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

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.340 now, head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.780 here's today's episode. I guess this week is Ethan Weiss. Ethan was a previous guest on episode

00:00:55.220 number 52 way back in May of 2019. At the time, Ethan was a professor of cardiology at UCSF.

00:01:03.680 Now, he still holds a position at UCSF where he focuses on preventative cardiology. But his main

00:01:09.440 job is as an entrepreneur in residence at Third Rock Ventures, where he is working on a project

00:01:14.220 related to cardiometabolic disease, something that we touch on in this episode. He continues to have a

00:01:19.220 small clinical practice in preventative cardiology. And a lot of our discussion really focuses on that.

00:01:23.220 I wanted to have Ethan back on to pick things up where we left off. Over the past couple of years,

00:01:28.320 Ethan and I always stay in touch and exchange emails. And at some point, those emails reach

00:01:32.660 a critical mass where we decide, hey, probably time to bring this discussion to a bunch of listeners,

00:01:38.800 namely you. In this episode, we focus a lot on ASCVD, of course, and we talk about the diagnostic

00:01:44.540 tools available to understand risk. Because I realized that many listeners weren't necessarily

00:01:49.560 listeners back three or four years ago, we go through a pretty good overview of the difference

00:01:55.280 between a CAC and a CTA as diagnostic tools that give us enormous insight into someone's existing

00:02:01.120 and future risk of ASCVD across various different risk factors. We speak about some of the newer

00:02:06.560 versions of the CTAs, which really aren't so much about the CTAs, but are about some of the software

00:02:12.300 overlays that are used to at least theoretically make the CTA more valuable.

00:02:17.160 We talk a little bit about how extreme endurance athletes may or may not be at higher risk for

00:02:24.320 calcification, and we talk about potentially the role of statins in that. We then move on to a

00:02:29.440 discussion about blood pressure. And in reality, I think this is such an important point that this

00:02:33.420 will not be the final word on blood pressure. But it is important to keep in mind that we do pay a lot

00:02:40.240 of attention to lipids on this podcast. And lipids, of course, form part of the holy triad of risk

00:02:46.240 for cardiovascular disease. But the other two things, smoking and blood pressure, are obviously

00:02:51.760 worth mentioning. Now, smoking seems so obvious that it really warrants little attention on a

00:02:56.020 podcast like this. Most of the people tuning into this are quite health conscious. They're generally

00:02:59.980 not smoking. And we have done at least one podcast on smoking cessation. But I think in some ways,

00:03:04.680 the discussion on blood pressure has been a little bit lacking. And that's why I really wanted to have

00:03:09.520 that discussion today. So we talk about the importance of knowing your blood pressure,

00:03:12.820 how to actually check your blood pressure, why high blood pressure is problematic beyond just the

00:03:18.960 heart. And spoiler alert, if you think it's bad for your heart, wait till you see what it does to

00:03:23.780 your kidney. And then we talk about the different pharmaceutical agents out there and the trials

00:03:28.640 that have taught us how these things work and when they should be instituted. Finally, we end the

00:03:33.580 conversation looking at what we know and don't know about how metabolic health plays a role in ASCVD.

00:03:39.700 Because if earlier I mentioned the holy triad of hyperbeta lipoproteinemia, which is just a fancy

00:03:44.960 word for elevated ApoB, smoking and blood pressure, there is still residual risk in people who have

00:03:52.160 perfectly low and normal lipids who don't smoke and have normal blood pressure. That doesn't mean

00:03:56.780 your risk of ASCVD goes to zero. In fact, we know it does not. And in fact, we talk about what that

00:04:02.880 X factor is. What is it about metabolic ill health that drives residual risk in ASCVD? Anyway, this is

00:04:11.300 a fascinating discussion, and I suspect it's only the thin end of the wedge into more exploration

00:04:16.600 into blood pressure and some of the more nuanced cellular metabolic ill effects towards ASCVD. So

00:04:24.120 without further delay, please enjoy my follow-up conversation with Ethan Weiss.

00:04:34.000 All right, Ethan, thanks so much for making time to sit down again. This is round two, although I kind of

00:04:38.580 don't remember when round one was. I think it was 2019, but it might have been 2018, right?

00:04:43.340 I think it was 18, which is just a function of the fact that neither of us can remember tells us how long ago it was.

00:04:49.240 Yeah. Well, that time we spoke in person and we sat in your office at UCSF, but you're sitting in a new

00:04:55.280 office today and we're not in person. But more importantly, where are you sitting today? And

00:04:58.440 there's been a bit of a change in your life in the past year, huh?

00:05:00.940 It's been an evolutionary change over the past couple of years, but I did have sort of a midlife

00:05:05.260 crisis and decided that I didn't envision myself doing the same thing I'd been doing for the prior 25

00:05:10.380 years for the next 25 years, if I should be lucky enough to be around in 25 years. And I was given the

00:05:16.020 opportunity to get involved with a local group of investors who create biotech companies and they

00:05:22.260 asked me to help them conceive and eventually they started a new biotech company. So I closed my lab

00:05:28.100 and have become a volunteer clinical faculty at UCSF and see patients infrequently and spend most of my

00:05:35.260 time over here working to build this new company that I can at least tell you a little bit about later

00:05:41.360 on. I know we're going to talk about some of the science that the company is interested in because

00:05:46.500 it factors in directly to what we wanted to talk about today. So there will be a chance to talk

00:05:51.120 about that for sure. But in some ways, this podcast is really just a compilation of our email exchanges

00:05:58.640 over the past couple of years. And so I think at some point we said, we should just do another

00:06:02.480 podcast because we keep emailing each other about these things. And I suspect as is often the case,

00:06:06.340 there's value in sharing what it is that we talk about with others. So let's just start with a quick

00:06:12.620 recap of what a calcium score is. And then we'll follow that up by what a CT angiogram is, because

00:06:18.540 I think those two need to be understood to understand much of what we'll talk about in the

00:06:22.940 next God knows how long. We talked about this the last time. I think I do remember that we spent a lot

00:06:27.180 of time talking about the distinction between calcium scanning and CT angiography. As we discussed last

00:06:32.640 time, I think, you know, you've used the analogy before the calcium scan that sort of demonstrates

00:06:36.980 a site of a prior injury. What we know is that quantitatively, the amount of calcium that is in

00:06:43.500 the distribution of the coronary arteries is correlated significantly with adverse outcomes.

00:06:49.180 So the more calcium you have in your arteries, the worse you do, the higher the risk of both

00:06:53.880 cardiovascular and all cause problems. And the reason we suspect is that that calcium represents

00:07:00.260 a healed plaque. And that's so the amount of calcium you have in your arteries is

00:07:04.380 strongly related to the amount of plaque they have in your arteries. We know that the amount

00:07:07.620 of plaque you have in your arteries is related to your risk of having heart attacks and dying from

00:07:11.640 heart attacks. So calcium scans are great ways to kind of analogy I use for my patients is that it's

00:07:17.520 a sort of a satellite image of your heart and gives you a sense of has there been damage there

00:07:22.980 over your lifetime. And then also gives you a nice adjunct indicator of your overall risk of dying from

00:07:30.760 heart attack, which people like to know. And one of the nice things about a calcium score is it's

00:07:36.260 very, very low in radiation. I mean, it's really even CTAs are now low. We'll talk about that. But

00:07:41.280 the calcium scan is a really low radiation and a very inexpensive tool as well. There are places that

00:07:47.700 are doing these scans for a couple hundred dollars nowadays. Not all places. No, that speaks to the

00:07:52.900 problem in U.S. health care where you'll still find some places charging $2,000 while some will do

00:07:57.180 the exact same scan for literally $200. But it needn't be an expensive procedure. It's a low-risk

00:08:03.020 procedure. It doesn't require dye. So it's effectively a zero-risk, low-cost procedure that at least at the

00:08:11.120 population level, as you say, has really great insight, especially the first time it's done, right?

00:08:16.340 Absolutely. And I think we talked about this the last time, but I'll just say it again for those

00:08:20.200 who weren't around back then. I did a full 180 on these. When I first started practicing as an

00:08:26.500 independent cardiologist back in the early 2000s, I would get patients showing up with these calcium

00:08:30.700 scans. And I really sort of wanted to make them go away. I thought they were annoying and I didn't

00:08:37.480 know what to do with them. And it really has been a full 180. I do find value. Obviously, there's

00:08:42.880 epidemiologic value and understanding the risk of different populations.

00:08:46.340 But I do find that there is value in many contexts and even in individual patients. And we can talk

00:08:52.320 about which contexts I think are most valuable. It's certainly not everybody. I think a calcium

00:08:56.540 scan in a 25-year-old is probably not worth anything. It's just not worth doing. So yeah,

00:09:02.400 I've come around now to seeing the value of calcium scanning as a tool that I use regularly.

00:09:07.680 And I know we did talk about this, but again, I learned that one of the things that makes

00:09:11.080 podcasting difficult is it's very difficult for people to go back and listen to them. There's just too much

00:09:15.620 volume. So we should never apologize for repeating stuff that we talked about more than four years

00:09:20.540 ago. And the way that I kind of explain it to patients as well is that if you have a two-by-two

00:09:25.900 of young versus old and zero versus non-zero as the calcification, there are two areas where the scan

00:09:35.240 provides insight. And there are two areas where the scan doesn't really provide insight. And so one of

00:09:40.300 them, as you said, if a 40-year-old shows up, has a calcium scan of zero, I haven't really learned a

00:09:46.280 lot. And if a calcium scan of zero in a 40-year-old is accompanied by other risk factors, I would not be

00:09:53.080 dissuaded from aggressively treating those risk factors. And similarly, when an 80-year-old with

00:09:59.540 lots of risk factors shows up and has a zero calcium scan, we'll talk about the false negative

00:10:05.820 right there. All things equal, you might be less inclined to push for aggressive measures. Would

00:10:11.380 you agree with that? I do. I think there's a group of very committed, whatever you want to call them,

00:10:18.560 calcium scanographers who believe in the power of zero and believe that a calcium score of zero is

00:10:24.600 meaningful no matter where it comes. But I just think that defies logic. If you shouldn't have any

00:10:28.700 calcium when you're 25, I'm not sure what you learned there. There may be edge cases where one in

00:10:34.560 several million people will have some calcium. But I just think mostly the two cases you described

00:10:39.900 are where I find the most value. Well, this gets to something that I think I've learned a little bit

00:10:45.580 more about both through personal experience and also just kind of spending more time in the literature

00:10:49.920 on this is that a calcium scan is a relatively imprecise measure. So the thickness of the slices that are

00:10:58.280 used in that scan are significantly greater than the slices that are used in the CT angiography.

00:11:04.860 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

00:11:09.120 this story last time, although clearly not all of it because I just learned more recently. So

00:11:12.460 in 2008 or 2009, when I was in my mid thirties, I had my first calcium scan. Now at the time my doctor

00:11:20.320 thought this was a crazy idea. I was 35. I was exercising at least 24 hours a week. It was no seemingly

00:11:27.020 relevant reason for me to waste insurance money and do this, but I had a horrible family history and it

00:11:33.140 didn't seem to make sense. It wasn't like everyone in my family was smoking or anything like that. So

00:11:36.440 anyway, I had the calcium scan and it showed that I had a score of six. So I had a single foci of

00:11:43.100 calcium in the small LAD. And interestingly, despite being in my mid thirties with that calcium score

00:11:49.280 of six, nobody really seemed to care either. That was viewed as, well, I mean, look, your lipids are

00:11:53.800 really not that bad. My LDL cholesterol was about 120, 110 to 120 milligrams per deciliter.

00:11:59.440 So nobody took that terribly seriously. Of course, it changed my life and it changed my interest in

00:12:04.340 this field forever. Fast forward to 2016, call it six, seven years later, I went and had a CT

00:12:13.140 angiogram and a calcium scan and the calcium scan had a score of zero. The CT angiogram, which now is

00:12:20.380 at much finer resolution, indeed found a tiny speck of calcium in the proximal LAD. No other finding.

00:12:27.620 Bob Peters, who is the remarkable radiologist that now sees a lot of our patients, explained to me,

00:12:33.260 not uncommon at all. That little speck that you had six years ago can easily be missed. If you had

00:12:39.520 five calcium scans, half of them would miss it because it's just too small. But now in the CTA,

00:12:44.080 we can see it. So we repeated the CTA. Now I'm just kind of partially interested in progression,

00:12:49.440 more of soft plaque. I had it repeated very recently. So call it 2022. This time the calcium score

00:12:55.440 came out as two. And the CT angiogram was identical to what it was in 2016, six years earlier.

00:13:03.180 So you could certainly believe that if I had a CTA in 2008 or 2009, it would have looked similar.

00:13:10.460 And you would argue that for basically the same lesion, the score was six and two and zero.

00:13:15.480 Sorry, six and zero and two in that order. Have you seen this yourself in patients where you've had

00:13:20.820 the luxury of both longitudinal assessment and simultaneous CAC and CTA?

00:13:27.160 Off the top of my head, I can't think of anybody, but I would ask you, and this may be a leading

00:13:31.080 question, but what were the percentiles of those? I mean, I would imagine that calcium score of six

00:13:36.220 when you were 35 was 99th percentile. It was 75th to 90th percentile at that age. That's right.

00:13:42.180 But there's a big difference even between six and two and a huge difference between six and zero.

00:13:46.040 Yes, exactly. I haven't seen it, but it doesn't surprise me.

00:13:50.380 My guess is at a low enough calcium score, that's not uncommon. Of course, that then

00:13:54.120 got me into the literature and I realized that 15% of people who have a zero calcium score

00:14:01.500 have a finding on CTA that is either as mine was, meaning a calcification that was not picked up

00:14:08.880 or a soft plaque. Furthermore, 2% or maybe it's 1.5% of those people who are deemed with a negative

00:14:18.920 CAC have an unstable plaque on CTA. It's not just the 15% that have something, but 10% of those people

00:14:27.040 have something that would be deemed relevant if we saw it on the CTA. Just back to our prior

00:14:33.320 discussion on age and utility of the scan, not familiar with the data, but I would imagine that

00:14:39.220 that 15% is largely represented in younger people or is that not the case?

00:14:43.640 I'd have to go back and look. It's a great question. I'd have to go back and look at the

00:14:46.520 study because it's been probably about six months since I looked at it. We'll find it and we'll link

00:14:50.540 to it in the show notes so that it's unambiguous and we'll include the table that summarizes all

00:14:55.220 this, which would hopefully include age. If not, it'll be in the fine print.

00:14:58.440 Then the other question I have for you, Peter, is over the course of the whatever it was,

00:15:01.620 15, 16, 17 years since your first calcium scan, what's your average APOB been?

00:15:06.240 Yeah. That's the point. It's been lower and lower and lower. That's about the time I met

00:15:11.660 Tom Dayspring and began to learn. I didn't know what APOB was at the time. At first, I was just

00:15:16.100 bombarding LDL-C and then that turned into really now targeting APOB. My target APOB is between 30 and

00:15:23.860 40 milligrams per deciliter. That's where I aim to be day in and day out. Obviously, that requires

00:15:29.440 pharmacological intervention. Now, again, I never really had a particularly high APOB,

00:15:33.360 but in some ways that actually gave me more concern, Ethan, because I didn't have the obvious

00:15:39.080 risk factors, right? I'm normotensive. I don't smoke. My APOB at the time was probably about 85

00:15:48.060 to 90 milligrams per deciliter. I mean, very few doctors would get phosphorylated over that APOB

00:15:54.160 in someone in their late 30s or mid 30s at the time. But again, I'd watched countless men in my

00:16:01.560 family die, some of them as young as in their late 40s from heart attacks. And you start to realize,

00:16:09.440 A, this is probably quite polygenic. And B, there's something going on here that's not just

00:16:13.520 standard plug and play risk factor stuff, which of course is your practice, right? I mean,

00:16:18.820 you get these really tough cases where it's not just, oh, you know, the LDL is too high.

00:16:24.880 It is my practice. And unfortunately, at least for now, the only set of tools that we have are

00:16:29.520 aimed at, well, I should say independent of blood pressure, which is a different conversation we'll

00:16:34.020 have later. But the tools we have now are focused really on lowering the APOB through any number of

00:16:39.060 different means. I think we all expect that there's something else there. There was clearly

00:16:45.440 something else there in you. It's hard to make the argument that you were sort of a ticking time

00:16:49.400 bomb with a widowmaker that you were going to drop dead of a heart attack. You had a tiny, 0.69

00:16:53.400 minuscule lesion. The question would have been what happened to you over the next 15 or 20 years

00:16:58.540 had you not taken the intervention that you did pharmacologically.

00:17:02.600 Yeah. As I approach 50 now, I do find it interesting to play the thought experiment of

00:17:08.620 had I been on a different path in life, had I never looked at that 15 years ago, had I never cared,

00:17:14.260 what would it look like today? What would that CTA look like today? How significant would that

00:17:19.160 lesion be? Would there be others? And my belief is we should obviously talk about this. I think that

00:17:25.440 the epidemiology, the clinical trial data, and the Mendelian randomization to my reading of this

00:17:31.700 literature, and I don't think there's anything I pay closer attention to truthfully, is that ApoB is

00:17:37.760 a necessary but not sufficient criteria for atherosclerosis. And as such, removing it removes

00:17:45.780 atherosclerosis. And so my best guess as to why there has likely been no progression of this disease

00:17:53.220 in 15 years, at least to the level that it can be detected by a CT angiogram, is that we've basically

00:17:59.540 taken away the causal agent? Yeah, I think I mostly agree with you. I think it's absolutely

00:18:04.780 necessary. I think the data really do suggest that if it's bottomed out, absent some really bizarre,

00:18:10.400 probably monogenic things that we don't see very often, that you can't get atherosclerosis. I think

00:18:14.980 that's demonstrated not just in humans, but across many other animal species. The one place where I

00:18:19.680 might quibble a little bit is that I do think it's probably sufficient in some cases, that in FH,

00:18:24.500 for example, it's probably sufficient. In other words, I don't think you have to have something

00:18:28.480 else to get athero in cases where the ApoB is sky high. The sufficiency is complicated. I mean,

00:18:36.320 I suppose there are people with FH that don't go on to develop ASCVD. I mean, that's sort of the

00:18:42.140 argument that, and I don't know if we're going to get into this or if I ever want to talk about this

00:18:45.500 ever again, but this lean mass hyper nonsense, that's the argument that they make, that having a

00:18:51.160 high ApoB is not sufficient. And it's definitely true that there are some people with FH who don't

00:18:55.880 go on to have ASCVD. It's interesting. I mean, obviously suggest some other genetic modifier or

00:19:02.660 something else that protects them. So I think that one could argue that ApoB is not sufficient,

00:19:09.040 but is necessary, which is how I feel, and still take it very seriously. Because let's look at another

00:19:15.200 obvious example, which is smoking. And again, is smoking even, I would argue smoking is even weaker.

00:19:20.540 Smoking is neither necessary nor sufficient for the development of, let's just pick lung cancer.

00:19:27.460 Let's just pick the most smoking associated cancer. So small cell lung cancer. Smoking is 0.62

00:19:32.300 neither necessary nor sufficient, but there's nobody in their right mind that would argue

00:19:37.700 that not smoking, if in our analogy, that's the equivalent to reducing ApoB, does not improve risk.

00:19:44.800 Absolutely.

00:19:45.240 So I just think that to point to people with elevated ApoB as an example of why it is safe

00:19:52.080 has never made sense to me. And I'll tell you another reason it's never made sense. I know I'm

00:19:56.360 not going to get an argument out of you, but I'm hoping we can try to formulate some argument here,

00:20:00.760 is there are other ways to treat ApoB besides diet. And so I feel like if part of the argument for,

00:20:07.060 I need to have this ApoB high is because the diet that's making it high is producing other benefits,

00:20:13.900 that's sort of not necessary. One can consume a diet that if it needs to be in a certain way

00:20:20.040 and produce a high ApoB, you could still continue to consume that diet and just

00:20:24.500 pharmacologically address the ApoB problem.

00:20:27.080 Yeah. It's the sort of mind numbing incongruity of this whole discussion. And again,

00:20:32.980 it makes my skin sort of want to fall off. I think you made a great point about smoking and

00:20:37.200 frankly, any other risk factor for any other disease. Replace smoking for coronary disease

00:20:41.920 with smoking for cancer. We all have lots of stories of people who smoked four packs of cigarettes

00:20:46.920 a day or even emphysema, right? Where the toxicity is much more direct. It's part of the nature of

00:20:53.680 the heterogeneity of response that this penetrance in this case of an environmental factor is not 100%.

00:21:01.020 I guess there are some that are, right? Cyanide probably is. But most of the things that we

00:21:06.480 encounter in our environment don't have that level of penetrance in terms of causing risk.

00:21:11.260 It's certainly not the ones that we encounter frequently. So yeah, cyanide is a great example, 1.00

00:21:15.000 100% penetrance. Carbon monoxide at a certain concentration, 100% penetrance.

00:21:20.160 Okay. So let's go back to our discussion and now contrast the calcium scan with the CTA.

00:21:25.920 And then especially we'll use this to now explain these other variations of CTAs that have shown up

00:21:31.560 where they're more like software additions to CTA. What I tell patients is that what you get from a

00:21:38.520 CTA is clarity and more information, which in most cases is really, really good. And that comes at a

00:21:45.220 small cost in terms of increased radiation. And I guess, you know, some potential risk of the

00:21:50.580 contrast, although it's relatively small, the biggest cost and the biggest reason that I don't

00:21:56.760 use it in all of my patients in whom I'm thinking about these kinds of things is it's hard to get

00:22:02.500 it paid for. So it is actually in this case, more expensive if you pay for it yourself out of pocket,

00:22:06.900 which almost all of the calcium scans that I order end up getting paid for out of pocket. Almost none of

00:22:12.600 them as of today, at least are reimbursed by insurance. But as you said, you can get them.

00:22:17.720 That's calcium scans and CTAs. They're both just out of pocket these days.

00:22:21.860 No, no, no. Calcium scans are almost exclusively out of pocket. I would say 90 plus percent of them

00:22:26.040 are paid for by patients themselves. But again, as you said earlier, it's a couple hundred bucks.

00:22:30.840 And almost everybody can make that leap and convince themselves that it's worth whatever

00:22:36.120 it is, 10 Starbucks. But for CT angiograms, the cost is much higher. And again, I don't know,

00:22:42.440 and this is one of the problems with their healthcare system. I don't want to get distracted in that,

00:22:45.240 but it's transparent to me what the cost is to my patients unless they go and do some digging.

00:22:50.420 And what's really annoying is that it's often not clear to them what they're going to pay for

00:22:54.520 until after they already have it. So the cost of a CT angiogram is much higher. It depends on

00:22:59.840 the insurance that you have. And even if you pay out of pocket, so even if it's not covered,

00:23:05.200 the negotiated rate is going to be different based on whatever carrier you have. So I would say much

00:23:11.220 fewer than 50% of my patients have coverage. And we can talk about what would justify coverage for

00:23:18.320 a CT angiogram. And I've sort of gotten a little bit more sophisticated in trying to be able to get

00:23:23.900 around some of what I think are these sort of absurd blockers for coverage. But then obviously,

00:23:29.480 depending on the patient, spending anywhere from, let's just say, $700 to $2,000 or $3,000 on a scan

00:23:35.160 may be more or less of an issue. And in some patients, it's enough of an issue that they don't

00:23:40.540 get it. So I think that's just worth pointing out. The world in which they were covered universally,

00:23:46.060 and we could have access to the data, that in my opinion, at least, it provides so much more

00:23:51.400 information than a calcium scan that I'd probably just go straight there. And especially because in

00:23:56.780 a lot of these cases we're talking about, like you and your 35-year-old self, these are cases where

00:24:02.680 we just don't have a lot of data. And the calcium itself is just not going to add that much.

00:24:08.940 Yeah, I agree. And we kind of have that discussion with our patients as well, which is that, look,

00:24:13.120 the IV contrast is virtually a non-risk outside of a handful of settings, which are clearly well

00:24:17.720 understood and can be, we know how to handle those pretty well. The radiation these days is so low.

00:24:23.000 It's really in the neighborhood of two millisieverts for a person our size. That's 4% of your annual

00:24:28.840 allotment of radiation. But you're right, the cost, I mean, we sort of assume $2,000 to $2,500

00:24:34.940 is pretty standard for that test. Yeah, when it's paid for out of pocket,

00:24:38.980 I would say that's probably average. But there are some, for whatever reason,

00:24:42.120 and I don't understand insurance in this country at all, but for whatever reason,

00:24:45.180 some insurance carriers are able to negotiate a lower rate for their members. And so I've seen

00:24:50.900 some people get, and it's very different institution to institution, right? So you could

00:24:54.660 go to UCSF and it would be $700. You might go to Stanford, it would be $1,500 or the other way

00:24:58.780 around. And so I do advise people when it comes to these decisions, if the money's an issue,

00:25:03.560 which it is for almost everybody, because it's a significant amount of money to shop around a

00:25:07.840 little bit. And then the question of sort of, all right, well, what do I get for my money? And

00:25:12.280 we know that right there are different scanners in different places, and those different scanners

00:25:16.700 provide different information in terms of resolution, but they also provide differences in terms of how

00:25:21.300 much radiation exposure. So that's another variable that we kind of have begun to address a little

00:25:26.260 bit. And those are the two things we always sort of say, I mean, we have places we send people because

00:25:31.160 we know the answers to those questions. But if it's not convenient for them, we're sort of saying,

00:25:35.300 you've got to ask what the radiation burden is. And it's actually, it can be a 10x difference.

00:25:39.880 I've seen scanners out there that are at 20 millisieverts. So now you're up to 40% of your annual

00:25:45.100 allotment of radiation for one screening scan, which personally, I think is too much. I just don't think

00:25:49.560 it's worth it, even if you're saving a bit of money. It's just another layer of complexity and

00:25:54.140 sort of how you think about applying these different tests and getting this information.

00:25:59.120 It's just really important to make sure not to forget about it.

00:26:02.440 So every time I've had these CTA scans, we get these beautiful images and they're 3D reconstructed

00:26:08.980 and then they're 2D sectioned. And we're looking at the lumen, the tube of the artery. In both cases,

00:26:15.120 that little speck of calcium shows up in the wall of the artery. And then we're also looking for sort

00:26:20.540 of soft plaque as well. And fortunately there hasn't been any, but that's, you know, soft plaque

00:26:24.900 doesn't show up anywhere in the calcium score. So you can have a significant burden of cardiovascular

00:26:29.420 disease without any calcium. I think that's the thing that maybe gets missed a lot. And that shows

00:26:35.040 up in that 15% of people who have a zero calcium score. A lot of them still have a significant

00:26:40.620 burden of disease. As you mentioned earlier, I mean, it could be that that calcification

00:26:46.220 where it's actually placed is not problematic. It's just that it's a harbinger of whatever it

00:26:52.120 took to get there. Do you look at patients with high burden of soft plaque and no calcification is

00:26:58.760 even higher risk? I don't really, just because I don't think I, by the idea I suggest that I think

00:27:05.000 a high burden of plaque period is a problem. Do I believe that a high burden of calcified plaque might be

00:27:10.200 less risky because it's more stable, I guess in theory, but I get really nervous about sort of

00:27:15.620 trying to impute plausibility and things like that to drive clinical decision-making. I think

00:27:20.840 the reality is a lot of plaque is bad. I mean, we know that people who have a calcium score of 4,000,

00:27:26.680 which by definition means they've got a shitload of calcium, that that's a high risk. And even if

00:27:31.420 they don't have any soft plaque, the risk is still high. So I don't pay too much attention. It's part of

00:27:37.280 the reason why I actually, if again, if everything else is equal, I prefer the information I get out

00:27:42.180 of a CTA. Of course, I'm greedy. I want more. And I feel like we just get so much more information

00:27:47.160 and don't have to make that distinction between soft and hard plaque. And frankly, I'm not sure

00:27:53.200 we're at a point in this field yet where we can make a compelling argument about plaque

00:27:58.520 characteristics. It's been a field that I think has evolved now since the early days, right? Since

00:28:04.340 the 70s, probably when the pathologists were doing autopsies on people who died of sudden

00:28:08.360 cardiac death. And, you know, we've been trying to understand the vulnerable plaque and different

00:28:12.620 plaque characteristics and what confers risk of rupture and ultimately an event. I just don't

00:28:18.220 think, at least in my estimation, and I'm certainly no expert, it's not, we're not there yet. I don't use

00:28:22.520 it anything other than as a sort of how much plaque is there tool.

00:28:27.060 Yeah. It's really interesting that we don't yet have a better tool to explain what vulnerability

00:28:34.840 means or to predict what vulnerability is. Do you think that in the research setting,

00:28:38.780 things like intravenous ultrasound or intravascular ultrasound, where they can actually look and measure

00:28:44.840 the thickness of the cap on the atheroma, do you think that in a theoretical sense, those things are

00:28:49.660 any better, even if they're impractical from a clinical perspective?

00:28:53.320 I guess, but ultimately, as a lot of things in biology, this is just so stochastic. I think we

00:28:58.760 might convince ourselves that it means something that it doesn't. So I think, you know, we've learned

00:29:03.320 a lot that, again, from the early days of even understanding that ruptured plaque leads to a

00:29:08.680 thrombosis over the surface of the ruptured plaque, and that's what causes a heart attack. That was a

00:29:11.960 debate until 1979, or even maybe even a few years after that. It really wasn't settled until ISIS-2 was

00:29:18.480 published in the late 1980s that showed that if you gave streptokines or aspirin, that you could reduce the risk.

00:29:23.320 I think we'd learned early on that it wasn't necessarily that 75% or 80% or even 90% plaque

00:29:28.640 that led to the big one, that oftentimes the plaques that ruptured and led to sudden cardiac

00:29:34.880 death were the smaller plaques, the 30% plaques, which kind of makes sense in the context of how

00:29:40.160 we think about, we'll all hear these stories, and I'm sure you get patients coming to you

00:29:43.940 after somebody prominent dies. I'll mention the name just because I think this is an example,

00:29:48.480 and I don't know Cheryl, but when Cheryl Samberg's husband died on a treadmill a few years ago, I mean,

00:29:53.420 I had probably 25 people call me that week to want to come in and get a risk assessment.

00:29:58.060 That happens a lot. I don't know anything about his case, and I don't know anything about the

00:30:01.160 pathology, but my guess is in younger people who die of heart attacks suddenly that oftentimes it's a

00:30:06.080 relatively mild plaque that wouldn't trigger any discussion of revascularization and wouldn't make

00:30:13.500 anybody nervous at all, that those are the plaques that end up causing problems. And we can begin to

00:30:19.140 weave together reasons why that might be, right, that maybe in a person who's got more plaque burden

00:30:24.680 that there's more chance for ischemic preconditioning and therefore the chance of an arrhythmic, malignant

00:30:30.340 arrhythmic response to the ischemia is lessened because of that. But my point is, I don't think we have

00:30:37.720 an understanding of, to me at least, that satisfactorily would allow me to change the way

00:30:43.400 I practice clinically based on the characteristics of the plaque, even the volume of the plaque. And so

00:30:48.380 for that reason, I treat people with plaques, any plaque, 30% plaque, pretty much the same way that I

00:30:54.680 treat people with extensive plaque. And I treat them maximally with sort of the best optimal medical

00:31:00.400 therapy I can offer. We feel so similarly about this, Ethan, that we're going to have a hard time

00:31:04.700 coming up with something to really clash about here because this is basically the same discussion

00:31:09.040 we have with our patients, which is I'm treating the causative risks, not the end stage problems.

00:31:16.040 Like if the goal is I need to wait until you have a 30% stenosis or a calcium score of 200 to start

00:31:23.560 acting, that's insane. It goes back to the smoking analogy. I want to tell someone the second they pick

00:31:29.840 up a cigarette to put it down, not until I see that their pulmonary function tests are problematic or

00:31:36.880 they've been smoking for 20 years and their risk is significant. And this is the sort of eye bleeding

00:31:42.320 experience that I have with insurance companies talking about adding PCSK9 inhibitors to statins and

00:31:47.920 whatever else they're on. And often they'll say, well, they need to have an event first. I'm thinking

00:31:52.460 to myself, so backwards, you're going to ask me to let my patient have a heart attack so that I can

00:31:56.560 prescribe the drug that's going to prevent them from having a heart attack. I mean, it's really

00:31:59.840 incredible. Hopefully we won't practice that way down the line. The problem of course is that,

00:32:05.260 and I don't want to get distracted, but all of these trials are so incredibly expensive to do

00:32:08.740 that the information that we're going to get from sort of the most rigorous randomized clinical trials

00:32:13.380 is going to be limited just because we're not going to be, you know, all the questions that I want

00:32:16.540 to ask and answer, I'm sure that all the ones you want to ask and answer are just not going to be

00:32:20.120 feasible to do because they're going to be overwhelmingly expensive. So we have to find a way to make

00:32:25.240 decisions to treat patients independent of this gold standard level evidence. And hopefully the

00:32:30.380 insurance companies come around. I've kind of accepted the fact, Ethan, we're never going to

00:32:34.200 have the gold standard evidence that we need in the most important demographic, which is the demographic

00:32:38.600 for whom we have the most runway to effect change. So in other words, there will never be the study

00:32:43.640 done in 40-year-olds that says, what is the 30-year risk of ASCVD in a cohort of 40-year-olds,

00:32:52.820 one group whose APO-B is reduced to 30 because we've used a PCSK9 inhibitor plus or minus whatever

00:32:59.120 other agent we need versus the group that's managed with standard of care or some placebo or something

00:33:04.040 else. And I feel more convinced of the outcome of that theoretical trial than I do virtually any other

00:33:10.120 theoretical trial I could ever muster up in my brain. And yet it'll never be done. And therefore,

00:33:15.060 there will never be an evidence-based case for true prevention of ASCVD.

00:33:19.180 I say something very bold in my upcoming book, which is that ASCVD should basically be an orphan

00:33:25.600 disease. There's actually no reason it needs to be the leading cause of death. It really doesn't

00:33:29.560 even need to be in the top 10. It's that preventable if you start early enough and if you're maximally

00:33:35.220 aggressive. And really at that point, I think it just becomes a question of working through the

00:33:39.900 challenges of tolerating side effects in patients who are sensitive. And I think there are going to be

00:33:43.420 patients who are going to be challenging, but with a long enough runway, this disease is sort of

00:33:47.760 irrelevant. Let's talk a little bit about these flavors of CTAs that keep showing up. So I guess

00:33:55.400 we'll start with the CTA FFR because we did speak about it briefly. We don't have to go back into all

00:34:00.480 of the detail of, and I'm blanking on the name of the trial. There were two trials that looked at FFR

00:34:06.160 in angiography. Fame and Fame 2, I think. That's right. Yeah. Fame and Fame 2. I guess give the short

00:34:14.000 version of what those trials looked at, what the technology was, and then we can talk about

00:34:18.500 the CT side of it. Well, I mean, the original FFR was performed, it is still now performed in a

00:34:24.620 cath lab, is basically a way to detect a pressure gradient across the stenosis. The simplest thing I

00:34:30.020 use to explain to patients is if you take a garden hose and squeeze it, that there's a gradient of

00:34:34.480 pressure, right? That there's going to be pressure proximal to this, your finger squeezing the garden

00:34:37.960 hose, and the pressure on the other end is going to be lower. And what they effectively do is to put 0.86

00:34:43.120 a wire with a pressure sensor on one end of the wire on the other end of the blockage, and they put

00:34:48.780 one on the near end of the blockage, and they can measure the delta. And that using a mathematical

00:34:54.860 formula, you'll know the name of it. I'm blanking on it. You can impute the diameter of the artery

00:35:00.360 relative to the diameter of the unobstructed artery, or the garden hose in this case. And so that

00:35:06.140 kind of gives you a way to get at the severity of the blockage. And I guess what this stems from is

00:35:12.700 the 40-year odyssey to try to take a very qualitative measure, which happens in a catheterization

00:35:19.300 laboratory, which is measure the percent stenosis, which is done, if you've ever seen it, it's done

00:35:23.720 very much sort of by like Gestalt. And the people who are good at it are pretty good at it. But if you

00:35:28.880 watch it, you understand that the difference between 30 and 50 is probably not that meaningful.

00:35:34.500 When there are severe blockages or stenosis, you can sort of all agree that it's really high-grade.

00:35:40.440 So I think of things in high-grade, modest, and low. So this has been one of a number of tools that

00:35:47.620 have been developed to try to supplement the information you get from that sort of very

00:35:51.520 qualitative assessment of visually how bad does that lesion look. And many of these things have

00:35:57.220 happened over the year. You know, IVUS, you mentioned earlier, is one of them. There have been a

00:36:01.360 quantitative coronary angiography where they actually try and take cursor and electronically

00:36:05.880 draw around the diameter of the vessel. Mike Gibson, you know, back in the old days used to do

00:36:11.460 this blush thing. I can't remember what it was called, but basically it would count the number

00:36:15.720 of frames it takes for the contrast dye to leave the myocardium. And that was sort of another indication

00:36:22.340 of how severe the lesions were. FFR evolved as a hemodynamic way to be able to impute the severity

00:36:30.340 of this stenosis. And so I think FAME was the first of these studies. And it showed that if you

00:36:36.260 had a significant pressure drop, if the ratio of the pressure and the sort of upstream sensor was,

00:36:43.420 you know, higher than the downstream sensor, that that conveyed that there was a bad lesion and that

00:36:48.580 it conveyed worse outcomes in people who didn't get stented. I can't even remember the design of the

00:36:54.660 trials, but basically it was a way to kind of... I think the idea was basically, look,

00:36:57.500 there's no ambiguity in two subsets of people who should be stented, right? So somebody who's

00:37:02.160 actively having an MI, they show up in the ED with chest pain, enzymes are leaking. I mean,

00:37:07.640 we just go to the cath lab. There's no need to putz around. I mean, what's the algorithm on

00:37:12.240 clot versus stent in the active MI in the ER? Oh, in the modern era, if there's a cath lab within

00:37:19.260 whatever it is, I think, I don't know what the exact number is in the latest guidelines, but it might be

00:37:23.080 like 90 miles. It's really the amount of time you have to calculate the amount of time it takes to get

00:37:26.840 transported to a place where there's a cath lab that does stenting, primary PCI. So primary PCI

00:37:31.600 is the standard of care. I think thrombolytics are used sparingly in this country and only in

00:37:36.560 remote places where there's no access. Where they can't get to the cath lab.

00:37:39.340 Yeah. So in an ST elevation MI, it's primary PCI is the standard of care, class one, the whole deal.

00:37:45.440 And as quickly as you can get there. And then the other indication in the non-MI setting is

00:37:51.220 symptomatic, right? If you have a person who is... If someone has a stress test,

00:37:55.120 on the stress test, you see ST changes. Is that an indication for a PCI as well?

00:38:00.120 So we'll back up. STEMI, ST elevation MIs, where there's a complete, in physiology or pathophysiology

00:38:06.240 is a complete obstruction of blood flow. ST segments go up, you go in, there's no blood

00:38:11.820 beyond the blockage. That's clear and everyone understands. What we're now calling ACS, which

00:38:17.760 we used to call unstable angina or non-ST elevation MI, which is same pathophysiology, right? Ruptured

00:38:23.220 plaque, a thrombus sitting on the plaque, but it doesn't completely obstruct blood flow. I think there's

00:38:28.480 general consensus, even among some of the more conservative groups out there, that those

00:38:33.520 people benefit from going to the cath lab early and having a stent to fix that blockage. I would

00:38:40.620 say it's generally accepted on the order, if I had to guess, of 85 or 90% of people would practice

00:38:46.260 that way. And when I mean early, I mean within the first 24 hours. So it's not a sort of code level

00:38:51.680 emergency. Now most hospitals have these STEMI teams where they'll automatically, the emergency

00:38:57.240 department will page the pager and everybody comes in from the technicians in the cath lab

00:39:01.240 to the interventional cardiologist, to the fellows and everybody else. They all just assemble there

00:39:04.800 to get there as quickly as possible. That doesn't happen. There's no STEMI activation for a non-STEMI

00:39:10.020 or a ACS event, but I think there's still general consensus that that disease is treated best with

00:39:15.980 early intervention. And the only distinction between those people is the ST change on the EKG

00:39:20.620 when they present? That's right. That is the distinction. And of course that is sensitive,

00:39:25.700 but not a hundred percent sensitive. There are certain lesions that are obscure, right? Where

00:39:29.860 you would, for example, a posterior MI, you'd have to do posterior leads to be able to see that.

00:39:33.600 But mostly STEMI is an emergency, go straight to the cath lab, don't pass go. Non-STEMI or ACS is

00:39:41.040 urgent and generally people end up in the cath lab. And it wouldn't be a bad thing to have them go there

00:39:45.840 relatively quickly, depending on how unstable they are. Obviously, if anybody has unstable symptoms,

00:39:50.880 no matter what they have, in other words, if their blood pressure was labile or if they had heart

00:39:54.700 failure or ongoing chest pain that was refractory to medical management, then that would also become

00:39:59.200 a sort of don't pass go, go straight to the cath lab. So I would say those things generally end up

00:40:03.980 getting stented. This is my opinion, my read of the literature, but over the past 15 years,

00:40:09.600 what has changed is people with plaque, but without symptoms generally don't get stented. Even the most

00:40:16.260 aggressive interventional cardiologists, I won't mention names, would probably agree that people

00:40:20.540 who have a lot of plaque, maybe with the exception of proximal LID or left main, there might be still

00:40:26.100 some people who would think, gosh, even without symptoms, I'm going to put up a stent in this

00:40:29.240 person. But generally people with plaque, no matter how bad the plaque looks angiographically,

00:40:35.960 those people are treated medically if they don't have symptoms. Where things have gotten

00:40:40.720 interesting is in these cases for symptoms, right? Because I think most of us have...

00:40:45.760 And sorry, when you say symptoms, Ethan, you mean symptoms in day-to-day life, or do you mean

00:40:50.720 under stress and provocation? Good question. Yeah. So no. So rest symptoms is unstable symptoms,

00:40:56.920 and that falls into that first category. And those people should be hospitalized when they would go

00:41:01.860 in that first 24-hour window. So any symptoms at rest without doing anything, we can debate about

00:41:07.880 what happens if you have an argument with your wife and you get chest pain, is that unstable or stable?

00:41:11.900 But mostly it's the sort of non-classic exertional angina where you're walking up a hill and you

00:41:17.960 get chest pressure, you get chest tightness, rarely pain. You stop, it gets better. You take a

00:41:22.700 nitroclosure and it gets better. Classic stable angina. People who have plaque but do not have

00:41:27.440 stable or unstable symptoms at all in general these days are treated medically, with some exceptions.

00:41:33.340 It's the people who have this classic stable angina, stable symptoms. So they go out and walk up a hill,

00:41:40.480 they get chest tightness, feels like somebody's tightening a belt around their chest. They stop,

00:41:45.100 it gets better. It's those people who I think are kind of the most interesting today in the

00:41:50.260 contemporary practice setting. And those are the people I think that require the most thought.

00:41:54.460 And I think we hadn't put it on our list of things to discuss. I don't remember if we discussed

00:41:58.200 these trials the last time around, but obviously Courage was the trial that sort of taught us that

00:42:03.100 it's okay to have a lot of plaque and not necessarily intervene on it. There have now

00:42:07.600 been several other trials to get at that question of is, and this is part of the reason why FAME is

00:42:12.920 to me like not that interesting because we've kind of already answered the question in all comers

00:42:16.720 that stenting people without symptoms, even if they have significant lesions, doesn't offer a

00:42:23.500 benefit over optimal medical therapy. There's now I think some discussion around even patients

00:42:28.580 with symptoms. The range of opinion I think goes from anybody with symptoms should be stented or

00:42:34.680 revascularized in edge cases with bypass. Some people think medical therapy in all cases, and then

00:42:41.960 I think there's sort of this nuance in between people who think give a trial of medical therapy and

00:42:46.300 see if you can get the symptoms better. It's not an automatic take to the cath lab, but try to

00:42:52.040 optimize medical therapy. And if you can make the symptoms go away, then there's no need to go

00:42:56.020 and stent that artery. And that's probably where I land right now is I still use interventional

00:43:01.540 cardiology. I certainly don't use it as much as I did in the past, but I do use it for people who do

00:43:06.720 have what I would consider to be refractory symptoms. And then obviously for the unstable

00:43:11.620 emergency acute settings, that's a different story. And if you had a patient with a really high

00:43:16.140 calcium burden, so they're north of a thousand and they never experienced symptoms and they're young

00:43:21.720 in their fifties or something like that, would you put them on a treadmill and push them as hard as

00:43:28.220 you could possibly go and assume that like, Hey, they're not necessarily exercising that hard every

00:43:32.280 day. I want to really see if they have any ST changes or wall motion abnormality when I make them

00:43:39.400 go to 15 meds. I don't, because like I said, I sort of land in that camp of, even if you had

00:43:45.160 symptoms, you'd still probably treat you medically. I would still try to optimize medicines. Now, if

00:43:50.680 somebody came in and was on great medicines and was still having symptoms, then obviously it's a

00:43:55.740 different story. But yeah, I don't routinely do anything to people who have high calcium. In fact,

00:43:59.680 if you have a high calcium score, whatever it is, a thousand, to me, it triggers a response and it's

00:44:05.060 the same. I don't think you need a CTA in that case. And in fact, a CTA might not be very useful

00:44:09.840 because there may be so much calcium that it kind of obscures the ability to be able to see

00:44:13.120 into and beneath the vessel. So to me, I don't automatically do stress testing in somebody like

00:44:19.300 that. I often will see patients who've been completely freaked out by the result and they'll

00:44:24.360 have had a big workup, including potentially stress testing and a CTA angiogram, but I don't do that.

00:44:29.700 And I likewise don't do any routine stress testing anymore as a way to follow

00:44:34.440 coronary disease, right? That was something we used to do in the old days when somebody had a

00:44:38.700 lesion, you knew they had a lesion, you'd kind of exercise them over, you know, once a year or

00:44:42.900 something to see how they progress. I don't do that anymore either. So in light of that,

00:44:49.940 FAME, if I recall, basically said, or sought to answer the question, if you took a bunch of 1.00

00:44:56.980 asymptomatic people and you did this FFR on them, you measured the fractional flow reserve.

00:45:02.980 If you took the people who had a pressure drop of, I think it was either 30% or more,

00:45:10.180 I think it was a 0.7 P2 to P1, but maybe- 0.8 or 0.7.

00:45:14.440 Something like that. It was either a 20 or 30% drop. If those people automatically got stented

00:45:19.800 and the others did not, and these are both asymptomatic, would we see better outcomes in

00:45:25.760 the more aggressive stenting strategy? Isn't that effectively what the trial-

00:45:29.320 That was the design and that was the result. So therefore, that became standard of care in a

00:45:34.160 cath lab. In most cath labs that we were doing FFR on a lot of patients where initially FFR was

00:45:40.400 there for these ed cases where you weren't sure, is this significant or not? Should we stent it?

00:45:44.180 Should we not stent it? I think it went through a period, and I think it's now come back, but I think

00:45:48.260 it went through a period where it was being used a lot based on FAME with the sort of assumption that

00:45:53.660 you're impacting people's outcome, hard outcomes based on your decision-making, and that there

00:45:58.640 were certain groups of people who benefited tremendously from getting stented, and our job

00:46:03.300 was just to identify who they were. On the surface, that's not an absurdity. That's definitely a

00:46:07.420 possibility, but I think after however many years now of understanding the data, I think the consensus

00:46:13.740 is it's just not necessary. I think really mostly it comes from the sort of line of evidence that

00:46:18.780 we've had through Courage, Ischemia, Orbita, all these different trials showing really that the

00:46:24.400 take-home is that optimal medical therapy, even in a mildly symptomatic patient, is quite effective.

00:46:30.500 So all of this basically is prelude to a CT-based version of this study, which of course can't do the

00:46:39.240 intervention, but it can identify people who are getting CTAs, which are far more than the people

00:46:46.060 who are getting traditional angiography, to say, hey, maybe you do need an intervention. So again,

00:46:51.800 in theory, the idea here is, well, you had a CTA. I see a stenosis there. It's a 50% stenosis.

00:46:59.160 Is it significant or not? I can't tell. I don't have a pressure transducer in there that I can measure,

00:47:04.900 but I can run this algorithm on it, and the algorithm will tell me what the pressure drop is.

00:47:10.620 So of course, question one is how successful is that algorithm? I don't know myself. I assume that

00:47:15.700 there was a head-to-head that was done where you had a whole bunch of people that actually had cath,

00:47:20.340 that actually had pressure transduction, and then concurrently had CTA, and then they could

00:47:25.240 actually see how predictive they were. I have to believe that was done, right?

00:47:29.120 Yeah, there was a trial. I don't remember the details of it. I guess the questions are,

00:47:33.240 in my mind, so does the physics, and I don't understand the physics, but does it make sense?

00:47:37.080 Can you actually really make this calculation in a meaningful and reproducible way in these people?

00:47:42.740 Well, I imagine back in the day when the method was being validated that there was some comparison.

00:47:46.860 The FDA required some comparison to be able to say, just as they probably required something to clear

00:47:51.620 the catheters themselves, they probably required something. It probably was close enough. I don't

00:47:56.660 have any knowledge that the thing is a random number generator. To me, that's a distraction. I think

00:48:03.040 there are plenty of people who go down that path. To me, the question remains, what are we doing?

00:48:07.680 And really, in the way I practice, do we need to identify asymptomatic people who are at higher risk?

00:48:14.100 Is there a group of these people who are special and might show something that no other group of

00:48:19.680 patients has ever shown in the history of interventional cardiology, which is a benefit

00:48:22.640 from stenting? I know that my interventional cardiology colleagues are going to hate what I just said,

00:48:27.600 but we've been doing this for a long time now, and we've been looking for any group of people

00:48:33.860 who would benefit from outside of the ketomy setting, which we've talked about, any group of

00:48:38.040 people who would benefit from a stent being placed in their artery. And we've had a hard time doing

00:48:42.940 that. And it's not for lack of trying. It's been, I mean, again, courage, which sort of was the

00:48:46.860 beginning of the end of this in some sense, that was a trial that was conceived of and executed by a

00:48:52.620 group of interventional cardiologists who wanted to demonstrate the superiority of stenting over

00:48:57.200 medical therapy. It was designed that way, and all of the bias was weighted towards getting that

00:49:02.880 outcome. It did not get that outcome. And frankly, there have been however many dozens of studies

00:49:08.860 since then. And at least from my point of view, there's nothing that screams at me that, hey,

00:49:13.560 look, our job as preventive cardiologists or thoughtful internists should be to go looking for

00:49:20.540 people who might benefit from a stent in the absence of symptoms. And that's where I'm left today

00:49:25.540 is that I don't see any evidence yet that there's something magical about some group of people

00:49:31.600 where they derive that much more benefit from a stent beyond truly optimal medical therapy.

00:49:37.140 And I think, as you said earlier, if everybody got truly optimal medical therapy, like if we

00:49:42.360 didn't have barriers to using all these tools and everybody, I think this disease would largely

00:49:46.580 be controlled. Now, I do believe there's something else going on that's residual.

00:49:51.580 And you're an example, I think, potentially. But yes, I think the quality of medical therapy we have

00:49:57.180 today is so good that it's going to be really hard to demonstrate the value of stenting people.

00:50:03.440 That assumes that stenting doesn't do something harmful. And again, I think that's an open question.

00:50:11.580 Why, if you have a very high-grade lesion, even before there was great PCSK9 inhibitors,

00:50:17.540 right, there were just Zocor or something, why wouldn't opening that artery lead to improved

00:50:22.520 outcomes outside of the acute MI setting? That's a question that always plagued me. Even as a

00:50:27.780 cardiology fellow, I was like, this doesn't make any sense. It should. You're opening up an artery

00:50:31.940 that severely blocked and restoring blood flow back to the heart. And there are lots of explanations

00:50:37.340 for why that might be. I don't think we have a good one, but you could imagine that going in there

00:50:41.080 and blowing up a balloon inside that artery and deploying a stent, that you're elaborating the

00:50:45.580 contents of that plaque downstream. And much like what happens when you break up a beaver dam in a

00:50:50.700 stream. It's just going downstream and causing its own set of problems. That's just me speculating

00:50:56.660 and making it up. But to me, it's an interesting question why it wouldn't be or why there would be-

00:51:02.360 Has the study been done, for example, where they take a group of individuals who were

00:51:06.480 asymptomatic at the time of being stented, or they weren't being stented in an acute STEMI,

00:51:10.720 who then go on to have subsequent events, what the location is of the plaque. In other words,

00:51:17.200 when a person gets stented in the mid-LAD and they go and have another event, is that other event,

00:51:25.640 can we identify a pattern? So for example, is it distal in the LAD? Is it in a part of the heart

00:51:32.300 where you could say, maybe there was some mechanical change that took place as a result of that stent?

00:51:37.800 Or maybe it was, hey, you know what? The reason it doesn't work is you're playing whack-a-mole and

00:51:44.120 this person had lots of disease. You just happened to pick the one that had the most stenosis. Although

00:51:51.280 stenosis by itself is actually a really crappy predictor of future events. So you weren't more

00:51:58.080 likely to do anything here. Maybe if you stented the entire vasculature, you would have, but of course

00:52:03.240 you can't do that. So it really comes down to how lousy is playing up stenosis as a predictor of

00:52:10.560 subsequent events. It's a good predictor. As we discussed earlier, these plaques that end up

00:52:15.980 leading to bad things often are not the plaques that would get stented anyway. So I think there's

00:52:20.740 that, which is sort of the- And that's my point. Because another explanation, which I think you had

00:52:24.680 a good one, is if you have a 90% stenosis and you haven't experienced symptoms as a result of that

00:52:32.380 yet, that's probably telling that if you throw a clot there, you're going to survive.

00:52:38.380 That's right. Because there's collateralization. And we know that, right? From seeing these,

00:52:42.140 you know, you can see that. And that's probably the mechanism, right? That this ischemic

00:52:46.080 preconditioning leads to this growth of collaterals. And basically it's like, if there's an accident on the

00:52:50.880 freeway, it's like I tell my patients that you get off on the side streets and you wind your way

00:52:54.060 through, it takes a lot longer. And it's not great when there's like a lot of traffic, but if there's

00:52:58.100 no traffic and it's relatively light flow, you do fine. Right. But that 30% lesion hasn't been

00:53:03.840 tested yet. No, it hasn't. So you don't really know how it's going to respond. It can't be tested

00:53:08.640 because you would never stent a 30% lesion. Yeah. So there's that. And then the other thing I think

00:53:12.940 is that if you look at, and now with the advent of sort of high sensitivity troponins and other

00:53:18.240 more sensitive measures, if you look at say troponin or CK elevations after a long intervention,

00:53:25.960 they most certainly go up, not in all cases, but they do go up. And so the question is, are you

00:53:30.000 doing, are you basically creating a little MI in the process of putting the stent in? And does that

00:53:35.800 then cause downstream risk in the form of arrhythmias or other issues later on in life? And that to me is

00:53:42.140 sort of an interesting thing to think about. Obviously there's no great data at this point, but I think

00:53:47.120 there are data, at least observational data, looking at the area under the curve of the

00:53:52.560 troponin elevations post-PCI as a predictor of outcomes. I think obviously the more troponin

00:53:59.000 you have, the worse you do, as you'd expect. Okay. So there was this study that I don't think

00:54:03.920 is published yet, but I think you and I saw it and emailed each other about, is it the precise trial

00:54:08.640 that we saw the abstract for? Remind me. This is the one that did the, I think, this is the one that

00:54:13.920 did the FFR and it found no difference in all-cause mortality, no difference in mace,

00:54:21.860 but a reduction in the need for catheterization. Right. So this has now become the sort of value

00:54:29.900 add of doing these non-invasive adjuncts to CT angiography. And it's the reason that we, UCSF,

00:54:37.040 now do CTFFR on not all of it, most of the CTAs that we do is that in theory, you've reduced the

00:54:46.560 number of people who go to the lab. You only reduce the number of people who go to lab if you

00:54:50.080 send people to the lab. If you're not sending people to the lab, you're not reducing the number

00:54:54.540 of people. So again, to me, it comes back to the primary issue, which is that people with plaque

00:55:00.860 probably, in the absence of symptoms, people with plaque should probably be optometically treated

00:55:06.160 and left alone. And that taking it to the cath lab is of very little value. And obviously,

00:55:12.960 if they get to the cath lab, the chance of them getting stented goes up astronomic once they're

00:55:17.760 there. So yes, you do theoretically prevent unnecessary stents with CTFFR, but you can do

00:55:25.820 that without the FFR. You don't need the FFR. Yeah, I think that's really well said because

00:55:30.440 to me, I don't get hung up when a study like that doesn't find a difference in ACM because I think

00:55:35.760 that's a short time horizon. But I do get a bit alarmed when there's absolutely no difference in

00:55:41.080 MACE, right? When you see no difference in anything related to cardiac pathology. And the only difference

00:55:48.040 is an algorithmic difference that to your point, you can make on your own. Again, I think we should

00:55:54.040 maybe reserve judgment until the final study is published. So we'll wait for that. I don't know

00:55:57.960 when that's coming out. But I found myself very underwhelmed by this. And it didn't change my

00:56:03.200 thinking, which is that at this time, I'm struggling for the use case of FFR. And as such, we really don't

00:56:09.300 employ it with our patients. I think that the issue is sort of, you have all these levers you can pull.

00:56:14.520 And so your job is to kind of figure out which levers am I going to pull. And I think sometimes

00:56:18.480 people overcomplicate it, right? That there are going to be relatively low risk people,

00:56:22.700 you could get away with statin or maybe statin and a very low dose of Zetia. I mean, in my opinion,

00:56:28.620 if you have plaque, a plaque, they say a 30% plaque or greater in an artery, in your coronary

00:56:34.800 vasculature, I'm pulling all the levers. I don't need any other information. I don't need more. And

00:56:40.480 that's a pretty good intervention, pulling all those levers. By the way, to your point earlier,

00:56:45.200 let's just assume there's something in me that's off. I think the fact that the moment I had a

00:56:51.700 six-score Ditzel, every lever got pulled, is probably why 15 years later, it looks like a

00:56:57.900 Ditzel still. Nothing's changed. Which means if we just pulled all the levers all the time,

00:57:03.160 we could kind of take this disease off the table for virtually entire population.

00:57:08.060 This is the mission statement of my friend, St. Catharison's company, Verve. They want to

00:57:12.100 CRISPR out PCSK9. Not necessarily initially in everybody, but he believes that if you did that,

00:57:18.220 you'd eradicate this disease. I don't totally agree with him, actually. I'd

00:57:21.700 disagree a little bit on sort of some of these things. But in general, I think he's probably

00:57:26.040 right. The question is, do you need to go to that extreme to solve for this problem? And could you

00:57:31.380 apply that solution to everybody feasibly worldwide? That's his problem to think about,

00:57:37.240 not mine. I'd love to have Seth on to talk about any of these things. Okay. So let's talk about two

00:57:42.700 other things before we leave CTA. There's the fat attenuation index, FAI. What is that exactly?

00:57:50.540 I'm going to be totally honest. I have no idea. Okay. You've seen it, I assume it's been presented

00:57:55.640 to you? Maybe. I sort of have learned in now doing this for as long as I have. So I graduated from

00:58:01.300 medical school in 1996 and did my residency for two years and then started my cardiology fellowship

00:58:05.960 here 25 years ago. So I've sort of learned to tune out, like put blinders on and to some of this stuff,

00:58:12.240 just because it's something new every few weeks. It's been that way, like consistently. So I'm sorry,

00:58:18.960 I'm not like completely up to speed on this latest and greatest fat attenuation index. I imagine it's

00:58:23.880 some CT-based way to look at the characteristics of the plaque and to see if it's potentially

00:58:28.400 vulnerable. Is that the idea? No, it looks, and I'm not an expert in this. I was hoping you were.

00:58:32.560 So it is a CTA bolt-on just like the FFR is, but it looks at the characteristics of the fat around the

00:58:39.820 plaque. So it's not trying to predict vulnerability per se. It's actually trying to predict how much

00:58:45.360 inflammation is, I hope I'm getting this right, but I think it's looking for how much inflammation

00:58:49.220 is around the plaque. I see. I don't, I'm not familiar. I am familiar with PET-CT. You know,

00:58:54.860 the amount of it, you can measure using FTG PET, you can measure the amount of inflammation in a

00:58:58.780 plaque that can be done quantitatively. There's a group of people who've been doing that for years.

00:59:03.000 And I think certain pharmaceutical and biotech companies have used that as a way to kind of gauge

00:59:07.180 efficacy in evaluating new molecules to see if they can have an impact there. That I don't think is

00:59:15.080 being used now clinically, at least to my knowledge and routinely. I'm not familiar with the fat

00:59:20.140 attenuation index. It kind of makes sense. So it's epicardial fat. That's right. Okay. I mean,

00:59:25.600 it's an interesting idea, right? I mean, epicardial fat is visceral fat and it probably does impact

00:59:30.640 risk in some way. Again, what are you going to do with that information? You're already pulling all

00:59:35.640 the levers. I guess maybe you'd focus a little bit more on metabolic stuff, I guess.

00:59:40.140 Which we'll come back to. Okay. Let's pivot to another topic that seems to come up from

00:59:44.860 time to time online, I guess. Which is, are there subsets of people in whom an elevated CAC

00:59:51.960 is not a predictor of risk? So there's been some confusion about this. I think it's maybe worth

00:59:57.080 clarifying this for folks. So James O'Keefe has commented on the fact that certain athletes who

01:00:04.580 exercise a lot, so very high degrees of cardiorespiratory fitness, might have a higher

01:00:09.600 frequency of coronary calcification. So let's first talk about that. How robust are those data?

01:00:16.200 And more importantly, what does it mean? Well, I think it's plausible. We know that

01:00:21.600 increasing shear forces across endothelial surface can certainly lead to damage and that would

01:00:27.360 potentially increase calcification. We know that in, say, patients with a bicuspid aortic valve,

01:00:32.740 that people who exercise at extreme levels do appear to have an increased rate of calcification of that

01:00:38.040 valve. And I say appear to because none of these studies are controlled, but it does seem that

01:00:42.900 that's the case and it makes sense and is plausible, as dangerous as that word is. I think the same

01:00:48.160 thing could be true in a coronary artery vascular bed, that increasing shear as you would expect to by

01:00:55.600 increasing flow as you would during extreme exercise could potentially lead to some damage and

01:01:02.060 therefore calcification. So I do think it's plausible. And sorry, I do think there is this one

01:01:07.960 example where there is a disconnect between the amount of calcification in the artery and the

01:01:12.700 amount of risk, and that is within people taking statins. And that's a very difficult concept for

01:01:16.520 people to grasp. And frankly, it's a difficult concept for me to explain. I do find myself getting

01:01:22.080 tied up and trying to explain it, and I can make up explanations like, you know, what you're doing is

01:01:27.500 healing the plaque and stabilizing the plaque, which we think statins are doing, and that that's a good

01:01:31.360 thing and not a bad thing. But I think it's incontrovertible that statins probably do increase the risk of

01:01:36.400 calcification despite lowering the risk of events. So there is this one example. So is it possible

01:01:42.340 that exercise could be similar to that? Maybe. But we don't have the flip side, right? We don't have the

01:01:48.560 40 years of really rigorous randomized trials showing that some exercise versus some version of placebo

01:01:56.180 does that. Would I say don't exercise? Absolutely not. Would I tell some patients not to exercise to that

01:02:02.060 extreme level? I don't know. I'm on the fence there. And the question is, let's just assume that it is

01:02:07.920 the case that high, high amounts of cardiorespiratory fitness come at the expense of some endothelial

01:02:15.680 damage. I don't know if it's true, but I agree with you. There's certainly mechanistic plausibility

01:02:20.200 there. The question is, if a person goes from, call it, I don't know, 50 met hours per week of

01:02:29.740 exercise to 100 met hours per week of exercise. And let's assume that doing that increases their

01:02:36.240 calcification. A, is that with or without more risk? Let's assume it is with more risk. But is that

01:02:42.860 risk more or less than the benefit that they gain going from the 25 or 50 to the 100 met hours a week

01:02:49.500 of exercise? In other words, this is what makes exercise a bit more complicated here, which is most of

01:02:54.940 the other things that are increasing the burden of calcification are net negative. Smoking more,

01:03:00.120 having higher blood pressure, having worse lipids. But the correction of that moves in the same

01:03:05.200 direction, works in the same direction as the improvement of the risk modifier. With exercise,

01:03:09.380 it's not the same. What's I think unambiguous though, and we were talking about this earlier,

01:03:14.780 more exercise is better than less and more calcium is worse than less. I've yet to see an exception to

01:03:21.720 that rule in terms of cardiovascular health. That's right. And that discordance, I think,

01:03:26.500 is only mimicked by the statin story, right? Where we know more statins are better and also lead to

01:03:31.800 more calcium. Look, here's the thing. If you put it back into sort of the terms and the context of

01:03:37.360 a patient comes to me and says, hey, I got this calcium score, whatever, let's call it 800. I don't

01:03:44.740 know, whatever you want to call it, 500, 300, 200, 100. I don't think it means anything because I

01:03:49.420 exercise a lot. That's the question that gets presented to us at an individual level. And I guess

01:03:54.560 what I'm saying is that I'm not yet comfortable saying, oh, don't worry about that. Whereas I am

01:03:59.380 comfortable saying, don't worry about that if it's because they're on a statin. So what I would say

01:04:05.520 to that patient is we have to assume that that calcium is representative of plaques in the arteries

01:04:12.160 and that having plaques in the arteries is a bad thing, that we should treat you accordingly,

01:04:16.080 even though you exercise a lot. And if you want to be sure, then we could do a CT angiogram to kind

01:04:22.500 of see how much plaque you actually have. Because I don't know of any evidence that this calcification

01:04:27.460 is not plaque related, that it's somehow extravascular calcification or it's beyond the,

01:04:33.940 it's in the intima or something or media, I guess. But that's how I would approach it today is I just

01:04:39.080 can't tell you, I can't give you a free pass on the calcium because you exercise a lot. Exercising is

01:04:44.360 great. Keep exercising. Don't stop exercising. But I think the burden of proof is on us to show that

01:04:50.580 that is not risky. And if we did a CT angiogram and it showed you didn't have any plaque and all

01:04:56.580 the calcium is sort of extravascular somewhere else, then sure, I'd be okay with that. But that

01:05:02.520 if we do it and we see plaque, I'm not aware of any data that would say, let's not treat you,

01:05:07.080 which is sort of the subtle but important difference between the statin store, because

01:05:10.800 the people on statins are already by definition on the risk-reducing therapy that's been shown to

01:05:16.320 save lives. It's not like, what are you going to do to that person because their calcium score is

01:05:21.680 higher? Would you be more aggressive, I guess, is one question people might ask. But that's the

01:05:25.780 difference is that there's that lever still to pull in the exercise person who's statin naive.

01:05:30.420 What percentage of your patients take statins?

01:05:33.920 I mean, it's a completely biased group of people because it's all self-selected.

01:05:37.600 Of course, of course.

01:05:38.620 90, I'm guessing. 90, 95 maybe.

01:05:41.560 And is the implication that the 5% to 10% who don't have some side effect that they aren't able

01:05:47.080 to tolerate? There's those for sure. Although I think that's less frequent now because,

01:05:51.860 would you say statin or any other or PCSK9 inhibitor? Because I do have a few patients who can't

01:05:57.020 tolerate. I would just say statin to start. What I want to sort of explore for

01:06:00.360 a moment is, what are the real world implications of the use of these drugs? What are the real world

01:06:06.680 side effects? What are the real world conditions that prevent people from being maximally medically

01:06:12.440 treated?

01:06:13.360 Small number of patients of mine who don't take them because of true side effects. A equally,

01:06:19.520 maybe even slightly larger group of patients who don't take them because they're afraid of them.

01:06:23.660 And I don't mean that to be pejorative. I think there's been a tremendous campaign,

01:06:29.220 a propaganda campaign to demonize statins that's been going on for a long time, 25 or 30 years.

01:06:36.040 And it's been very successful. And people are terrified of statins. You know, I mean,

01:06:40.140 there've been documentaries made on how statins are poison and they're killing people.

01:06:44.100 And while not everybody, or even maybe most people are aware of that, plenty of people who

01:06:48.440 spend any amount of time online are. I do spend a lot of time with patients who come to see me

01:06:52.960 because I have some openness to at least having that conversation with them. And I'm not going to

01:06:56.840 force them. I have a patient of mine who came to see me with a tremendous amount of skepticism,

01:07:01.700 had every risk factor, was probably having angina when he first came to see me.

01:07:05.280 And I recommended that he start taking a statin that first day. And he was afraid to because

01:07:11.140 of stuff that he'd read about how dangerous they were. He ended up, needless to say, a few months

01:07:15.720 later in the ER with an acute MI. And fortunately, the outcome was good. He ended up with a stent.

01:07:21.420 And he's stayed on a statin ever since then. So that sort of was enough of an experience for him

01:07:26.360 to change his mind. But I have a number of people who just flat out either won't, or it takes me

01:07:31.760 years to convince them to. Years. Some people I've seen for years, I've had the same conversation

01:07:37.280 year after year after year after year. And some people never change their minds. Some people change

01:07:42.460 their minds because of other things happening, like this patient having an MI. And some people change

01:07:47.540 their minds because finally they are convinced. But I never force it.

01:07:52.600 What's the core belief that's at the root of the fear, you think? Again, and I say this just

01:07:57.360 acknowledging that, yeah, probably about 5% of patients are going to experience muscle side

01:08:02.080 effects that are going to warrant not taking a statin because it's going to impede in their

01:08:06.100 quality of life. So if you just acknowledge unemotionally that there are side effects, you're going to see

01:08:10.520 transaminase elevations that are just too much, especially if mixed with Zetia. If you acknowledge all of 1.00

01:08:15.500 those things, there's obviously some deeper seated fear in something that can't be seen or measured or

01:08:20.540 quantified. Where do you think that comes from? Why don't we see that with other classes of drugs to

01:08:26.260 the same extent? I think we do. I just think this happens to be one of the most prescribed classes of

01:08:32.400 drugs in the history of humankind. And so it's just the denominator is bigger. I think this is sort of

01:08:38.760 the same thing that gets at a lot of skepticism around science and big pharma. And, you know,

01:08:44.640 I mean, there's a whole world of people out there with these like vast conspiracy theories about the

01:08:48.720 development of statins and, you know, about how Rory Collins is an evil person. He's engineered this

01:08:55.060 whole conspiracy to try to get the whole world on these poisons. And there are people out there who

01:08:59.720 really believe that. And if you hear something enough and you aren't an expert and don't have access

01:09:05.280 to all the data that we have access to, it can be compelling. And I've watched some of these

01:09:09.520 documentaries. They're terrifying, just as I'm sure, you know, the documentaries that were made

01:09:14.560 after the Wakefield experience in the late 90s were terrifying to young mothers who were worried

01:09:20.500 about giving their kids MMR vaccines or whatever. It's very easy to convince people to be scared of

01:09:26.040 something. It's a lot harder to make people unscared of something. And this is just an example,

01:09:32.620 I think, where there's a group of people out there who just don't believe in this whole

01:09:38.000 enterprise for whatever reason, very skeptical of big science and big pharma. And don't get me

01:09:44.000 wrong. Obviously, there are plenty of things that big pharma has done wrong. And we can go through the

01:09:48.260 examples of that. This happens not to be one of them. The sad thing about how demonized statins have

01:09:54.360 been is that it's one of the most profoundly important interventions that we have in modern medicine.

01:09:59.760 And it's astonishing to me that this is being compared effectively to smoking, to cigarette

01:10:06.620 companies. I haven't heard that comparison, but certainly people will quickly point to Purdue

01:10:11.700 and the opioid crisis as proof positive that the pharma entities are evil. And there's no question

01:10:19.300 that Purdue Pharma is indeed evil. And again, I've said this before on the podcast, I think it's really

01:10:24.160 difficult for us as a species to think dialectically and to hold seemingly contradictory truths

01:10:30.800 simultaneously that pharma companies can do good things and bad things. And that seems to be true

01:10:36.800 across the board. That seems to be true of every person as well, right? Any given individual can do

01:10:40.720 something good and something bad. The exceptions would be those that are universally good or universally

01:10:46.220 bad as people.

01:10:47.660 Yeah. There are people out there who just are clearly bad.

01:10:49.860 And there are people who are probably clearly always good and I'm not either of those, so.

01:10:54.280 I'd like to meet them.

01:10:55.240 Let's talk about blood pressure. I think this is one of those areas that I've personally become more

01:11:00.420 and more interested in over the past year. And it's actually become more of a concern to me,

01:11:06.700 maybe over the past two years, through the lens of the kidney. So we have this organ that just

01:11:12.800 doesn't get much attention. I'm trying to think, outside of my podcast with Chris Sonnenday,

01:11:17.560 where we talked about kidney and liver transplantation, I don't think I've got a

01:11:22.240 single podcast that deals with the kidney. And it's a really special organ. And I sort of explained

01:11:27.640 to my patients that in our bootstrapping approach to living an extra few years on this planet,

01:11:34.900 a lot of it requires a phase shift in time, right? So if you're 50 years old, you really need to be

01:11:42.460 held to the standard of a healthy 40-year-old if you want to live an extra 10 years. That's the way

01:11:46.900 you want to think about it. You want to think about that in terms of your mind. You want to

01:11:50.360 think about that in terms of your body. You want to think about that in terms of your coronary

01:11:53.080 arteries. You want to think about it in terms of your bone density. But you got to think about it

01:11:57.360 in terms of your kidneys. And so when we look at a person and estimate their glomerular filtration

01:12:04.020 rate, which we use, you know, cystatin C to measure that, we've largely abandoned creatinine.

01:12:09.100 And it's really tempting to say, well, you know, this guy's 55 years old. His EGFR is 70 mils per

01:12:17.460 minute. That's good enough. But in reality, it's not actually. It's far from good enough. And the

01:12:24.980 kidney is not uniquely, but exquisitely sensitive to high blood pressure. I'm not a nephrologist and

01:12:31.700 I never really, I don't think I remember much from nephrology, but I certainly remember that

01:12:36.280 something about its vasculature is incredibly sensitive, right? It probably has to do with

01:12:40.580 the fact that it's such a tiny organ that takes such a high amount of our cardiac output.

01:12:45.000 And I suspect just like the heart and the brain, it's very sensitive to pressure. And so that really

01:12:50.780 is the lens through which I think about this first and foremost, meaning even the slightest amount of

01:12:56.300 elevation in blood pressure is going to interfere with long-term kidney health and also with heart and

01:13:02.560 brain health. So there's a win across the board if we just normalize blood pressure. So I'll posit

01:13:07.840 that and have you just kind of explain from the ASCBD perspective, the importance of blood pressure

01:13:13.000 and how it stacks up with smoking, ApoB, and some of the other heavy hitting risk factors.

01:13:18.760 I just want to acknowledge how strongly I agree with you about how much we neglect the kidney as an

01:13:23.180 organ and nephrology as a subspecialty of medicine. I actually used to give a lecture on

01:13:30.000 hypertension in the first year medical students at UCSF. And I did that in conjunction with a

01:13:33.740 kidney pathologist who interestingly was, had been at Hopkins when I was a medical student,

01:13:38.500 was my advisor, very interesting woman who's now retired, Jean Olson. And she co-gave the lecture.

01:13:43.880 She gave the pathology part and I gave the clinical part. And I learned so much about the importance of

01:13:49.940 the kidney and regulating blood pressure in giving that lecture with her for however many years it was,

01:13:53.900 10 years. So it's both an important cause of blood pressure. And in fact, I think if you go back and

01:14:00.520 look at Rick Lifton, who's sort of one of the premier human geneticists in history, member of

01:14:05.320 the National Academy, some probably should win a Nobel Prize. He characterized all of the single

01:14:10.100 gene mutations that lead to extreme increases or decreases in blood pressure. You know, I think at

01:14:16.180 the time, and this is 20 years ago, there were 10 single gene mutations that led to people who had

01:14:20.960 really, really low blood pressure, had to constantly supplement salt and do things like

01:14:25.500 that. And then 10 that led to extremely high blood pressure. And I think like nine or whatever it is,

01:14:31.500 19 out of 20 of these things were located in the same location in the proximal collecting

01:14:36.400 doctor in the tubule. It was like, you couldn't have picked a place that was more important

01:14:42.940 evolutionarily for how we handle volume and salt and solute. So it's an incredibly important organ,

01:14:50.640 both as a cause of high blood pressure and also as a consequence. And those experiments,

01:14:57.040 you know, Gene showed these beautiful slides that I'll send along sometime, you know, pictures of

01:15:00.960 what happened to your kidney after it's exposed to increased levels of blood pressure over time.

01:15:06.700 It was interesting because I was giving this lecture as a cardiologist during the kidney block.

01:15:10.300 I felt out of place.

01:15:12.180 So most people kind of know that when they go to their doctor and they get their blood pressure

01:15:16.520 checked, normal is about 120 over 80 millimeters of mercury. What do we know about how much that

01:15:25.820 changes in a healthy person across the course of the day? So when they're sleeping, when they're

01:15:33.140 ambulatory and walking around, but not under stress, i.e. not exercising, when they are exercising

01:15:40.240 vigorously, when they're under stress, physiologic stress, psychological stress, all of these different

01:15:48.180 things that we do every single day, surely our blood pressure must change. And yet most of us,

01:15:54.280 myself included, have virtually no idea of how our blood pressure is changing under those situations,

01:16:00.040 even if under perfect optimal conditions, i.e. sitting down, legs uncrossed for five minutes,

01:16:06.940 it reads 120 over 80. So what do we know about the rest of the time?

01:16:11.200 I don't want to get too distracted, but I think it's fascinating. I've thought about this a lot.

01:16:14.000 And the question of what's normal is, you know, we all assume 120 over 80 is normal.

01:16:19.020 If you look at blood pressures across different animal species, it's mostly in that range. There

01:16:24.200 are some that are outliers. Obviously a giraffe is the best example of an outlier species with

01:16:28.960 much higher blood pressure it needs to have to be able to pump blood up to that very,

01:16:33.760 that head that's sitting way up high. It is weird to me, from an evolutionary perspective,

01:16:39.680 why we would have the same blood pressure as a mouse. It's a little tiny creature who walks around

01:16:43.640 on four legs. Why should we have the same blood pressure? It speaks, I think, to the conservation of

01:16:48.440 this sort of vascular system that we have. I think most people, when I was a medical student,

01:16:53.820 I'm sure you were the same, were taught that 120 over 80 is normal, but that's just normal,

01:16:57.680 whether you're 7, 17, or 75. I don't think we have a good understanding of, well, we have an

01:17:09.380 understanding of what is epidemiologically normal as we age. And so we know that blood pressure does

01:17:15.320 go up with each decade of life. If I had access to that lecture I used to give, I could show you

01:17:20.300 what happened. But certainly with each decade of life, your blood pressure goes up. On average,

01:17:26.100 if you're looking at a population of people, is that normal? Is that part of normal healthy aging?

01:17:31.720 Or is that just a function of pathology? Is it a function of something going wrong over time?

01:17:36.380 To your point, is it something about decreased kidney function? Or maybe is it increased vascular

01:17:40.960 stiffness over time? I think all of those things are possible and probable. So for a long time,

01:17:46.760 it was assumed that a blood pressure that was normal for somebody in their 20s and 30s

01:17:52.260 was probably too low and not normal for somebody who was in their 60s and 80s. And so we sort of

01:17:58.680 had this permissive hypertension in elderly people because we thought, well, gosh, they required it. It's

01:18:05.300 just part of the aging process. And it really hasn't been until the past really 10 plus years that we've

01:18:13.480 begun to ask specifically in really well-designed clinical trials, is that the case? And is it the

01:18:20.820 case when it comes to looking at important clinical outcomes? And I think my take on this now is

01:18:27.060 different than it was 15 years ago. And that is that 120 over 80 is normal no matter where you are

01:18:33.480 in life. And that anything above that is abnormal. And just to kind of get to the punchline, what I

01:18:38.540 tell patients is that my aspiration is that we can get you as close to 120 over 80 as we can without

01:18:44.640 harming you. Because there are certainly potential harms that are associated with treating people to

01:18:50.060 these low numbers. They can be in the form of side effects or impacts on lifestyle. They can be in

01:18:56.700 the form of real toxicity. Hyperkalemia of risk of death. I mean, there's all kinds of potential

01:19:01.400 issues. It's not just a simple intervention like treating LDL or APOV lower and lower and lower.

01:19:07.580 There's really no consequence at all. There is a consequence of lowering blood pressure too low in

01:19:11.860 this case. So that's my overall philosophy of how to think about blood pressures. I do think there's

01:19:17.800 now evidence from good clinical trials that 120 over 80 is normal and that we should try to get there

01:19:23.740 as best we can without making a mess. So through that lens, basically we're saying that the amount

01:19:31.560 of float that we see in blood pressure, again, we're talking about blood pressure in a very narrow

01:19:36.160 instance, which is seated, resting, et cetera. We'll come back to the other point, but just to build off

01:19:41.100 that when that drifts up to 125, 130, 135, 140 in an aging population, we're actually calling that

01:19:49.860 pathologic in the same way that I think we would all agree that the reduction in glomerular filtration

01:19:56.000 rate, the reduction in ejection fraction, the reduction in pulmonary function. Okay. Yes,

01:20:02.760 that occurs with aging, but that doesn't mean that it's not part of an aging process and therefore

01:20:07.600 part of something we want to minimize, correct? That's right. We lose muscle mass as we age.

01:20:12.220 Is that something we want to accept and that's normal or do we want to try to do what we can to

01:20:15.700 preserve the muscle mass that we had younger in life? And again, I think here the crutch that we

01:20:20.780 fall back on and is good, high quality, well done clinical trials. And in this case, we now have them

01:20:27.020 and it's not just sort of an opinion based thing that says, oh, we'll really get closer to 120 over 80.

01:20:32.460 We actually have evidence that being closer to 120 over 80 impacts mortality and that permitting

01:20:38.120 people to run higher to a level that we used to consider to be just basically pre-hypertension or

01:20:43.320 just normal, even an older person, 140 over 90, that that leads to a significant increase in risk of

01:20:48.160 dying. So to me, I think we've learned a lot and I don't consider it to be a normal function of aging.

01:20:56.480 I think there may be a process. There's obviously a process that goes along with aging, that there's a

01:21:01.220 decrease in function of a lot of different things that combines to lead to this increase in blood

01:21:04.700 pressure, but I don't leave it alone. I think that makes sense to me as well. Let's ask the second

01:21:10.180 question now, which is the one that vexes me the most. How much of a given day, let's assume I sit

01:21:17.260 down three times a day for five minutes, relax, don't look at my phone, don't drink coffee, don't cross my

01:21:24.200 legs. I'm perfectly zen. I put the cuff on my arm. I measure the blood pressure. It's 120 over 80.

01:21:30.660 Let's assume I do that three times a day and I get that number. How reflective is that of what

01:21:35.880 my blood pressure is when I'm sleeping? Let's say I'm sleeping eight hours. When I'm exercising,

01:21:41.740 let's say I'm exercising for an hour, 90 minutes a day. And when I'm sitting at my desk,

01:21:46.880 stressing out over email, how much variation am I getting?

01:21:50.780 Tons. So the first time I ever was in the cath lab, it was really amazing to me to see the variation

01:21:55.400 in blood pressure just in a patient lying on a table based on before they were sedated and after

01:22:02.040 they were sedated. You know, there are all kinds of things. So there's no doubt that there's a huge

01:22:05.440 amount of variation from second to second, minute to minute, hour to hour, day to day and beyond in

01:22:10.940 blood pressure. And I think it's very easy to get distracted by that. And I do all the time. And

01:22:16.120 obviously when I'm sitting in traffic, my blood pressure is not 120 over 80. When my kid spills coffee

01:22:22.400 all over the computer, it's not 120 over 80, right? When I'm exercising, it's not 120 over 80.

01:22:27.740 There's physiology and there's pathophysiology. So physiologically, our blood pressure does go up

01:22:32.100 and it's meant to go up during some of these cases. It's a function of increased cardiac output,

01:22:37.180 which is one of the components of blood pressure. So it's understandable. The question then is what do

01:22:43.200 you do about that and sort of how best do you measure blood pressure? And so again, and this is a

01:22:48.360 broken record, I'll just keep doing this, but I fall back on the clinical trials. And just as,

01:22:54.240 you know, we try to practice as best we can with some sort of fidelity to the way the trials are

01:22:58.380 done, I go back to sort of how are they measuring blood pressure in these trials? And therefore,

01:23:02.080 how were the decisions made to adjust medications? And how did that influence the practice of the

01:23:07.980 trial? And therefore, how should that influence our practice? Because those are the outcomes that we

01:23:11.400 look at. So this got a lot of attention. When Sprint was first published, which was I think 2014 or 15,

01:23:16.580 I can't remember the exact date, but it got a huge amount of attention. There was all kinds of

01:23:21.480 pushback from almost every angle you could think of. There were a lot of people out there who felt

01:23:26.040 like this is just yet another example of medicine trying to do too much. The less is more crowd hated

01:23:31.580 it. This is just over-medicalizing normal aging. There was a significant amount of attention paid on

01:23:39.340 how they actually measured the blood pressure because it wasn't the way that we typically measure blood

01:23:44.740 pressure. And it was the way that we probably ought to measure blood pressure, but it certainly wasn't

01:23:49.640 the way that we typically measure blood pressure. So if you go back and you look at the methods,

01:23:53.040 what they did was they had people in a quiet room. They had an automated cuff, one of the sort of

01:23:57.840 standard best in class at that time, automated cuff. They put the cuff on the person. They had them

01:24:03.160 seated and relaxed in a quiet room by themselves. And they had the blood pressure measured three times,

01:24:09.480 five minutes in between. So total of once, five minute break, one more, five minute break,

01:24:15.340 and once more. And they took the average of those blood pressures. And that's obviously much different

01:24:21.580 than having somebody rush in after parking their car and run into the office in a sweat and show up and

01:24:28.780 somebody slaps a cuff on them and measures the blood pressure. But my point is that that optimal way of

01:24:34.540 measuring blood pressure, even if it ends up yielding numbers that are lower than what we typically

01:24:40.220 get, that led to the result in that trial, which was so spectacular that the trial was stopped early.

01:24:46.620 And this is not, to all the conspiracy theorists out there, this was not a pharma-sponsored trial.

01:24:52.500 This is an NIH-sponsored trial, the government-sponsored trial, and was agnostic to different agents. It was not

01:24:59.340 about the physicians who enrolled patients in the trial had access to almost any therapy during that

01:25:05.900 trial. So this was not about sort of proving the benefit of one drug over another. This was purely

01:25:10.600 about testing the hypothesis that getting as close to 120 over 80 rather than letting people sort of

01:25:16.640 float up to 140 over 90 was better or not. And it turned out that it was, with caveats.

01:25:22.540 Let's talk about that methodology, and then let's talk about the algorithm agents and then the

01:25:27.440 potential downsides. So I have started testing my blood pressure six months ago. And the reason

01:25:32.620 for it, so I shouldn't say that, I have always checked my blood pressure because both my parents

01:25:36.880 have hypertension. I was like, well, look, I'd always attributed to the fact that I had low blood

01:25:41.200 pressure to the fact that I was super healthy and did all these other things. But I realized, look,

01:25:45.060 there's genetics to this as well. So I'm just going to start checking my blood pressure every couple of

01:25:49.780 days. And I did. And so for a couple of years, I just checked my blood pressure three, four times a

01:25:54.760 week, just when I'm sitting at the desk working, never attempting to relax or rest or do anything.

01:26:00.200 And it was pretty low, probably averaged 110 over 70 was sort of a typical reading of while I was

01:26:05.840 sitting there working. And then something happened in August. It was consistently a little bit higher

01:26:12.300 than that. Not a lot higher, but it was 125 to 130. And it was more or less 80 in the denominator.

01:26:21.460 This made me get a little more serious. I got another cuff. And now I started doing the full

01:26:26.700 sit protocol three times a day with both the Omron cuff and the Withings cuff.

01:26:34.020 And what I realized were two things. The first is I can always breathe my blood pressure down to

01:26:40.100 normal. In other words, there's never been a five minute window when if I don't sit there and really

01:26:46.040 focus on breathing, I can't get that blood pressure to come to normal. But most often than not, that

01:26:52.000 first reading, the second I sit down, especially in August, it got better in October and September

01:26:58.460 was kind of a transition month. It's kind of normalized now, but it was not uncommon for that

01:27:03.200 first one to be as high as 140 over 90. If I just was literally doing something, not exercising, but if I

01:27:10.040 was doing something active and then I went and sat down, like the equivalent of the guy who shows up from

01:27:15.060 the parking garage, just parked the car, had to walk up one flight of stairs, sits down 140 over 90.

01:27:21.020 Five minutes later, it's 117 over 74. And I've been in sort of a back and forth discussion with my

01:27:30.320 doctor and with my colleagues about, is this something I need to care about? Because now,

01:27:35.500 if you look at my spreadsheet and all of my phone data, my blood pressure looks perfectly normal.

01:27:40.640 For the last six months, I've averaged below 120 over 80. But I kind of feel like I'm cheating,

01:27:47.320 Ethan, because to guarantee that it's low, I have to take five minutes of being calm.

01:27:54.040 Which then makes me wonder, I know that that's in line with how the sprint study was done. And you

01:27:58.500 could argue, well, Peter, you're simply, you're actually doing something that's less extreme than

01:28:01.740 what they did because they did three measurements over 10 minutes. But deep down, I know my blood

01:28:06.120 pressure is not 120 over 80 when I'm sitting at my computer writing. Because when I check that blood

01:28:12.780 pressure straight away, it's above that. So what I think I'm hearing you say is, based on the way the

01:28:17.400 trial was done, we have to assume that the other people, when they first sat down, might have been

01:28:21.820 higher as well. Here's what I would say. Sounds like something changed in you.

01:28:26.520 Yeah. A book deadline is definitely what changed in August. So there's no question that was a change.

01:28:31.820 Well, so if that's the case, then that's understandable. And that's okay. I think in

01:28:35.960 your case, it sounds like what I was going to say was, if it was truly a change, and there was no

01:28:40.000 explanation for it, like a lot of things in medicine, then I probably would have paid more

01:28:44.680 attention to it, even though it was going from what was normal to normal. It sounded like something did

01:28:49.860 change. But in this case, it sounds like there is an explanation and that you had this stress in

01:28:53.320 your life in the book. So I guess the cheating thing reminds me of my daughter, I think I told you

01:28:58.300 before, is my younger daughter is legally blind and plays basketball. And we were discussing a

01:29:03.260 potential, this is such a crazy little aside, but I thought I'd tell the story because it's kind of

01:29:06.660 cute. We were discussing a potential procedure she could have to improve her vision. Because part of

01:29:12.160 her decrement of visual acuity is that she has pretty bad lateral nystagmus. And the ophthalmologist

01:29:17.680 was saying that if you can sort of make that better, understandably, you'll improve her visual acuity.

01:29:22.140 And that somebody stumbled onto the idea that if you cut the extraocular muscles and just reattach

01:29:28.080 them, don't do anything else, but just sever them and reattach them, that nystagmus can go away.

01:29:33.520 And that people's visual acuity can improve a lot. So we thought, well, gosh, that sounds really

01:29:37.080 interesting. We should do that. It's fascinating how that might happen. But she said she didn't want

01:29:42.260 to do it. Because she was like, that's cheating. This is a kid who runs around with a visual acuity of

01:29:45.780 20 over 200. And she was like, that's cheating. So we haven't been able to convince her to do it yet.

01:29:51.400 We'll see if she changes her mind someday. But I don't think you're cheating. What you're doing is

01:29:56.060 optimizing the measurement. I think what you could do if you want to, and maybe you've already done

01:30:00.780 it, if you really want to get a sense, and it would be great to have this over time serially,

01:30:05.980 is to do a 24-hour ambulatory blood pressure monitor to really get a sense of what is the

01:30:10.520 average blood pressure you're seeing over a 24-hour period. Because there is a difference.

01:30:15.760 When you're sleeping, your blood pressure should be low. That's physiology. When you're out and

01:30:20.420 about doing these, it's going to be higher. And they can quantify all the spikes. And it's actually

01:30:26.420 a really nice tool that I'll use, especially in people who have some degree of what's commonly

01:30:32.040 termed white coat hypertension, which is kind of what, I mean, white coat hypertension is real life.

01:30:35.920 White coat hypertension is living in the real world.

01:30:38.220 How does an ambulatory BP cuff work? It's presumably a cuff that sits on the arm,

01:30:43.220 and then it straps to a device like a halter would?

01:30:45.940 It's funny. I don't think I've ever seen the device. I've ordered a bunch. It's a cuff. So it's

01:30:49.560 really old school, right? It's not like this is new technology where they can measure blood pressure

01:30:53.200 without doing the old sphincter manometer. So it's a cuff. It's, I think, got a self-inclusive,

01:30:59.380 I would imagine it's got some hardware attached to it that tells it to inflate and measure blood

01:31:04.900 pressure just as you would with one that you have in your office. And it does that once a minute or

01:31:08.920 whatever it is over the course of 24 hours. So it's constantly inflating, deflating over the

01:31:14.480 course of the day. Patients of mine who've warned them say that after a while you get used to it and

01:31:19.080 just can ignore it. It seems to me like it would be really annoying to have this thing like

01:31:22.900 inflating and deflating all the time. But that's what it is. What it does, though, is it buys you sort

01:31:28.740 of a distraction from real life. It buys you sort of when you're not thinking about things,

01:31:33.540 when you're clearly not stressed or you shouldn't be stressed, i.e. when you're sleeping.

01:31:37.420 What is your blood pressure? And we know that blood pressure, that hypertension during sleep

01:31:42.240 is abnormal. It should really be a time when your blood pressure is the lowest. So it's just

01:31:47.580 another tool that we have to kind of get at that question. It is always interesting to me that we

01:31:52.020 measure blood pressure not just once 10 or 30-second interval in a 24-hour day, but that we do that

01:32:00.000 on average once or twice a year. And that we assume that this very variable number is actually

01:32:08.680 meaningful. And it's remarkable to me that it has been even meaningful the way that we've been

01:32:13.220 measuring it because it is such a poor sample. And our patients will ask them to do twice-a-day

01:32:19.780 checks at home, same method that I'm using, for at least two weeks once a year. And if we have reason

01:32:27.020 to believe that that suspect will do it more, so even though that's much more than they would be

01:32:31.640 asked to do normally, it still feels woefully inadequate. And I've tried a bunch of devices

01:32:38.240 that's supposed to measure, supposedly measuring blood pressure, like little wrist-based devices.

01:32:43.660 I've never found them to work. Is there anything on the horizon that's closing the gap on that?

01:32:49.640 You'd think so. You know, there was a period of time where people were using a cell phone camera,

01:32:55.180 and you could press your finger on the camera, and that it could basically detect the pulsation. It

01:33:00.060 could almost calculate a pulse wave, and that could give you a sort of imputed systolic and

01:33:06.180 diastolic blood pressure. That never made it. We're not seeing those around. We're not seeing any other

01:33:10.620 devices that people can wear that can accurately measure blood pressure. So I do think it's an

01:33:15.480 interesting question. You'd have to think that at some point, even if it's an intravascular device,

01:33:20.680 that you could put a miniature device, you know, much like, you know, we're now using,

01:33:25.460 I don't know how much you use them, but I use them a lot, these implantable event monitors,

01:33:30.140 these loop recorders. We use them to detect arrhythmias. It sounds bad, right, when you think

01:33:35.680 about it, but it's really not that big of a deal. There has to be a way to get a pressure transducer

01:33:39.900 into an artery safely that you could leave there for some period of time. Feels like that's going

01:33:46.180 to come, but I haven't seen it, and then non-invasively would be amazing, but I just, again,

01:33:50.440 haven't seen it. As you know, I find CGM to be kind of a remarkable tool. I would think this is

01:33:55.620 even more important because glucose, in many ways, is less variable than blood pressure, or at least

01:34:01.700 its variability is more predictable. In other words, you could, I think, much more easily get by

01:34:06.720 with just spot checks of glucose than you can with just spot checks of blood pressure. To have a true

01:34:11.680 continuous ambulatory BP monitor, that would really be a game changer in medicine. Again, when you think

01:34:17.800 about the heart, when you think about the brain, when you think about the kidneys, it's such an

01:34:20.900 important thing. I agree with you. I think that said, the intervention that was used in Sprint

01:34:26.740 still showed a remarkable benefit. So we can't exist with the tools we have, and while they're not

01:34:32.840 optimal, they're probably adequate. And they're definitely better. If you go back and look,

01:34:36.900 and this is part of this lecture I used to give, if you look at sort of the percentage of people that

01:34:40.240 have either diagnosed blood pressure, how many people are known to have hypertension who actually

01:34:47.700 do have it, how many people are treated at all on any medicine, and how many people are controlled.

01:34:54.140 If you look back in time, when this was first done in the first inning survey, in the whatever,

01:35:00.860 1975, 76, whatever that was, only 50% of people who had hypertension were even aware of it. Only 30%

01:35:07.540 were actually ever treated, and only 10% were controlled. And I don't know what the most current

01:35:13.220 numbers are, but awareness has gone up. It must be north of 80% now. Treatment is probably 75 or 80%,

01:35:20.380 and control is probably somewhere around 50%. So we're still missing the opportunity to treat 50%

01:35:27.540 of people with this disease. Let's go back to Sprint. This trial was drug agnostic, right? Is this the

01:35:33.980 one that basically said, you know, start with a thiazide, move to a calcium channel blocker,

01:35:39.460 and then an ACE or vice versa? Actually, I don't remember the algorithm for Sprint, but I think it was

01:35:44.680 relatively agnostic. So ALHAT was the first NIH-sponsored blood pressure trial. That was in

01:35:50.700 early 2000s, like 2002, 2003. And that tested five different classes of medications, two of which

01:35:56.740 were discontinued. So I believe it was calcium channel blockers, ACE inhibitors, and the calcium

01:36:02.060 channel blocker at the time was amyloidipine, ACE inhibitors, diuretics, thiazide diuretics,

01:36:06.640 or clorthalidone, beta blockers, and alpha agonists. Because at the time, they were being used for blood

01:36:12.380 pressure. And both the alphas and the betas were stopped early because they were harmful.

01:36:18.300 And so what the result of that trial was that using any of the other three classes was first

01:36:23.000 line and treatment of primary hypertension. So calcium channel blockers.

01:36:26.180 And that was lisinopril and lodipine and a thiazide, correct?

01:36:30.820 I believe the thiazide they used was clorthalidone. And we can talk a little bit about the difference

01:36:34.940 between clorthalidone and hydrochlorothiazide. But in general, clorthalidone is more potent. And that's

01:36:40.060 the one that was, I think, used in the ALHAT trial, but I'd have to double check.

01:36:43.460 If I recall, the amyloidipine, lisinopril, and the thiazide all ended up having similar

01:36:48.580 outcomes, which were all better.

01:36:50.400 Yeah, no real differences. Yeah. I think there were maybe some stroke. It's been like so long

01:36:55.020 since I've reviewed it, but I think there might've been like a minor difference in stroke risk in the

01:36:59.760 amyloidipine. But the take home of that and what became contemporary practice was

01:37:03.960 use any of these three agents as first line in primary hypertension.

01:37:07.220 And the target was 120 over 80.

01:37:10.120 Well, that was, yeah. I mean, it was the target. It certainly wasn't, the emphasis was not,

01:37:18.840 the definitions definitely changed, right? Because there was this sort of category in,

01:37:24.100 I think it was JNC6 or something. There was a category for normal. Ah, that's right. So it was

01:37:31.800 normal was actually 120 to 130 over 80 to 85. Borderline was 130 to 140 over 85 to 90. And it

01:37:41.320 was only then hypertension if you're greater than 140 over 90. And then they called it stage one,

01:37:45.900 two, and three. So then when they redid it in JNC7, it was normal, was less than 120 over 80.

01:37:51.880 Pre-hypertension was then at 120 to 140. And hypertension was then above 140 over 90.

01:37:58.260 That was the difference between JNC7 and JNC6. JNC8, I believe, gosh, I can't remember what

01:38:06.700 happened. There was some controversy. And then they stopped after that. NHLBI said,

01:38:11.920 we can't do this anymore because there was too much controversy over these.

01:38:15.660 What was the impetus for Sprint? The impetus was to test a new hypothesis that was,

01:38:20.540 should we be more aggressive in the management of hypertension?

01:38:23.020 So the impetus was that there were epidemiological observational studies,

01:38:28.700 and I can send you one or two, that showed that it appeared that the risk of bad outcomes,

01:38:35.180 mostly coronary, cardiovascular disease, was lower, step function lower in patients who had

01:38:40.880 optimal blood pressure. This is according to the old classification, people whose blood pressure is

01:38:44.000 120 over 80 or less, optimal. And then a small step increase in people who had what was then classified

01:38:49.360 normal. And then a large step increase in people who were considered high normal or even early stage

01:38:56.640 hypertension. And so, but this was all observational. It was on a prospective study. So the NIH designed a

01:39:02.020 study to prospectively evaluate whether treating people to these two different goals, and these

01:39:07.280 were aspirational goals, whether that resulted in a change in outcomes. And so they randomized these

01:39:14.220 people. Again, the doctors were given leeway as to which agents to use, and you can look through the

01:39:18.980 supplemental tables and see which ones were used. But there was really nothing, at least to my

01:39:23.020 recollection, there was nothing about the different agents that was that meaningful. Clearly, people got

01:39:28.740 to the two goals that they were assigned to randomly. It was obviously not blinded because you couldn't be

01:39:34.680 blind to your blood pressure. But they got to the two goals. So the people assigned to the more

01:39:38.900 aggressive 120 over 80 got to like 123 over whatever it was, 82. And the people into that 140 over 90

01:39:45.620 were more like 137. You can look at the curves in the New England Journal paper, and they separated

01:39:50.920 beautifully. And then they- Yeah, I think it was 121 versus 136.

01:39:55.240 Yeah. It was something like that. But it was a significant difference. And obviously, the amount

01:40:00.320 of medication usage was much higher in the people who were assigned to that more aggressive arm. And there

01:40:05.460 are some questions there was, well, was it a benefit of the medicines? Or was it a benefit of

01:40:08.820 the blood pressure? Look, I mean, we can ask all these questions forever and ever. But the reality

01:40:12.880 is this was a really striking difference such that the NIH stopped the trial early because of benefit

01:40:19.320 in that lower group. And I think it was one of the most important and practice-changing trials that

01:40:25.460 we've had. I don't think that it came without some cost risk. It would be silly to just completely

01:40:32.880 dismiss this. There were real issues, right? There was a greater increase in the risk of falls and

01:40:38.100 syncope. And I think even in the risk of significant kidney dysfunction, it was all reversible, but it

01:40:43.860 was all there. And so what we took away or what I took away from that trial was, it looks like you

01:40:50.080 get a mortality benefit for getting closer to 120 over 80. So let's get there if we can without

01:40:54.960 creating one of these problems. So obviously, if you're falling all over the place because you're

01:40:59.200 dizzy or if your kidney function deteriorates because your kidneys aren't getting enough blood flow

01:41:03.740 or whatever, something else bad happens, then we're not going to do that. But we're going to

01:41:08.220 get you as low as we can, as close to that target as we can without making a mess.

01:41:12.560 That's sort of why my doc has been relatively unexcited about doing anything in me is he still

01:41:18.640 remembers a year and a half ago or less than that, just over a year ago when under my normal set of

01:41:23.540 relatively low blood pressure, I stood up in the morning too quickly, fell, face planted,

01:41:29.960 split my head on the table. And that was an occurrence like once, maybe twice a week, I'd

01:41:36.200 get up and need to sit back down again in the mornings. Understandably, his appetite for trying

01:41:43.020 to correct an average blood pressure of 120 over 78 is pretty low. And I'm not keen to take any

01:41:51.420 medication either, clearly.

01:41:53.380 There is no doubt in blood pressure, unlike in cholesterol, there is a U-shaped curve, right?

01:41:58.460 Too low is definitely bad. And I think your body was telling you that your blood pressure is

01:42:03.640 probably right about where it ought to be and maybe even a tad too low. Maybe you're just like

01:42:08.380 a little dehydrated in the morning. It sounds like your doctor made the right decision. I don't think

01:42:13.080 there's any evidence that I'm aware of that treating you to below 120 over 80 is advantageous.

01:42:20.160 No, it was more just my question was, should we treat such that I never have a reading above 120

01:42:25.460 over 80? And again, I think that's probably too aggressive based on these side effects.

01:42:31.280 Well, I don't think it's even feasible. I mean, the way you exercise, there's just no way. I would

01:42:35.280 imagine if you wore a 24-hour ambulatory blood pressure, when you're exercising, especially doing

01:42:39.460 isometric resistant training, your blood pressure is going to go way up.

01:42:42.980 I think that's a great idea. I've wasted a little bit of time in the last two years looking for new

01:42:49.120 technology to measure blood pressure in a continuous ambulatory way. And every device I've tried has

01:42:54.660 failed. So I think I just need to bite the bullet and do the old school low-tech way.

01:42:59.760 If some smart engineer out there wants to figure out a great, important thing to work on,

01:43:05.780 this is definitely-

01:43:07.280 I would agree.

01:43:07.920 At or near the top of my list in terms of things that haven't been solved. So go for it. It would be great.

01:43:13.020 As you say, there isn't really anything now other than the old school, old-fashioned

01:43:16.460 single manometer just attached to your arm.

01:43:18.580 So what about the STEP trial last year? Did that sharpen our thinking at all?

01:43:22.880 I think it just assuaged any fears that people had that there was something unusual in that

01:43:27.300 sprint. And of course, there was this concern over the trial being stopped early, which does risk

01:43:32.760 stuff better than I do. But it does risk the possibility that the result was spurious. So I think STEP

01:43:38.720 is a nice confirmation.

01:43:39.960 Because I think that sprint was stopped at three and a quarter or something, three and

01:43:43.620 a half years, something like that.

01:43:44.720 It was definitely stopped early. And again, it was pre-specified and there was a DSMB and

01:43:48.720 the whole deal. And again, it wasn't industry that stopped it. It was the government that

01:43:52.520 stopped it because of overwhelming benefit. You could have made the argument to keep going.

01:43:57.260 A lot of people did. They felt like this was an important, you could calculate the number

01:44:01.760 of people who were undertreated and that they could calculate the impact on mortality even here

01:44:07.340 within the United States for every day that you didn't get this result out there. And so they made

01:44:11.860 the decision to go ahead and stop the trial and report the results. And like I said, there were a lot

01:44:16.480 of reasons people didn't like the trial. Lots. And that's fine. There are lots of reasons that we

01:44:21.100 can all find fault with a lot of different things we do. Anyone who's done a scientific experiment knows

01:44:25.720 that there's plenty of people out there to find fault with all of the things that you did or

01:44:29.880 didn't do correctly. So the, what I took away from the step was that it was a nice confirmation that

01:44:34.820 sprint was probably not spurious, that the result of the sprint was real and robust and repeatable.

01:44:40.480 I think the other thing step had going for it over sprint is it included patients with type two

01:44:44.940 diabetes, which I believe were excluded. You had a longer trial, you had a more representative

01:44:50.360 population. So I'll tell you, and we can leave this after we're done with this,

01:44:55.080 cause I want to make sure you have some time to talk about the metabolic stuff, but

01:44:57.520 do you have any thoughts on the specifics of various agents? So you have these two really

01:45:05.120 good trials that were largely drug agnostic. And yet I still, when I'm hanging out at the bars at

01:45:12.920 night talking to, no, I'm kidding. This is not, I was going to say that, but you hear this little

01:45:18.620 bit of ARB versus ACE versus calcium channel blocker. And basically the question is independent

01:45:26.620 of the effect on blood pressure. So if you have two agents, an ACE inhibitor or an angiotensin

01:45:32.060 receptor blocker, for example, or throw in a calcium channel blocker that can equally lower blood

01:45:37.800 pressure, they can get everybody down to 120 over 80, and they can, the symptoms and side effects become

01:45:43.740 non-issue. And each of those will have a slightly different set of symptoms. We know, do we have

01:45:48.180 one reason to prefer one over the other? For example, when it comes to renal protection?

01:45:53.880 My first answer is because of the conversation we had earlier about the sort of lack of awareness

01:45:58.500 and lack of treatment and lack of control of blood pressure. My first advice to people is get the

01:46:02.580 blood pressure control. And that's what I tell patients, right? That let's just get the blood

01:46:05.980 pressure control. And then if we want to try to optimize and find out what the right combination of

01:46:10.900 things is for you, given your other circumstances, NIH used to use this term extenuating our special

01:46:17.560 circumstances. You know, for example, if somebody had angina, even though beta blockers were no longer

01:46:22.360 first line for treatment of primary hypertension, if you had angina, you'd include the use of a beta

01:46:27.200 blocker in that hypertensive regimen. It was really anti-anginal, but it lowers blood pressure. So I think

01:46:32.420 the first step is just get to goal. I do tend to do things differently in some contexts. So age to me has a

01:46:39.260 big deal in both directions, right? Young people don't like taking diuretics. And in old people, 0.95

01:46:44.900 diuretics can be a little bit more challenging, right? So there are more electrolyte abnormalities.

01:46:49.180 I see a much greater incidence of sort of hyponatremia and other electrolyte problems. And of course,

01:46:54.480 the kidney issue is there too. So while I think if I had to pick my favorite agent that I think probably

01:47:02.960 among the three classes is the best at managing sort of all comers of high blood pressure, it would be

01:47:09.220 chlorothaladin or thiazide diuretic. I don't use it as much just because it's harder to use. I think

01:47:16.560 amlodipine is a great drug because it's easiest to use. It doesn't require any monitoring, right? You

01:47:23.440 don't have to monitor electrolytes. You don't have to monitor kidney function. It's a benign drug,

01:47:28.380 super easy, very few side effects other than a not super infrequent amount of what's considered to be

01:47:36.160 swelling in the ankles. It's not really edema, but it's the sort of non-edema ankle swelling that

01:47:40.920 people just don't like, especially women don't like having. So aside from that, it's a very easy 1.00

01:47:46.160 drug. For ACE inhibitors or ARBs, and I mostly don't make the distinction between the two. I probably

01:47:52.140 should, but I don't. There are data I think that do suggest that those drugs may be more indicated in

01:47:59.160 certain subpopulations. So for example, there was the HOPE trial, right? Which was, I think,

01:48:03.340 mid-2000s. And so it suggested there may be a benefit in people that have atherosclerotic

01:48:08.740 coronary disease to have an ACE inhibitor on board. So maybe in people with ASCVD or ACVD risk,

01:48:14.900 I'll use that one over the others as a first line. It's also, you know, there's the whole ARB and

01:48:22.360 aortic diameter thing, right? So people who may have a little increase, whether you want to call it an

01:48:27.720 aneurysm, but just an increase in aortic size, that there may be a benefit to ARBs.

01:48:33.100 You can start, begin to weave together all these little things. I like ACE inhibitors and ARBs

01:48:37.520 probably the best. They do require monitoring, right? So they do require that you get electrolytes

01:48:44.740 because there can be, in some patients, there can be issues, especially with potassium. And that can

01:48:50.060 impact kidney function. So it's this weird thing where the benefit to people with kidney disease is high,

01:48:55.420 but then kidney doctors are also very nervous about the potential toxicity, kidney toxicity

01:49:00.680 of ACE inhibitors and ARBs. So it's this weird thing. To answer your question, I think in people

01:49:06.520 with existing kidney disease, that that's probably the drug. The other place that I use ACE inhibitors

01:49:13.200 and ARB first line is in patients with diabetes, because that's been shown, they've been shown to

01:49:18.260 reduce the progression to diabetic nephropathy again and again. So I think-

01:49:21.720 So somewhat renal protective again.

01:49:23.240 Renal protective, yeah. I think they are probably the most renal protective beyond just getting the

01:49:27.940 blood pressure lower, which is still to me primary, the most important thing.

01:49:33.320 So really what you're saying is, look, the first, second, third order term is take that 50% up to

01:49:39.240 100% in terms of effectively lowering blood pressure. And when everybody's at 120 over 80,

01:49:45.180 we can, and we're doing it without causing ancillary side effects. So that's the third,

01:49:51.560 fourth, fifth order term. The tail end of this polynomial is the nuance around actual class

01:49:59.160 of drug inside. I think that makes a lot of sense.

01:50:03.120 And tolerability. Because I do think we probably don't pay enough attention to that. It's probably

01:50:08.440 the biggest reason for noncompliance. And I hate that term.

01:50:11.120 Yeah. I kind of include that in the second bucket, right? Is anything, whether it be ankle swelling

01:50:15.140 or a dry cough that obviously tends to occur in some people with ACE inhibitors, those things have

01:50:20.480 to be-

01:50:20.700 Older people who tend to get more orthostatic, right? I'd stay away from diurex for them. Because 1.00

01:50:25.220 falls in older people, I mean, you're not old. And you're obviously not at risk for having a

01:50:29.720 significant injury from falling. But it's a huge source of injury in older people.

01:50:34.640 Did you see my face after I fell?

01:50:36.140 You had a great story about the bar you were in the night before.

01:50:40.120 Look, I think falling is an enormous risk for an elderly population. And it's between the head 0.98

01:50:45.400 bleed and the femur fracture. I mean, these are devastating consequences for someone in their

01:50:50.500 eighth decade and beyond. I mean, absolutely life-changing and sadly often life-ending.

01:50:55.700 Yeah. And I say that with a 81, almost 82-year-old father who has unfortunately fallen now several

01:51:01.600 times. It's a bad thing.

01:51:03.180 So let's spend a minute, Ethan, talking about one other thing, kind of bringing it all the

01:51:07.280 way back full circle in the atherosclerosis world. I generally tell my patients that there

01:51:13.220 are four big pillars of risk in ASCVD. Smoking, hypertension, ApoB, and metabolic health. And that

01:51:22.860 last one is kind of squirrely because I can't point to one number that tells me, like, I can

01:51:28.980 point to your ApoB, I can point to your blood pressure. You're either smoking or you're not

01:51:32.460 smoking. But here I talk about the sources of fat that exist outside of your subcutaneous

01:51:39.720 depots of fat. And I typically talk about five of them, but I know you tend to focus on a

01:51:44.500 couple. So I want to double click on those, but just for folks listening, right? I think

01:51:48.400 the generally accepted principle of this is we as a species, one of our remarkable advantages

01:51:54.860 in evolution was our ability to store energy. Without this capacity, we wouldn't exist. And so

01:52:00.580 we have this vast network of subcutaneous adipose tissue, white adipose tissue that is incredibly

01:52:06.900 adept at storing triacylglycerides. And I think what appears very clear is that different people

01:52:13.040 have a different genetic capacity for how much they can store. So I kind of liken this to a

01:52:17.240 bathtub. Everybody has a different size bathtub. And the water coming in the bathtub is how much

01:52:23.240 you're eating. And the water leaving through the drain is how much energy you're expending.

01:52:27.120 And if you're accumulating fat, you are obviously consuming more than you're expending. But at

01:52:34.160 some point you could fill that bathtub up and water can escape the bathtub. And that's when 0.97

01:52:37.980 really bad stuff happens, right? That's when it gets into the floorboards, the electrical

01:52:43.080 stuff, and that's a disaster. And you don't need to get a lot of water out of the tub for 0.92

01:52:48.100 really bad things to happen. Ask anybody who's gone through a leak in their house. You might

01:52:54.000 have 100 gallons in the bathtub. If two gallons escape in the wrong place, it can be a disaster.

01:52:59.780 And so talk about the places where it escapes. So around the viscera, within the muscle itself,

01:53:04.600 in the pancreas specifically, which we can talk about maybe why that's so problematic,

01:53:09.040 pericardial fat. Tell us a little bit about why this is so problematic.

01:53:13.180 Well, first of all, I'm so incredibly impressed at how you tell that story because it's exactly how we

01:53:17.660 tell the story. And we learned it from Steve O'Reilly, who I think is the sort of godfather of this

01:53:22.300 concept. I think we've all appreciated for some time that there's a relationship in terms of risk

01:53:28.460 and weight, that that's imperfect in BMI, right? That BMI is not a great measure of risk. It is

01:53:35.900 in epidemiology. It is in large populations. We also know that how much fat you carry. So overall

01:53:41.300 adiposity is important. But what we've learned really in the past 20 years is that, as you've said,

01:53:46.120 that it's not so much even how much fat you have, it's where you carry it. And that we are

01:53:50.340 evolutionarily programmed to store energy in these places around our hips and our butt and our legs

01:53:56.760 and not as much up here in our bellies and definitely not in our organs. That's a bad thing.

01:54:04.740 And that has been shown to be a very potent predictor of risk and that there are a number of

01:54:11.500 genetic alleles that predispose to both these differences in body composition, but also to

01:54:17.560 differences in risk of developing diseases like coronary disease and diabetes. So super fascinating

01:54:23.200 area that I'm going to devote the rest of my life to understanding and trying to fix. The question

01:54:29.180 you ask, which is why is it that if you overwhelm the bathtub and leaks out, gets into the floorboard,

01:54:36.460 why is that so bad? The answer is not one I can give you, but we started our sort of process and

01:54:43.940 thinking about this problem and thinking about the extremes of biology in particular,

01:54:48.880 these rare genetic diseases that are called lipodystrophies, where people are born with the

01:54:53.780 inability to store fat at all in generalized lipodystrophy or with just an isolated inability

01:55:00.520 to store fat in the gluteo-femoral and subcutaneous regions in the legs. They have a selective loss of

01:55:05.860 adipose tissue in their butt and their legs and therefore a huge overabundance of fat in the abdomen,

01:55:12.420 in the viscera, in the liver, in the pancreas, in the heart, as we talked about. And those people

01:55:17.160 have tremendous metabolic disease and extraordinary levels of risk, right? I mean, there's small numbers

01:55:22.880 of people that have rare diseases and all of these studies are observational, but there's a beautiful

01:55:28.880 paper from Canada from 20 years ago showing that people born with these sort of congenital forms of

01:55:38.560 severe insulin resistance, be it either lipodystrophy or type A insulin resistance,

01:55:43.020 have astronomical coronary artery disease risk. There are women who are having bypass operations

01:55:47.980 in their 30s and 40s, which is basically unheard of in women. So I think the question of why that is

01:55:56.060 remains unanswered. I think there are lots of different potential hypotheses. You know, I think

01:56:02.180 the role of insulin and its impact on different organs and tissues and cells is interesting.

01:56:09.740 We don't have an answer yet. What we do know is that there's this very strong now association

01:56:15.400 between these different shapes, body shapes, right? The apple pear thing and risk of developing these

01:56:21.360 diseases. And so I think if you look at the epidemiology curves of say coronary disease over

01:56:27.120 the past 30 years, we've done an amazing job of reducing the risk of coronary artery disease events

01:56:31.740 using all the tools we have at our disposal, whether that's, you know, blood pressure, smoking cessation,

01:56:36.700 lipid management, et cetera, et cetera. Yet, as you mentioned at the very beginning, it's still the

01:56:41.860 number one cause of death in the world and even in the COVID era. And so it's still a huge problem.

01:56:49.000 So the question then to all of us is, what is that? Is that just that we're not adequately using the

01:56:54.200 tools we already have? Or is it that we're missing something else or is it a combination? And I guess

01:57:00.220 I would sort of probably bet that it's some combination of sort of, we're just not doing

01:57:04.840 a good enough job with what we have and there's probably something else there. And so that's the

01:57:09.280 focus of sort of what I want to spend, like I said, the rest of my life thinking about.

01:57:13.060 I would agree with you. I think it's really a combination. I think we start too late and don't

01:57:17.460 go low enough on lipids. We fail to recognize and don't get enough traction on blood pressure.

01:57:24.760 I still think nearly 20% of people still smoke. So it's not like we've taken that one out of the

01:57:29.240 gate. And then I do think that this pillar of poor metabolic health is so improperly understood.

01:57:36.600 And I don't think we're identifying people at risk because I think about how little I know about my own

01:57:42.600 state here. I have a pretty good sense from any blood test you can do. I can do a DEXA scan. It

01:57:47.340 tells me how much VAT I have. My transaminases are adequate. So I'm going to assume and based on last

01:57:53.860 test, no liver fat. But other than that, it's a real blind spot, right? I mean, I don't have the

01:58:00.020 clarity that I would have about my APOB, for example, or my blood pressure. And that's, I think,

01:58:06.000 because we're sort of increasing our very poor resolution of this problem, starting with the most

01:58:10.460 blunt tool of all, which is BMI and then moving to other things. And even what you just said,

01:58:14.820 I think it still represents probably a very low resolution image into this, just focusing on VAT.

01:58:22.220 We know that's bad, but here's a question, right? Just a thought experiment is, is the problem with

01:58:27.280 VAT, is that a defect in the ability to store fat where it should be stored in the gluteal femoral

01:58:32.400 depot? And is that just a manifestation of that? Is there something different about VAT? Is there

01:58:36.900 truly a benefit to having more fat in the gluteal femoral? So in other words, to your

01:58:41.180 bathtub analogy, if you could make a bigger bathtub, would you be more metabolically healthy?

01:58:45.240 Well, certainly there's one experiment that Gerald Schulman did that obviously it's a contrived

01:58:49.800 experiment, but it would certainly suggest in the model. So he looked at a mouse model where the mice

01:58:54.440 had profound insulin resistance and he would just put more and more subcutaneous fat into those mice

01:59:00.400 and they got fatter and they got less insulin resistance. They actually got paradoxically fatter and

01:59:05.420 healthier. So in at least that intervention, allowing them to get fatter, making them have a

01:59:10.820 bigger bathtub improved them. But it's not clear that that's the same thing, right? In other words,

01:59:16.480 that doesn't answer the question, is VAT bad simply because it's not in the subcutaneous space or is it

01:59:23.540 doing something fundamentally different? And I think that's where we want to sort of eventually

01:59:27.240 understand, right? Is are there cytokines that are coming out of those cells that are different from

01:59:33.260 the cytokines coming out of the other cells? And how does that, you know, factor into it?

01:59:38.420 There are all kinds of things that we're learning about the difference in basal lipolytic rate between

01:59:41.880 the two depots. And again, we're just describing these depots based on what we can see and how we

01:59:45.760 can describe them based on a dexoscopy. Right. So it's just so low resolution compared to what we care

01:59:50.300 about. It's very low resolution at this time. I think what we can say is that in a patient with lipid

01:59:56.700 is an extreme who has normal lipids, right? Not normal triglycerides. So L may be a modest elevation

02:00:02.620 in ApoB, but ApoB triglyceride, that those people have extreme increases in risk independent of their

02:00:08.040 traditional risk factors. We think that there's a group of people, and I've now, as I've been

02:00:13.440 thinking about this, begun to see these people all over. And once you see them, you can't not see

02:00:17.380 them. But we think there are a group of people here who represent probably some polygenic version of

02:00:21.440 this where there's a relative decrease in fat in the legs. Like I can think of patients now who've

02:00:26.140 come to my practice who may have a tiny little pot belly, but their lipids were sort of not that bad

02:00:33.480 and their legs are super skinny and they had a bypass at 38 or 40 or 41. And the number of people

02:00:39.800 I can think of like that keeps getting bigger and bigger. And I think what we're going to learn is

02:00:44.960 that gluteal femoral storage capacity is going to be an important driver of risk in this context.

02:00:50.460 And finding ways to change that if it's possible would be of great benefit. I think

02:00:56.020 it remains to be seen if it can be changed. There is some very poor evidence, right? If you

02:01:01.640 talk to the plastic surgeons, they've begun to understand that there are metabolic consequences

02:01:07.960 to taking fat out of places like the legs and the hips that are very different from taking fat out of

02:01:14.460 the belly. It's like Jerry's experiment of putting in more subcutaneous fat. It's just helping to guide

02:01:20.820 us towards this idea that there's something there. I think it's really going to be interesting,

02:01:25.560 Ethan, is when you start to look at this in the much larger and less extreme population of those

02:01:32.360 without lipodystrophy. So the cases you're describing are profound. But the question is,

02:01:37.940 this is probably also playing a very big role in people who aren't the ones showing up for bypass at

02:01:43.880 38 years old, who don't have the complete lipodystrophy where they have no ability to store

02:01:48.920 fat on their legs and hips. And so the question is, are there targeted and directed therapies that

02:01:55.820 can be aimed at the metabolic tip of that spear? That's what we're doing. So my answer to you is

02:02:02.720 we think so. We need to do the experiment to demonstrate that. But using human genetics as a

02:02:08.220 guide, there are a number, large number of alleles that seem to confer this concordance of changes that

02:02:17.580 are in both directions. So for example, people who have alleles that confer more gluteal ephemeral.

02:02:24.040 So really what's important is not so much the amount of visceral fat you have and an absolute

02:02:28.260 censored amount of gluteal ephemeral fat. It's really the ratio in DEXA terms that may be on your

02:02:33.440 DEXA reports called fat mass ratio. And there are different levels that are normal or abnormal for

02:02:38.120 women and men. But having a high fat mass ratio, meaning having more fat up here and less fat down here 0.96

02:02:43.380 is bad. And there are alleles that confer that and that they do also confer a bunch of changes in

02:02:50.900 other things that we know are bad, including lipid-based biomarkers and then diseases like

02:02:56.260 coronary disease. How concordant are these alleles? So do you have enough data to look at identical

02:03:00.780 twins and say that the genes are completely concordant between them and the phenotype?

02:03:07.020 I don't know of any twin data, but I do know that there are certain of these that are common

02:03:11.560 enough that you can find heterozygotes and homozygotes and it looks like there's a dose

02:03:15.060 response. And again, it's not just one. It's not like there's just one of these things. So I do think

02:03:20.240 there will be targeted therapies and we'll test one sooner than later. We'll probably begin by testing

02:03:26.560 it in patients with lipodystrophy. But the hope and expectation is that we'll move beyond that and

02:03:32.020 to eventually try and target other metabolic-associated diseases and ultimately the most

02:03:37.140 metabolic-associated disease, which is coronary disease.

02:03:40.580 What percentage of the patients with a phenotypically appreciated lipodystrophy

02:03:44.280 have an identified set of genes or gene that results in that?

02:03:48.760 It's probably on the order of 50%. It's a great question because we don't really look.

02:03:53.120 Recognition and diagnosis of lipodystrophy is abysmal. And Steve O'Reilly, who at some point,

02:03:57.300 if you ever can convince him to come on, he's one of the most entertaining human beings I've ever been

02:04:01.520 around. And I love every moment I spend with him. And read his Banting Medal lecture from 2019,

02:04:06.220 which was just astonishingly brilliant. He gave it at the ADA, which was here in San Francisco that

02:04:11.500 year. But Steve will say that the problem is that we don't take our patient's clothes off. If you don't

02:04:17.620 undress your patient, you'll never see it. And actually, we have some patients with lipodystrophy

02:04:22.360 who are big in the advocacy groups and they've been incredibly helpful to us. And they often tell the

02:04:29.700 story that their own personal diagnosis of lipodystrophy happened by accident because it

02:04:33.820 happened to be a warm summer month and they were wearing a skirt. And a doctor was able to see

02:04:37.180 that their legs were super skinny and muscular. So I can't answer your question because we just

02:04:41.280 don't know what the denominator is. Partial lipodystrophy is characterized or classified in

02:04:46.040 how it's been defined historically. And there's familial partial lipodystrophy 1, 2, 3, 4, and beyond.

02:04:52.720 And FPLD 1 doesn't have a monogenic cause. It's by far and away going to be the most common.

02:04:59.040 But there's not an agreed upon way to make that diagnosis today, which I think is a major problem

02:05:03.480 and is going to need to be addressed. Because a doctor, if you talk to an average doctor,

02:05:07.700 will never have heard of lipodystrophy, would clearly never even be thinking about it. And I'm

02:05:11.140 saying this having had the experience myself where I probably just never thought about it. We're

02:05:16.440 conditioned to think that leanness is good. Leanness and muscularity are good. And if you see

02:05:20.900 leanness and muscularity, if you haven't even seen it, it's a good thing. You never would think,

02:05:24.920 well, this is a problem. Look, to me, this is interesting in that it becomes the index

02:05:29.380 upon which you can build a far greater set of insights. Because again, while I think this

02:05:34.580 population experiences such an extreme consequence of this, I think I share your belief that this,

02:05:42.460 even absent a lipodystrophy, this is still a problem. You know, the lipodystrophy patient has a

02:05:46.920 broken bathtub. Of course. It's not like a normally shaped bathtub. It's a jagged bathtub

02:05:52.440 that is more quick to overflow because it's simply smaller and therefore they show up much sooner with

02:06:00.140 this problem. And to your point, if the clinician would simply walk in the bathroom and go, how come

02:06:05.220 that's not an oval? Well, I need to be looking harder. And I think that's the expectation is that

02:06:10.100 they represent a very rare version of what happens when the whole thing goes awry, but that they're

02:06:15.940 going to be more common versions of this that exist. And it's very similar, I think, to the

02:06:20.300 distinction between familiar hypercholesterolemia and run-of-the-mill hypercholesterolemia. And

02:06:25.180 we've learned a lot from rare diseases. This is a case where we'll learn a lot. And in this case,

02:06:30.000 we already have an abundance of human genetic data that suggests this sort of polygenic version of this

02:06:36.920 thing. And there'll be some papers coming out soon with collaborators of ours that will show

02:06:42.060 that the FMR itself conveys more risk even than smoking status. And that's a pretty amazing

02:06:52.600 finding, right? That if you have a high FMR, meaning you have a lot of fat up here and not

02:06:57.360 very much fat down here, that your risk of significant bad things in the form of coronary

02:07:02.460 disease events is higher than it would be even if you smoked cigarettes, which is astonishing. And I

02:07:07.200 think none of us would have believed that. I do like the analogy of FH because FH is also

02:07:13.480 a very, very heterogeneous wastebasket of genetic things. More than 3,000 different genotypes that

02:07:21.140 produce this phenotype. But interestingly, at least one of them has now become, I think,

02:07:27.000 the most powerful drug we have on the market, right? Which is the PCSK9 mutation.

02:07:30.360 So it'll be interesting to know if how much the genetic insights will also form therapeutic

02:07:38.580 options for the people that don't have lipodystrophy.

02:07:42.760 In this case, at least what I can say with some confidence is that the rare genetics are probably

02:07:47.220 not going to be as informative, certainly not as informative as PCSK9, which I think stands alone

02:07:52.780 in terms of the quality of its informativeness, both as a rare disease mutation, but also as a common

02:07:58.780 disease variant. But the genes that underlie the common variation in these phenotypes are,

02:08:05.920 I think, going to be very interesting. And so I think that's where we're focused. Because the

02:08:09.280 rare disease, the single gene mutations, you know, one of the most common, the disease underlying

02:08:14.980 FPLD2 is a mutation in laminate. We know that this leads to progeria, it leads to cardiomyopathy,

02:08:21.000 it leads to muscular dystrophy, it leads to lipodystrophy. It's a complicated mess of a protein

02:08:26.140 that's expressed in the nuclear laminate. It's hard to kind of imagine that common variation in

02:08:31.200 that gene is going to lead to problems. It might, but it's not obvious.

02:08:35.360 Well, Ethan, this is really interesting. We've covered a lot of ground. Some of it we repeated

02:08:38.460 from before, but I think it was necessary both because I just don't think everybody has the

02:08:41.380 capacity to go back and listen. But I also think we have a couple more years of insight. So thanks

02:08:45.040 again for making time. And for me personally, this whole getting deeper down the rabbit hole on

02:08:49.280 blood pressure thing, I'm hoping that enough other people are equally becoming interested in this

02:08:53.960 because I just worry that there are too many people walking around out there who have no idea

02:08:58.140 what their blood pressure is. And even if they're just 10 millimeters of mercury above normal, as you

02:09:06.120 pointed out, you know, the consequences are significant. And again, it's just such an eminently

02:09:09.940 treatable thing. It's a tragedy. This is not a new problem. And I'm glad that you're latched on

02:09:15.960 because it is one of these terms of things that probably are lowest bang for the buck in public health

02:09:21.480 these days, maybe short of vaccines. This is at the top of the list. If we could just raise awareness

02:09:26.280 and treat this, because I think we've done a really good job on the lipids. The lipids,

02:09:30.460 you know, what's left over now is probably, it's not awareness. But blood pressure is one of these

02:09:34.840 funny things. For whatever reason, it's just not sexy. And it's very hard to convince somebody

02:09:39.940 to do something that doesn't make them feel better. And in some cases may make them feel worse.

02:09:45.180 We've known that for a long time. And this is one of these things where you're trying to get

02:09:48.760 somebody to understand that it's not going to have any impact on positive impact on them for years,

02:09:53.760 decades. All righty. Thanks very much. And good luck as you continue to work on this problem.

02:09:57.900 Yeah, I look forward to seeing you in person someday. Hopefully, we'll hook up.

02:10:01.420 Sounds good, man. Thank you. All right. Thank you.

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02:12:35.220 Thank you.

02:12:41.960 Thank you.

02:12:42.900 Thank you.

02:12:50.760 Thank you.

02:12:51.940 Thank you.

02:12:52.580 Oh.

02:12:53.000 Thanks.

02:12:53.020 I'll tell you.

02:12:53.160 Thank you.

02:12:54.500 Thanks.

02:12:55.220 Thanks.

02:12:56.140 Thanks.

02:12:56.560 Thanks.

02:12:57.140 Thanks.

02:12:58.260 Thanks.

02:12:58.780 Thanks.

02:13:00.120 We'll call you.

02:13:01.080 Thank you.

The Peter Attia Drive - March 20, 2023

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

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