other metabolic associated diseases and ultimately the most metabolic associated disease, which is coronary disease. What percentage of the patients with a phenotypically appreciated lipidistrophy have an identified set of genes or gene that results in that? It's probably on the order of 50%. It's a great question because we don't really look. Recognition and diagnosis of lipidistory is abysmal and steve or isle. At some point, if you ever convince him to come on, he's one of the most entertaining

human beings I've ever been around and I love every moment I spend with them. And Reed is banding metal lecture from 2019, which was just astonishingly brilliant. He gave it at the ADA, which was here in San Francisco that year. But Steve will say that the problem is that we don't take our patients' clothes off. If you don't address your patient, you'll never see it. And actually, we have some patients by the history who are big in the advocacy groups and they've been incredibly helpful to us. And they often tell the story that their own personal diagnosis of lipid history happened by accident

because it happened to be a warm summer month and they were wearing a skirt and a doctor was able to see that their legs were super skinny and muscular. So I can't answer your question because we just don't know what the denominator is. Partial lipid history is characterized or classified and how it's been defined historically and there's some familial partial laboratory one, two, three, four, and beyond.

FPLD1 doesn't have a monogenic cause. It's by far and away going to be the most common. But there's not an agreed upon way to make that diagnosis today, which I think is a major problem. And it's going to need to be addressed. Because a doctor, if you talked to an average doctor, will never have heard of my pedestrian would clearly never even be thinking about it. And I'm saying this, having had the experience myself where I probably just never thought about it, we're conditioned to think that leanness is good.

Leanness and muscularity are good. And if you see leanness and muscularity, if you haven't even see it, it's a good thing you never would think, oh, this is a problem. Look, to me, this is interesting in that it becomes the index upon which you can build a far greater set of insights, because again, while I think this population experiences such an extreme consequence of this, I think I share your belief that this even absentee to lipidistrophy, this is still a problem. You know, the lipodistory patient has a broken bathtub.

Of course. It's not like a normally shaped bathtub. It's a jagged bathtub that is more quick to overflow because it's simply smaller. And therefore they show up much sooner with this problem. And to your point, if the clinician would simply walk in the bathroom and go, how come that's not an oval? Well, I need to be looking harder. And I think that's the expectation is that they represent a very rare version

of what happens when the whole thing goes awry, but that they're going to be more common versions of this that exist. And it's very similar. I think the distinction between familiar hypercholestolumia and run of the mill hypercholestolumia. And we've learned a lot from rare diseases. This is a case where we'll learn a lot. And in this case, we already have a abundance of human genetic data that suggests this sort of

polygenic version of this thing. And there'll be some papers coming out soon with collaborators of ours that will show that the FMR itself conveys more risk even than smoking status. And that's a pretty amazing finding, right? That if you have a high FMR mean, you have a lot of fat up here and not very much fat down here, that your risk of significant bad things in the form of corner or disease events is higher than it would be if you smoked cigarettes, which is astonishing. And I think none of us would have believed that. I do like the analogy of FH because FH is also a very, very heterogeneous waste basket of genetic things, more than 3,000 different genotypes that produce this phenotype. But interestingly, at least one of them

has now become, I think the most powerful drug we have on the market, right, which is the PCSK9 mutation. So it'll be interesting to know if how much the genetic insights will also form therapeutic options for the people that don't have lipidistrophy. In this case, at least what I can say with some compasses,

is that the reagent X are probably not going to be as informative, certainly not as informative as P6K9, which is, I think, stands alone in terms of the quality of it's informativeness, both as a rare disease mutation, but also as a common disease variant. But the genes that underlie the common variation in these phenotypes are, I think, going to be very interesting. And so I think that's where we're focused. Because the rare disease, the single gene mutations,

you know, one of the most common the disease underlying FPLD2 is of mutation in LAMNA. We know that this leads to progeria, leads to cardiomyopathy, leads to muscular dystrophy, leads to lipid history. It's a complicated mess of it, protein that's expressed in a nuclear laminate. It's hard to kind of imagine that common variation in that gene is going to lead to problems in my, but it's not obvious. Well, Ethan, this is really interesting. We covered a lot of ground. Some of it we repeated from before, but I think it was necessary both because I just don't think everybody has the capacity to go back and listen, but I also think we have a couple more years of insight. So thanks again for making time. And for me personally, this whole getting deeper down the rabbit hole on blood pressure thing,

I'm hoping that enough other people are equally becoming interested in this because I just worry that there are too many people walking around out there who have no idea what their blood pressure is. And even if they're just 10 millimeters of mercury above normal, as you pointed out, the consequences are significant. And again, it's just such an eminently treatable thing. It's a tragedy. This is not a new problem. And I'm glad that you're latched on, because it is one of these, in terms of things

that probably are lowest bang for the buck and public health these days, maybe short of vaccines. This is at the top of the list. If we could just raise awareness and treat this, because I think we've done a really good job on the lipids, the lipids, you know, what's left over now is probably, it's not awareness, but blood pressure is one of these funny things

for whatever reason it's just not sexy. And it's very hard to convince somebody to do something that doesn't make them feel better. And in some cases, it may make them feel worse. We've known that for a long time, and this is one of these things where you're trying to get somebody to understand that it's not gonna have any impact on,

positive impact on them for years, decades. All right, thanks very much. And good luck, as you continue to work on this problem. Yeah, I look forward to seeing you in person someday. Hopefully I'll hook up. Sounds good, man. Thank you. All right, thank you. Thank you for listening to this week's episode of The Drive.

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