247 ‒ Preventing cardiovascular disease: the latest in imaging, blood pressure & metabolic health

1. 0:00 – 0:08

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Attia.

2. 0:08 – 2:03

   Ethan’s entrepreneurial work in the cardiometabolic disease space

   1. PAPeter Attia0:09

      All right, Ethan, thanks so much for, uh, for making time to sit down again. This is, this is round two, although I kinda don't remember when round one was. I think it was 2019, but it might've been 2018, right?

   2. EWEthan Weiss0:20

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

   3. PAPeter Attia0:29

      Yeah, yeah. Well, that time we spoke in person, and we sat in your office at UCSF. Um, but you're sitting in a new office today, and we're not in person, but more importantly, where, where are you sitting today and, uh, there's been a bit of a, a change in your life in the past year, huh?

   4. EWEthan Weiss0:42

      Yeah, so I did... Uh, it's been an evolutionary change over the past couple of years, but I did, uh, have sort of a midlife crisis and decided that I, 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, uh, I was given the opportunity to get involved with a local, uh, group of investors who create biotech companies, and they asked me to help them conceive and eventually, uh, start a, a new biotech company. So I, I closed my lab and have become a volunteer clinical faculty at UCSF and see patients infrequently and, and spend most of my time over here, uh, working to, to build this new company that I can at least tell you a little bit about later on.

   5. PAPeter Attia1:29

      Yeah. Well, I know we're gonna talk about some of the science that the company is interested in 'cause it factors in directly to what we wanted to talk about today. So there will be a chance to talk about that for sure. Um, but in some ways, this podcast is really just a compilation of our email exchanges over the past couple of years. [chuckles]

   6. EWEthan Weiss1:50

      Yeah.

   7. PAPeter Attia1:50

      Uh, and, 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, I suspect, as is often the case, um, there's value in sharing what it is that we, we talk about with others. So, um,

3. 2:03 – 7:15

   Calcium scans (CAC scores) & CT angiography (CTA), & how it informs us about ASCVD risk

   1. PAPeter Attia2:03

      let's just start with a quick recap of what a calcium score is and, uh, 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, uh, God knows how long.

   2. EWEthan Weiss2:19

      Yeah. Uh, so you know, 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 s- s- calcium scanning and CT angiography. And as we discussed last time, cal- I think, you know, you've used the analogy before, the calcium scan d- sort of demonstrates a site of a prior injury. Uh, what we know is that quantitatively, the amount of calcium that is in the distribution of the coronary arteries is, uh, 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. Uh, and the reason we suspect is that that calcium represents, uh, a healed plaque, and that so the amount of calcium you have in your arteries is, is rel- 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 the, your, your risk of having heart attacks and dying from heart attacks. So calcium scans are great ways to kind of, uh... The way I-- The analogy I use for my patients is that it's a, you know, sort of a satellite image of your, of your heart and gives you a sense of has there been damage there over, over your lifetime. Uh, and what-- And then also gives you a, a nice adjunct indicator of your overall risk of dying from a heart attack, which people like to know.

   3. PAPeter Attia3:39

      And one of the nice things about a calcium score is it's very, very low in radiation. I mean, it's really-

   4. EWEthan Weiss3:45

      Right

   5. PAPeter Attia3:46

      ... you know, even CTAs are now low. We'll talk about that. But, but the, the calcium scan is a really low radiation and a very inexpensive tool as well. Um, there are, you know, places that are doing these scans for a couple hundred dollars, uh, nowadays.

   6. EWEthan Weiss3:59

      Yeah, that's right.

   7. PAPeter Attia4:00

      So-

   8. EWEthan Weiss4:00

      Not all places. [chuckles]

   9. PAPeter Attia4:01

      No.

   10. EWEthan Weiss4:02

       Uh-

   11. PAPeter Attia4:02

       That's the, that-

   12. EWEthan Weiss4:02

       Yeah

   13. PAPeter Attia4:02

       ... that speaks to the problem in U.S. healthcare-

   14. EWEthan Weiss4:04

       Yeah

   15. PAPeter Attia4:04

       ... where you'll still find some places charging two thousand-

   16. EWEthan Weiss4:07

       Yeah

   17. PAPeter Attia4:07

       ... while some will do the exact same scan for literally two hundred.

   18. EWEthan Weiss4:09

       Yeah, yeah.

   19. PAPeter Attia4:10

       Um, but it needn't be an expensive procedure.

   20. EWEthan Weiss4:13

       No.

   21. PAPeter Attia4:13

       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?

   22. EWEthan Weiss4:28

       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, that 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 s- 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. Uh, but I do find that there is value in, in many contexts and even in individual patients, and we can talk about which contexts I think are most valuable. It's certainly not everybody. I think, you know, a calcium scan in a 25-year-old is probably not worth anything. Uh, it's just not worth doing. Uh, so yeah, I think I've, I've come around now to seeing the value of calcium scanning as a tool that I use regularly.

   23. PAPeter Attia5:23

       Yeah. And I, and I know we did talk about this, but again, I, I, I've 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, uh, we should never apologize for repeating stuff that we talked about [chuckles] more than four years ago.

   24. EWEthan Weiss5:38

       True. Yeah.

   25. PAPeter Attia5:39

       Um, and, and the way that I kind of explain it to patients as well is that, uh, if you have a two by two of sort of, you know, young versus old and zero versus non-zero as the calcification-

   26. EWEthan Weiss5:52

       Mm-hmm

   27. PAPeter Attia5:52

       ... you know, there are two areas where the scan provides insight, and there are two areas where the scan doesn't really provide insight. And so one of them, as you said, you know, if a 40-year-old shows up, has a calcium scan of zero ... haven't really learned a lot. And if a calcium scan of zero in a 40-year-old is accompanied by other risk factors, I would not be dissuaded from aggressively treating those risk factors. And similarly, when an 80-year-old with lots of risk factors shows up and has a zero calcium scan, we'll talk about the false negative rate there, um, all things equal, you might be less inclined to push for aggressive measures. Would you, would you agree with that framework?

   28. EWEthan Weiss6:35

       I do. Yeah. I think there's a, uh, a group of very committed, uh, whatever you wanna call them, calcium scanographers who, uh, believe in the power of zero and believe that a calcium score of zero is me- meaningful, no matter where it comes, but I, I just think that defies logic, right? You, you shouldn't have any... If you shouldn't have any calcium when you're 25, uh, I'm not sure what you learn there. There may be edge cases where, you know, one in several million people will have some calcium, uh, but I just think mostly the two, two cases you described are, are where I find the most value.

4. 7:15 – 12:07

   Peter’s historical CAC scores, CTA results, & how one can be misled

   1. PAPeter Attia7:15

      Well, this gets to something that I think, uh, I've learned a little bit more about, both through personal experience and, and also just kind of spending more time in the literature on this, is that a calcium scan is, is a relatively imprecise measure. So the, the thickness of the slices that are used in that scan are significantly greater than the CT, the slices that are, uh, used in the CT angiography. And I'll, 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 'cause I just learned more recently. So i- 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. Um, there s- was no seemingly relevant reason for me to waste insurance money and do this. Um, but I had a horrible family history, um, 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, uh, scan, and it showed that I had a score of six. Uh, so I had a, uh, a single, uh, foci of calcium in the, uh, proximal LAD. Um, and interestingly, despite being in my mid-30s with that calcium score of six, nobody really seemed to care either. [chuckles] 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. Um, 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, so call it six, seven years later, I went and had a CT angiogram and a calcium scan.

   2. EWEthan Weiss8:58

      Uh-huh.

   3. PAPeter Attia8:59

      And the calcium scan had a score of zero. The CT angiogram, which now is at much finer resolution, indeed found a tiny speck of calcium in the proximal LAD. No other finding. Uh, Bob Peters, who is the, uh, r- remarkable radiologist that now sees a lot of our patients, explained to me, "Not uncommon at all." Like, that little speck that you had six years ago, uh, can easily be missed. If you had five calcium scans, half of them would miss it 'cause it's just too small. But now in the CTA, we can see it. So we repeated the CTA. Now I'm just kind of partially interested in progression, more of soft plaque. I had it repeated very recently, so call it 2022. This time the calcium score came out as two, and the 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 six and two and zero. In the, uh, sorry, six and zero and two in that order. Um, have you seen this yourself in patients where you've had the luxury of both longitudinal assessment and simultaneous CAC and CTA?

   4. EWEthan Weiss10:19

      You know, I can't... Off the top of my head, I can't think of anybody, but I would ask you, and this may be, uh, a leading question, but what were the perc- percentiles of those? I mean, I would imagine that calcium score of six when you were 35 was 99th percentile.

   5. PAPeter Attia10:33

      It was 75th to 90th percentile at that age.

   6. EWEthan Weiss10:36

      Yeah.

   7. PAPeter Attia10:36

      That's right. Yep.

   8. EWEthan Weiss10:37

      Yeah. But there's a big difference even between six and two, and a huge difference between six and zero.

   9. PAPeter Attia10:42

      Yes.

   10. EWEthan Weiss10:42

       Uh-

   11. PAPeter Attia10:42

       Exactly.

   12. EWEthan Weiss10:44

       Yeah.

   13. PAPeter Attia10:44

       So-

   14. EWEthan Weiss10:44

       Uh, I haven't seen it, but-

   15. PAPeter Attia10:46

       So, so, so-

   16. EWEthan Weiss10:46

       It doesn't surprise me

   17. PAPeter Attia10:47

       ... yeah, m- exactly. My guess is at a low enough calcium score, that's not, that's not uncommon. Of course, that then got me into the literature, and I realized that 15% of people who have a zero calcium score have a finding on CTA that is either, as mine was, meaning a calcification that was not picked up, or a soft plaque. Furthermore, 2%, or maybe it's 1.5% of those people who are deemed with a negative, uh, CAC, have an unstable plaque on CTA. So it's not just-

   18. EWEthan Weiss11:22

       Yeah

   19. PAPeter Attia11:22

       ... the 15% that have something, but, like, 10% of those people have something that's, would be deemed relevant if we saw it on the CTA.

   20. EWEthan Weiss11:32

       And just back to our, uh, prior discussion on, on sort of age and utility of the s- of the scan, I would imagine, I don't know the, not fa- familiar with the data, but I would imagine that that, that 15% is largely represented in, in younger people, or is that not the case?

   21. PAPeter Attia11:47

       I'd have to go back and look.

   22. EWEthan Weiss11:48

       Okay.

   23. PAPeter Attia11:48

       It's, it's a great question. I'd have to go back and look at the study 'cause it's been probably about six months since I, I looked at it. Um, um, but yeah. So we'll, we'll find it, and we'll link to it-

   24. EWEthan Weiss11:58

       Yeah

   25. PAPeter Attia11:58

       ... in the show notes so that it's-

   26. EWEthan Weiss11:59

       Yeah

   27. PAPeter Attia11:59

       ... unambiguous, and we'll include the, the table that, that summarizes all this, which would hopefully include age. And if not, it'll be in the fine print.

   28. EWEthan Weiss12:06

       And then the other question

5. 12:07 – 19:39

   How Peter’s CTA results prompted him to lower his apoB

   1. EWEthan Weiss12:07

      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?

   2. PAPeter Attia12:14

      Yeah. So that's the point. It's been lower and lower and lower, right?

   3. EWEthan Weiss12:17

      Yeah.

   4. PAPeter Attia12:17

      So I immediately... You know, that's, that's about the time I met Tom Dayspring and, you know, 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 thirty and forty milligrams per deciliter. That's sort of where I aim to be, uh, day in and day out, and obviously that requires, you know, 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 eighty-five to ninety milligrams per deciliter. I mean, very few doctors would get phosphorylated over that apoB-

   5. EWEthan Weiss13:05

      Yeah

   6. PAPeter Attia13:06

      ... in someone in their late thirties or mid-thirties at the time. But again, I'd watched countless men in my family die, some of them as young as in their late forties, 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.

   7. EWEthan Weiss13:28

      Yeah. Yeah.

   8. PAPeter Attia13:30

      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.

   9. EWEthan Weiss13:39

      Yeah. It's, it is my practice, and unfortunately, at least for now, the, the only s- tool, set of tools that we have are aimed at... Well, I should s- independent of blood pressure, which is a different conversation we'll, 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 wasn't... I mean, again, I don't think, uh, uh... It's hard to make the argument that you were sort of a ticking time bomb with a widowmaker that you were gonna drop dead of a heart attack. You, you had a tiny, uh, you know, minuscule lesion. The question would've been what happened to you over the next fifteen or twenty years had you not taken the intervention that you did pharmacologically?

   10. PAPeter Attia14:24

       Yeah. As I approach fifty 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 fifteen years ago, had I never cared, what would, what would it look like today? What would that CTA look like today? How significant would that lesion be? Would there be others? Um-

   11. EWEthan Weiss14:43

       Yeah

   12. PAPeter Attia14:43

       ... a- a- and my belief is that be- uh, you know, and we, we should obviously talk about this. I, I think that the epidemiology, the clinical trial data, and the Mendelian randomization to my reading of this literature, and I don't think there's anything I pay closer attention to truthfully, is that apoB is a necessary but not sufficient criteria for atherosclerosis, and as such, removing it removes atherosclerosis. And so my best guess as to why there has likely been no progression of this disease in fifteen 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.

   13. EWEthan Weiss15:30

       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, uh, 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, uh, in humans, but across many other animal species.

   14. PAPeter Attia15:47

       Yep.

   15. EWEthan Weiss15:48

       The, the one place where I might quibble a little bit is that I do think it's probably sufficient in some cases, right? That-

   16. PAPeter Attia15:54

       Interesting

   17. EWEthan Weiss15:54

       ... uh, that in FH, for example, uh, it's probably sufficient. In other words, I don't think you have to have something else, uh, to get athero in, in cases where the, uh, apoB is sky high.

   18. PAPeter Attia16:07

       The sufficiency is complicated, right? I, uh, I, I mean, I suppose there are people with FH that don't go on to develop ASCVD.

   19. EWEthan Weiss16:18

       Yeah. Lots.

   20. PAPeter Attia16:19

       Yeah.

   21. EWEthan Weiss16:20

       I mean, that's sort of the argument that the sort of... And I don't know if we're gonna get into this or if I ever wanna talk about this ever again, but this lean mass hyper nonsense-

   22. PAPeter Attia16:29

       Mm-hmm

   23. EWEthan Weiss16:29

       ... uh, that this, that's the argument that, that they make, that it's not su- that having a high apoB is not sufficient. And, um, 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.

   24. PAPeter Attia16:50

       Yeah. I mean, I, I... So I think that one could, could, could argue that, that apoB is not sufficient but is necessary, which is, is how I feel, and still take it very seriously because let's look at another obvious example, which is smoking.

   25. EWEthan Weiss17:06

       Right.

   26. PAPeter Attia17:06

       Right? Um, smo- a- and again, is smoking even... I, I would argue smoking is even weaker, right?

   27. EWEthan Weiss17:12

       Yep.

   28. PAPeter Attia17:12

       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.

   29. EWEthan Weiss17:21

       Yep.

   30. PAPeter Attia17:21

       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.
6. 19:39 – 28:07

   Calcium scans vs. CT angiogram (CTA)

   1. PAPeter Attia19:39

      okay, so let's go back to our discussion and now, um, contrast the, the, 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, uh-

   2. EWEthan Weiss19:55

      Sure

   3. PAPeter Attia19:55

      ... more like software additions to CTA.

   4. EWEthan Weiss19:57

      Sure. I mean, look, uh, in, uh... What I tell patients is that what you get from a CTA is, uh, is clarity and more information, which in most cases is really, really good, and that comes at a small cost, uh, in terms of increased radiation. Uh, and I guess, you know, some potential risk of the, of the contrast, although it's relatively small. The biggest cost and the biggest reason that I don't use it, uh, in all of my patients in whom I'm thinking about these kinds of things is, is that it's hard to get it paid for. So it is actually m- 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, by insurance. But as you said, you can get it-

   5. PAPeter Attia20:50

      That, that's calcium scans, you mean-

   6. EWEthan Weiss20:51

      Yeah

   7. PAPeter Attia20:51

      ... and CTAs. They're both just out of pocket these days.

   8. EWEthan Weiss20:54

      No, no, no. Calcium scans are, are al- almost exclusively out of pocket. I would say 90-plus percent of them are paid for by patients themselves. But again, as you said earlier-

   9. PAPeter Attia21:01

      But it's so inexpensive. Yep

   10. EWEthan Weiss21:02

       ... it's a couple hundred bucks. And almost-

   11. PAPeter Attia21:04

       Yep

   12. EWEthan Weiss21:04

       ... everybody can make that leap and sort of, uh, convince themselves that it's worth a, you know, whatever it is, 10 Starbucks. So, uh, but for CT angiograms, the cost is much higher. You know, and again, I don't know, and this is one of the problems with our healthcare system, I don't wanna 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 gonna pay for it until after they already have it. Um, and so the, 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 gonna be different based on whatever carrier you have. So I would say much fewer than, uh, 50% of my patients, uh, have coverage. And we can talk about what would justify coverage for a CT angiogram, and I've sort of gotten, I think, a little bit more sophisticated in trying to be able to get around some of what I think are these sort of absurd, uh, blockers for, for coverage. Uh, 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. Um-

   13. PAPeter Attia22:25

       Yeah

   14. EWEthan Weiss22:25

       ... so I think that's just worth pointing out that i- i- in a world in which they were covered universally and we could have access to the data, uh, 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, like you and, 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 gonna add that much, so.

   15. PAPeter Attia22:56

       Yeah. Yeah, I agree. Um, a- and, and we kind of have that discussion with our patients as well, which is that look the, um, the IV contrast is virtually a non-risk outside of a handful of settings, which are clearly well understood and can be, you know, you know... We know how to handle those pretty well. The radiation these days is so low. It's really in the neighborhood of two millisieverts for a person our size, so you know, that's 4% of your annual allotment of radiation. Uh, but you're right, the cost, I mean, we sort of assume 2,000 to 2,500 is pretty standard for that test.

   16. EWEthan Weiss23:32

       Yeah. When it's paid for out of pocket, it, it is, uh, 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, for their members. And so I've seen some people get... And it, and it's very different institution to institution, right?

   17. PAPeter Attia23:51

       Mm-hmm.

   18. EWEthan Weiss23:51

       So you could go to UCSF and it would be $700. You might go to Stanford, it'd be 1,500 or the other way around. And so I do advise people when it comes to these decisions, if the money's an issue, which it is for almost everybody 'cause it's, you know, a significant amount of money, to shop around a little bit. And then, you know, the question of sort of, all right, well, what do I get for my money and- Uh, 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, uh, that's another variable that we kind of have begun to address a little bit.

   19. PAPeter Attia24:26

       And those are the two things we always sort of say. I mean, we have places we send people that we... 'cause we know the answers to those questions. But if it's not convenient for them, we're sort of saying, you, you've got to ask what the radiation bur-burden is. And, and it's actually, it can be a 10X difference.

   20. EWEthan Weiss24:40

       Yeah.

   21. PAPeter Attia24:40

       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, uh, screening scan, which, you know, personally I think is, is too much. I just don't think it's worth it, even if you're saving a bit of money.

   22. EWEthan Weiss24:53

       I agree. I, uh, I, I agree. And it's just another layer of complexity and sort of, uh, how you think about applying these different tests and getting this information. It, it's just really important to, to make sure not to forget about it.

   23. PAPeter Attia25:10

       So every time I've had these CTA scans, you know, we get these beautiful images, and they're 3D reconstructed, uh, and then they're 2D sectioned, and, you know, we're looking at the lumen, right? The, the, the tube of the artery. Um, in both cases, that little speck of calcium shows up in the wall, uh, of the artery. Um, and then we're also looking for sort of soft plaque as well, and fortunately there, there hasn't been any, but that's... You know, soft plaque doesn't show up anywhere on 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, 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, uh, 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 a high burden of soft plaque and no calcification as even higher risk?

   24. EWEthan Weiss26:15

       Uh, I don't really just 'cause I don't think I buy that their, uh, data suggests that. I think a high burden of plaque, period, is a problem. Uh-

   25. PAPeter Attia26:23

       Mm-hmm

   26. EWEthan Weiss26:23

       ... uh, do I believe that a high burden of calcified plaque might be less risky 'cause it's more stable? I guess in theory, but it's super... 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. Uh, I mean, we know that people who have a calcium s-score of 4,000, which by definition means they've got a sh-shitload of calcium, uh, that that's a high risk.

   27. PAPeter Attia26:51

       Yeah.

   28. EWEthan Weiss26:51

       Uh, and even if they don't have any soft plaque, the risk is still high. So I, 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, you know, I'm greedy. I want more. And I feel like we just get so much more information and don't have to make that distinction between soft and hard plaque. And, and frankly, I'm not sure we're at a point in, in this field yet where we can make a compelling argument about plaque characteristics. It's been a field that I think has evolved now since the early days, right? Since the '70s probably when the pathologists were doing autopsies on people who died of sudden cardiac death, and, uh, you know, we've been trying to understand the vulnerable plaque and different plaque characteristics and what confers, what confers risk of rupture and, uh, ultimately of a, an event. I just don't think, at least in my estimation, and I'm certainly no expert, I, it's not... we're not there yet. So I don't, I don't use it anything other, uh, than as a sort of how much plaque is there, uh, tool.

   29. PAPeter Attia27:56

       Y-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, right? I mean, I think,

7. 28:07 – 34:12

   How Ethan makes clinical decisions based on CTA results & plaque burden, & the importance of starting treatment early to prevent ASCVD

   1. PAPeter Attia28:07

      um... Do you think that in the research setting, things like intravenous ultrasound, um, or intravascular ultrasound, where they can actually look and measure the, the thickness of the cap on the atheroma, do you think that in a theoretical sense those things are, are any better, even if they're impractical from a clinical perspective?

   2. EWEthan Weiss28:26

      I guess, but ultimately, as a lot of things in biology, this is just so st-stochastic that it... I think we, we might convince ourselves that it means something that it doesn't. So I think, you know, we've learned a lot that, you know, again, from the early days of trying, of even understanding that ruptured plaque leads to a thrombosis on, over the, 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, then you could reduce the risk. I think, um, I think we'd learned early on that it didn't necessarily, 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 the s- smaller plaques, the 30% plaques, which kind of makes sense in, in the context of how we think about, you know... We'll all hear these stories, and I'm sure you get patients coming to you after somebody prominent dies. Uh, and I, and I won't- I won't mention the name just 'cause I think this is an example, and I, I don't know Sheryl, but when Sheryl Sandberg's husband died on a treadmill a few years ago, I mean, 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 sort of relatively mild plaque that wouldn't trigger any discussion of revascularization, um, and, you know, wouldn't make anybody nervous at all, that those are the plaques that end up causing problems. And, and we can begin to weave together reasons why that might be, right? That, that maybe in a person who's got more plaque burden, that there's more chance for ischemic preconditioning, and therefore the l- the chance of an arrhythmic Sort of malignant arrhythmic response to the ischemia is lessened because of that. Um, but I think 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, characteristics of the plaque, even the volume of the plaque. And so for that reason, I treat people with plaques, you know, any plaque, 30% plaque, pretty much the same way that I treat people with extensive plaque and, and I treat them maximally with sort of the best optimal medical therapy I can, I can offer.

   3. PAPeter Attia30:57

      Yeah. So [chuckles] boy, we, we, we, we feel so similarly about this, Ethan, that we're gonna have a hard time coming up with-

   4. EWEthan Weiss31:02

      [laughs]

   5. PAPeter Attia31:02

      ... with some- some- some- something to really clash about here because, um, y- you know, this is basically the same discussion we have with our patients, which is I don't... I mean, 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.

   6. EWEthan Weiss31:28

      Right.

   7. PAPeter Attia31:29

      I want to tell someone that-- Sorry, I was-- I wanna tell somebody 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 at-- and their risk is significant.

   8. EWEthan Weiss31:46

      Yeah. And this is the sort of eye-bleeding experience that I have with insurance companies talking about a- adding PCSK9 inhibitors to what, you know, sort of statins and whatever else they're on. And, uh, and often they'll say, "Well, they need to have an event first." And I'm, and you know, I'm s- I, I'm thinking to myself-

   9. PAPeter Attia32:02

      So backwards

   10. EWEthan Weiss32:03

       ... like you're, you're s- you're gonna ask me to let my patient have a heart attack so that I can prescribe the drug that's gonna prevent them from having a heart attack? I mean, it's really incredible and, uh, hopefully we won't practice that way down the line. I, the, the problem of course is that, and I don't wanna get distracted, but all of these trials are so incredibly expensive to do that the information that we're gonna get from sort of the most rigorous randomized clinical trials is gonna be limited just 'cause we're not gonna be able... You know, all the questions that I wanna ask and answer, I'm sure that all the ones you wanna ask and answer are just not gonna be feasible to do 'cause they're gonna be overwhelmingly expensive. So we have to find a way to be able to make decisions to treat patients independent of this gold standard level evidence. Um, and hopefully the insurance companies come around.

   11. PAPeter Attia32:48

       Yeah. 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 effect change.

   12. EWEthan Weiss32:57

       Yeah.

   13. PAPeter Attia32:57

       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, I mean, again, I, I, I feel m- 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. Um, and yet it'll never be done and therefore there will never be an evidence-based case for true prevention of ASCVD. Uh, I say something very bold in my upcoming book, which is that ASCVD should basically be an orphan disease. Um-

   14. EWEthan Weiss33:48

       Yeah

   15. PAPeter Attia33:48

       ... there's actually no reason it needs to be the leading cause of death. It, 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. Um, 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-

   16. EWEthan Weiss34:06

       Yeah

   17. PAPeter Attia34:06

       ... gonna be patients who are gonna be challenging. But, um, with a long enough runway, this disease is sort of irrelevant.

8. 34:12 – 43:31

   Improved methods of CTA to grade plaque lesions & how it’s shaped medical decisions such as stenting

   1. PAPeter Attia34:12

      Let's, let's talk a little bit about these flavors of CTAs that keep showing up. So-

   2. EWEthan Weiss34:19

      Sure

   3. PAPeter Attia34:19

      ... um, I guess we'll start with the, this, this, the CTA FFR 'cause 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. Um-

   4. EWEthan Weiss34:33

      FAME and FAME 2, I think.

   5. PAPeter Attia34:35

      That's right. Yeah. FAME and FAME 2.

   6. EWEthan Weiss34:37

      Yeah.

   7. PAPeter Attia34:37

      Um, I guess give the, give the, the short version of what those trials looked at, what the technology was, and then we can talk about the, the CT side of it.

   8. EWEthan Weiss34:46

      Well, I mean the original FFR that was performed that is still now performed in a cath lab is, uh, is basically a way to detect a pressure gradient across a stenosis, right? So 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 gonna be pressure proximal to this, your fing- your finger squeezing the garden hose, and the pressure on the other end is gonna be lower. And that what they effectively do is to put a wire with a, uh, with a pressure sensor on one, 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 f- mathematical formula that I've... You'll know the an- name of it. I, I, I'm blanking on it. You can impute, you can impute the diameter of the, of the artery relative to the diameter of the unobstructed artery, or the garden hose in this case. Uh, and so that kind of gives you a way to, uh, to get at the severity of the, of the blockage. And I guess what this stems from is, is a m- 40-year odyssey to try to take a very qualitative measure, which happens in a, in a cath- catheteriz- catheterization laboratory, which is to sort of measure the pernet- percent stenosis, which is done, if you've ever seen it. It's done very much sort of by like, uh, gestalt. And the people who are good at it are pretty good at it. But if you watch it, you, you understand that the difference between 30 and 50 is probably not that meaningful. Um- When there are severe blockages or stenoses, you can sort of all agree that it's really high-grade. So I think, you know, I think of things in sort of that sort of high-grade, modest, and, and low. Um, 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. You know, IVUS, you mentioned earlier, is one of them. Um, there have been a, you know, quantitative coronary angio-angiography where they actually try and take a cursor and electronically draw around the, the diameter of the, of the vessel. Um, Mike Gibson, you know, back in the old days used to do this, um, blush thing. I can't even remember what it was called, but basically it would-- he'd count the number of frames it takes for the, for the contrast dye to leave the myocardium, and that was sort of another indication of how severe the, um, the lesions were. FFR evolved as a sort of hemodynamic way to be able to im-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, um, if the ratio of the pressure and the sort of upstream s- uh, s- uh, sensor was, was much, you know, higher than the, uh, downstream sensor, that that, uh, conveyed that there was a bad lesion and that it conveyed worse outcomes in people, uh, who didn't get stented. I can't even remember the design of the trials. But basically, I mean, the way they kind of-

   9. PAPeter Attia37:59

      Yeah, I mean, I th- I think the idea was basically, look, uh, 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, we just go to the cath lab. There's no need to putz around, right? Um, or I mean, what's the algorithm on, uh, um, [lip smack] a clot, uh, dissolve versus stent in the active MI in the ER?

   10. EWEthan Weiss38:27

       Oh, in the modern era, if there's a cath lab within whatever it is, I think, you know, I don't know what the exact number is in the latest guidelines, but it might be like ninety 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.

   11. PAPeter Attia38:41

       Yep.

   12. EWEthan Weiss38:41

       So primary PCI is the standard of care. Uh, I think, uh, thrombolytics are used sparingly in this country and only in remote places where there's no access to a cath lab.

   13. PAPeter Attia38:49

       Where they can't get to a cath lab.

   14. EWEthan Weiss38:50

       Yeah.

   15. PAPeter Attia38:50

       Okay. So-

   16. EWEthan Weiss38:51

       So in an ST elevation MI, it's primary PCI is the standard of care, class one, the whole deal, and, uh, as quickly as you can get there.

   17. PAPeter Attia39:00

       And then the other indication in the non-MI setting is, is symptomatic, right? If you have a person who is, who for example on a str-

   18. EWEthan Weiss39:08

       Uh-huh.

   19. PAPeter Attia39:08

       If someone, if someone has a stress test and on the, on the stress test you see ST changes, does that, is that an indication for a PCI as well?

   20. EWEthan Weiss39:16

       So we'll back up. So, uh, STEMIs, ST elevation MIs, where there's a complete in the 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.

   21. PAPeter Attia39:33

       Yep.

   22. EWEthan Weiss39:33

       What we're now calling ACS, which we used to call unstable angina or non-ST elevation MI, which is not, is same pathophysiology, right? Ruptured plaque, a, 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, uh, to fix that blockage. I would say it's generally accepted on the order, if I had to guess, of eighty-five or ninety percent of people would practice that way. And what I mean early, I mean within the first twenty-four hours. So it's not a sort of code-level emergency where you, you know, 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, and 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 that disease is treated best with early intervention.

   23. PAPeter Attia40:40

       And the only distinction between those people Ethan, the only distinction-

   24. EWEthan Weiss40:43

       Yeah

   25. PAPeter Attia40:43

       ...is the ST change on the EKG when they present?

   26. EWEthan Weiss40:46

       That's right. Yeah. I mean, that's the, that is the distinction. Uh, and of course, that is sensitive, but not a hundred percent sensitive. There are certain, um, lesions that are obscured, right? Where you would, you know, for example, a posterior MI, you'd have to do posterior leads to be able to see that. So but mostly it's STEMI is a, is a emergency go, go straight to the cath lab, don't pass go. Um, non-STEMI or ACS is, is urgent and generally people end up in the cath lab. And it wouldn't be a bad thing to have them go there, you know, relatively quickly, depending on how unstable they are. Obviously, if anybody has unstable symptoms, no matter what they have, in other words, if their blood pressure was labile or if they had heart failure, um, 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. The, the, and this is a, this is my opinion, my read of the literature, but over the past fifteen years, um, 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 LAD or left main, there might be still some people who would think, "Gosh, even without symptoms, I'm gonna put a, I'm gonna put a stent in this person." Uh, but generally people with, with plaque, no matter how bad the plaque looks angiographically Those people are treated medically if they don't have symptoms. Where things have gotten interesting is in these cases for symptoms, right? 'Cause I think most of us have-

   27. PAPeter Attia42:26

       And sorry, when you say symptoms, Ethan, you mean symptoms in day-to-day, uh, life or do you mean under-

   28. EWEthan Weiss42:31

       Sorry

   29. PAPeter Attia42:31

       ... stress and provocation?

   30. EWEthan Weiss42:32

       Good question. Yeah, so no. So rest symptoms is unstable symptoms, and that falls into that first category, and those people would be, should be hospitalized and they would go in that first 24-hour window. So any symptoms at rest without doing anything, uh, we can debate about what, what is... Like, what happens if you have an argument with your wife and you get chest pain, is that unstable or stable? You know. 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 or rarely pain. You stop, it gets better, or you take a nitroglycerin, it gets better. Classic stable angina. So st- people have plaque but do not have stable or unstable symptoms at all in general these days are treated medically with some exceptions. Um, it's the people who have this classic stable angina, stable symptoms, so they go out and walk up a hill and they get chest tightness. You know, feels like somebody's tightening a belt around their

9. 43:31 – 57:23

   Why Ethan favors optimal medical therapy over stenting outside of particular situations

   1. EWEthan Weiss43:31

      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, you know, we, we hadn't put it on our list of things to discuss, and I don't remember if we discussed, you know, these trials the last time around, but, 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, is... And this is sort of part of the reason why FAME is, to me, like, not that interesting, 'cause we've kind of already answered the question in all comers that stenting people without symptoms, even if they have some significant lesions, doesn't offer a benefit over optimal medical therapy. There's, uh, there's now I think some discussion around even patients with symptoms, whether they, uh, uh... The range of opinion I think goes from anybody with symptoms should be stented or revascularized, you know, in edge cases with bypass. Uh, some people think, you know, medical therapy in all cases, and then I think there's sort of this nuanced in between people who think give a trial of 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. Um, and that's probably where I land right now, is I don't, 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 sort of emergency acute settings, that's a different story.

   2. PAPeter Attia45:13

      And if you had a patient with a really high calcium burden, so they're north of 1,000, um, and they never experience symptoms, would... And they're young. They're, you know, 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 wanna really see if they have any ST changes or w- uh, wall motion abnormality when I make them, you know, go to 15 mets"?

   3. EWEthan Weiss45:43

      I don't. But, um, because, because like I said, I sort of land in that camp of even if you had symptoms, I'd still probably-

   4. PAPeter Attia45:52

      You'd still medically manage them

   5. EWEthan Weiss45:53

      ... treat them medically. I-

   6. PAPeter Attia45:54

      Yeah

   7. EWEthan Weiss45:54

      ... yeah, probably. I would still try to optimize medicines. Now, if somebody came in and was on great medicines and was still having symptoms, then obviously y- 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, 1,000, it, to me it triggers a response and it's the same. I don't think you need a CTA in that case. And in fact, a CTA might, might not be very useful because there may be so much calcium that it kind of obscures the ability to be able to see-

   8. PAPeter Attia46:22

      Yeah

   9. EWEthan Weiss46:22

      ... uh, into and beneath the vessel. So, uh, and it- it's, 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 that- and they'll have had a big workup, uh, including potentially stress testing and, and a CT angiogram, but, but I don't do that. And, and, 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, uh, to see how they progress. I, I don't do that anymore either.

   10. PAPeter Attia47:02

       Okay. 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 [clears throat] and you did this FFR on them, you measured the fractional flow reserve. If you took the people who had a pressure drop of, I think it was either 30% or more, I think it was a .7 P2 to P1 or maybe-

   11. EWEthan Weiss47:31

       .8 or .7, yeah. I can't remember

   12. PAPeter Attia47:32

       ... yeah, some- something like that.

   13. EWEthan Weiss47:33

       Yeah.

   14. PAPeter Attia47:33

       It was either a 20 or 30% drop.

   15. EWEthan Weiss47:35

       Yeah.

   16. PAPeter Attia47:35

       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-

   17. EWEthan Weiss47:47

       That was the design and that was the result. And, uh, and so therefore, that became standard of care in a cath lab, in most cath labs that, uh, [laughs] in fact we were doing FFR on a lot of patients where... Yeah. Initially, FFR was there for these edge cases where you weren't sure, is this significant or not? Should we stent it? Should we not stent it? I think it's, it went through a period, and I think it's now come back, but I think it went through a period where it was being used a lot based on FAME with the sort of assumption that you're impacting people's outcome, heart outcomes based on your decision-making, and that there were certain groups of people who benefited tremendously from getting stented, and our job is just to identify who they were. On the surface, that's not an absurdity, right? That, that's definitely a possibility, but I think, uh, you know, after however many years now of understanding the data, I think the consensus is it's just not necessary. And I think really mostly it comes from the sort of line of evidence that we've had through, you know, courage, ischemia, orbita, all these different trials showing really that the take-home is that optimal medical therapy, even in a mildly symptomatic pers- patient, is, is quite effective.

   18. PAPeter Attia48:56

       So all of this basically is prelude to, um, 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, um, to say, "Hey, maybe you do need an intervention." Uh, so again, in theory, the idea here is, well, you had a CTA. I see a stenosis there. It's a fifty percent 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, I'm, I don't know myself. Um, 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, I, I have to believe that was done, right?

   19. EWEthan Weiss50:00

       Yeah, there was a trial. Uh, I, I don't remember the details of it. Uh, I guess the questions are in my mind, so does the physics m- 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, uh, 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 that this is... Just as they probably required something to clear the FFR catheters themselves, they probably-

   20. PAPeter Attia50:29

       Yeah

   21. EWEthan Weiss50:29

       ... required something. It probably was close enough. Um, I don't have any knowledge that the thing is a random number generator. Uh, to me, the, that's a distraction. I think there are plenty of people who, who go down that path. To me, the question remains, what are we doing? And r- really in the way I practice, do we need to identify asymptomatic people who are at higher risk? Is there something about, 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? And I, I know that my interventional cardiology colleagues are gonna hate what I just said. Um, 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 acute MI 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 in- interventional heart cardiologists who wanted to demonstrate the superiority of stenting over medical therapy. It was designed that way, and all the bias, you know, sort of was, was weighted towards getting that outcome. It did not get that outcome. And, and frankly, there have been, you know, 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 interve- or pre- preventive cardiologists or, you know, thoughtful internists should be to go looking for people who, who might benefit from a stent in the absence of symptoms. And that, that's where I'm left today is that I just can't, 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 could-- didn't have barriers to using all these tools in everybody, I think this disease would largely be controlled. Now, I, I do believe there's something else going on that's residual, and you're an example, I think, potentially. Um, but, uh, but yes, if, if, uh, you know, I think the quality of the, of the 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, right? That, and, and again, I think that's a open question, why if you have a very high-grade lesion, even, you know, before there was great PCSK9 inhibitors, right? There were just, you know, Zocor or something. Why wouldn't opening that artery lead to improved outcomes outside of the acute MI setting? That, that's a question that always plagued me, even as a cardiology fellow. I was like, "Well, this doesn't make any sense. It should, right?" You're opening up an artery that, 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 in going in there and put- blowing up a balloon inside that artery and put, and deploying a stent, that you're elaborating the contents of that plaque downstream, and that mu- much like what happens when you break up a beaver dam in a, in a stream. It's just going downstream and causing its own set of problems. I, I don't-- That's just me speculating and making it up. But to me, it's an interesting question why, why it wouldn't be.

   22. PAPeter Attia54:05

       Has the, has the study been done, uh, for example, where they take a group of individuals who were, um, asymptomatic at the time of being stented, or they weren't being stented in an acute, uh, STEMI, um, who then go on to have subsequent events, what the location is of the, uh, plaque? In other words, when a person gets stented in the mid LAD And they go and have another event. Is that other event more-- Do, do we, can we identify a pattern? So for example, is it distal in the LAD? Is it, you know, in a part of the heart where you could say, you know, maybe there was some mechanical change that took place as a result of that stent? Or maybe it was, "Hey, you know what? The reason it doesn't work is you're playing Whac-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 y-y-you weren't more likely to do anything here. You know, maybe if you stented the enti-- Maybe if you, you know-

   23. EWEthan Weiss55:13

       Yeah

   24. PAPeter Attia55:13

       ... stented the-

   25. EWEthan Weiss55:14

       Yeah

   26. PAPeter Attia55:14

       ... entire vasculature you would've, but of course, you can't do that.

   27. EWEthan Weiss55:17

       Yeah.

   28. PAPeter Attia55:18

       So it really comes down to how lousy is plain up stenosis as a predictor of subsequent events.

   29. EWEthan Weiss55:24

       Well, I think it's, it's a good predictor that c- with the, as we discussed earlier, these plaques that end up leading to bad things often are not the plaques that we would get stented anyway. So I think there's that, which is sort of the-

   30. PAPeter Attia55:35

       That, that, and that's my point, right? Which is-
10. 57:23 – 1:01:31

    The need for FFR CTA, & the potential for medical therapy to eliminate ASCVD

    1. PAPeter Attia57:23

       Okay, so there was this study that I don't think is published yet, but I think you and I saw it and emailed each other about. Was it, was, is it the PRECISE trial that was, that we saw the abstract for?

    2. EWEthan Weiss57:33

       Remind me.

    3. PAPeter Attia57:35

       This is the one that did the e- 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.

    4. EWEthan Weiss57:50

       Right. Yeah, yeah. So this has now become the sort of, um, value add of doing these non-invasive adjuncts to CT angiography. And-

    5. PAPeter Attia58:00

       Right

    6. EWEthan Weiss58:00

       ... uh, it's the reason that we at UCSF now do s- CTFFR on, not all of it, 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 lab if you send people to the lab, right? It, it, it... If you're s- not sending people to the lab, you're not [chuckles] reducing the number of people. So again, to me it comes back to the primary issue, which is that people with plaque probably, you know, in the absence of symptoms, people with plaque should probably be op- optimally medically treated and left alone, and that taking them to 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 astronomically w- once they're there. So yes, you do theoretically prevent unnecessary, unnecessary stents with CTFFR, but you can do that without the FFR. You don't need the FFR.

    7. PAPeter Attia58:59

       Yeah, I think that's really well said, right? Because to me, I don't get hung up when a study like that doesn't find a difference in ACM [clears throat] 'cause I think that's a short time horizon, but I do get a bit alarmed when there's absolutely no difference in MACE, right? When you see no difference in anything related to cardiac pathology, and the only difference is an algorithmic difference that, to your point, you can make on your own. Again, I think we should maybe reserve judgment until the final study is published. I mean, 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. Um, it, it's-

    8. EWEthan Weiss59:45

       Yeah, I mean, I, 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 gonna pull? And I think sometimes people overcomplicate it, right? That, you know, there are gonna be relatively low-risk people whom, whom you could get away with statin or maybe statin and a very low dose of Zetia. I mean, you know, in my opinion, if you have plaque, significant, a plaque, so you know, they say a thirty percent plaque or greater in an artery in your coronary vasculature, m- I'm pulling all the levers.

    9. PAPeter Attia1:00:14

       Yeah.

    10. EWEthan Weiss1:00:14

        Like that, I don't need any other information. Like I don't need more, and th- that's a pretty good intervention, pulling all those levers.

    11. PAPeter Attia1:00:22

        By the way, to your point earlier, let's just assume there's something in me that's off. I think the fact that the moment I had a six score DIZZLE Every lever got pulled.

    12. EWEthan Weiss1:00:34

        Yeah.

    13. PAPeter Attia1:00:34

        That's probably why 15 year laters-

    14. EWEthan Weiss1:00:36

        Yeah

    15. PAPeter Attia1:00:36

        ... 15 years later it looks like a DTSEL still. Nothing's changed. Which means i- if we just pulled all the levers all the time, we could t- kinda take this disease off the table for m- virtually entire population.

    16. EWEthan Weiss1:00:48

        This is the mission statement of my friend Seth Kathiresan's company, Verve, right? I mean, this is, they wanna CRISPR out PCSK9, not necessarily initially in everybody, but they, uh, you know, he believes that if you could did that you'd eradicate this disease. Uh, I don't totally agree with him, actually. I, uh, 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 l- extreme to be able to, to solve for this problem, and could you apply that solution to everybody, you know, feasibly and worldwide? That's his problem to think about, not mine.

    17. PAPeter Attia1:01:24

        That's an, that's a, it's a very, and, and I'm gonna, I th- I, yeah, I, I, I, I'd love to have Seth on to talk about many of these things.

11. 1:01:31 – 1:04:00

    The fat attenuation index (FAI) & other ways to measure inflammation in a plaque

    1. PAPeter Attia1:01:31

       Um, okay, so let's talk about two other things before we leave CTA. Um, there's the fat attenuation index, FAI. What is, what is that exactly?

    2. EWEthan Weiss1:01:42

       I actually, I'm gonna be totally honest, I have no idea.

    3. PAPeter Attia1:01:44

       [laughs] Okay.

    4. EWEthan Weiss1:01:47

       I don't have any idea.

    5. PAPeter Attia1:01:47

       You've seen it, I assume? It's been, it's been presented to you.

    6. EWEthan Weiss1:01:49

       Maybe. I guess I sort of have learned in now doing this for as long as I have, right? I mean, 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, um, to some of this stuff, just 'cause it, it's something new every, like few weeks. It's been that way, like consistently. Um, so 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, that the idea?

    7. PAPeter Attia1:02:27

       Uh, no, it looks, um, uh, and I'm not an expert in this-

    8. EWEthan Weiss1:02:30

       Yeah

    9. PAPeter Attia1:02:30

       ... I was hoping you were. So, so it basically-

    10. EWEthan Weiss1:02:32

        Yeah [laughs]

    11. PAPeter Attia1:02:32

        ... it is a CTA bolt-on-

    12. EWEthan Weiss1:02:33

        Yeah

    13. PAPeter Attia1:02:33

        ... just like the FFR is.

    14. EWEthan Weiss1:02:35

        Yeah.

    15. PAPeter Attia1:02:35

        But it looks at the characteristics of the fat-

    16. EWEthan Weiss1:02:38

        Yeah

    17. PAPeter Attia1:02:38

        ... around the plaque. Um, yeah-

    18. EWEthan Weiss1:02:41

        Wow

    19. PAPeter Attia1:02:41

        ... so it's not trying to predict vulnerability per se, it's actually trying to predict how much inflammation is in-

    20. EWEthan Weiss1:02:48

        Ah

    21. PAPeter Attia1:02:48

        ... I hope I'm getting this right, but I think it's looking for how much inflammation is around the plaque.

    22. EWEthan Weiss1:02:52

        I see. That, that's interesting. Uh, that's interesting. I, I don't, I'm not familiar. I am familiar with PET/CT. You know, we, the, uh, the amount of it 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, if they can have an impact there. Uh, that I don't think has been, being used now clinically, at least to my knowledge, and routinely. Uh, I don't, I'm not familiar with the fat attenuation index. It kinda makes sense, so it's ep- it's epicardial fat, not-

    23. PAPeter Attia1:03:37

        That's right.

    24. EWEthan Weiss1:03:37

        Yeah. Okay.

    25. PAPeter Attia1:03:39

        Yeah.

    26. EWEthan Weiss1:03:39

        Yeah. I mean, it's an interesting idea, right? I mean, epicardial fat is visceral fat, and there's, uh, it probably does impact risk in some way. Again, what are you gonna do with that information? You're already pulling all the levers. Uh, I guess maybe you'd focus a little bit more on metabolic stuff-

    27. PAPeter Attia1:03:57

        Yeah

    28. EWEthan Weiss1:03:57

        ... I guess.

    29. PAPeter Attia1:03:58

        Which w- which we'll come back to.

12. 1:04:00 – 1:10:54

    Statins & exercise may increase the risk of calcification, but what does this mean for risk?

    1. PAPeter Attia1:04:00

       Okay.

    2. EWEthan Weiss1:04:00

       Yeah.

    3. PAPeter Attia1:04:00

       Let's now, let's pivot to another topic that seems to come up from time to time, um, online, I guess, which is are there subsets of people who, 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, um, the fact that certain athletes, you know, 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. What, h- how robust are those data? And more importantly, what does it mean?

    4. EWEthan Weiss1:04:46

       Yeah. Well, I think it's plausible. I mean, we know that s- sort of increasing sheer forces acro- uh, you know, across an end- 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 ex- 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, and it makes sense and is plausible, as dangerous as that word is. Uh, I think the same thing could be true in, in a coronary, uh, artery vascular bed, that increasing sheer, as you would expect to by increasing flow as you would during ex- extreme exercise, could potentially, uh, lead to some damage and therefore calcification. So I do think it's plausible. Uh, I guess I don't, I still don't think... 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 with, in 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. Uh, and, uh, I do find myself getting tied up in trying to explain it, and I can make up explanations like, you know, what you're doing is healing the plaque and stabilizing the plaque, which we think statins are doing, and that that's a good thing and not a bad thing. But I think that 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, uh, we don't have the flip side, right? We don't have the, you know, 40 years of, of really rigorous randomized trials- Showing that some e- exercise versus some version of placebo does that. Uh, would I say don't exercise? Absolutely not. Would I sell- tell some patients not to exercise to that extreme level? I don't know, I'm on the fence there.

    5. PAPeter Attia1:06:53

       And, and the question is, what's the be- So, so each... Let's just assume that it is the case that high, high amounts of cardiorespiratory fitness come at the expense of some endothelial damage. Again, I, I don't know if it's true, but I agree with you.

    6. EWEthan Weiss1:07:08

       Right.

    7. PAPeter Attia1:07:09

       Um, 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.

    8. EWEthan Weiss1:07:36

       Yeah.

    9. PAPeter Attia1:07:36

       But is that risk more or less than the benefit that they gain going from the 25-

    10. EWEthan Weiss1:07:41

        Yeah

    11. PAPeter Attia1:07:41

        ... or 50 to the 100 met hours a week of exercise? Um, in, 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, right? Obviously-

    12. EWEthan Weiss1:07:55

        Yeah

    13. PAPeter Attia1:07:55

        ... smoking more, having higher blood pressure-

    14. EWEthan Weiss1:07:57

        Sure

    15. PAPeter Attia1:07:57

        ... having worse lipids. Uh, but the correction of that moves in the same direction as the correction of the, of the calcification works in the same direction of the, of the, as the calcification of, uh, uh, works in the same direction as the improvement of the risk modifier, which like I said, is not the same. Um, 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. The, the-

    16. EWEthan Weiss1:08:25

        That's right, and-

    17. PAPeter Attia1:08:25

        I've, I've yet to see an exception to that rule-

    18. EWEthan Weiss1:08:27

        That discordance, I think-

    19. PAPeter Attia1:08:27

        ... in terms of cardiovascular health

    20. EWEthan Weiss1:08:29

        ... I, I agree with you, and I think that discordance is only mimicked by the statin story, right? Where-

    21. PAPeter Attia1:08:34

        Yeah

    22. EWEthan Weiss1:08:34

        ... we know more statins are, are better and, and also lead to more calcium. Look, here's the thing. If you put it back into sort of the terms and the context of a patient comes to me and says, "Hey, I got this calcium score of whatever, let's call it eight hun- I don't know, whatever you wanna call it, five hundred, three hundred, two hundred, one hundred. Uh, but I, I, I don't think it means anything because I exercise a lot." Like that's the quest- right, that's the question that gets presented to us sort of at an individual level. And I guess what I'm saying is that I'm not yet comfortable saying, "Oh, don't worry about that." Whereas I am comfortable saying, "Don't worry about that," if it's because they're on a statin. And so what I would say to that patient is, "We have to assume that that calcium is representative of, of plaques in the arteries, and that having plaques in the arteries is a bad thing, and 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." Uh, because, you know, I don't know any evidence that this calcification is not plaque related, that it's somehow extravascular calcification or it's beyond the, it's in the intima or something, uh, or media, I guess. But, uh, 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, uh, 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 it, all the calcium is sort of extravascular somewhere else, then sure, I'd, I'd be okay with that. But that if we do it and we see plaque, I'm not, I'm not aware of any data that would say, "Let's not treat you." Which is sort of the subtle but important difference between the statin story because the people [chuckles] on statins are already by definition on the ther- on the risk reducing therapy that's been shown to save lives. So like it's, uh, it's not like what are you gonna do to that person because their calcium score is higher. You know, would you be more aggressive, I guess, is one question people might ask. But I think it's a little bit of that's the difference, is that there's that leverage still to pull in the exercised person who's statin naive.

13. 1:10:54 – 1:17:07

    The root cause of statin hesitation

    1. PAPeter Attia1:10:54

       So what percentage of your patients take statins?

    2. EWEthan Weiss1:10:59

       I mean, it's a completely r- uh, biased group of people 'cause it's all self-selected.

    3. PAPeter Attia1:11:04

       Of course, of course.

    4. EWEthan Weiss1:11:04

       But they're-

    5. PAPeter Attia1:11:05

       Yeah, yeah

    6. EWEthan Weiss1:11:05

       ... uh, ninety, I'm guessing. Ninety, ninety-five maybe.

    7. PAPeter Attia1:11:09

       And is the implication that the five to ten percent who don't, um, have, have some side effect that they aren't able to tolerate?

    8. EWEthan Weiss1:11:17

       Uh, there, there's those for sure, although I think that's less frequent now because... Uh, would you say statin or any other, like, or PCSK9 inhibitor? 'Cause I do have a few patients who can't tolerate-

    9. PAPeter Attia1:11:29

       No, I would, I would just say statin to start 'cause w-

    10. EWEthan Weiss1:11:31

        Uh

    11. PAPeter Attia1:11:31

        ... what, what I wanna sort of explore for a moment is what, what are the real world implications of the use of these drugs? What are the real world side effects? What are the real world, um-

    12. EWEthan Weiss1:11:42

        Right

    13. PAPeter Attia1:11:42

        ... conditions that prevent people from being maximally, uh, medically treated?

    14. EWEthan Weiss1:11:48

        Small number of pat- patients of mine who don't take them because of true side effects. A equally, maybe even slightly larger group of patients who don't take them because they're afraid of them. And, uh, and I, 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, twenty-five or thirty years, and it's been very successful, and people are terrified of statins. And, uh, you know, I mean, there have been documentaries made on how statins are poison 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. And so that is a, I do spend a lot of time with patients who come to see me because I have some openness to at least having that conversation with them, and I'm not gonna force them. I have a f- patient of mine who, uh, came to see me with a tremendous amount of skepticism, had every risk factor, and was probably having angina when he first came to see me, and I recommended that he start taking a statin. That first day and he was afraid to because of stuff that he'd read about how dangerous they were. He ended up, needless to say, a few months later in the ER with an acute MI and, uh, 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. I mean, some, some people I, I've seen for years, I've had the same conversation year after year after year after year, and some people never change their mind. Some people change their minds because of other things happening, like this patient having an MI, and some people change their minds 'cause finally they are convinced, but I never force it.

    15. PAPeter Attia1:13:35

        What's the, what's the core belief that's at the root of the, of the fear you think? Uh, I mean, again, and I say this just acknowledging that, yeah, probably about 5% of patients are going to experience muscle side effects that are gonna warrant-

    16. EWEthan Weiss1:13:48

        Yeah

    17. PAPeter Attia1:13:48

        ... not taking a statin because it's gonna impede in their quality of life, and that, you know. But so if you just acknowledge unemotionally that there are side effects, you're gonna see transaminase elevations that are just too much-

    18. EWEthan Weiss1:13:58

        Right

    19. PAPeter Attia1:13:58

        ... especially if mixed with Zetia. Um, but if you, if you acknowledge all of those things, there's, there's obviously some deeper-seated fear in something that can't be seen or measured or quantified. W- where do you think that comes from? Uh, why don't we see that with, with other classes of drugs to the same extent?

    20. EWEthan Weiss1:14:15

        I think we do. I just think this happens to be, you know, one of the most prescribed classes of drugs in the history of, of humankind, and so it's just the denominator is bigger.

    21. PAPeter Attia1:14:24

        Mm.

    22. EWEthan Weiss1:14:25

        I think this is sort of the same thing that gets at a lot of skepticism around science and big pharma and, you know, I mean, there's a whole world of people out there with these, like, vast conspiracy theories about, about the development of statins and, you know, about how Roy Collins is an evil, you know, person and, you know, he's engineered this whole conspiracy to try to get the whole world on these poisons. And I mean, there, there are people out there who really believe that and, and look, 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, 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, to young mothers who were worried about giving their kids MMR vaccines or whatever, you know, any other... I think it's very easy to convince people to be scared of something. It's a lot harder to make people un-scared [laughs] of something.

    23. PAPeter Attia1:15:22

        Yeah.

    24. EWEthan Weiss1:15:23

        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. They're, for whatever reason, very skeptical of, of big science and big pharma, and don't let... get me wrong, obviously, there are thing, 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. Uh, you know, the, the sad thing about how demonized statins have been is that the... it's one of the most profoundly important interventions that we have in modern medicine, and it's, it's astonishing to me that, like, this is being compared effectively to, to smoking, right? To cigarette companies.

    25. PAPeter Attia1:16:05

        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, um, uh, it's, again, it's, uh, th- there's no question that Purdue Pharma is indeed evil, and, uh, again, I've said this before on the podcast, I think it's really difficult for, 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-

    26. EWEthan Weiss1:16:38

        That's right

    27. PAPeter Attia1:16:38

        ... uh, you know, um, that, that, that seems to be true across the board. That seems to be true of every person as well, right? [laughs] Any given individual can do something good and something bad. Um, the exceptions would be those that are universally good or universally bad-

    28. EWEthan Weiss1:16:52

        That's right

    29. PAPeter Attia1:16:52

        ... as people, right, so.

    30. EWEthan Weiss1:16:54

        Yeah. No, I mean, I think, you know, there are people out there who just are clearly bad and-
14. 1:17:07 – 1:28:59

    Importance of keeping blood pressure in check, defining what’s normal, & whether we should just accept higher blood pressure with age

    1. PAPeter Attia1:17:08

       okay, let's, let's talk about blood pressure 'cause I, I think this is one of those areas that I've personally become more and more interested in over the past year. Um, and it's actually become more of a concern to me maybe over the past two years through the lens of the kidney. So we have this organ that just doesn't get much attention. I, I'm trying to think. Outside of my podcast with Chris Sonnaday where we talked about kidney and liver transplantation, I don't think I've got a single podcast that deals with the kidney. Um, and it's a really special organ, and I sort of explain 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 wanna live an extra 10 years. That's the way you wanna think about it. You wanna think about that in terms of your mind, you wanna think about that in terms of your body, you wanna think about that in terms of your coronary arteries, you wanna think about it in terms of your bone density, but you gotta 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, uh, uh, creatinine. Um, 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. Uh, it's far from good enough. And The kidney is not uniquely but exquisitely sensitive to high blood pressure. Um, a-again, I'm, I'm not a nephrologist and I never really [chuckles] ... 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. Um, and I suspect just like the heart and the brain, it's very sensitive to pressure. Um, and so that really is the lens through which I think about this first and foremost with, with the... m-meaning even the slightest amount of elevation in, in, uh, blood pressure is going to interfere with long-term kidney health and also with heart and brain health. So, so really there's a win across the board if we just normalize blood pressure. So I-I'll pause at that and, and, and have you just kind of explain from the, um, ASCVD perspective the importance of blood pressure and how it stacks up with smoking, apoB, and some of the other heavy-hitting risk factors.

    2. EWEthan Weiss1:19:55

       Yeah. So I, I, I guess I, I just want to acknowledge th-how strongly I agree with you about the neglect, how much we neglect the kidney as an organ and nephrology as a subspecialty of medicine. Uh, I actually used to give, uh, 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, uh, had been at Hopkins when I was a medical student, was my advisor, very interesting woman who's now retired named Jean Mo- Jean Olson. And she, she and I 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 in regulating blood pressure in that, you know, in giving that lecture with her for however many years it was, 10 years. Um, so it's, it's, uh, it's both an important cause of blood pressure and in fact I think if you go back and look at, um, you know, Rick Lifton, who's sort of one of the premier human geneticists in, in, you know, history, member of the National Academy, and at some point probably should win a Nobel Prize, he characterized all of the single gene mutations that lead to extreme increases or decreases in blood pressure. Uh, you know, I think at the time, and this is 20 years ago, there were, there were like, you know, 10 each, 10, 10 single gene-

    3. PAPeter Attia1:21:13

       Mm-hmm

    4. EWEthan Weiss1:21:13

       ... mutations that led to people who had sort of 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 like nine or whatever it is, 19 out of 20 of these things were located in the same location in the, uh, in the proximal collecting duct or in the tubule. It was, it was like you couldn't have picked a place-

    5. PAPeter Attia1:21:38

       Wow

    6. EWEthan Weiss1:21:38

       ... that was more important evolutionarily for how we handle volume and, uh, and salt and solutes. So, uh, it's an incredibly important organ both as a cause of high blood pressure and also as a consequence. And, and those experiments, you know, Jean showed these beautiful slides and I, I'll send along sometime, you know, pictures of what happens to, to your kidney after it's exposed to low- increased levels of blood pressure over time. So, um, it, it was interesting 'cause I was giving this lecture as a cardiologist during the kidney block. I always felt, I felt out of place.

    7. PAPeter Attia1:22:16

       So most people kind of know that when they go to their doctor and they get their blood pressure checked, normal is about 120 over 80 millimeters of mercury. Um, what do we know about how much that changes in a healthy person across the course of the day? Uh, so when they're sleeping, when they're ambulatory and walking around but not under stress, i.e. not exercising, when they are exercising vigorously, when they're, you know, under stress, ph-physiologic stress, psychological stress, uh, all of these different things that we do every single day, surely our blood pressure must change and yet most of us, myself included, have virtually no idea of how our blood pressure is changing under those situations even if under perfect optimal conditions, i.e. sitting down, legs uncrossed for five minutes, it reads 120 over 80. So what do we know about the rest of the time?

    8. EWEthan Weiss1:23:21

       So I guess it's, it-- we don't-- I don't want to get too distracted, but I, I think it's fascinating. I've thought about this a lot and the question of what's normal is, you know, 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, is the best example of an outlier species with-

    9. PAPeter Attia1:23:42

       Mm-hmm

    10. EWEthan Weiss1:23:42

        ... much higher blood pressure that it needs to have to be able to pump blood up to that very h- that head that's sitting way up high. Um, it is weird to me from an evolutionarily, evolutionary perspective why we would have the same blood pressure as a mouse, right? It's a little tiny creature who walks around on four legs. Why should we have the same blood pressure? It speaks, I think, to the conservation of the sort of 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 over 80 is normal, that that's just normal whether you're, uh, you know, seven, 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. Um, if I had access to my, to that lecture I used to give, I could show you what happens, but, 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 a- healthy aging or is that just a function of pathology? Is it a function of something going wrong over time? To your point, is it something about Decreased kidney function or maybe as an increased vascular stiffness over, over, over time. I think all of those things are possible and prob-probably 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 let-- had sort of had this permissive hypertension in elderly people because we thought, "Well, gosh, they require it. It's just part of the aging process." And it really hasn't been until the past really ten-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, at im-important clinical outcomes? And I think, uh, you know, my take on this now is different than it was fifteen years ago, and that is that one twenty over eighty is normal no matter where you are in life, and that anything above that is abnormal. And, you know, 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 one twenty over eighty as we can without harming you because there are certainly ha- 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, um, you know, hyperkalemia, risk of death. I mean, there's all kinds of potential issues that it's not just a simple intervention like treating LDL or apoB lower and lower and lower where 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 kind of philosophy of how to think about blood pressure is I do think there's now evidence from good clinical trials that one twenty over eighty is normal, and that we should try to get there as best we can without making a mess.

    11. PAPeter Attia1:26:57

        So through that lens, basically we're saying that the amount of float that we see in blood pressure, again, we're all-- we're talking about blood pressure in a very narrow instance, which is seated, resting, et cetera.

    12. EWEthan Weiss1:27:09

        Ah, yeah. Yeah.

    13. PAPeter Attia1:27:10

        We'll come back to the other point.

    14. EWEthan Weiss1:27:11

        Yeah.

    15. PAPeter Attia1:27:11

        But, um, just to build off that, that when that drifts up to one twenty-five, one thirty, one thirty-five, one forty 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 reject-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?

    16. EWEthan Weiss1:27:42

        That's right. We lose muscle mass as we age. Is that something we want to accept and that's normal, or do we want to try to do what we can to preserve the muscle mass that we had at younger in life? And again, I think here the, the crutch that we fall back on and is good, high quality, well done clinical trials, and in this case, we have now have them and it's not just sort of an opinion-based thing that says, "Oh, we'll really get closer to one twenty over eighty." We actually have evidence that being closer to one twenty over eighty impacts mortality and, uh, 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, one forty over ninety, that that leads to an, a significant increase in risk of dying. So to me, I think, uh, we've learned a lot, and I don't, I don't consider it to be a normal function of aging. I think there may be a process. There's pro- obviously a process that goes along with aging, that there's a decrease in function of a lot of different things that le- combines to lead to this increase in blood pressure, but I don't leave it alone.

    17. PAPeter Attia1:28:47

        Okay. Uh, I think that makes sense to me as well. Um, let's, let's ask this second question now, which is the one that vexes me the most,

15. 1:28:59 – 1:45:05

    Blood pressure variability, how to best measure it, & data suggesting the enormous impact of keeping blood pressure down

    1. PAPeter Attia1:28:59

       um, which is how much of a given day... Uh, uh, 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 one twenty over eighty. 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, ninety minutes a day, and when I'm sitting at my desk stressing out over email? How, how, how much variation am I getting?

    2. EWEthan Weiss1:29:42

       Tons. So, you know, it-- the first time I ever got-- 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. Or, I mean, like, you know, there are all kinds of things.

    3. PAPeter Attia1:29:57

       Yeah, yeah, yeah.

    4. EWEthan Weiss1:29:57

       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, and I do all the time. And obviously, when I'm sitting in traffic, my blood pressure is not one twenty over eighty. When my kid, you know, spills coffee all over the computer, it's not one twenty over eighty, right? That when I'm exercising, it's not one twenty over-- There's physiology and there's pathophysiology.

    5. PAPeter Attia1:30:28

       Mm-hmm.

    6. EWEthan Weiss1:30:28

       So physiologically, our blood pressure does go up, and it's meant to go up during some of these cases. It's, it's a function of increased cardiac output, which is one of the components of, of blood pressure. So, uh, I think it's understandable. The question then is what do you do about that relative and sort of how best do you measure blood pressure? And so again, and this is a broken record, I'll just keep doing this, but I fall back on the clinical trials and just as, you know, we try to practice as best we can with some sort of fidelity to the way the trials are done, I go back to sort of how are they measuring blood pressure in these trials, and therefore, how are the decisions made to adjust medications and- How did that influence the, you know, the practice of the trial, and therefore how should that influence our practice? 'Cause those are the outcomes that we look at. So this got a lot of attention. When SPRINT was first published, which was I think twenty fourteen or fifteen, 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, right? That this is just over-medicalizing normal aging, right? Da, da, da, da, da, da. There was a significant at- amount of attention paid on how they actually measured the blood pressure, because it wasn't the way that we typically measure blood pressure, and it was the way that we probably ought to measure blood pressure, but it certainly wasn't the way that we typically measure blood pressure. So if you go back and you look at the da- if 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, you know, sort of, um, best in class at that time, automated cuff. They put the cuff on the person. They had them sit- seated and relaxed in a quiet room by themselves, and they had the blood pressure measured three times, five minutes in between, right? So a total of once, five-minute break, one more, five-minute break, and, 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 m- my point is that that optimal way of bloo- measuring blood pressure, even if it ends up yielding numbers that are lower than our, what we typically get, that led to the result in that trial, which was so spectacular that the trial was stopped early. And this is not [chuckles] to all the, you know, conspiracy theorists out there. This was not a pharma-sponsored, sponsored trial. This was an NIH-sponsored trial, a government-sponsored trial, and was agnostic to different agents, right? I mean, it was not about the, the physicians i- who enrolled patients in the trial had, had access to almost any therapy during that trial. So this was not about sort of proving the, the benefit of one drug over another. This was purely about testing the hypothesis that getting as close to one twenty over eighty rather than letting people sort of float up to one forty over ninety was better or not, and it turned out that it was, with caveats.

    7. PAPeter Attia1:33:36

       So let's, let's talk about that methodology, and then let's talk about the algorithm agents and then the, the potential downsides. So, um, I have started testing my blood pressure six months ago, uh, and the reason for it... So I've-- I shouldn't say that. I have always checked my blood pressure because both my parents have hypertension. I'd always attributed to the fact that I had low blood pressure to the fact that I was super healthy and did all these other things, but I realized, look, there's genetics to this as well. So I'm just gonna start checking my blood pressure every couple of days, and I did. And so for a couple of years, I just 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. You know, probably averaged one ten over seventy was sort of a typical reading of while I was sitting there working. Um, and then something happened in August. It was consistently a little bit higher than that. Not a lot higher, but it was one twenty-five to one thirty, and it was, you know, more or less eighty 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.

    8. EWEthan Weiss1:34:52

       Mm-hmm.

    9. PAPeter Attia1:34:53

       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 one forty over ninety. If I just, you know, was literally doing something, not exercising, but if I was, you know, doing something active, and then I went and sat down, like the equivalent of the guy who shows up from the parking garage, [chuckles] you know?

    10. EWEthan Weiss1:35:39

        Yep.

    11. PAPeter Attia1:35:39

        Just parked the car, had to walk up one flight of stairs, sits down, one forty over ninety. Five minutes later, it's, you know, it's one seventeen over seventy-four. And, you know, I've been in sort of a back-and-forth discussion with my doctor and with my colleagues about is this something I need to care about? Because now, if you look at my spreadsheet and all of my phone data, my blood pressure looks perfectly normal. For the last six months, I've averaged below one twenty over eighty. 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-

    12. EWEthan Weiss1:36:21

        Well-

    13. PAPeter Attia1:36:21

        I know that that's in line with how the SPRINT study was done, and you could argue, "Well, Peter, you're simply-- you're actually doing something that's less extreme than what they did," 'cause they did three measurements over ten minutes. But I think, but deep down, I know my blood pressure's not one twenty over eighty when I'm sitting at my computer, you know, writing, because when I check that blood pressure straight away, it's, it's, it's above that. So I hear your point that it's ok- I mean, 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.

    14. EWEthan Weiss1:36:54

        Yeah, so here's what I would say is I think, uh, sounds like something changed in you, and I think-

    15. PAPeter Attia1:37:02

        Yeah, a book deadline is definitely what changed [chuckles] in August.

    16. EWEthan Weiss1:37:05

        So, so that-

    17. PAPeter Attia1:37:06

        And there's no question that was, that was a change

    18. EWEthan Weiss1:37:07

        Well, so if that's the case, then that's understandable, and that's That's okay. I think, uh, in your case, it sounds like what I was gonna say was if it was truly a change and there was no explanation for it, like a lot of things in medicine, uh, then I probably, uh, would have paid more attention to it even though it was going from what was normal to normal, right? That you just-- But it sounded like something did change, but in this case, it sounds like there is an explanation and that you had the stress in your life from the book. Uh, so I guess the cheating thing reminds me of my daughter, who I think I told you before is, uh, my younger daughter is legally blind and she plays basketball, and we were discussing a potential, uh, this is such a crazy little aside, but I thought I'd tell the story 'cause it's kind of cute. She-- We were discussing a potential procedure she could have to improve her vision, uh, 'cause part of her decrement of visual acuity is that she has pretty bad nystagmus, uh, lateral nystagmus. And the ophthalmologist was saying that if you can sort of make that better, you'll incri- impr- understandably, you'll improve her visual acuity. And that they-- Somebody stumbled onto the idea that if you cut the optic, 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." Uh, it's fascinating how that might happen, but, uh, she said she didn't wanna do it 'cause she was like, "That's cheating." This is a kid who runs around with a, you know, visual acuity of twenty over two hundred and, um, 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. Uh, 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 wanna get a sense, and it would be great to have this over time serially, is to do a twenty-four-hour ambulatory blood pressure monitor to really get a sense of what, what is the average blood pressure you're seeing over a twenty-four-hour period, 'cause there is a difference. When you're sleeping, your blood pressure should be low, right? That's physiology.

    19. PAPeter Attia1:39:11

        Yep.

    20. EWEthan Weiss1:39:11

        When you're out and about and doing these, it's gonna be higher. So what is the, you know, sort of average? And they can quantify all the spikes and it's actually a really nice tool that I'll use in peop- especially in people who have some degree of what's f- you know, commonly termed white coat hypertension, which is kind of what-- I mean, white coat hypertension is real life, right? White coat hypertension is l- living in the real world. Um, so.

    21. PAPeter Attia1:39:33

        So how d- how does a, how does an ambulatory, uh, BP cuff work? Um, it's, it's presumably a cuff that sits on the arm, and then it straps to a device like a halter would.

    22. EWEthan Weiss1:39:44

        I, I actually-- It's funny, I don't think I've ever seen a device. Uh, I've ordered a bunch. Um, I-- 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 sphygmomanometer. So it's a cuff. It's, I think, got a self-incl- I would imagine it's got some, you know, hardware attached to it that tells it to inflate and measure blood pressure just as you would a, with a, one that you have in your office, and it does that once a, a minute or whatever it is over the course of twenty-four hours. So it's constantly inflating, deflating over the course of a, of a day. Patients who have-- mine who've worn them say that after a while you get used to it and just you can ignore it. It seems to me like it would be really annoying to have this thing, like, inflating and deflating all the time, but that's what it is. What it does, though, is it buys, it buys you sort of a, a, a distraction from real life. It buys you sort of when you're not thinking about things, when you're clearly not stressed or you shouldn't be stressed, i.e. when you're sleeping, um, what is your blood pressure? And we know that blood pressure, that hypertension during sleep is abnormal. It's the-- It should really be a time when your blood pressure is the lowest. So it's just a to- 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 a, you know, ten or thirty second interval in a twenty-four-hour day, but that we do that, you know, on average, you know, once or twice a year and th- that we assume that this very variable number is actually meaningful, and it's, uh, remarkable to me that it has been even meaningful the way that we've been measuring it, um, because it is such a poor sample.

    23. PAPeter Attia1:41:25

        I mean, we, we, we, in our patients, we'll, 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, you know, if we have reason to believe that that suspect will do it more, and yet-- 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, you know, supposedly measuring blood pressure, like little wrist-based devices.

    24. EWEthan Weiss1:41:56

        Yeah.

    25. PAPeter Attia1:41:56

        I've never found them to work. Is there anything on the horizon that's, that's, uh, that's closing the gap on that?

    26. EWEthan Weiss1:42:03

        You'd think so. Uh, you know, there was a period of time where people were using a cell phone camera, and you could press your finger on the camera, and then it could basically detect the pulsation. It could almost calculate a, uh, you know, a pulse wave-

    27. PAPeter Attia1:42:18

        Hmm

    28. EWEthan Weiss1:42:18

        ... and it could give you a sort of imputed systolic and diastolic blood pressure. That never made it. Obviously, we don't, 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 a interesting question. I'd-- You'd have to think that at some point, even if it's an intravascular device, that you could put a miniature device, you know, much like, you know, we're now using, uh, I don't know how much you use them, but I use them a lot, these, uh, uh, 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 a, into an artery safely that you could leave there for some period of time. It feels like that's gonna come, but I haven't seen it. And then noninvasively would be amazing, but I just, again, haven't seen it, so.

    29. PAPeter Attia1:43:12

        Yeah. It's, uh, you know, I, I-- 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. Um, in other words, you could, I think, much more easily get by with just spot checks of glucose than you can with just spot checks of, of blood pressure. To have a true continuous, uh, ambulatory BP monitor, I mean, that, 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.

    30. EWEthan Weiss1:43:47

        I d- I agree with you. I think that said, the intervention that was used in SPRINT still showed a remarkable benefit and so we can exist with the tools we have.
16. 1:45:05 – 1:48:27

    Drugs for treating high blood pressure recommended by the ALLHAT trial

    1. PAPeter Attia1:45:05

       So let's go back to SPRINT. This was, th- this trial was drug agnostic, right? Is this the one-

    2. EWEthan Weiss1:45:11

       Correct

    3. PAPeter Attia1:45:11

       ... that basically said, you know, start with a thiazide, move to a calcium channel blocker and then an ACE or vice versa?

    4. EWEthan Weiss1:45:19

       No. That, uh... Actually, I don't remember the algorithm for SPRINT, but I, I think it was relatively agnostic. So 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-

    5. PAPeter Attia1:45:37

       Okay

    6. EWEthan Weiss1:45:37

       ... two of which were discontin- so I believe it was calcium channel blockers, uh, ACE inhibitors and the calcium channel blocker at the time was, uh, amlodipine. ACE inhibitors, diuretics, thiazide diuretics or chlorthalidone, um, beta blockers and, uh, I don't remember what it was. Oh, it was alpha. Uh, uh, it was, it was a, uh, alpha agonist. Um, so, 'cause at the time they were being used for blood pressure and both the alphas and the betas were stopped early 'cause they were harmful. And so what the result of that trial was that using any of the other three classes was first line in primary hypertension, treatment of primary hypertension. So calcium channel-

    7. PAPeter Attia1:46:19

       And that was lisinopril, amlodipine and a thiazide, correct?

    8. EWEthan Weiss1:46:23

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

    9. PAPeter Attia1:46:37

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

    10. EWEthan Weiss1:46:44

        Yeah, no real differences. Yeah. Yeah.

    11. PAPeter Attia1:46:46

        And, and then it, it-

    12. EWEthan Weiss1:46:46

        No real dif- I think there were maybe some stroke if I... It's been like so long since I've reviewed it, but I think there might have been like 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 if you need more, you add another.

    13. PAPeter Attia1:47:04

        And the target was 120 over 80.

    14. EWEthan Weiss1:47:07

        Well, that was... Yeah. I mean, it was the target. Uh, it certainly wasn't a... The emphasis was not... The definitions definitely changed, right? 'Cause there was this sort of category in, I don't remember which JNC, so you know. I think it was JNC-6 or something there was, there was a category for normal... Ah, that's right. So it was normal was actually 120 to 130-

    15. PAPeter Attia1:47:38

        Mm

    16. EWEthan Weiss1:47:38

        ... 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 one, two and three. So then when they redid it in JNC-7 it was normal was less than 120 over 80. Pre-hypertension was then at 120 to 140 and hypertension was then above 140 over 90. That was the, that was the difference in between JNC s- seven and JNC s- six. Um, JNC-8 I believe, uh, gosh, I can't remember what happened. There was some controversy and then they stopped after that. There was like basically they had... And, and NHLBI said, "We can't do this anymore," 'cause there was too much controversy over these.

    17. PAPeter Attia1:48:26

        So

17. 1:48:27 – 1:54:04

    What the SPRINT trial says about the aggressive treatment of hypertension, & the risks of such treatment

    1. PAPeter Attia1:48:27

       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?

    2. EWEthan Weiss1:48:36

       So the impetus was that there were epidemiological observational studies, uh, and I can send you one or two, that showed that it appeared that the risk of, of bad outcomes, mostly coronary, cardiovascular disease, was lower, step function lower in pat- patients who had optimal blood pressure. This is b- you know, according to the old classification, people whose blood pressure was 120 over 80 or less, optimal. And then a small step increase in people who had what was then classified normal and then a large step increase in people who were considered high normal or even early stage hypertension. And so, but this was all observational. It wasn't, you know, there wa- it was-

    3. PAPeter Attia1:49:17

       Mm-hmm

    4. EWEthan Weiss1:49:17

       ... it was not 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 The, 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 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. Uh, clearly people got to the two goals that they were assigned to randomly. It was obviously not blinded 'cause you couldn't be blind to your blood pressure. Uh, but they got to the two goals, so the people assigned to the more aggressive 120 over 80 got to, like, 123 over whatever it was, 82, and the people into that 140 over 90 were more like 137. You can look at the, the curves in the New England Journal paper, and they separated beautifully. And then they-

    5. PAPeter Attia1:50:13

       Yeah, I think it was 121 versus 136.

    6. EWEthan Weiss1:50:16

       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, right? I mean, it would be silly to, to just completely dismiss this. There were real issues, right? There was a g- greater increase in the risk of falls and syncope, and I think even in the risk of significant kidney dysfunction. It was all reversible, but it was all there. And so what we took away or what I took away from that trial was it looks like you get a mortality benefit for getting closer to 120 over 80, so let's get there if we can without creating one of these problems. So obviously if you're falling all over the place 'cause you're dizzy or if your kidney function deteriorates 'cause your kidneys aren't getting enough blood flow or whatever, something else bad happens, then we're not gonna do that, but we're gonna get you as low as we can, as close to that target as we can without making a mess.

    7. PAPeter Attia1:51:37

       Yeah, and I think that's, that's sort of why my doc has been relatively unexcited about doing anything in me, is he, he still remembers a year and a half ago or le- less than that, just over a year ago, when under my normal set of relatively low blood pressure, I stood up in the morning too quickly, fell, face-planted, split my head on the table, um, 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. Um, and so y- understandably, his appetite for trying to correct an average blood pressure of 120 over 78 is pretty low, um, and, and, and I, I'm not, I'm not keen to take any medication either, clearly.

    8. EWEthan Weiss1:52:23

       Well, and, and there is no doubt in blood pressure, unlike in, in cholesterol, if we want to go back, there is a U-shaped curve, right? But too low is definitely bad, and, uh, I think your body was telling you that your blood pressure's probably right about where it ought to be and maybe even a tad too low. Maybe you're just, like, s- a little dehydrated in the morning or have some orthostasis, but it, it sounds like your doctor made the right decision in you. I don't think there's any evidence that I'm aware of that treating you to below 120 over 80 is advantageous.

    9. PAPeter Attia1:52:56

       No, it was more just my question was should we treat such that I never have a reading above 120 over 80? You know?

    10. EWEthan Weiss1:53:03

        Yeah.

    11. PAPeter Attia1:53:03

        And again, I, I think that's probably too aggressive, um, based on these, based on these side effects.

    12. EWEthan Weiss1:53:10

        Well, and I don't think it's even feasible. Um-

    13. PAPeter Attia1:53:12

        Yeah

    14. EWEthan Weiss1:53:12

        ... I mean, the way you exercise, I would be shocked. There's just no way. I would imagine if you wore a 24-hour ambulatory blood pressure, when you're exercising, especially doing, you know, isometric, you know, resistance training, your blood pressure's gonna go way up.

    15. PAPeter Attia1:53:23

        Yeah, yeah. No, actually I, I think that's a great idea. I, I, I, I've, I've, I've wasted a little bit of time in the last, uh, 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 [laughs] uh, low-tech way.

    16. EWEthan Weiss1:53:43

        If some smart engineer out there wants to figure out a great, important thing to work on, this is definitely at or near the top of my list in terms of things that haven't been solved.

    17. PAPeter Attia1:53:53

        I, I would agree. I, I would, I would-

    18. EWEthan Weiss1:53:55

        So go for it

    19. PAPeter Attia1:53:56

        ... I would completely agree.

    20. EWEthan Weiss1:53:56

        It would be great. Right, as you're, as you say that there isn't really anything now other than the old-school [laughs] fashioned sphygmomanometer just attached to your arm.

18. 1:54:04 – 2:03:06

    Confirmatory results in the STEP trial for blood pressure, & how Ethan uses the various drugs to lower blood pressure in patients

    1. PAPeter Attia1:54:04

       Yeah.

    2. EWEthan Weiss1:54:04

       So.

    3. PAPeter Attia1:54:05

       So, so what about the STEP trial last year? Did that, did that sharpen our thinking at all?

    4. EWEthan Weiss1:54:09

       I think it just assuaged any fears that people had that there was something unusual in that SPRINT, and of course, there was this concern over the trial being stopped early, which, you know, does r- risk, you know, does risk a, a, what is it? A type... You know this stuff better than I do. But it does risk the possibility that the result-

    5. PAPeter Attia1:54:30

       Yeah

    6. EWEthan Weiss1:54:30

       ... was spurious.

    7. PAPeter Attia1:54:31

       Yeah.

    8. EWEthan Weiss1:54:31

       Um, so I think STEP does sort of, is a nice confirmation that-

    9. PAPeter Attia1:54:34

       'Cause, 'cause I think that, um, I think SPRINT was stopped at, like, three and a quarter or something, three and a half maybe.

    10. EWEthan Weiss1:54:40

        Yeah.

    11. PAPeter Attia1:54:40

        Something like that, right?

    12. EWEthan Weiss1:54:41

        It was, it was definitely stopped early, and again, that was because... And it was pre-specified and there was a DSMB and the whole deal, uh, and again, it wasn't industry that stopped it. It was, it was the government that stopped it, and, um, because of overwhelming benefit. And, you know, you could have made the argument to keep going. A lot of people did. Um, 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 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. Uh, 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 [laughs] with all of the things that you did or didn't do correctly. So I think The, what I took away from STEP was that it was a nice confirmation that, that SPRINT was probably not spurious, that the result from SPRINT was real and robust and repeatable.

    13. PAPeter Attia1:55:44

        I think the other thing STEP had going for it over SPRINT is it included patients with type 2 diabetes, which I, I believe-

    14. EWEthan Weiss1:55:49

        Yep

    15. PAPeter Attia1:55:49

        ... were excluded. So you, you had a longer trial, you had a more representative population. Um, and yeah, I, I, again, so I'll tell you, and, and we can leave this after we're done with this 'cause I wanna 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 ag- agnostic.

    16. EWEthan Weiss1:56:17

        Yeah.

    17. PAPeter Attia1:56:18

        And, and yet I still, when I'm hanging out at the bars at night talking to... No, I'm kidding. Uh, you, this is not bar discussion, but-

    18. EWEthan Weiss1:56:25

        I was gonna say that.

    19. PAPeter Attia1:56:25

        [laughs] Um, you hear this little bit of-

    20. EWEthan Weiss1:56:28

        Is there something I need to know?

    21. PAPeter Attia1:56:29

        ... you know, ARB versus ACE versus calcium channel blocker and, and, 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 so that, you know, they can all- they can get everybody down to 120 over 80, and they can – the symptoms and side effects become non-issue, and each of those will have a slightly different set of symptoms we know. Do we have one reason to pres- to, to, to prefer one over the other, for example, when it comes to renal protection?

    22. EWEthan Weiss1:57:10

        Uh, okay, so 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 wanna try to optimize-

    23. PAPeter Attia1:57:26

        Mm-hmm

    24. EWEthan Weiss1:57:26

        ... and find out what the right, you know, combination of things is for you, given your other circumstances, uh, the NIH used to use this term extenuating or special circumstances. You know, for example, if somebody had angina, even though beta blockers were no longer first line for treating a primary hypertension, if you had angina, you'd have- you'd include the use of a beta blocker in that hypertensive regimen. It was really an antianginal, but you know, it lowered blood pressure. So I think the first step-

    25. PAPeter Attia1:57:53

        Yeah

    26. EWEthan Weiss1:57:53

        ... is just get to goal. Uh, th- I do tend to, to do things differently in some contexts, so age to me has a big deal, um, in both directions, right? 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, right, is, is there too. Um, so while I think if I had to pick my favorite agent who I- that I think probably among the three classes is the best at managing sort of all comers of, of high blood pressure, it would be chlorthalidone or a thiazide diuretic. I don't use it as much just because it's harder to use.

    27. PAPeter Attia1:58:41

        Mm.

    28. EWEthan Weiss1:58:42

        I think, um, amlodipine is a great drug because it's the 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 r- r- amount of, of, of what's cur- considered to be, um, 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. Um, w- 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, there are data I think that, that do suggest that those drugs may be more indicated in certain subpopulations. So for example, there was the HOPE trial, right? Which was, um, I think, you know, mid-2000s.

    29. PAPeter Attia1:59:40

        Yep.

    30. EWEthan Weiss1:59:40

        Uh, and so it suggested there may be a benefit in people that have atherosclerotic coronary disease to have, to have an ACE inhibitor on board. Um, so maybe in people with, with, uh, you know, with ASCVD or ASCVD risk, I'll use that one over the others as a first line. It's also, you know, there's the whole ARB and, and aortic diameter thing, right? So in people who may have a little, um, you know, increase, whether you wanna call it an, uh, an aneurysm, but just an increase in aor- in aortic size, that there may be a benefit to ARBs. Um, you can start, begin to weave together all these little things. I, I like ACE inhibitors and ARBs probably the best. They do require monitoring, right? So they do require that you get, you know, electrolytes 'cause there can be, in some patients, there can be issues, especially with, with potassium. Um, and they can impact kidney function. So it's this weird thing where, uh, 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 or ARB first line is in patients with diabetes 'cause that's been shown to p- they've been shown to reduce the progression to diabetic nephropathy again and again. So I think if-
19. 2:03:06 – 2:08:50

    The role metabolic health in ASCVD

    1. PAPeter Attia2:03:06

       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. Um, I generally tell my patients that there are four big pillars of risk in ASCVD: uh, smoking, hypertension, apoB, and metabolic health. And that last one is kinda squirrely 'cause, you know, 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. Um, but here I talk about the sources of fat that exist outside of your subcutaneous, uh, you know, uh, depots of fat. And I typically talk about five of them, but I, I know you tend to focus on a couple, so I wanna double-click on those. But just for folks listening, right? I think the generally accepted principle of this is we as a species, um, one of our remarkable advantages in evolution was our ability to store energy, uh, th- 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 kinda liken this to a bathtub. Everybody has a different size bathtub. Um, and you, the water coming in the bathtub is how much you're eating, and the water leaving through the drain is how much energy you're expending. And if you're accumulating fat, you are, you know, obviously, uh, 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, you know, 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, right? Ask anybody who's gone through a leaking, uh, a leak in their house. So you can, you might have 100 gallons in the bathtub. If two gallons escape in the wrong place, it can be a disaster. And so talk about the places where it escapes, so around the viscera, uh, within the muscle itself, in the pancreas specifically, which we can talk about maybe why that's so problematic, pericardial fat.

    2. EWEthan Weiss2:05:29

       Liver.

    3. PAPeter Attia2:05:29

       Tell us a little bit about why this is so problematic.

    4. EWEthan Weiss2:05:33

       Well, first of all, I'm so incredibly impressed at how you tell that story 'cause it's exactly how we tell the story and, and we learned it from Steve O'Reilly, who I think is the sort of godfather of this concept. Uh, I think we've all appreciated for some time that there's a relationship in terms of risk and weight, that that's imperfect in BMI, right? That their BMI is not a great measure of risk. It is in epidemiology, it is in large populations.

    5. PAPeter Attia2:05:59

       Right.

    6. EWEthan Weiss2:05:59

       We also know that how much fat you carry, so overall adiposity is important, but what, what we've learned really in the past 20 years is that to y- as you've said, that it's not so much even how much fat you have, it's where you carry it, and that, 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 organs, right? That that's a bad thing. Uh, and that has been shown to be a very potent predictor of risk, um, 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 coronary disease and, and diabetes. So, super fascinating area that I'm gonna devote the rest of my life to understanding and trying to, to fix. Uh, 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 ri- why is that rot- why is that so bad? The answer is not one I can give you, but I, we started our sort of process in thinking about this problem, in thinking about extreme, 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 gluteofemoral and subcutaneous regions in the legs, so they, they have a selective loss of adipose tissue in their, 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. Um, and those people have tremendous metabolic disease and extraordinary levels of risk, right? I mean, they're small numbers of people, they have rare diseases, and all of these studies are observational, but There's, uh, there's a, you know, beautiful paper from, from Canada from 20 years ago showing that people born with these sort of congenital, uh, 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, and, uh, uh, you know, s- in women. So, uh, I think the question of why that is remains unanswered. I think there are lots of different potential hypotheses. Um, you know, I think the role of insulin and, you know, its impact on different organs and tissues and cells is, is interesting. We don't have an answer yet.

20. 2:08:50 – 2:24:54

    The impact of fat storage capacity & location on metabolic health & CAD

    1. EWEthan Weiss2:08:50

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

    2. PAPeter Attia2:09:57

       Yeah, I, 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, I mean, I s- 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, uh, is, is, is so improperly understood. Um, and I don't think we're identifying people at risk because, I mean, I think about how little I know about my own state here. I mean, I, you know, 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 l- my, you know, my transaminases are adequate, so I kind of assume, and based on last test, no liver fat. But I don't... Other than that, it's a real blind spot, right? I mean, I don't have the clarity that, that I would have about my apoB, for example, or my blood pressure.

    3. EWEthan Weiss2:10:58

       And that, and that's, I think, because we're sort of increasing our very poor resolution of this problem, starting it with, like, the most blunt tool of all, which is BMI, and then moving to other things.

    4. PAPeter Attia2:11:07

       Yeah.

    5. EWEthan Weiss2:11:07

       And even what you just said, I think it still represents probably a very low resolution image into this, right? Just focusing on VAT. Uh, we know that's bad, but... So here's a question, right? Uh, just a thought experiment is what is, is the problem with VAT, is that a defect in the ability to store fat where it should be stored in the gluteofemoral depot, and is that just a manifestation of that or is there something different about VAT? Is there truly a benefit to having more fat in the gluteofemoral? So in other words-

    6. PAPeter Attia2:11:36

       Yeah

    7. EWEthan Weiss2:11:36

       ... to your bathtub analogy, if you could make a bigger bathtub-

    8. PAPeter Attia2:11:39

       Yeah

    9. EWEthan Weiss2:11:39

       ... would you be more metabolically healthy?

    10. PAPeter Attia2:11:41

        Well, certainly there's one experiment that Gerald Shulman did that, y- you know, obviously it's a contrived experiment, but it, it would certainly suggest in the model. So he looked at, uh, a mouse model where the mice had profound insulin resistance, and he would just put more and more subcutaneous fat into those mice.

    11. EWEthan Weiss2:11:58

        Yeah.

    12. PAPeter Attia2:11:58

        And they got fatter, and they got less insulin resistance. They-

    13. EWEthan Weiss2:12:01

        Yeah

    14. PAPeter Attia2:12:01

        ... 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, 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?

    15. EWEthan Weiss2:12:22

        Yeah.

    16. PAPeter Attia2:12:22

        Or is it doing something fundamentally different? And-

    17. EWEthan Weiss2:12:24

        Yeah

    18. PAPeter Attia2:12:24

        ... and I think that's where we wanna sort of eventually understand, right? Is, are there cytokines that are coming out of those cells that are different from the cytokines coming out-

    19. EWEthan Weiss2:12:34

        Sure

    20. PAPeter Attia2:12:34

        ... of the other cells? And, and how does that manufacture into-

    21. EWEthan Weiss2:12:36

        Yeah, I mean, there are all kinds of things.

    22. PAPeter Attia2:12:38

        Yeah.

    23. EWEthan Weiss2:12:38

        There are all kinds of things that are, we're learning about the difference in li- basal lipolytic rate between the two, 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 DEXA scan or an MRI. I think, uh-

    24. PAPeter Attia2:12:50

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

    25. EWEthan Weiss2:12:52

        ... it's very low resolution at this time. I think what we can say is that in a patient with lipodystrophy as an extreme who has normal lipids, right, not normal triglycerides, so el- 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 is a group of people, and I've now, as I've been thinking about this, begun to see these people all over and, and once you see them, you can't not see them. But we think there are a group of people here who represent probably some polygenic version of this, where there's a relative decrease in fat in the legs. Like, I can think of patients now who come into my practice who may have a tiny little potbelly, but you know, their lipids were sort of not that bad and their legs are super skinny, and they had a bypass at thirty-eight or forty or forty-one. And the number of people I can think of like that keeps getting bigger and bigger.

    26. PAPeter Attia2:13:45

        Hmm.

    27. EWEthan Weiss2:13:46

        And I think what we're gonna learn is that sort of that gluteofemora- gluteofemoral storage capacity is gonna be an important driver of risk in this, 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. Uh, there is some, you know, very poor evidence, right? 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. And so I think, you know, again, we're just getting at sort of something... It's like Gerry's, you know, experiment of putting in more subcutaneous fat. It's just helping to guide us towards this idea that there's something, there's something there. And I think-

    28. PAPeter Attia2:14:33

        And, and especially where it's-- Oh, go ahead.

    29. EWEthan Weiss2:14:35

        No, no, it's fine.

    30. PAPeter Attia2:14:37

        No, I was just gonna say, where I think it's really gonna be interesting, Ethan, is when you start to look at this in the much larger and less extreme population of those without lipodystrophy. So, so the-

Episode duration: 2:24:54