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

Hey everyone. Welcome to the Drive Podcast. I'm your host Peter Attia. This podcast, my website and my weekly newsletter all 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 peterattiamd.com subscribe Now without further delay. Here's today's episode. My guest 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 wanted 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 decide, hey, probably time to bring this discussion to a bunch of listeners, namely you. In this episode we focus a lot on ascvd, 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 ASCVD 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. Most of the 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 end 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 hyperbaita, lipoproteinemia, 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 ASCVD 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. All right, Ethan, thanks so much for making time to sit down again. This, this is round two. Although I kind of don't remember when round one was. I think it was 2019, but it might have been 2018, right?

I think it was 18, which is just a function of the fact that neither of us can remember tells us how long ago it was.

Yeah, well, that time we spoke in person and we sat in your office at ucsf, but 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?

It's been an evolutionary change over the past couple of years. But I did I have sort of a midlife crisis, decided that I didn't 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 a local group of investors who create biotech companies and they asked me to help them conceive and eventually they started a new biotech company. So I closed my lab and have become a volunteer clinical faculty at UCSF and see patients infrequently and spend 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 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 spent a lot of time talking about the distinction between calcium scanning and CT angiography, as we discussed last time. I think you've used the analogy before. The calcium scan sort of demonstrates a site 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 so the amount of calcium you have in your arteries is strongly related to the amount of plaque that you have in your arteries. We know that the amount of plaque you have in your arteries is related to your 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 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 from a heart attack, 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 dye. So 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. And I think we talked about this the last time, but I'll just say it again, for those who weren't around back then, I did a full 180 on these. You know, 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 in 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 context I think are most valuable. Certainly not everybody. I think a calcium scan and 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 calcium 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 2 by 2 of young versus old and 0 versus non 0 as the calcification, 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 if a 40 year old shows up, has a calcium scan of zero, I haven't really learned a lot. And if a calcium scan of 0 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 scanographers 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 logic if you shouldn't have any calcium when you're 25. I'm not sure what you learned there. There may be edge cases where one in 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 then also just kind of spending more time in the literature on this is that a calcium scan is a relatively imprecise measure. So the thickness of the slices that are used in that scan are significantly greater than the slices that are used in the CTN 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, at the time, my doctor thought this was a crazy idea. I was 35, I was exercising at least 24 hours a week. There 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, had the calcium scan and it showed that I had a score of 6. So I had a single foci of calcium in the LAD. And interestingly, despite being in my mid-30s with that calcium score of 6. 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 deciliter. 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, call it six. Seven years later, I went and had a CT angiogram and a calcium scan, and the calcium scan had a score of 0. The CT angiogram, which now is at much finer resolution, indeed found a tiny speck of calcium in the proximal lady. 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 2. And the CT angiogram 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. 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 calcium score of 6 when you were 35 was 99th 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.

My 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 1/2% of those people who are deemed with a negative CAC have an unstable plaque on CTA. So it's not just the 15% that have something, but 10% of those people have something that 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 familiar with the data, 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. It'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 would hopefully include age, and if not, it'll be in the fine print.

And then the other question I had 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 Dayspring and began to learn. I didn't know what APOB was at the time. At first, I was just sort of bombarding LDL C. And then that turned into really now targeting APOB. And so my target APOB is between 30 and 40 milligrams per deciliter. 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 particularly 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 normotensive, 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, I should. Independent of blood pressure, which is a 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, minuscule lesion. The question would have been, what happened to you over the next 15 or 20 years had you not taken 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 been 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. In other words, I don't think you have to have something else to get athero in cases where the APOB is sky high.

But sufficiency is complicated. I mean, I suppose there are people with fh that don't go on to develop ascvd.

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 APOB 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 APOB 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 is 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 if 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 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 incongruity 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. Replace smoking for coronary disease with smoking for cancer. We all have lots of stories of people who smoked four packs of cigarettes a day or even emphysema. Right. Where the toxicity is much more direct. It's part of the nature of the heterogeneity of response that this penetrance in this case of an environmental factor is not 100%. I guess there are some that are right. Cyanide 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 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 it paid for. So it is actually, in this case, more expensive if you pay 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, no. Calcium scans are almost exclusively out of pocket. I would say 90 plus percent of them are paid for by. By patients themselves. But again, as you said earlier, but it's so inexpensive, it's a couple hundred bucks. And almost everybody can make that leap and convince themselves that it's worth whatever it is. 10 Starbucks. But for CT angiograms, the cost is much higher. And again, I don't know. And this is one of the problems with our healthcare 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. And 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. So the cost of a CT angiogram is much higher. It depends on the insurance that you have. And 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 angiogram. 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 sort of 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 2 millisieverts 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 UCSF and it would be $700. You might go to Stanford, it'd be 1500 or the other way around. 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 sort 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 variable 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 burden 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 in 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, you know, we get these beautiful images, and they're 3D reconstructed, and then they're 2D sectioned. And, you know, 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. And fortunately, there hasn't been any. But that's, you know, 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, by the data, suggest that. I think a high burden of plaque, period, is a problem. Do I believe that a high burden of calcified 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. We know that people who have a calcium score of 4000, 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 the information I get out of a cta. Of course I'm greedy. I want more and more. 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, since the 70s, probably, when the pathologists were doing autopsies on people who died of sudden cardiac death. And 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, and 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 their 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 intravascular 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 a debate until 1979, or even. Maybe even a few years after that. It really wasn't settled until ISIS 2 was published in the late 1980s that showed that if you gave streptokinase or aspirin, that 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 ruptured and led to sudden cardiac death were smaller plaques, the 30% plaques. Which 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 somebody prominent dies. I'll mention the name just because I think this is an example. And I don't know Sheryl. But when Sheryl Sandberg's husband died on a treadmill a few years ago, I had probably 25 people call me that week to want to 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 attacks suddenly, that oftentimes it's a relatively mild place plaque that wouldn't trigger any discussion of revascularization 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 ischemic preconditioning and therefore the chance of an arrhythmic, malignant arrhythmic response to the ischemia is lessened because of that. But 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. I want to tell someone the second they pick up a cigarette to put it down. Not until I see that their 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 bleeding 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 to myself 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, and 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 sort of the most rigorous randomized clinical trials is going to be limited just because we're not going to be, 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 evidence. And hopefully the insurance companies come around.

I've kind of accepted the fact, 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 ASCVD 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 ascvd. I say something very bold in my upcoming book, which is that ASCVD 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 going to be patients who are going to 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 ctafr, 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 2, I think that's right, yeah.

Fame and Fame 2. I guess give 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 basically a way to detect a pressure gradient across a stenosis. The simplest thing I use 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 to 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 aim of it. 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 measure the percent stenosis, which is done, if you've ever seen it, it's done very much sort of by like 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 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 years. Ibis, you mentioned earlier, is one of them. There have been a quantitative coronary angiography where they actually try and take cursor and electronically draw around the diameter of the vessel. Mike Gibson, 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 hemodynamic way to be able to impute the severity of the stenosis. 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 in 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 stented. I can't remember the design of the trials, but basically it was a way to kind of.

I think the idea was basically, look, there's no ambiguity in two subsets of people who should be stented. 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 putz around. I mean, what's the algorithm on 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 cath lab that does stenting 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 cath lab.

Yeah. So in an ST elevation mi, 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 stemi, ST elevation mis, where there's a Complete and full physiology or pathophysiology is a complete obstruction of blood flow. ST 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 angina or non ST elevation mi, which is same pathophysiology. Right. Ruptured 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 order, if I had to guess of 85 or 90% of people would practice 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 pager and everybody comes in from the technicians in the cath lab to the interventional cardiologist to the fellows and everybody else. They all just assemble there to get there as quickly as possible. That doesn't happen. There's no STEMI activation for a non STEMI or a 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 SO symptoms, no matter what they have, in other words, if their blood pressure was labile or if they had heart failure or ongoing chest pain that was refractory to medical management, then that would also become a sort of don't pass, go, 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 interventional cardiologists, I won't mention names, would probably agree that people who have a lot of plaque, maybe with the exception of proximal LED or left main, there might be still some people who would think, gosh, even without symptoms, I'm going to put up a stent in 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, 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 and they would go in that first 24 hour window. So any symptoms at 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, you get chest tightness, rarely pain, you stop, it gets better. You take a nitroglycerin, 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 quantity, classic stable angina, stable symptoms. 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 that 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 obviously Courage was the trial that sort of taught us that it's okay to have a lot of plaque and not necessarily intervene on it. There have now been several other trials to get at that question of is, and this is part of the reason why Fame is to me, not that interesting because we've kind of already answered the question in all comers that stenting people without symptoms, even if they have significant lesions, doesn't offer a benefit over optimal medical therapy. There's now, I think, some discussion around even patients with symptoms. The range of opinion I think goes from anybody with symptoms should be stented or revascularized. In edge cases with bypass, some people think medical therapy in all cases. And then I think there's sort of this nuanced in 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 stent 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 50s, 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 treat, you'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. And in 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 a 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 or 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 0.7 P2 to P1, but maybe 0.8 or 0.7, 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. So therefore that became standard of care in a cath lab, in most cath labs that we were doing FFR and a lot of patients where initially FFR was there for these ED 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 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 were on the surface. That's not an absurdity, that'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 had 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 cath, 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 validated that there was some comparison, the FDA required some comparison to be able to say, 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 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 of patients has ever shown in the history of interventional cardiology, which is a benefit from stenting? I know that my interventional cardiology colleagues are going to 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 TMI setting, which we've 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. And it's not for lack of trying. It's been, I mean, again, courage, which sort of was the beginning of the end of this. In somewhat sense, that was a trial that was conceived of and executed by a group of interventional cardiologists 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 stent 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 stent beyond truly optimal medical therapy. And I think as you said earlier, if everybody got truly optimal medical therapy, like if we didn't have barriers to using all these tools in 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 PCSK9 inhibitors, they were just Zocor or something. Why wouldn't opening that artery lead to improved outcomes outside of the acute MI 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's 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 stent, 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 stuff 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 would be.

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 stemi 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 lady 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 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 stented the entire vasculature, you would have. But of course, you can't do that. So it really comes down to how lousy is plane up stenosis as a predictor of subsequent events.

It's a good predictor. As we discussed earlier, these plaques that end up leading to bad things often are not the plaques that would 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 ischemic preconditioning leads to this growth of collaterals. And basically it's like if there's an accident on the freeway. It's like I tell my patients 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 fine.

Right. But that 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 stent a 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 troponins and other more sensitive measures, if you look at, say, troponin or CK elevations after a long intervention, they most certainly go up. Not in all cases, but they do go up. And so the question is, are you doing. Are you basically creating a little MI in the process of putting the stent in? And does that then cause downstream risk in the form of arrhythmias 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 troponin elevations post PCI as a predictor of outcomes. I think obviously the more troponin 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 is 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 cause mortality, no difference in mace, but a reduction in the need for catheterization.

Right. So this has now become the sort of value add of doing these non invasive adjuncts to CT angiography. And it's the reason that we, UCSF now do CTFFR on not all, but Most of the CTAs that we do is that in theory you've reduced the number of people who go to the lab. You only reduce the number of people who go to the 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 medically treated and left alone. And that taking in the cath lab is of very little value. And obviously if they get to the cath lab, the chance of them getting stented goes up astronomic once they're there. So yes, you do theoretically prevent unnecessary stents 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, 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 complicate it, right, that there are going to be relatively low risk people and you could get away with statin or maybe statin in a very low dose of Zetia. I mean, you know, in my opinion, if you have plaque, significant a plaque, they say 30% plaque or greater in an artery in your coronary vasculature, I'm pulling all the levers. I don't need any other information. 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 6 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 Sig Catharisson's company, Verve. They want to crispr out pcsk9. Not necessarily initially in everybody, but he believes that if you did 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 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 attenuation index, fai. 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. I'm sorry, I'm not like completely up to speed on this latest and greatest fat attenuation index. I imagine it's some CT based way to look at the characteristics of the plaque and to see if 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. Not familiar. I am familiar with PET ct. You know, 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 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 going to 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 cardiorespiratory 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 shear forces across endothelial surface 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 because none of these studies are controlled. But it does seem that that's the case, and it makes sense. And as plausible, as dangerous as that word is, I think the same thing could be true in a coronary artery vascular bed. The 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 in the artery and 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 what you're doing is healing the plaque and stabilizing the plaque, which we think statins are doing, and that that's a good thing and not a bad thing. But I think it's incontrovertible that statins 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 cardiorespiratory 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, 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. With exercise, 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 lead to more calcium. Look, here's the thing. If you put it back into sort of the terms in the context of a patient comes to me and says, hey, I got this calcium score of whatever, let's call it 800, 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 were on 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 could do a CT angiogram to kind of see how much plaque you actually have. Because I don't know of 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 is I just can't tell you, I can't give you a free pass on the calcium because you exercise a lot, exercising 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 angiogram and it showed you didn't have any plaque and all the calcium is sort of extravascular 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 statins store because the people on statins are already by definition on the risk reducing therapy that's been shown to save lives. It's not like what are you going to do to that person because their calcium score is higher. Would you be more aggressive? I guess is one question people might ask. But that's the difference is that there's that leverage still to pull in the exercise person who's statin iu, what percentage.

Of your patients take statins?

I mean it's a completely biased group of people because it's all self selected, but 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 aren't able to tolerate?

There's those for sure. Although I think that's less frequent now because. Or would you say statin or any other or PCSK9 inhibitor? 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 conditions that prevent people from being maximally medically treated?

Small number of patients of mine who don't take them because of true side effects. A equally, maybe even slightly large group of 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. 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 any amount 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 going to 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, 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 acute mi, and fortunately the outcome was good. He ended up with a stent. He's 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 minds. 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 transaminase elevations that are just too much, especially if mixed with Zetia. If you acknowledge all of those things, there's obviously some deeper seated fear in something that can't be seen or measured or quantified. Where do you think that comes from? 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. I mean, there's a whole world of people out there with these vast conspiracy theories about the development of statins. And you know, about how Roy 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 if 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 that 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 unscared of something. And 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 Pharma. And don't get me wrong, obviously there are plenty of things that Big Pharma 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 statins 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 this is being compared effectively to. To smoking, to cigarette companies.

I haven't heard that comparison, but certainly people will quickly point to Purdue and the opioid crisis as proof 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 just are clearly bad, and there are.

People who are probably clearly always good. And I'm not either of those.

So 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 for 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 Sonandeh, 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 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 got to 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 creatinine. It's really tempting to say, well, you know, this guy's 55 years old, his EGFR is 70 mils 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, 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 ASCVD 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 nephrology as a subspecialty of medicine. I actually used to give a lecture on hypertension to the first year medical students at ucsf. And I did that in conjunction with a kidney pathologist who interestingly was, had been at Hopkins when I was a medical student, was my advisor, very interesting woman who's now retired, Jean 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. In 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 one of the predictions, mere human geneticists in history, member of the national academy, some probably should win a Nobel prize. He characterized all of the single gene mutations that lead to extreme increases or decreases in blood pressure. I think at the time, and this is 20 years ago, there were 10 single gene mutations that led to people who had really, really low blood pressure, had to constantly supplement salt and do things like that, and then 10 that led to extremely high blood pressure. And I think nine or whatever it is, 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 an incredibly important organ, both as a cause of high blood pressure and also as a consequence. And those experiments, Gene showed these beautiful slides. I'll send along sometime pictures of what happens 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 felt out of place.

Most people know that when they go to their doctor and they get their blood pressure checked, normal is about 120 over 80 millimeters over 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, that is 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, that is sitting down, legs uncrossed for five minutes, it reads 120, 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've 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, walks around on four legs. Why should we have the same blood pressure? It speaks, I think, to the conservation of this vascular system that we have. I think most people, when I was a medical student, I'm sure you were the same, were taught that 120, 80 is normal, that 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's something about decreased kidney function or maybe as an 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 had this permissive hypertension in elderly people because we thought, well, gosh, they required it. 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, hyperkalemia, risk of death. I mean, there's all kinds of potential issues. It's not just a simple intervention like treating LDL or APOB lower and lower and lower. There's really no consequence at all. There is a consequence of lowering blood pressure too low in this case. So that's my overall philosophy of how to think about blood pressure is 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, 130, 135, 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 glomerular 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, and that's normal, or do we want to try to do what we can to preserve the muscle mass that we had younger in life? And again, I think here the crutch that we fall back on 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 over 80. We actually have evidence that being closer to 120 over 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 an 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 to 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, let's assume 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, 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, 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 over 80. Right. When I'm exercising, it's not 120 over. There's physiology and there's pathophysiology. So 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 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, how were 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 15, 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 is more crowd hated it. This is just over medicalizing normal aging. Da da da da da. 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 pusher. So if you go back and you look at the methods, what they did was they had people in a quiet room, they had an 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 cuff on them and measures their 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 in that trial, which was so spectacular, the trial was stopped early. And this is not to all the conspiracy theorists out there, this was not a pharma 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 was 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 downsides. 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 going to start checking my blood pressure every couple of days. And I did. And so for a couple of years, I just checked 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 110 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 14090. If I just 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, so sits down 140, 95 minutes later, it's 117 4. And 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 looks perfectly normal. For the last six months, I've averaged below 120 over 80. But I kind of feel like I'm cheating, Ethan. Cause 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 could argue, well, Peter, 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, 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 going to 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, it sounded like something did change. But in this case, it sounds like there is an explanation and that you had this stress in your life from the book. So I guess the cheating thing reminds me of my daughter, who I think I told you before, my younger daughter is legally blind and plays basketball. And we were discussing a potential. This is such a crazy little aside, but I thought I'd tell the story because it's kind of cute. We were discussing a potential procedure she could have to improve her vision because part of her decrement of visual acuity is that she has pretty bad lateral nystagmus. And the ophthalmologist was saying that if you can make that better, understandably, you'll improve her visual acuity. And that somebody stumbled onto the idea that if you cut the extraocular muscles and just reattach them, don't do anything else, but just sever them and reattach them, that nystagmus can go away and that people's 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 a visual acuity of 20 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. That's physiology. When you're out and about and doing these, it's going to be higher. So what is the. And they can quite quantify all the spikes and it's actually a really nice tool that I'll use, 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 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 sphingomanometer. 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 to 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 a day. Patients of mine 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 have this thing 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 when you're not thinking about things when you're clearly not stressed or you shouldn't be stressed, that is 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 the lowest. 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 that we do that on average once or twice a year. That we assume that this very variable number is actually meaningful. And it's 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's 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 that could give you a sort of imputed systolic and diastolic blood pressure that never made it. We're not seeing those 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 you use them, but I use them a lot. These implantable event monitors, these loop recorders, we use them to detect arrhythmias. It sounds bad right 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 going to come, but I haven't seen it. And then non 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 than you can with just spot ticks 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 spite of 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 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 NHS survey, in 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. TR 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 thiazide, move to a calcium channel blocker and then an ACE or vice versa?

Actually, I don't remember the algorithm for Sprint, but I think it was relatively agnostic. Allhat 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 amlodipine, ACE inhibitors, diuretics, thiazide diuretics or chlorthalidone, beta blockers and alpha agonists, because at the time they were being used for blood pressure, and both the alphas and the betas 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 lisinopril, amlodipine and a thiazide, correct? Yes.

I believe the thiazide they used was chlorthalidone and we can talk a little bit about the difference between chlorthalidone and hydrochlorothiazide but in general chlorthalidone is more potent and that's the one that was I think used in the All Hat trial. But I'd have to double check.

If I recall, the amlodipine, lisinopril and the thiazide all ended up having similar outcomes which were all better.

Yeah. No real differences. Yeah, I think there were maybe some stroke. It's been so long since I've reviewed it. But I think there might have been a minor difference in stroke risk in the amlodipine. 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 JNC6 or something. There was a category for none normal. Ah, that's right. So it was normal was actually 120 to 130 over 80 to 85. Borderline was 130 to 140 over 85 to 90. And it was only then hypertension if you were greater than 140 over 90 and then they called it stage 1, 2 and 3. So then when they redid it in JNC 7 it was normal was less than 120. 80 pre hypertension was then at 120 to 140 and hypertension was then above 140 over 90. That was the difference between JNC 7 and JNC 6, JNC 8, 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?

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 patients who had optimal blood pressure. This is according to the old classification, people whose blood pressure is 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. 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, whether that resulted in a change in outcomes. And so they randomized these people. Again, the doctors were given leeway as to which agents to use, and you can look through, 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 over 80, got to 123 over whatever it was 82. And the people into that 140 over 90 were more like 137. You can look at the curves in the New England Journal paper, and they separated beautifully. And then they.

Yeah, I think 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 much higher in the people who were assigned to that more aggressive arm. And there are some questions there was, 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. And 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 silly to just completely dismiss this. There were real issues. There was a greater increase in the risk of falls and syncope, and I think even in the risk of significant kidney dysfunction. That 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 enough blood flow or whatever, something else bad happens, then 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 faceplant, 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 shaped curve. 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. And 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 wore a 24 hour ambulatory blood pressure when you're exercising, especially doing isometric resistant training, your blood pressure's gonna go way up.

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, at 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 other than the old school cool old fashioned sphinggo manometer just attached to your arm.

So what about the step trial last year? Did that sharpen our thinking at all?

I think it just assuaged any fears that people had that there was something unusual that Sprint. And of course there was this concern over the trial being stopped early, which does risk, you know, stuff better than 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 print 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 in the whole deal. And again, it wasn't industry that stopped it, it was the government that stopped it because of overwhelming benefit. 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 undertreated and that they could calculate the impact on mortality even here within the United States 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 from a 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.

I was going to say that, but.

You hear this little bit of ARB 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 angiotensin receptor blocker, for example, or throw in a calcium channel blocker that can equally lower blood pressure, they can get Everybody down to 12080 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 sort of lack of awareness and lack of treatment and lack of control of blood pressure. My first advice to people is get the blood pressure controlled. And that's what I tell patients, right? That let's just get the blood pressure controlled. 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. NIH used to use this term extenuating or special circumstances. For example, if somebody had angina, even though beta blockers were no longer first line for treatment of primary hypertension, if you had angina, you'd include the use of a beta blocker in that hypertensive regimen. It was really an anti angina, but it lowered 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 sort 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 favorite agent that I think probably among the three classes is the best at managing sort of all comers of high blood pressure, it would be chlorthalidin or thiazide diuretic. I don't use it as much just because it's harder to use. I think amlodipine 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 edema, but it's this sort of non edema 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 subpopulations. So for example, there was the Hope trial, right. Which was I think mid 2000s. And so it suggests that there may be a benefit in people with atherosclerotic coronary disease to have an ACE inhibitor on board. So maybe in people with ASCVD or ASCVD risk, I'll use that one over the others as a first line. It's also there's the whole ARB and aortic diameter thing. So people who may have a little increase, whether you want to call it an aneurysm, but just an increase in aortic 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. So they do require that you get electrolytes because there can be in some patients there can be issues especially with potassium and they can impact kidney function. So it's this weird thing where the benefit to people with kidney disease 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 nephropathy again and again.

So I think so somewhat 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. I think that makes a lot of.

Sense and tolerability because I do think we probably don't pay enough attention to that. It's probably the biggest reason for non compliance. And I hate that term.

Yeah, I kind of include that in the second bucket. Right. Is anything whether it be ankle sweet swelling or a dry cough that obviously tends to occur in some people with ACE inhibitors.

Those things have to be older people who tend to get more orthostatic. I'd stay away from diuretics for 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 night before.

Look, I think falling is an 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 atherosclerosis 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 squirrely because I can't point to one number that tells me like, I can point to your apob, I can point to 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 in 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 triacylglycerides. 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 exposed. 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 2 gallons escape in the wrong place, it can be a disaster. And so I 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 Riley, who I think is the 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, that BMI is not a great measure of risk. It is in epidemiology. It is in large populations. 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 but 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 evolutionarily programmed to 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 carnage disease 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 overwhelm the bathtub and leaks out gets into the floorboards, why is that so bad? The answer is not what I can give you, but we started our process in thinking about this problem and thinking about the extremes of biology, in particular these rare genetic diseases that are called lipodystrophies, where people are born with the inability to store fat at all in generalized lipodystrophy, or with just an isolated inability to store fat in the gluteal, femoral and subcutaneous regions in the legs. They 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 and the liver and the pancreas and the heart, as we talked about. And those people have tremendous metabolic disease and extraordinary levels of risk. I mean, there are small numbers of people, they're 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 lipodystrophy or type A insulin resistance, have astronomical coronary artery disease risk. There are 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. I think the role of insulin and its impact on different organs and tissues and cells 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, right, the apple pear thing, and risk of developing these diseases. And so 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 probably bet that it's some combination 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 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. I have a pretty good sense from any blood test you can do, I can do a DEXA scan. It tells me how much VAT I have. My transaminases are adequate. So I going to assume, and based on last test, no liver fat. But other than that, it's a real blind spot, right? I mean, I don't have the clarity that I would have about my apob, for example, or my blood pressure.

And that's, I think, because we're sort of increasing our very poor resolution of this problem, starting with the most blunt tool of all, which is 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 vat. We know that's bad. But here's a question right now, just a thought experiment. Is the problem with VAT is that a defect in the ability to store fat where it should be stored in the gluteal ephemeral depot? And is that just a manifest manifestation of that? Is there something different about vat? Is there truly a benefit to having more fat in gluteal? So in other words, to your bathtub analogy, if you could make a bigger bathtub, would you be more metabolically healthy?

Well, certainly there's one experiment that Gerald Shulman 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 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 VAT 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, 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 rate between the two depots. And again, we're just describing these depots based on what we can see and how we can describe them based on a dexoscopy.

Right. So it's just so low resolution compared to what we care about.

It's very low resolution at this time. I think what we can say is that even in a patient with lipodystrophy as an extreme, who has normal lipids, not normal triglycerides, so maybe a modest elevation in apob, but apob triglyceride, 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. 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 gluteal femoral storage capacity is going to 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 very poor evidence. If you talk 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 lipodystrophy. So the cases you're describing are profound. 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 lipodystrophy 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 human genetics as a guide, there are a number, large number of alleles that seem to confer this concordance of changes in both directions. So for example, people who have alleles that confer more gluteofemoral. So really what's important is not so much the amount of visceral fat you have in an absolute sense or the amount of gluteofemoral fat. It's really the ratio in DEXA terms and maybe on your DEXA reports called fat methods 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 in other things that we know are bad, including lipid based biomarkers and then diseases like coronary disease.

And how concordant are these alleles. So if you do you have enough data to look at identical twins and say that the genes are, are completely concordant 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 heterozygous and homozygous. 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 expectation is that we'll 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 lipodystrophy 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 lipodystrophy is abysmal. And Steve O'Reilly, who at some point, if you ever can 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 him. And read his Banting medal 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 patient's clothes off. If you don't undress your patient, you'll never see it. And actually, we have some patients with lipodystri 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 lipodystri 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 lipidistry is characterized or classified in how it's been defined historically. And there's familial partial lipidistry, 1, 2, 3, 4, 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 talk to an average doctor, will never have heard of lipodystrin, 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 if we're conditioned to think that leanness is good, leanness and muscularity are good, and if you see leanness and muscularity, if you happen to even see it, it's a good thing, you never would think, well, 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 absent a lipodystrophy, this is still a problem. You know, the lipodystrophy 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 there are going to be more common versions of this that exist. And it's very similar. I think the distinction between familial hypercholesterolemia and run of the mill hypercholesterolemia. And we learn a lot from rare diseases. This is a case where we'll learn a lot. In this case, we already have an abundance of human genetic data that suggests this sort of polygenic version of this thing. And there will 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 coronary disease events is higher than it would be even 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 wastebasket 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 lipodystrophy, in this case at least. What I can say with some confidence is that the rare genetics are probably not going to be as informative, certainly not as informative as PCSK9, which is, I think, stands alone in terms of the quality of its 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, one of the most common, the disease underlying FPLD2 is a mutation in Lamin A. We know that this leads to progeria, it leads to cardiomyopathy, it leads to muscular dystrophy, it leads to lipodystrophy. It's a complicated mess of a protein that's expressed in the nuclear lamina. It's hard to kind of imagine that common variation in that gene is going to lead to problems. It might, but it's not obvious.

Well, Ethan, this has been 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, you know, 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 in 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. 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 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 going to have any impact on positive impact on them for years, decades.

All righty. 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 we'll hook up.

Sounds good, man. Thank you.

All right, thank you.

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