The Peter Attia Drive - #52 - Ethan Weiss, M.D.: A masterclass in cardiovascular disease and growth hormone - two topics that are surprising interrelated

Episode Date: May 6, 2019

In this episode, Ethan Weiss, Hopkins trained preventative cardiologist at UCSF, discusses two topics that on the surface may seem unrelated which is cardiovascular disease, and the role of growth hormone and IGF in disease. Ethan provides a masterclass in everything from acute coronary syndrome to all of the complex nuances around stent placement, as well as how calcium scores and results from CT angiograms shape his treatment of patients. He also shares how his idea to study the sex differences in blood clotting as it relates to coronary disease lead him to pursue the field of endocrinology, and specifically what he found with respect to the effect of growth hormone and IGF on the liver, the brain, and overall human longevity.  We discuss: Mutual love for hockey [7:15]; Ethan’s background and interest in cardiology [13:15]; Clinical definitions of a heart attack, clotting, and plaque: What causes the acute event? [24:15]; Defining coronary disease and myocardial infarction: The evolving nomenclature [32:00];  What happens when someone comes to the ER with a STEMI (ST elevation myocardial infarction)? [47:15]; Stents [54:45]; Treatment protocol for both acute and chronic coronary artery disease: History, controversy, and important distinctions [1:06:30]; Using stents to treat stable angina: What we learned from the COURAGE AND ORBITA trials [1:15:30]; The “art” of longevity: The challenge of preventative medicine and understanding risk [1:31:45]; Understanding CAC scores, and CT angiogram results [1:40:15]; How sex differences in clotting and heart disease got Ethan interested in growth hormone and IGF [2:01:00]; Impact of growth hormone on the liver [2:07:00]; Growth hormone and insulin sensitivity [2:18:00]; The role of GH and IGF on chronic disease and cancer [2:23:30]; Will taking growth hormone promote longevity? [2:32:30]; GH and IGF as a treatment for early stage dementia? [2:34:30]; What happens to IGF while fasting and what about fasting improves longevity?  [2:35:15]; The importance of becoming scientifically literate and making science more exciting for future generations [2:38:30]; Ethan’s new company: Keyto [2:43:45]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information

on today's episode and other topics at peteratia-md.com. [♪ OUTRO MUSIC PLAYING [♪ Hey everybody, welcome to this week's episode of The Drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about, professionally, are how to live longer and how to live better. I have a complete fascination and obsession with this topic.

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If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. I guess this week is my good friend, Dr. Ethan Weiss. Ethan and I have known each other for a few years. We both sit on the advisory board of a company called Virta Health. And we've always found ourselves sitting around the table at these meetings or elsewhere, just having super nerdy discussions and we just decided we got to at least put some of these discussions on the podcast. So what follows is a really deep and for me, certainly interesting discussion, about two topics that at the surface seem completely unrelated. Cardiovascular disease and the role of growth hormone and IGF in disease.

Now, it won't be clear from what I just said, why one guy would be an expert on both of those things. But as the story unfolds, you'll see that Ethan is quite a unique individual. By training, he's a cardiologist. He specializes in preventative cardiology at UCSF, trained at Hopkins in both medical school and in his residency and then completed his fellowship at UCSF, where he has since remained. And his interest, you know, are wide ranging from prevention and all aspects of it, which

includes lipids and the management of blood pressure and the endocrine system, et cetera. But what I found most interesting in this discussion, in addition to just the master's class in understanding everything from acute coronary syndrome to all of the complex nuances around stent placement, which is something that I think anybody listening to this knows at least somebody who's had a stent placed and to sort of go through all of that literature

and detail and understand who were the ideal candidates versus who is not. All of that, I don't want to say paled in comparison because I would minimize it, but it was nothing compared to at least for me diving into what led him to pursue this field of endocrinology and specifically what he found with respect to growth hormone and IGF. And this is something I only knew about Ethan maybe six to nine months ago. It was really quite recent that this came onto my radar about his level of expertise in this.

So we just spent a great deal of time talking about this. And you could almost think of this as two separate podcasts, one that really deals with cardiovascular disease, specifically interventional radiology and diagnostic techniques. We talk extensively about calcium scores and CT and jugrams and things like that that we get asked about all the time. And then there's basically a second podcast here, which is a really interesting discussion around growth hormone, its effect on the liver, the brain, et cetera. Finally, we touched really briefly at the end on a company that Ethan has started quite

recently called Keto or Keto, depending on how you pronounce it, which is a breath analyzer for acetone. So again, nothing that novel there, but what is novel is the way this device works and socially kind of provides feedback and allows you to get great feedback when you're fasting or on a ketogenic diet or something like that. So I hope you enjoyed this podcast. This is one of those ones where the show notes are really going to be helpful, especially for people who actually want to go back and look through all of the literature in all of the clinical trials we talk about. And even just some of the diagrams, frankly, to even understand when we're talking about EKG changes and things like that, sometimes the diagrams help. So without further delay, please welcome my guest,

Dr. Ethan Weiss. [♪ music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, music playing in background, the glass whiteboard is just next level stuff. We got a little bit of flack when we picked these out. The architects, this is actually super fancy Italian glass and the architects sort of convinced us you'll really appreciate it. I love it. Actually, my kids love it too. They've daked out their own territory on this. I actually like that the kids have their drawings,

adjacent to the drawing of emtor. Yeah, perfect. I think you should always be able to mix those. The other thing that I don't know, I guess it's because I've never been to your office that I don't know how we have never discussed is our mutual appreciation for Wayne Gretzky. You have in front of me a home jersey, circa 1986, Edmonton Oilers signed by none other than the great one. Yeah. Look, I grew up in Baltimore, which was not really a hot bet of hockey. I think they were the skipjack, my early hockey team,

AAA team, I guess, I don't know if they call them that in hockey. Anyway, we had the skipjacks and the clippers, and I never really was too into hockey. I was a baseball fan and a football fan, but my dad had grown up in Chicago and really did like hockey. And one year we were back there visiting my grandparents for Christmas. I think it was the winter of 1979. He said, let's go to a black hockey game. So we went to the old Chicago stadium. It was my first introduction to this game that I basically fell in love with instantly. And at that time in the late 70s, early 80s, it was the birth of these dynasties, I think first the islanders and then they had been to the oilers. And you couldn't be a sports fan,

but you couldn't be a hockey fan, and not appreciate Gretzky. So I eventually developed into being a Washington Capital's fan, which was sheer torture until last June, which was super fun, but in the process of being a fan, of course I always remain true to Gretzky. Anyway, a couple of years ago, my mom said,

hey, look, I'm coming to California. We're going to go to LA. My uncle, my brother, my uncle is an oncologist down there. He's being honored by the Sarcoma Foundation. I said, sure, it's an hour flat. I can hop on. I'll come down. I'll join you.

So we go, it's one of these LA galas, and there's like a big series of tables with a bunch of silent auction items. And I walked by this jersey a couple of times and on the third or fourth time I walked by the guy who was mainly in the table stopped me and he said, Hey, you know, buddy, I see you walked by that a few times. You have any interest in it? I said, yeah, I've got interest in it, but there's I can't I can't afford that. And he said, now listen, I'm pretty sure if you bit the minimum, you'll get it. And the

minimum minimum bid was $100. And I said, you, listen, I'm pretty sure if you bit the minimum, you'll get it. And the minimum minimum bid was $100. And I said, you got to be kidding me. Gretzky played here in LA and how can that's impossible? It's a signed jersey. It's beautiful. The frame alone is worth more than $100. So he finally convinced me to do it. I put down the bid and I walked out with this jersey, which my wife instantly told me

she loved, but she loved it anywhere but our home. So I brought it here and it's awesome as a conversation starter when people come visit. What I immediately loved about it was when I was 10, so 1983. So just as the, it was kind of the year that the oilers lost their first-handly cup to the islanders who were winning their fourth. And I wanted that jersey for my birthday. And I got that jersey. It took a lot because the jersey cost $50. And I just asked my mom if I could ask all the kids at my birthday for money instead of gifts.

And I remember everyone showed up with $5 to $10, and it added up to $50. And I still remember it. Like it's really one of those amazing, really memories to go and be able to buy it. And I was really torn between the home and the away jersey. I went with the home jersey, which is the one you have. And it was so big.

Like I just couldn't, you know, I just wanted to make sure I never grew out of it. And I probably wore it for like, you know, every day for three years. The sad thing is I don't have it anymore. I, it really bums me out that it somehow got lost because it would be such a cool thing to show my kids and have them roll their eyes out one day. That one's amazing. So wait, you grew up in Toronto.

Yeah. And you were in a leather stand? I was. I mean, the Leafs were not Toronto's such a great hockey town that going to games was, I mean, just the greatest highlight of my life. And I even got to see a few Euler games. You know, always in the cheapest seats in the house, Maple Leaf Gardens had sort of this color system.

So the gray is up at the very top, as we're usually sad. But back then, it was so unsophisticated that if the game was a blowout by the third period you could sneak down into the golds and you could be like right there. I actually had dinner with Mark Messier a few months ago who I just met and he's just the most amazing guy. And we, I mean, I'm sure he's so tired of doing that, but we just rehashed all of the Euler glory days and it's sort of hard to believe that you could have Gretzky, Messier, Curry, coffee, Kevin Lowe, Grant Führer,

all on the ice at one point in time. It was hard to believe before I went to Edmonton, but I took my daughter four years ago now to go to the Women's World Cup and we decided to go to Edmonton for some reason. I can't remember, it was just like a best chance of seeing the American women's team play. So we spent three go to Edmonton for some reason. I can't remember, it was just like the best chance of seeing the American women's team play. So we spent three days in Edmonton in July

and we walked by the old, whatever it was. Northern lands call us in. I think they built a new one. In any case, I thought, wow, it was pretty amazing that these guys would all be here, but then you see Edmonton and you think, oh my God, like I cannot believe they kept them here as long as they did.

It's really a remarkably, I don't want to be harsh about Edmonton. I mean, I'm sure they're great things about it, but it's not glamorous. It's certainly not like that. Yeah, it's not like that was the New York Rangers. No, yeah. Or even Vancouver. Or Toronto or Montreal.

Not at all. Yeah, we share something in common, which I guess is this Hopkins thing. You were a few years ahead of me. So you did med school and residency there, didn't you? I tell people I kind of grew up in the hospital. I wasn't born in Baltimore, but my dad moved. thing. You were a few years ahead of me. So you did med school and residency there, didn't you? I tell people I kind of grew up in the hospital. I wasn't born in Baltimore, but my dad moved. So I was born in Ann Arbor, Michigan, where my dad had done his internship. And I like

a lot of people of his, at that time and of his age in a sort of effort to avoid going to Vietnam. He picked up from Ann Arbor and moved to Bethesda, where he worked at the NIH for a few years. It's actually a pretty funny side story, which I didn't really understand what my dad was doing. I was young, I was only two. And I found a bunch of marijuana cultivation books in his office when I was a kid.

And I said, Dad, is there something I don't know about you? Because you don't strike me as the kind of person who would be, he said, no, this is what I was working on the lab. We were working on marijuana. He was working in Julie Axelrod's lab. So we ended up living in Bethesda for a couple of years and eventually he finished and he went back to,

he went to Baltimore where he finished his residency and then did his fellowship and joined the faculty at Hopkins in cardiology and he remains on the faculty there has been on the faculty for over 40 years. So I grew up going to the hospital as a kid to visit my dad at work and then My very first summer job was to work in that hospital So it was sort of a second home for me and then I went away to college and came back and I did medical school there and Stayed around for residency and then moved to San Francisco in 1998 20 20 years ago. Did you always want to do medicine?

No, never It was a combination of sort of, I think, not really wanting to do exactly what my dad had done, but also not having the aptitude for it. And I was a pretty bad, I was a very average student in high school, but particularly in an average, or mediocre science student. And so I went off to college, I went to a vassar,

which is a liberal arts school, and intended to study music. Actually, I really kind of was going to study music. And realized I didn't have the talent to do that either. And just sort of on a whim decided to take a science course. And it was one of these sort of freak accidents that happened to be a place where science was friendly and presented in a way that was appetizing to me and non-threatening. And I think if I'd gone to a place like Harvard, there's no way in the world I'd be sitting here right now doing what I'm doing. So I really enjoyed science at that

stage in life. And eventually when I figured I wasn't going to be able to do music, I said, you know, maybe I can go off and do medicine, but I'll do something very different. I had no intention of doing science. I had less than the bare minimum science requirements for medical school. So when I got to Hopkins in the fall of 1991, I was probably one of 10 non-hard science majors. And at that time, there were as many biochemistry majors as there were biology majors, it was really unusual to have a humanities people. And we were ranked in the class, you know, 1-0-120.

We all ended up in the, you know, bottom. We were 110, 111 through 120, and struggled mightily with, especially with the first year. It was a tough sledding for me. I can't imagine what Hopkins was like then. So I'm obviously a few years behind you, and I got into Hopkins for medical school in 96 or 97.

I would have matriculated in 97. I remember even at the time you'd now interviewed at a bunch of schools so you sort of saw the way it was here versus there. And I was like, wow, this place is going to be rough sledding. I mean, it still had letter grades when most schools had gone to pass fail or high pass, pass fail. And you just got this sense like this place was, if it didn't kill you, it would make you stronger, but there was a non-trivial chance it would kill you. It was interesting because of course, you know, from the outside you have people coming.

I was a student member on the admissions committee. And so you got to hear firsthand what people would think. And there was this story that you probably heard because this was probably around the same time when I was doing it that Hopkins was this like super intense pressure cooker and everybody was a gunner and you'd never survive. And it was just a miserable place to be a student. It was actually a beautiful place to be a student and my fellow classmates were really supportive. Everybody was just an incredibly strong achiever on their own. They didn't care how they just wanted to do the best for them.

So it was really inspirational. I think after I got over the shock of not being able to keep up, because really the disparity in information was tremendous. I had had one semester of biology and I'm hanging out with guys who had been working in a lab since they were seven and understood things that I still today don't understand. And I mean, it was guys like David Sabatini and Dave Brett and my high school classmate Andy Cameron. I mean a bunch of people who were just so far ahead of me and where I'd ever be. It was a fun place to be. Once I got over the idea like, hey look, I was used to being a pretty good student. And by definition, most of us probably came in here because we were at or near the top of our class. And it ain't gonna happen that way now, right?

There are 120 of us, and not all 120 of us can get an A. And once I got over that and kind of decided that I was okay with not having all A's unless I wanted to die, it was great. I think I forgot that you were in the same class as David, which of course would put you in the same class as Andy Cameron. And there's an obviously interesting story there is Andy Cameron being the son of John Cameron,

who was the chairman of surgery. And one of the main reasons I ultimately did go to Hopkins for my residency, his father of course being a luminary in the field. And of course, David Sapatini is no stranger to anybody listening to this. So yeah, I was sort of like, I guess going to med school at Hopkins in that era, it was like playing for the Yankees. In the end, I agree with you. After I interviewed there and I made a point to stay in extra two days, I came away way more

bullish on the idea that it could be a great experience. And in the end, it really came down to, I wouldn't say a coin toss. I mean, I think in the end Stanford won out for a number of reasons. I don't think it was as good at medical school as Hopkins, at least not according to the rankings. Hopkins was the best, but I think just living in California as a kid coming from Toronto seemed like a great opportunity. Well, and I did it the opposite way. I mean, I knew I had to get out after having been there for seven years and I haven't grown up in that environment.

And my dad being there made things complicated. So I knew I had to leave. And it's funny because when I got here, lifestyle is much more central to people here in California and I didn't appreciate that. And of course now I do. But I wouldn't trade that experience. It was an amazing experience and all this people.

I mean, I remember operating, I did, as a medical student, I did GI gold. You know, that was back when Cameron Yo and when was Kurt Campbell, the other attending on at that time? No, I think he was a chief resident. I'm pretty sure he was. Yeah, so I spent a lot of time in the operating room

with Dr. Cameron and wow, I mean, what an entertaining human being and master Sergiano, were they still doing Sunday school when you were there? Oh, yes. In fact, Ted Schaefer and I did an interview a while ago where we talked about our fondness for Sunday school. It was one of the highlights of internship. It was incredible. I mean, as a student, you were terrified because they told you,

you know, residents would tell you, like, you're going to go in there, you're going to present a case, you'll get through seven words maybe if you're lucky and he's going to cut you off, and then he's going to start asking you questions. So, I mean, this is Sunday morning sitting around this huge boardroom table and you're a little puny medical student in front of the entire surgical house staff, and a lot of that. And the most famous surgeon in the United States. Yeah, but of course he had a wonderful way of not humiliating people.

I mean, he was rough, but it was an amazing experience. I was really one of my favorite things that I remember about being a medical student back there. I have nothing but fond memories from my time there despite the challenges. Now, what was a medicine residency like in the 90s? It still must have been pretty freaking rough, especially at Hopkins.

So I was an intern in 1996. I think it was the first year they switched from Q3 to Q4 call, and it had been not that long since they switched from Q2 to Q3, but there were still a few rotations where you did every other night call. So as an intern in the medical ICU and the CCU, we did every other night call. And that's again, it's one of these things that you look back on.

You think, I don't know how I survived it, but in retrospect, it was really fun. But I mean, just imagine what you're doing. You're going in, you start rounds at whatever 8 o'clock in the morning, you go all day. At that time, you never left the unit. So people would bring you food. There was a bathroom and a call room adjacent to the unit. You never left the unit. And then you'd stay up all night, taking care of patients.

You'd get to rounds the next day, you'd finish by 11 o'clock, and we had this tradition of going out to have breakfast and beer with the ICU nurses. And then you'd go home, you'd take a little nap, wake up, you'd have some dinner, you'd go back to sleep, you'd do the whole thing all over again. So for 30 straight days, you basically did nothing but sleep or be in the hospital. But it was fun. It was

a incredible experience. I mean, there was still a lot of active HIV disease. And one of my favorite inpatient rotations was doing what they used to call the Osterate rotation, which is the inpatient HIV ward. And I mean, you did that as a junior resident with two other junior residents, and there was no one else around. And it's basically ICU level care. Maybe there was some of the sickest people in the world. This is a pre-protease inhibitor. So six, six, six people.

But amazing. I mean, I remember doing procedures on people who are still my dear friends, fellow residents. Really an amazing experience. So how did you pick cardiology? Well, again, so the background is I'm a second generation cardiologist, so my intention was to avoid it for a lot of reasons, but I also just wasn't really drawn to it.

But actually I did a CCE rotation as a medical student and I'll never forget we had a series of people, patients come in who were kind of in their late 30s, early 40s who had myocardial infarction had a heart attack and had relatively absent any obvious risk factors. So our assessment of risk factors for coronary disease hasn't changed a lot in the past 20, 25 years. But what I'm saying is that they had normal lipids, normal blood pressure, nothing identifiable. And I thought, wow, this is really kind of fascinating. So I worked the sour between first and second year.

I worked in a lab. I worked in a neurosciences lab. I was working on the genetics of trinocletal repeat diseases. It hadn't been proven yet, but there was a strong suspicion that some of these psychiatric diseases like schizophrenia and bipolar depression were mediated by trinocletal repeats. And it was my first time in a lab and I loved it. So I knew I wanted to go back and do that. I ended up basically asking a bunch of people.

I said, you know, is anybody here doing work on the pathogenesis of, it wasn't called ACS, or key corner center back then, but the pathogenesis of unstable engine or RMI and young people without risk factors? So I got pointed to this guy who was a young, at that time, assistant professor, Belgian guy, who went on later to be the dean of the medical school at the University of Miami. He had a blastery as academic career.

His name is Pascal Goldschmitten. So I met with Pascal and I said, Pascal, I'd love to come spend a year working in your lab. And he said, great. So that sort of was my next introduction to science. And it was really that experience, which was phenomenal on career defining for me that drove my clinical interest more than the other way around. So I kind of at that point had thought,

well, this is kind of fun, but maybe I'll do adult cardiology or maybe I'll do pediatric cardiology. And I'm not entirely convinced I know the answer yet, but ended up eventually deciding that I didn't like parents. And so I went down the path of doing adult cardiology. I want to touch on all the stuff you just brought up because you and I have had so many discussions about this over the past couple of years and I've always found you to be one of the most lucid people at describing these distinctions and sort of synthesizing this.

And for someone like me who is not really on the front lines of acute cardiology problems, it can be an overwhelming body of literature. So let's just start with some of the semantics, acute coronary syndrome, unstable angina, stable angina. How would you define all these terms for folks? And what's the framework in which you anchor these things? This is what's amazing is if you go back in time, it was relatively recent in history that there was a debate about the cause of most micro-real infarctions. 99% of heart attacks in this

country happened because of a ruptured atherosclerotic plaque. And that's worth even pausing on for a moment because I don't even think that most people realize that. I think most people think that a heart attack occurs when the pipe narrows, narrows, narrows, narrows, and finally closes so that when you hear about so-and-so, who has a 95% occlusion in the artery on the end, you know, my God, that's just 5% away from killing them. And they sort of don't understand what I think you just said. So can you double click on that point? Yeah. Well, this is what's so amazing is that if you go back not that far in the literature, you'll find articles where people are having a debate about whether the, so they, they

did autopsies on people who presented with sudden cardiac death. So somebody would show up dead from a heart attack. They do an autopsie. They'd open up the heart, open up the artery, and they'd find a clot there. And there was a debate about whether that clot was primary or secondary. Was it there before or after the person died? Was it the basis? It really was the work of Michael Davies in the late 1970s and early 1980s that kind of demonstrated proof the idea

that this was actually causal. And then early 1980s, I think it was, I can't remember the exact trial they went in and actually aspirated out clots and people who showed up in the emergency department with a heart attack. And those people got better So this was pre angioplasty, but they were able to aspirate out the clot using a suction catheter and people got better And that was the the first demonstration that this clot event was the primary cause of most heart attack

so again the pathologist leading the discussion on how that happened and what you could see in anybody was you'd see a lot of these plaques. And Davies described, I think I can't remember which paper was off the go back and find it for you, but he describes something that stuck with me, which was that if you look at an autopsy, somebody who presents with a heart attack and dies, you'll find, you can tell by looking at the histology, how many times the plaque is actually ruptured, a much like you'd look at the age of a tree. So you can see that there's plaque rupture,

and then there's healing. And actually now, you know, other pathologists like Reno-Varamina, others have said that a lot of the progression of coronary disease, so getting narrow on narrow was probably that event happening sequentially. So plaque rupture healing, and then as you do that, you're laying down more

virus tissue. So he could see how many times, and on average, these people in that first series had had seven plaque ruptures in their culprit artery before they died. At the same point in the artery, or along different points. In the same plaque. So in the same plaque. And so that told. So basically a seven-ringed tree on the cover of Starry's Pathology book, which is, I've talked about this before,

it's sort of one of the most important books I have to explain atherosclerosis to patients. There's actually a picture on the cover that shows a very comparable lesion to that, which is just these concentric rings, where the final one, you have this big dark bloody clot in there, which was obviously the fatal one. That was what lit the fire for me scientifically

back when I went to Pascal. I was struck with this idea, well, gosh, if it like, why didn't somebody die at the first, why don't they die after the first one? Like, if the reaction is, so just for listeners, the contents of that plaque, what we're calling this atherosclerotic plaque, it's rich with lipids and inflammatory cells, but the thing that causes the heart attack is not on that stuff. It's that the macrophages, which are these white blood cells, carry around this protein called tissue factor, which is then basically the instigator or the trigger for the clotting cascade. What you're doing is exposing blood, flowing blood to tissue factor, which is basically

a wound healing signal. So if you cut yourself, we have tissue factor underneath the anithelium, which is that interlying of our blood vessel, and that's there to sense injury. And when the blood sees tissue factor, the blood had, there's a biochemical reaction that we've been described per decades that ends up resulting in a blood clot. It's sort of an epoxy, you know, those epoxies that come in two separate tubes, taken alone, they're not sticky, but when the tube combines them, it becomes like rock solid glue. So the macrophage exposes the tissue factor. Now the blood passing through becomes the other tube of the epoxy.

And boom, you get this acute brick. I've been describing it as substrate and trigger, but I think that's a much better, I like your description. So, and that was, again, a debate not that long ago about what the cause of these things was. Eventually, within a 10-year period, we learned so much because it was, again, a debate not that long ago about what the cause of these things was. Eventually, within a 10-year period, we learned so much because I think 1988 that ISIS 2 was published and ISIS 2 was the, this is out the top of my head, but I think it was a comparison of aspirin and streptokinase versus aspirin alone in patients who presented

with heart attack. It tell folks what streptokinase does. Streptokinase is what's called a thrombolytic. So streptokinase is a natural substance that we make or we make something similar that dissolves clots. So clouting is sort of this balance, this battle between pro forces and anti forces. Because if you think about it, if you're a mammal and you have a circulatory system,

you have to be able to sense injuries so you can keep your blood from flowing out of you. So the system has to be incredibly tuned, and you as an engineer will appreciate how you must be able to respond incredibly quickly, but it has to be specific, so you can't get clots happening. We all know what happens. That's such a great point to make, right? So let's go back and think about this with the lens of evolution.

You get a scratch across you. As bad as that scratch or cut is, it still represents a fraction of the surface area of your vascular system. So, to your point, you have to have a system in place that can identify the area that needs to be fixed hence the two-check system where I have to have the tissue factor which allows for the local aggregation. And then very quickly you have to respond. And yeah, if it was just a diffuse response, well, you'd kill the organism by clotting everything within the circulatory system. Well, that's right. And we really appreciated that through human genetics

and then later mouse genetics. So if you knock out any of the pro-quagulant coagulation factors, say, you know, any of the one, you know, factor two, pro-throwman, you'll get a sick mouse, but the mouse will survive through development. So they will survive, and then when it kills them is the process of being born.

So they'll die right after birth. If you knock out one of the anticoagulants, a knockout, say protein C, protein S, any of the anticoagulants, the mouse won't make it through half of the embryonic, basically day seven or day eight, they die. And then there's the whole other interesting language we won't have time to get into today, which is the role of the placenta and help placenta don't clot off. And there's just unbelievable fascinating evolutionary biology

that we can send out. Unless someone else helps syndrome, that becomes this awful exception to that rule where you get these infarcted clotted placentas. And then the fetus is usually underdeveloped. So well, not an expert, but I think that one of the most common causes of fetal loss of idiopathic fetal loss, so women who end up losing multiple pregnancies again and again, is an undiagnosed, hyperquagulable state, I think, because basically the placent ends up clotting off. You're saying in the case where you don't have an obvious aneuploidy that, or a chromosomal abnormality, you know.

So is it easier to talk about where we were 10 years ago, where we are today, or do you want to just define today? So you've talked about what a myocardial infarction is. Yeah, we got sidetracked. So, yeah, that's what I do here. I sidetracked. That's fun. So myocardial infarction was defined clinically

as most things were not pathophysiologically until recently. It was defined by the constellation of things that still I think make up most of the definition, which is chest pain changes in the electric cardiogram and presence of biomarkers. Let's explain what those three things are. So everybody understands what chest pain is. You have these classic symptoms that people understand. Elephant sitting on chest, radiating into left arm nausea, that sort of stuff, up into the neck. You mentioned the changes in the electrocardiogram will obviously link to photos of this sort of stuff.

But it's hard to do this because we're going to try to do it for the listener, but in it, every time the heart beats, there's a signature that can be measured electronically when you put leads on the chest. You have a little wave that symbolizes when the atrium is doing its contraction. It's called the p-wave. Then you have the big signal, which is this qrs spike, and that's this ventricular contraction. Then you have another little wave called a t-wave. I can't even remember. Is that the repolarization?

Ventricular repolarization. Ventricular repolarization. And then it goes again. So what are the signs on that that you are looking at when you're in the ER and somebody comes in to help you decide if this person is having a heart attack or maybe even has had one in the past? Yeah, it's important that we cover this now because actually after it was agreed upon that a ruptured plaque led to a clot, the clot led to basically the absence of any blood flow

distilled to that clot. So beyond the clot, so then any tissue beyond that blockage would then be start of oxygen and after some period of time a few minutes, five minutes would die. And wasn't that longer that the treatment of MI of heart attack was to put somebody in bed. And then there was the advent of beta blockers, a couple other blood pressure medicines, which were basically forced, you know, pharmacological bedrest, and then aspirin and then streptocinase, which we talked about, which is basically clot-dissolving medicine. That trial demonstrated that if you dissolve the clot pharmacologically, you could

rescue people. And then we got into actually going and doing these things with balloons and later with stints. But the no one creature at the time that I was a medical student was, you defined my cardione fraction. So, am I, by the presence or absence of the time that I was a medical student was he defined my cardio infarction. So am I by the presence or absence of the QAFC? You mentioned on the EKG, there was this big deflection that happens early on and that represents depolarization of the ventricle, so the biggest largest mass in the heart is your left ventricle. That's the pumping chamber that pumps blood out to the body.

And that has a very strong electrical signal. And if in certain areas regions on the EKG, so we do 12 leads and it creates a vector and we can basically recreate the heart in three dimensions. And so you're doing that by putting these leads, these electrodes across the chest and on the arms and the legs. And if after somebody had a heart attack, they developed a Q-wave in certain leads that signaled to us clinicians that they had what we, at that time,

called a Q-wave micro heart unvarction. And what that meant was that there was trans-mural all the way through cell death. So the entire wall, there had been an actual necrotic, basically, we had become necrotic and died. Whereas there was another version of heart attack at that time that we called non-key wave heart attack. And those people presented with the same clinical picture. So they had chest pain. They also had positive

biomarkers. At that time, we were measuring CK or Cretan kinase. And that's an enzyme that's leaked out of the siteosol of a muscle cell when there's damage to it. And so people have heart attacks. There are a bunch of these enzymes, myoglobin, and others that go up. And that's one of the ways that we define heart attacks. So people would come in, they'd have a positive biomarker that had chest pain, but they didn't have this Q-wave.

And so they were called non-Q-wave myocardial infarction. So basically the diagnosis was based on the chest pain and the leaking of the enzymes. So I'll say a little bit more about that because we're going to come back to it. But basically when a muscle dies, you can pick up signs of muscle death in the blood and CK being one of them. In fact, if someone goes out and runs a marathon, it's not uncommon that the next day if you draw their CK level, it's very elevated. They've broken down muscle. My recollection, because it's been so long since I've looked at CK,

is they used to even look at a fraction called the MB fraction, which would try to be more specific for cardiac muscle than say the muscles in your quads or something like that. So, if you had those two things, the pain and the enzyme findings, you were having an MI, the EKG was simply used to determine if it was Q-wave completely through or non-Q-wave, is that right? Mostly. I mean, the EKG is fundamental. I mean, it's really the first thing to get done when somebody shows out there actually doing them in the field now. And it does today define how we treat people. It defined it as well back then,

but things have changed significantly in the past 20 years and we can touch on that a little bit. But the EKG is a fundamental tool. We can't get away without it. So that was the way it was described. And then there was this other thing called unstable angina. An unstable angina was thought to be the same path of physiology, so ruptured plaque, but it was thought to be incomplete cessation of blood. So maybe the clot didn't completely block the artery, so there were still a little bit of blood flow getting through. So in that case, back then, and again, it's changed now, but back then, if you had chest pain and the EKG changes, but you didn't have a prize in the biomarker, you were said

to have unstable angina. And that was differentiated from stable angina based on what? Yes, so stable angina has been described forever, which is you walk and you get these symptoms that people describe, and we can come back and talk about what people, we call it chest pain. That's a garbage basket term that comprises a lot of different things, ranging from exercise and tolerance to actually that feeling of, you know, Fred Sanford talking about I'm having the big one or an elephant sitting on your chest.

That is a clinical term of art, basically, the way I think about it. So chest pain, presence or absence of the biomarker and the EKG, and that would define the symptom. Stable angina was defined as you're exercising, you're increasing demand. So again, what we're talking about is an imbalance between myocardial oxygen supply and demand. So what used to be called stable engine, and still mostly called stable engine

was thought to be a demand issue. So there would be a lesion that would narrow the artery and you'd only get chest pain when you increased demand. Sometimes people call it demand a schemeseard. And so the idea was that if you have this blockage that's 75% of the diameter of your artery, and you go out and you do something that causes you to increase your demand.

So you go walk up a flight of stairs or a hill here in San Francisco, you need to be able to deliver more oxygen to the tissue and you can't do that. So the way the coronaries work physiologically is that they augment blood flow by dilating. So it's a different physiology than most other vascular beds. So it's part of the reason these drugs like adenosine work is that they dilate the coronary.

That's why people are told to take nitrolycerin if they're having chest pain. That's right. But the problem is if you've got a fixed lesion there that's full of a calcified plaque with a bunch of different lipids and stuff in there, you can't really dilate. You can dilate the proximal segment before the blockage or you can dilate the distal

segment after, but you can't really deliver more. So you end up getting an increase in blood flow to all the other segments and then you get a little bit more of what, probably a little bit of corner steel. So in other words, you're getting more blood is even being taken away. So that syndrome is considered to be stable engine. So you're walking up a hill, you get chest pain, so on as a breath, whatever the symptom is, you sit down and you rest and it goes away. Or like you mentioned, you take a nitric glycerin and it goes away and that's stable.

That's actually the best explanation I've ever heard for it, understanding the fact that I'm a cardiologist and even when I was learning this stuff in medical school, maybe I just wasn't paying close enough attention. But I think the way you just explained it is great. It's not just that in the unstable case, you may have some actual plaque rupture. It's this idea that in the stable case, it's the inability to dilate the target lesion and the plausible steal of blood. So more philogically, it's a totally reversible process. Nothing has changed. There hasn't been a new injury, but under a certain period of stress, you're able to basically see this area that otherwise

can't function fully. That ties in together with sort of the way symptoms develop, the cremity of the problem, the fact that people talk about how stable engine doesn't typically kill people, it develops slowly over time, months or years. There can be a acute process that overlays that, but for the most part, it's slow, and that is the thing that we spend the lion's share of our time thinking about and talking about and treating, but really, it doesn't kill you. What kills you is the acute thing. So, just to kind of put this in a little bit of reference for you. So having coronary disease, which most Western adults will have by the time they get to be 50, meaning

if you looked by CT at me or you, maybe not you, but I'll probably have a little bit of plaque. But it's very unlikely that plaque, the amount of plaque is obstructing blood flow, either significantly arrest or with exertion. Over time, if that plaque gets bigger, at some point, it'll start to become apparent to me that when I'm walking, increasing my demand, that I'm not able to deliver oxygen, so it'll become symptomatic. And that the point at which we say most people become symptomatic is when the percent diameter stenosis or blockage is about 70%.

Conveniently, it's also the point when stress tests, whatever flavor you like, also begin to be able to detect coronary disease. So we have focused, I think, a lot of energy on this 70% number because it's what we can measure clinically, either through symptoms or through our testing. But there's nothing to suggest that there's a magic in that number that would put somebody at a greater risk, as opposed to somebody who had a, you know, 50 percent. And in fact, if you go back over time and again to the work of Michael Davies, I think, and I don't want to misspeak here, but I think a lot of the fatal plaque rupture events

that happened in this series of people who came in and died happened in in arteries that had only 30 or 40 percent. I think that's actually correct. I mean that's sort of one of the things I remember from that literature that was very surprising, which was it was very difficult a priori to predict which one of these things was going to be the fatal one. You could have these 90 percent occlusions that were highly symptomatic, but just incredibly stable and they were never going to be the fatal one. You could have these 90% occlusions that were highly symptomatic, but just incredibly stable, and they were never going to rupture, and they were never going to be the things that killed you. And in fact, there's almost a paradox, which is the more the stenosis

increases, the more likely it tells you that the downstream musculature has either found some other way to acquire it. So someone who's walking around with a 95% stenosis is very likely to suffer death in the case of that plaque rupturing. Of course, that's still a harbinger for what's going on elsewhere in the heart. So, they're obviously, you know, very few people are walking around with a single point of this injury. It's telling you that there's probably injury throughout the heart and that they could die from another one. But that, to me, which I want to come back to, right? Because I want to talk in depth about some of the diagnostic tools that we have,

especially to predict who's at risk, who's not at risk. And this is becoming increasingly more important as we have to decide both on the risks and costs of treatment as the treatments get more and more elaborate. And this ability to predict who's going to have the risks and costs of treatment as the treatments get more and more elaborate. And disability to predict who's going to have a fatal MI versus who's not, I'm not convinced we're that much better at it today than 20 years ago, are we?

I don't think so. I think we should definitely come back to that. That's a fascinating discussion. We could spend eight hours talking about that. Yeah, let's go to where we are today. So we've talked about QAV9Q. We've talked to me about what is the nomenclature today? The nomenclature evolved over the past 15 or 20 years and the reason it did was it was

sort of the advent of interventional cardiology and what people realized was in the acute setting of a heart attack. So I was talking about that QAVN before that appears days after a heart attack. But in the acute setting of a heart attack, there was a defining feature that seemed to predict whether there was a complete loss of blood flow. And that was something that we describe as called ST elevation. So you described beautifully the different waves. And so it's the QRS complex. So the end of that big squiggly complex, there's then a line, a direct line, a flat line that connects the end of the S wave to the beginning of the T wave. And that we call the ST segment.

And that is usually isoelectric. Isoelectric with the rest of the EKG. In other words, it's at the same level as the PR segment and everything else. What people realized was that if that segment gets increased above a couple of millimeters, and it does so in more than one lead, that that signal that there was a block a complete blockage of an artery. And that then evolved in this term that we use today still, which is called ST elevation MI or STEMI. And that is a medical emergency immediately signal.

We need to open this artery. And that's work that was done by Gene Brownwald and other people in the Timmy group. And he was done with a combination of pharmacology. So, stripped of kinase, but then also TPA and other thrombolytic agents. And then people realized you could actually go in there and open the artery manually with a balloon catheter. So, the standard of care in this country today is that if you show up with ST elevation and a clinical picture that looks like MI, you end up going to a cath lab within an hour and you get that artery opened up. What is the overlap between ST elevation and if you go back and look at all the EKGs that define Q wave and non-Q wave, I'm guessing the non-Q waves

rarely had ST elevation and some of the Q waves but not all of them did? Yeah, I think that's the right thing. So the way to think about it is the QAV and the STLVs and MI are probably the same. It's just you're seeing a later manifestation of the QAV. If somebody had showed up and if at that time they did EKGs on everybody who walked into the emergency room with chest pain like they do now, you probably would have seen the STLVs. They probably just missed it. So they saw the QAV because that was what came later. The non-QAVMI is probably now what we call non-STLVMI.

It's actually evolved to a different term, which is, I don't love what's it called, non-STLVMI, a QCornier syndrome. Which is just not as easy to say as non-STLVMI. No, so a QCornier syndrome, I think, the way I had to tell the students is, a QCornier syndrome is the entire collection. It's everything.

And it includes STEMIs, non-STEMIs, everything. And it includes what we used to call unstable and unstable. An unstable engine doesn't really exist anymore. So we now have ST elevation ACS or ST elevation MI and we have non-ST elevation ACS. And that's very simply defined by the presence or absence of ST elevation. Turns out that people who don't have ST elevation often have other ST segment abnormalities, most commonly their ST segments are actually depressed, and that has to do with changes in the repolarization that I'm not an electrophysiology,

but changes in the repolarization that happen when the muscle is completely starved of oxygen versus only partially starved. It's a super interesting thing that I've never understood. I probably should go learn why that is. So clinically, if somebody shows up in the emergency room with STOvation, it triggers 911, activate the cath lab, this patient goes straight in, they get hepper and they get aspirin,

they get all the other things, clip it a grill. And just to be clear, do we even check enzymes in those patients or we don't care? No, so it's an immediate thing. And in fact, in this change happened during the time I was a cardiology Philous, so when I was a cardiology philous somebody showed up in the emergency department with S television

They'd call me and I'd come down there I'd look at the EKG and then I would make the decision to activate or not activate the cathlaum But since Jean Brown will coin this term time as myocardium Since we understand that the longer the the heart is deprived oxygen, the less chance it's going to actually recover, there's been a push to speed things up. So now there's the ER can now make that call. Yeah. It's actually often made in the field. So the ER makes the call and the page goes directly to the International Cardiology team. The Cardiology fellow and the attending. So when I'm on service, I often learn about I'm the last one to hear about a patient of ours who's come in with a stemmy.

You hear about it when they're in the cath lab. I hear about it on the way out. Yeah, I hear about it when the student or the intern calls and says, what do you want this dose of this to be? And the old days wasn't that long ago, 15 years ago, this cardiology foe had to make that call. How much time has that saved if you think about where we are today versus 10 years ago? Is that a half an hour saving? Maybe. Maybe.

Maybe. I mean, every hospital now in this country is measuring their what's called door to balloon time. So or door to open artery time. It's a quality metric. And like every quality metric, they're trade-offs, right? So there are more people taken to the cath lab who probably don't belong there. There are some people taken there who are maybe, you know, DNR, DNI or have metastatic

cancer or there are other things that you don't have the time to have a nuanced conversation and you're not having a conversation with an expert. So there is a trade-off, but the overall net net, I think there's our society of people, citizens and cardiologists and other people and emergency room doctors, all I think I'll agree that this is better than it used to be. The daily dieting that would happen in the delays are gone. So the most important thing is get somebody up there. If it's a mistake, it's a mistake,

it's not the end of the world's a little bit of radiation. And since we're- So which tri- was it courage that made this case? Which is the trial that told us that what you just said was really the right way to do things, that opening the artery in the stemmy patients

is gonna save life? I'd have to go back. It was probably one of the early Timmy trials. I don't remember which one. I'd have to go back. It was probably one of the early Timmy trials. I don't remember which one. I'd have to go back and look about which one. There were a series of trials down in the 1990s comparing what used to be called primary angioplasty. So angioplasty is the Greek way of saying

opening an artery with a balloon. Can you explain just, I mean, there's gonna be a lot of people listening to this who won't necessarily know exactly what we mean. So when a patient goes into a cath lab, what actually happens? So again, a little bit different today than it was in the old days, because in the old days, almost everybody had basically a needle put into the femur artery. So the femur artery is a major offshoot of the aorta, feeds your leg, oxygen.

You go into the crease in the groin and you can, anybody can feel their pulse there. So if you feel that, that's your femoral artery. That's about the size of your, you know, somewhere between your pinky and your middle finger. I mean, that's a monster artery. And you're putting a catheter in there. There's a technique of the modified cellgender technique, which allows you to put a catheter into that artery. So that catheter then allows you to have access to the artery. At the tip of that catheter is a one-way valve. You put things in, but blood can't come back out. So that catheter then allows you to have access to the artery. At the tip of that catheter is a one-way valve. You put things in, but blood can't come back out.

So through the tip of that catheter, there's a little plastic one-way valve and you can thread things in. You can thread in other plastic catheters. So in this case, you thread in a regular corner catheter, which I think is like two millimeters. You thread that in. You can then under x-ray guidance with a wire to make it a little

stiffer, guide it all the way up around the arch of the order and back down. We'll have a figure of this for sure so people can see what that does. Back down to the base of the heart where the coronary osteoarth. So there are normal human beings, there's a left coronary osteoarth, and I'll write coronary osteoarth. And you can put that catheter and engage it. And then that allows you to inject contrast dye, which under X-ray will allow you to actually see the artery or see at least the inverse

of what the artery looks like. And then what people realize was you can deliver other things through these catheters too. You can deliver another smaller catheter and on the tip of that catheter, you could wrap a balloon. And then basically you could use a syringe to blow up that balloon, and that would basically crush open the blockage or clot or combination of whatever else it is that's there, and reestablish blood flow. So it's just, it's a very mechanical process. I mean, when people, I don't think necessarily people appreciate just how mechanical, and in some ways crude, this is, you know, you described an incredibly complex chemical reaction that is taking place. And one of our solutions is chemical, right?

We can inject something that can break apart the epoxy, but also we can put a balloon in and use that balloon to inflate open and try to crack it open. And as you'll mention in a moment, I'm sure you can put in these metallic things that spring open called stents. It's such a good point, Peter. I mean, it's really, it's as if you went to a stream and there were a beaver down there and you just take a bulldozer or you take a shovel

and just shovel all of it downstream. And so, one of the questions I've always asked is, well, why is this therapy not more effective? We'll get into where it's effective and not effective, but is there potentially a downside to elaborating all of that crap downstream? And does that have an effect on smaller blood vessels or smaller areas of muscle that end up getting occluded by all the stuff that you elaborate downstream when you're blowing open this artery?

And actually, it goes back to the question of when people were doing these trials to compare the efficacy of what's called primary angioplasty versus thrombolytics, TPA, or streptokinus, these chemical drugs. So the mechanical versus the chemical. That's right. The reason that those drugs are not more effective is not that they're not great at dissolving blood clots, although they're not perfect at it. But that by doing so, you're increasing the risk of dislodging a blood clot somewhere else that might be really important. So let's just say you had an injury in your head and there was a blood clot somewhere in your subdual area.

And so if you go in and you blow in this TPA, you're basically dissolving all blood clots and it's not precise. It's sort of an imprecise just every blood clot. So if you have one somewhere in your GI tract, you'll start bleeding out there. And so the consequences of doing that, I think we're great. And that's part of the reason why primary angioplasty

again became standard of care in this country. Because while the epoxy process requires two things and therefore is highly specific and be localized, the clot busting is not. You have to put that solution into the circulation and even though you apply it locally, every time that heart beats, it gets dissipated. So every part of the body is going to see it.

So there are certain circumstances where people try to deliver TPA or cousins of TPA locally. Like I think even in stroke, they're still injecting TPA and trying to keep it relatively local. But it's a very difficult process because as you say, circulation is circulation, right? I mean, it doesn't take that long for something that's part of your circulation to get around your whole body and come back again. So that's why I think, well, I should say when I was a cardiology fellow in 2001-2002,

we were still doing using TPA as a way of treating people who shut up with a heart deck at San Francisco General Hospital. That's not the case anymore. I think most almost all US hospitals now, it's primary angioplasty. And so after you mentioned these stents, these little metal scaffolds, they developed back in the 1990s as a means of treating stable angina. So if somebody came in and they were having stable angina, so they said, got, you know, doc, I'm walking up the hill and I get this, you know, burning in my chest

and I sit down and it goes away. And I can't now, I'm just not able to walk anywhere. So what can we do? Well, people realize that if you went in there, you blow up the balloon, this angioplasty thing. But if you wrap a metal scaffold around, it's almost like a slinky around the balloon, when you blow up that balloon, you leave behind, and that helps to keep the artery from

recoiling back down. And so that was more of a physical barrier to the artery coming back down. So people found that if you just did the balloon, this is back in the 1990s, again, and people with stable angia, a certain percentage of them, probably 40, 50, 60% of people would show up with what was called re stenosis. And re stenosis just meant that the artery would narrow back down again. Some of that was thought to be physical, some of it was thought to be secondary to the injury you caused when you blow up the balloon. So people thought, well, gosh, if you could believe this metal scaffold behind, you can actually improve the likelihood that it's not going to restand us. So stance completely cured the physical recoil problem,

which I think, you know, again, I don't know the exact number, but it was some non-zero number. But they left behind this other problem, which was the injury problem. And so what people realized was that in the act of blowing up the stint, you created a lot of injury on the vessel wall. And so the body's reaction, that was to create scar tissue. And so then you'd get what now was called instant restenosis, or ISR, instant restenosis, which was basically the formation of a bunch of fibers scar tissue inside the stand. So before the era of what are now called drug eluding stance, this is back in the 1990s. If you did a stand on somebody again, stable angina, you'd see that there was a like some likelihood that they'd come back within three to six months with recurrent symptoms and you'd do a stress test, you'd see that

there was, looked like there was a schemia, you'd come back in, you angiogram, you'd look at the artery, and there was narrowing again within the stent. And that was called instant recent osso. We went through this entire period of five or seven years of trying to find ways to solve recent osso. Including radiating the inside of the vessel also. But when I was a cardiologist, we'd have the radiation oncologist come into the cath lab with us and we would put

these radioactive beads up like in one of these balloon catheters into somebody's artery and basically try to almost kill the fibroblasts and other cells that we're going to make the scar tissue. And God knows what we're doing to each other and to the patients. But that went away in the early 2000s with the advent of what are called drug looting stents. And we can talk about those. But you probably already talked about them a bunch. Well, I was just going to make the point, right? Which is we've sure talked a lot about

my favorite drugs that end up in these drug looting stents. But why don't you take a moment to explain why a drug that inhibits mTOR would find its way onto the coating of a metal stent? I can't remember the exact story. I think it involved a guy who used to be a Columbia named Andy Marx. I think he actually figured this stuff out, but I will have to go back and do a deep dive on that. But basically these drugs, these rapamycin and other drugs, these mTOR inhibitors were known to be, I think, first before even they were modulators of the immune system, they were known to be anti-proliferative drugs that people used to treat cancer. So again, what I described in a simple way that I think about it is that it's a proliferation

problem, so that these cells that are making, in response to an injury, a real injury, they're making scar tissue. And so somebody realized, gosh, if you apply this drug, you can block that proliferative process. So you can block the smooth muscle cells and fire blasts and other cells that are making this scar tissue. And what they realized was that you could paint the outside of a stent with this drug. And so it would basically be there locally. And it wouldn't cause any systemic

toxicity or any other problems and it would just act on the cells that you wanted it to. So that mostly got rid of that problem that we used to call instant restinosis. For the most part, now that problem is no longer. And there was a bit of a hiccup in 0506, 07 when the drug eluding stents were briefly taken off the market. And my recollection is you had Medtronic still had a bare metal stent that was basically getting all the market share while Boston Scientific and Abbott were sitting their time out waiting for these drug eluding stents to come back. And I recall that they even at one point even, Scientific and Abbott had the same stent,

identical, but branded under different names. I mean, it was such an interesting time in the cardiology world. I don't remember all the details. I remember a lot of these reps from these companies were in the cath lab, and there was a big battle to get market share in these different stents. And there were other things besides which drugs

were on the stents, there were issues around deliverability and how stiff they were and how long, you know, all these other things besides which drugs were on the stents. There were issues around deliverability and how stiff they were and how long, you know, all these other things. And so it was a, you know, as a general cardiology fellow and somebody who was interested in basic science, I wasn't paying attention to the nitty gritty of kind of what was going on in this war for market share. But there definitely was a lot going on. The biggest problem with these drug-leading stents was, so if you back up to the early 1990s when stints first started getting used in coronaries, one of the biggest problems that happened was that you'd put the stint in there and then within a period of a few weeks, a non-trivial amount of people would come back with, effectively, was a stemmy.

The stint would clot off. That was happening and that was bad. So there were series of trials where people tried aspirin, I believe they tried warfarin, they tried everything and they actually couldn't. So aspirin and warfarin are both blood thinners through different mechanisms. That's right. So aspirin acts on platelets, warfarin, and blocks that coagulation cascade, you know, downstream tissue factor. But people couldn't use these stints for a while. And then in 1996, I know this because I, as a medical student, had the ridiculously good fortune of being the first author on a paper that was published in the, knowing

the Journal of Medicine. And that same issue, so our paper was, is forgotten mostly except for me. But in that same issue, and I looked at it the other day, was a trial that demonstrated that you could do stenting of coronary arteries safely with the addition of this drug that's no longer used because it had toxicity called tyclopidine, tyclid. And so tyclid was the first generation of these, what we call thine, appeared in, stine appeared in, act to block. At the time we didn't notice, but they block a receptor on the surface of a platelet that's called the ADP receptor. And it basically renders the platelet a little bit less sticky or less prone to be activated and become sticky. And what these guys demonstrated,

which was transformational for intervention cardiologies, if you gave people this drug, tyclid at the time they got their stint. The chance of the stint clotting off went to almost zero. And eventually that drug had some toxicity and was replaced with the drugs that used, in most cases, still today called Clopidogryl, which is acting on the same receptor.

It's the same biology. And patients might know that drug by a different name. Plavix, yeah. Right. So, today, when a patient gets their stent, they also get what, a year supply of plavix. How long do we keep it on? Yeah, so where I was going with that was that there was this thing called subacute stent thrombosis.

So, thrombosis is the word for blood clotting. Subacute means within a few weeks. So back in the day, if somebody stopped taking their plavix or didn't get their plavix, there was a likelihood that they would get this condition called subacute stent thrombosis. Again, for all intents and purposes, it's like a stemmy because it's a complete stoppage of blood flow. And it's critical and people can die. Which is kind of ironic, right? You can show up with a stable problem that's chronic

and through the intervention end up having an acute fatal complication. I mean, the stakes are so high. Huge. And people did, and it was bad. And, you know, there were lots of questions about why and all that was happening. That problem mostly got solved for the, again, 95 plus percent

of people. There was some discussion about plevix resistance and other things, but mostly that mostly got solved for the, again, 95 plus percent of people. There was some discussion about plavix resistance and other things, but mostly that problem got solved with plavix and people realized if you take plavix for a month after a bare-metal stent, you're good to go. So then people fast-forward and you were in the drug-leading stent era, and we've solved the restinosis problem, but people are showing up now. They've taken their plavix for a month, but now they're showing up at three months, six months, nine months with not subacute, but whatever the after subacute is, stent thrombosis, late stent thrombosis.

And having, again, the same life threatening, stemmy-like experience. And what people realized was in the process of inhibiting these cells, these smooth muscle cells and other cells that make the scar tissue, we're also inhibiting the endothelial cells. So one of the things that happens, if you take a patient who has a stent, and that patient say dies in a car accident, you look under the microscope pathologically, you'll see that that stent is now covered with endothelial cells after about three weeks. And it's the endothelial cells that prevent the blood clotting. So the stent struts themselves are probably pro-therombotic, so they probably trigger some clotting.

So what we realized was that your own body would basically wall out the stent. Which is exactly what you want. In a good way. To reproduce the endothelium that is this beautiful, you know, I try to explain to patients that, you know, ethoscrosis is complicated and the reason that there's no one single causal factor is you have to have this sort of perfect storm of endothelial injury and that can be anything from smoking cigarettes, I'll do that, to high blood pressure, we'll do that. You have to have a lipoprotein that can actually carry cholesterol through that injury, so you have that injury you can get around through.

That has to get oxidized and create an immune response that then has to lead to the formation of this plaque, which for reasons that aren't entirely clear, some rupture, some don't, and kick off the epoxy problem. So what you just described is the body will reproduce that beautiful endothelium around the metal stent again. And if that's what happens, you end up in the good camp. And if instead of that happening, you kick off this inflammatory cascade again,

you can get into a very bad situation very quickly. Basically, the way to think about it is that most people with a bare metal stand will re-entethylalyze the inside of the stand within like three weeks, four weeks. So the standard of care in 2002, 2003, but before drug-leading stance was take plavix for one month and you're done. And people degree.

And then drug-leading stance come along. They plavix for one month and you're done. And people degrade. And then drug-looting stents come along. They solved this one problem that they created a new problem. The problem was that in addition to inhibiting the proliferation of these smooth muscle cells and phytonyphilis, they inhibit the endothelial. Exactly. So people were in coming back with this stent thrombosis problem now, you know, months later, then it became unclear about what the correct amount of time to take your plavix or other drug was after a stint.

And I think now there's some great work being done by people. I think for the most part with these newest generation drug-leading stints that have the right mixture and cocktail of drug on them and they're really easy to deliver and cause a less injury, it's six months. If something's complicated, if the patient has diabetes or other risk factors, then you may extend the time. But again, what you're doing is you're buying bleeding risk by inhibiting this risk of stent thrombosis.

Obviously, stent thrombosis is the worst. You can't have that. So when I have a patient leaves the hospital and they say, what do I take? I say, listen, if you're going to an island and you can only bring one thing with you for the first, you know, whatever it is, a few months, all the matters is your plow.

So you've got to take it every day. Right, at this point, whether you remember to take your statin or your blood pressure drug, those are important, but yeah, that's a great way to put it. If the ship is sinking, the highest priority is the lifeboat. This is your lifeboat. It didn't get communicated clearly enough, I think, for a while. So when people would

shop in the hospital with stent thermobosis, it was often because they hadn't been told appropriately strongly enough that they had to take platyx. So you've done a great job of explaining the unambiguous part of interventional cardiology, which is the case where I think most people agree interventional cardiology, which is the case where I think most people agree interventional cardiology through the stent has provided a survival benefit. There are a whole bunch of other areas where that is quite gray. You and I have had some really interesting discussions about that going through some of the really important trials in the past decade that have tried to ask a question.

So let's begin with the case that you described a while ago, which is patient comes to see you in clinics says, you know, Dr. Weiss God, it's just every time I get on that treadmill, I just get a tightness in my chest. And the other day I was walking up the street and it was really steep and blah, blah, blah, blah. So they've got stable angina. Let's assume you decide it's worth doing an angiogram in that person you do and you see low and behold, there is a 60 or 70% occlusion smack in the middle of their left anterior descending

artery that runs right down the front of their left ventricle. What should you do? Maybe another way to say it is, what would people have normally said and what have the data now suggested? I mean, this is one of the most controversial areas, I think, and least well-understood areas of medicine. I'm not even gonna say cardiology. So, in the 1980s, that patient gets a prescription for nitroglycerin and beta blocker.

So beta blocker helped reduce the demand. So basically, it's like putting a governor on a car or golf cart, so you can't rev the engine as high, so you're gonna be less likely to get symptoms. And nitroglycerin, as we described described helps relax the blood vessels and maybe also decreases demand by decreasing blood pressure. So it's basically a couple of not great tools in the 1980s and then people would go to a point where they couldn't walk anymore and eventually they'd get bypassed because

there was no other option for what we now call re-vascularization. Eventually when stents became viable in the mid-1990s, people realized, well, gosh, that person, if you open that artery and put a stent in there, you can give somebody a really durable response and they want to take any of these medicines. And just to be clear, at this point in time, we only had one sort of plumbing solution that had been demonstrated to impact survival. And that, if I'm correct, it was Lima to LAD cabbage. So I'll explain what that is.

So everything, as you can tell in cardiology, is an acronym. So Lima stands for left internal memory artery. So when you open up the sternum, you have these arteries on the inside of the sternum. And the left and right version of these turn out to be the most important conduits that you can use to bypass because they're already attached on one end and your beautiful blood sources and you used to attach it what we call distally. So past the lesion and and by the way if my memory is correct it was only Lima to LED. And, and by the way, if my memory is correct, it was only Lima to LAD.

It wasn't Lima to circuit, wasn't Lima to right maintenance. There was nothing else. They did sham surgeries, if I recall, to demonstrate that. I don't know if they did sham surgeries back then, but you're absolutely right. It was only Lima to LAD, it was only a subset, right? So I think you had to have multivessel disease, blood ventricular dysfunction, diabetes.

I mean, there were a subset of people who's not everybody got a mortality benefit. I'd have to go back and look at the... Maybe those weren't the shams. But I know there were some sham surgeries that involved sternotomy, which when you think about that, I mean, imagine signing that consent form, oh, Lee.

So in defense of the cardiology community in the mid 90s, it wasn't an unreasonable hypothesis that, hey, if taking the Lima and attaching it to the LAD effectively bypassing this thing works, at least in a subset of patients, shouldn't we be able to rotor rooter this thing and open it up and get the same benefit, right? Right. And I think the important thing to remember is to define the benefit you're interested in. So we need to talk about the two things that matter.

And when a patient comes to see me in the office or you in the office, we often end up talking about two things. One is how do I feel? So presence or absence of symptoms. And the second is, is this going to impact how long I live? Mortality. And those are the two variables we think about every day in cardiology. And as you mentioned, there was evidence that this one procedure, or a subset of these

procedures, could confer a mortality benefit. But most of the time when we're talking about re-vascularizing or treating stable angina, we're talking about treating symptoms. That remains true today. And people sometimes poo poo that, but I think it's important, at least for me I like to dispel that because there's certainly I find a for me, I like to dispel that because there's certainly, I find a heavy dose of people in the peanut gallery who think if it doesn't impact all-cause mortality, it's never worth talking about. And I suspect these people have never taken care of patients. Of course not. No, I mean, look, if you can't walk up your stairs, you can't garden, you can't hike with

your wife, you can't go skiing with your children. I mean, there are a lot of things that we're... You can't have sex. Yeah, yeah, yes. And all that stuff, I think, is incredibly important. And it shouldn't, just because you're not conferring a mortality benefit, all calls mortality benefit. It doesn't mean that there's not benefit. So I think that the advent of the Stant Era was remarkable. It happened to coincide with the advent of the Statton Era, right? So the first stat and lowest stat was approved in 1988, I believe. So remember, I'd say that we were treating approved in 1988, I believe. So remember,

I'd say that we were treating people with hands, no, basically beta blockers and nitrates. And so then statins got added to the mix. They weren't initially added for treatment of stable disease. They were there for they were initially tested in people who were having unstable disease. But it quickly became obvious that they were going to become an important mainstay of treatment of people with stable coronary disease as well. So this idea that even if there's an intervention that doesn't extend life by one day, if it improves the quality of life, it should still be on the table. So walk us through a little bit of the trial architecture and how it navigated how we ought to treat these patients with stable angina, or you can even define it as the, if you

want to do it through the ACS language, feel free as well. Let's back up and just make sure we re-emphasize, because I don't think this point cannot be emphasized too many times. So if you show up in the hospital or in the emergency room or anywhere in the world with the ST elevation MI, a STEMI, in other words, that ST segment is increased above baseline, and you're having a heart attack. Yeah, it's a zero-not-pass code.

Do not collect $200. You're going straight to the capital. That's right. If you show up and you have having a heart attack. Yeah, it's a do not pass. Do not collect $200. You're going straight to the calf. That's right. If you show up and you have a non-stimme. So chest pain, let's say you have positive biomarker. So now a modern day, we use another biomarker called proponent, which is just a component of the architecture that allows muscles to contract. And there's an isoform, a flavor of it that's specific to cardiac muscle. So if you show up with some of that in your blood, it signals that your heart has suffered cell death, muscles have, and so that's part of the diagnosis. So you show up with chest pain, positive triponin, and an EKG change that is not a stillovation,

anything other than a stillovation. It could be normal. That puts you into a different category. And mostly in the United States, the management of non, depending on a couple of factors, but most people are managed either what's called medically, so with a bunch of medicines, or they go down a path of interventional cardiology. So now let me ask you a question, Ethan. We didn't distinguish this, but it's worth adding.

In the stemmy patient, you don't care if they're hemodynamically stable or not. In other words, if their blood pressure is stable, you know, they're having chest pain, but they're not in extreme distress, they're still going to the cath lab. In the non-stemmy patient has chest pain, patient has the enzymes, EKG looks normal, but presumably there are still cases

where those patients are not hemodynamically stable. So if you have what we would call complicated non-stimmy, so hemodynamic instability, I mean your blood pressure is very low or you have heart failure, you fluid in your lungs, something else that makes it complicated, or you can't treat people, you can't make their chest pain go away with medicine, something that makes it complicated or ongoing concerning EKG changes, or just you don't feel right, that patient also can go to the cath lab. It isn't an emergency unless there's hemodynamic instability,

but oftentimes people will go along the same timeline. It won't may not be within 60 minutes, but it'll be quickly, again, depending on how complicated if you have uncomplicated non-stimmy, so the blood pressure is fine, you don't have any evidence of congestive heart failure, there's nothing else that makes this look scary. Those patients can be managed either non-invasively with medicines or invasively, and we can talk

a little bit about how that happens. There was a period of time, I think, in this country where most of those people went into the interventional arm where they went and got, and they went to the catholic, and they would get a stand. And I think in the past few years, there have been questions about the sort of value of that and there's debate about that. But just to be clear, there's one area of medicine where there's no debate, which is there's a more clear mortality benefit by opening up the artery.

Again, if you're in Uganda and you don't have a cathab, then TPA is the best you can do, but open the artery saves lives in In the non-stammic situation, if you're hemodynamically unstable, again, same thing, opening the artery saves lives, if you're hemodynamically stable, the things start to become a little bit more gray. And then stable angina, which is the last thing we'll come back to, there's a huge amount of gray area. Again, about mortality, not symptoms. So let's talk about orbita.

What did that trial look at? What question did it try to answer? This trial was published in November of 2017, I believe. And it was done by a group in London who I had never heard of before this trial came out. I guess Darrell Francis was the PI. And I think he was well known in the international cardiology community,

but not to those of us who are not in that world. This trial shook the world. Actually, we should probably talk about courage before we talk about it. Let's do that. Yeah, thank you. Let's go, because I alluded to courage and then we got off topic.

Tell me about courage. So courage was published in 2007. And if anybody asks me what courage stands for, I don't remember. I don't remember either. Yeah, but it's an acronym that is put together to explain what the trial was about. And I also can't remember who the PI was, but that study, so again, we're talking at this

point back about stable angina. So people who have, are not showing up in the hospital with new symptoms or new EKG changes, this is a totally different animal. This is somebody who's been out living in their home and they have symptoms that have been going on for some period of time. So courage was designed to ask the question and answer the question is there an addition to a symptom relief that you'd get from putting a stint in an artery of somebody who's got a blocked artery and has stable angina? By the way, I'm just gonna

get into it. So I'm gonna make a plug for one of my favorite apps which is incredibly dorky. It's called Trials. I don't know if you've seen this app but let me show it to you and we'll make sure we link to it. So the app is called Journal Club. It's either free or very cheap. So if you go into Journal Club, you can search every single clinical trial in the history of mankind. So I just went courage and it pulled it up

and it gives you just a treatise on the topic, right? It gives you the bottom line and then it tells you what it stands for, okay? So the major points. So it's called clinical outcomes utilizing Revasculation and aggressive drug evaluation parentheses courage and then it goes through and explains everything about it So if you're listening to this and you're a physician and you don't have this app get it and

truthfully even if you just have a Tincture of interest in clinical trials, this is a great app to have. I must look at this like once every two or three days and you can screen and search by like sometimes if I'm just sitting around and I've got 20 minutes to kill and I'm kind of bored and it's, you know, I'm in the I'm on the runway and it's taken a while to take off. I'll just open it up and search by subjects like I went what's going on in oncology in the last two months. What new trials have come out?

So anyway, journal club is awesome. Well, now you can read it and see how close I am. So I'll try to be intentionally less detailed about how I described these trials. It's everyone's going to be reading along. So anyway, this trial was designed with one purpose. The purpose of this was to compare maximum medical therapy to stenting in patients with stable coronary disease. And the idea was, is there a benefit in terms of reducing the risk of heart attack or some other heart outcome like death in patients when you randomly

assign them in a non-blinded manner to be treated with maximum medicines or stents? Non-blinded meaning they did not do sham procedures in the people who randomized to no stent. That's right. So obviously you as a patient or you as a doctor know if you're going to go get a stent or not. So you were told you've been assigned to this category. You're going to get medical therapy and then they got medicines. This is something I have to go back and look at.

But I believe the people randomized to the New Rentshal arm also got aggressive medical therapy. I don't think there were huge differences, but that may be one of the areas where there was debate. But the net of this whole thing was that this trial was organized and run by interventional cardiologists and the purpose of it was to demonstrate that there's a benefit and hard outcomes by stenting, that we were gonna prove finally that opening the arteries

did more than just relieve symptoms. And it was negative was completely negative. So there was no difference between the two arms. I can't remember the details because it's been over 10 years, but there may have been... I remember, because like I said, I just saw that it was 2007. I was going to guess 2006, but I kind of remember where I was when that study came out. And boy, that was like a big hit in an industry where it was pretty much the wild west at that point in terms of the number of stents people were getting.

I mean, we used to joke about it kind of teasing these guys, which is like, kind of somebody looks at you wrong in the parking lot, you're going to put a stent in them. Well, it was and this was the era again where there were people like there was this hospital up north. I think it was like a tenant hospital where there was this guy who was sent, you'd show up there with like too much farting or something and then he'd do a calcium scan on you and he'd see like a, you know, calcium score of 20 and he'd say, we got to take you to the cath lab and then he'd put stints in you.

And there was really no way to argue against that even an asymptomatic people. It was just a crazy time. So this, this definitely was a big result in cardiology, particularly in the interventional cardiology. It was not met without criticism as you can imagine. And I can't remember all the details, but there were definitely some big questions raised. But the net of it was, hey, look, the other way to look at this is that we've been doing trials

of stenting for a long time now. And no one outside of the STEMI situation has demonstrated any benefit in hard outcomes that to date, so you could say the burden of proof the onus is on the original cardiology community to prove it, so they tried and they failed. So I think that was a big practice changer. I think what that told you was, look, again, back to what we were talking about earlier. This is a symptom management problem.

We're not doing this to extend life. It doesn't mean that it's not important. And it doesn't mean that you still don't use it as a tool. But maybe it shouldn't be the primary tool. Maybe the primary tool should be, hey, look, let's try and use these medicines, which are really effective. And we'll optimize them as best we can. And if that doesn't work, then we'll go down the path

of trying to open the artery. And so it really did change, I think, the way we managed people, again, mostly outpatients, mostly stable, legitimate patients. So then what was the impetus for orbita 10 years later? Well, I would have to ask Darryl, and I hope someday you could ask him because he's a phenomenally entertaining guy. Yeah, you got me on to him and his work, and I follow him on Twitter now. And I think he's in the the UK and I can't wait to hopefully meet him at some point. He made this like tremendous appearance and splash on Twitter a year and a half ago and like set the world on fire because he was fearless and obnoxious and just everything

you'd love about him and I guess he pissed a lot of people off and somebody basically pulled his plug. So he's been really quiet if not completely absent from Twitter for the past, I want to say six months But anyway, he was the PI on the study orbita and the impetus there was okay Well, what courage kind of established that there's not gonna be a benefit in terms of hard outcomes So we're really we've sort of settled on this idea that stents are there and they're useful for treating symptoms Impicions who failed medical therapy, but orbita was, our stance actually even doing what they're

supposed to do in terms of reducing symptoms. So Orbita, you mentioned sham trials. This was the first sham trial that I, the universal cardiology that I knew of. So Orbita stands for Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina. And one of the beauties of naming clinical trials is you can use a sentence with as many words in it as you want as long as you capitalize the beginning of the words that you want in your acronym You get it. So if you just heard me read that and said how the hell does that work out to Orbita? You only

Capitalize the objective randomized blinded therapy, angioplasty. Yeah. Well, that app would have been fun as a medical student because you used to get pimped on kind of what were the key trials and stuff. So anyway, the key differentiator of this trial was blinded, which meant there were sham procedures done. So what they did was they took people who had demonstrated documented angina and lesions. So they all had catheterizations, whereas I think in courage, they were randomized after a stress test. I don't think everybody had an angiogram before they got randomized. In this case, they got randomized after the angiogram showing that they had a blockage. They could not have

three vessel disease or left main disease. I think there were a few other exclusions, but these were people who could have one, two advanced disease and they could be tight lesions. They could be 95, 98% lesions. Then they were randomly assigned to get either optimized medical therapy or stent. And that was done blind to the patient and blind to not the, obviously the eventual cardiologist, but to the treated, referring physician. So if I sent you in to be randomized in this trial, you and I would not know what you got, because they would take you to the catheter, they'd put a catheter in your leg, they'd

wind a catheter up into your corner or osteoom, and they would pretend to blow up a balloon, and you wouldn't know what you got. And it was a small trial, which was one of the major criticisms, I think, because it was such a small trial, and I'm not a trialist, so I don't get into the nitty-gritty on kind of what makes trials more or less robust. Well, I mean, from a science perspective, the issue comes down to power. I think this is the biggest challenge of trial design.

People talk a lot about significance, which is what the p-value tells you, but people don't talk a lot about power, which is beta. And the idea here is, you have to have some sense, a priori of how much of a difference you will see to design your trial, because you have to know how many people to put in it. Because if the trial comes out and there

is a significant difference, a statistically significant difference, which is usually defined as a p value less than 0.05, meaning there is a less than 5% chance that the difference you have observed is due to chance, then power becomes irrelevant. It's just that power becomes so important when the opposite happens, when you don't see a difference. And it's your ability to say, we don't see a difference, and we believe that a difference is not there, versus we don't see a difference, but we didn't have enough people to look at it.

So, for example, if I was going to design a trial with me and Ethan, just as the two of us, it's quite likely I would never find a statistically significant distinction. But that doesn't mean that the metric I'm looking at doesn't exist. It's just with two people in a trial, the probability that I'm going to find it is incredibly low unless the difference is egregious. So I've always found this to be the biggest challenge of clinical trials, is that you have to have some sense of your expected outcome to select beta to power the study appropriately. And this was obviously the core place that people are, because it was a small trial,

and people said it's an underpowered study, and you couldn't see a difference. Study was interesting because they both asked people how do you feel in terms of your angina? So, every one of these patients had some frequency of anginal episodes. They'd get chest pain if they walked or did something. But then they did some objective things, too, so they did stress testing. I believe they did like the beat-a-means stress test. Basically, it's a way of looking to see objectively was there more or less ischemia, and they also did treadmill tests. So they looked at their exercise capacity and how long they could exercise before they got symptoms. And I don't want to get misbeac and piss off on my interventional friends, but for the most part, the thing was pretty negative. And I think there might have been a slight difference

in the treadmill time. There was something very slight, but for the most part, it was a negative study. And so the result, which ended up splashed all over the New York Times, the Wall Street Journal, and every other news organization you could think of, the conclusion that was sort of reported to the general public was stent not only do they

not reduce your risk of having a heart attack or die, they don't even reduce your symptoms. And so it became a sort of firestorm of conversation. And this was not long after former president George W. Bush had a stand placed after what I don't believe was a stemmy. That's right. He had stable andina, same thing. And this goes back to the old days of when people would do routine sort of surveillance stress testing in people to look for these 70% blockages and then

they go and stint them, right? This was the way things operated until relatively recently. So what we learned from that trial was look, this may have been underpowered, but at the very least it tells you again and again and again that medical therapy is really good. So modern medical optimized therapy is great. And so the way I took home from this trial and what I convey to my patients today, along with the important caveat that what I convey to you today is very likely to be a lot different from what I convey to you today is very likely to be a lot different from what I convey to you tomorrow. But I say what I convey to you today is that while stints may or may not be useful in some circumstances, reducing your symptoms if you have bad symptoms, it's very unlikely that

in stable engine, they're going to do anything else. But either way, it's our job to try to manage you as best we can with medicines before we go down to that path because there are going to be Consequences of putting a stent in you and we've all seen these patients who end up with 20 and 30 stent You know tons and tons of stents and again taking a stent is not just an isolated experience It means going on one of these powerful blood thinning medicines like plavix or a more powerful one and it means a lot of other things So we do and don't understand so what I say is look job, our obligation is to try as best we can to use medicines to optimize you. If we fail at that, we're going to keep that stenting procedure in our back pocket. If you come back to me in three months and you say, either one of two things, either these medicines are not working,

and I'm still having a lot of chest pain, then we go down, then we can say, let's go look at opening the artery with a stent. Or if you say to me, these medicines are making me feel miserable. Like I just, I don't like the way I feel. I want to take fewer medicines. I also believe it's reasonable at that point to say, all right, let's go see what we can do with a stent.

So I have not stopped referring people to interventional cardiology. In fact, I probably haven't changed dramatically how many people get sent. Courage probably did change it a little bit, but for the most part, I'm sending the same number of people. I'm sending the same people to the cath lab that as I did before. Or what? Yeah, it's probably just the composition of those patients is probably migrating constantly.

And that's, I think you know, you said something sort of interesting that I think for some people is frustrating to hear, which is, what do you mean what you're telling me today could be different tomorrow? But that's unfortunately the nature of science. One of the things I like to say, and I wish I knew who said it first because I feel like I'm plagiarizing it though I don't actually recall, is that all facts have a half-life. And in some ways, that's the single most exciting thing about science. I mean, it would be kind of boring if all of the natural universe and its laws were known.

And this was just a game of memorizing all those facts. I mean, I just don't think science would be nearly as interesting as the fact that we're constantly in the dark trying to refine our knowledge. You can say that on a micro level and a macro level. I mean, I always tell people that work with me and my lab and our lab that, you know, if you know the answer to the experiment before you do,

then we don't need to experiment. Just stop. We can write it up, right? What are we gonna learn? And the other thing is that the result of these experiments, whether they're experiments in a lab, cells and tissues or animals, or whether they're clinical experiments

that are done on lots of human beings, there is some likelihood that that result is quote unquote wrong. Even a p-value of .05 means that there's a 95% chance that it didn't happen by chance, but there's a 5% chance that result did happen by chance. So there is a constant refining of what is truth or what is as close as what we can call to truth. And so I think we have to stay humble.

I love it when I'm wrong. Then there have been a few examples this year where I've been wrong, brutally wrong, and it brings me joy. It's a great, I love being, I love it when something defies my expectation. I don't know that I can say enjoyed as much as you do, but if I just look at constantly being challenged, I mean, you know, at the time of this recording, there is just such a gauntlet being thrown down to challenge the dogma around utility of vitamin D and sunscreen. That's something that I've been spending a lot of time reading about in the past two months.

And I have to tell you, I don't know that I would say I love the fact that I probably know nothing about this now based on all of this new information that is emerging, but it's certainly exciting. I mean, it is so great to say, wow, I get to go back and learn this whole thing all over again. And you sort of have to hope that there hasn't been damage done in a previous paradigm that's being turned over. You know, you brought up your lab, so I want to talk about that, but I'm not ready to

leave this topic yet, because I want you to give us a quick or reasonably quick primer on other things that tend to confuse patients, such as calcium scores versus CT angiograms. And I even want to touch on heart flow in a minute because that comes back to it. So I think the listeners know what a calcium score is and a CT angiogram is. But so just give this the quickest sense of that because what I'm much more interested in is what do the results tell us? As a cardiologist practicing in 2019, I struggle with the question of whether I'm going to

help you or hurt you, that I feel this tremendous sense of uncertainty about whether I should be as aggressive as I can, picking up every rock and looking under everything and, you know, to optimize to the best of my extent, my ability versus whether that may be the best thing I can do is leave you alone. And you've probably seen examples too where I remember again as a choreography, maybe even as a resident where somebody would come in from an outside hospital sick as shit just absolutely on death's door. And all we did was just turn off everything and the patient got better because they were just overmanaged. And I think I struggle a little bit with this sort of where I want to be in that spectrum and how aggressive I should be in looking for, say, a cold coronary disease, which I think

is a question you get a lot and I get a lot. One of the major reasons somebody comes to see me as a preventive cardiologist is they say, I'm going to die of a heart attack. And what's my risk of dying from a heart attack? My brother died of a heart attack at 44, what should I do? And I still don't have an answer about how aggressive I should be and try to understand it. But a lot of these tests will talk about, I think, to feed into that. And I think ultimately what we're missing, and I hope we can eventually refine it and make it better,

is a good way to predict disease risk in these chronic diseases, these common chronic diseases like cardiovascular disease, metabolic disease. Don't now yet have the tools to be able to say, Peter, well, your risk is x, y, or z. And so therefore, we should do this or this or this in terms of prevention, understanding that there's going to be risk in each one of these things that we do, and there may be risk in even part of the process of getting from here to here, point eight to point B. So I'm glad you brought that up because it illustrates the challenge that frankly can't be explained or rationalized or described on Twitter, not to pick on Twitter, but just

to this. So there's this idea, which you've said, which is, I don't know sometimes how aggressive to be or not to be. And what you're really saying is, at the individual level, with you as my patient sitting in front of me, I don't know how aggressive to be or not to be. You're not asking the question on average. And yet, what tool are you given to guide you? You are given a tool called a clinical trial, which is by its very nature, all about averages.

And so therein lies the mismatch of what I've described as medicine 2.0. When I say describe meaning, I'm writing about it in this book, I'm working on that hopefully I'll have finished by the time I'm alive or not alive. And the idea is, it's not the poo poo clinical trials, it's just to acknowledge that clinical trials give us great information on averages and the larger and more robust the trial, generally the more heterogeneous, the data. But you've asked a question that comes down to judgment.

You know what it means to be aggressive and you know what it means to be conservative and you know what the corners of that box look like. What you're asking is, I could have two people in front of me that superficially look similar, but actually one of them is probably going to have a better outcome if I behave aggressively, and the other one might have a better outcome if I behave conservatively, it's the challenge to figure out which ones which. If you're a hammer and everything's a nail, even if you're acting as a hammer and nail in accordance with clinical trials,

I suspect you are still acting in a very blunt manner. 100%. But I'm also talking about these areas, and I think prevention is a great example that are sort of outside the boundary of what's been studied or is likely to be studied in the context of a clinical trial. I mean, there's not going to be a clinical trial to answer a lot of the questions that I have about how to manage my patients. And I feel the same way. I mean, prevention is not really amenable to this idea of medicine 2.0, which is clinical trial, average outcome, short duration, simple intervention, easy to measure outcome. It's the economic thing. I mean, you're a company and you wanna get your product to market whether that product is a standard or a drug or whatever it is.

And the best way to do that economically is the shortest amount of time. And so you wanna take the sickest people. So these trials, I mean, I joke that like a prevention trial, those kinds of trials that I wanna do would take 50 or 60 years. How do you convince somebody I'm about to be 50? I wouldn't wanna start a trial that I'm not gonna see the 50 or 60 years. How do you convince somebody I'm about to be 50? I wouldn't want to start a trial

that I would not going to see the answer from, the result from. So it's unsettling to me. And again, I think you just have to remain humble as I've tried to and hope that your patients, your human patients have some patients that were going to be wrong. There are litany of examples like Elpula de la

was something I didn't pay attention to until the past few years. Corner calcium scan, if somebody came to see me with a corner calcium scan 10 years ago, I would say, I wish I didn't have this information, but I never hoarded one before seven to eight years ago. So there are lots of examples of things that I didn't use to do that. Now, incorporated into my practice. And I'm doing so without that safety belt of evidence basis that we're used to, right? There's not going to be an orbital trial to help me decide whether I should be aggressive with lipid lowering in a 35-year-old. That's not going to happen with primary prevention. So we have a mutual patient in whom that's exactly the type of question that's being asked,

right? Yeah. And there's a term, and I know all these cute little terms and I never know who to attribute them to, but we talk about evidence-based medicine versus evidence-informed medicine. And to me, the latter just makes much more sense. Because these decisions that you have to make virtually every day, and I feel like I'm in the same situation, virtually nothing that I do can I point to the orbita or courage equivalent? I mean, it just doesn't exist. And certainly not, if you really wanted to scrutinize it, every single thing is a variation

on a theme that stems from some clinical trial. But if you really wanted to be a skeptic, you would say, nope, that's not the exact same patient and that's not the exact same situation. And therefore, you can talk yourself out of doing anything. And I'm super fond of saying that being a preventive cardiologist is no one should feel sorry for me. I have the best job in the world, but it's difficult in that we only know success by the absence of failure.

So there's no one who's going to come to me tomorrow and say, gosh, Ethan, thank you for the fact that I'm 46 that I did not have a heart attack in this year. It just doesn't happen. That's a great way to explain it. Whereas the other way around, like I've had a few patients. But it's an orthopedic surgeon, for example, that's right. You break your leg, you fix it. Or an interventional cardiologist, right? You show up in the cath lab with a stem, you know what you did. The outcome is clear. The outcome is not that clear in prevention unless there's failure.

So those examples, and I've had a few recently that I've been public about on Twitter that are treatment failures, but maybe not personal failures. In fact, I don't think I'd manage the patients incorrectly, but the fact is they had events while they were under my care, those live with you for a long time. And so then the question is, I know you're a race car driver,

the question is, is your reaction to that to then have a tendency to want to oversteer? So because I have these anecdotes, these very profound anecdotes of young people who had terrifyingly scary outcomes, and I was not as aggressive as I could have been, but probably still following the sort of guidelines. Is that going to guide me as a physician to be more aggressive in the future? And again,

we're not going to have clinical trial data to help us here. This is all art and judgment. The subtitle of my book, I'm hoping if the publisher lets me, is going to be called, the science and art of longevity. There's a title to it, but that's the subtitle, and I'm insisting upon that order, because normally you say it in the reverse, the art and science of whatever, but it's the science and art. You're informed by science, but in the end, this still comes down to an art. Well, it is the art of the science, too, as you said, right? I mean, it is sort of how do you put this, and then there's the whole other layer, which

is how do you communicate it with your patients, and how do you include them as a partner in making these decisions? I mean, that's where things get really interesting. And there are other physicians because typically these are not just discussions between two people. So what's a CAC? What's a CTA? And how do you use them?

The way I break this down is there's anatomy, so anatomic tests and their physiologic tests. So physiologic tests would be like a stress test, a treadmill test. So you get up on the treadmill, you walk, and then you have one of a few different ways to kind of determine, in addition to whether you have symptoms to determine whether there's a scheme, I mean, there's just a difference in the supply and demand of oxygen. So you can use kneecage here, you can use an echo,

or you can use what's called nuclear, which is basically a radio labeled potassium analog that lights up living cells. So that's one way, that's the physiology. And that's been the standard of care in this field for 40 years. In the past 20 years or so, people have started to explore

whether there's a role for an anatomy. So one anatomic test is an angiogram. So you can take somebody to the cath lab and you can put a catheter up there and inject some dye into the artery and you can see if it looks like there are blockages. That's not something that you would apply broadly to a population. You wouldn't use that as a screening test.

And patients often ask me, in fact, sometimes people will come in the office and they'll say, I should have an angiogram. No symptoms, just I want to have an angiogram. I want to know that I don't have an angiogram. Right, just to prevent it to get a baseline. Yes. Which is very much like, I want to make sure I don't have colon cancer or breast cancer. And the same things that come up as being difficult and controversial in any screening, you know, whether it's prostate cancer screening, breast cancer screening,

any of these screening areas are going to be super controversial here. But I think the community agrees mostly that screening and geography is not appropriate. But the question is, are there other things that could be appropriate in the right people? And in general, the population of people that we're talking about are people in this intermediate risk category. So if you're low risk, for the most part, there's not going to be much benefit to adding one of these tests. We're talking about asymptomatic people here. So if you're symptomatic, you fall into a different category altogether. So asymptomatic people. And if you're high risk, you probably fall into a different category as well. And what I tell people is that the results of these anatomic tests that we might

do are really about answering one question, which is how aggressive should we be with our medical therapy. And what they are, they are triggers for basically saying yes or no to statins or yes or no to statins and PCS can that image are basically it's a way of gauging how aggressive we want to be. So again low risk you're probably not going to use a statin anyway except in sort of unusual circumstances say somebody has like a very early and extreme family history or something else is funny. But if somebody falls into a low risk category they probably get left alone. So there's these intermediate risk people. So there was a doctor I believe he was from Houston named Agustin and he came up with this idea so people could see on chest x-rays back, you know,

100 years that if somebody had a blocked artery that there was a likelihood that you could see the outline of the artery on the chest x-ray, that's because calcium is radiopec, opaque. So people realized that these arteries, again by autopsies and other conventional imaging, that these arteries get calcified as they develop more plaque. And so this radiologist in Houston figured out that there was a linear relationship between the amount of plaque that you have and the degree of calcium that you have in your arteries. And so he developed a quantitative measure. And that's called the coronary artery calcium scan or score. And that is a low dose radiation screening test

that basically just looks for this one thing, which is calcium. And then it quantitatively tells you how much you have. And it then gives you on a percentile basis what you are, what you should be based on your age and sex. So that's a calcium scan. It's worth pausing for a moment to make sure, because this is a discussion I tend to have with patients a lot,

which is, what does it mean if it shows nothing, meaning your score is zero? What does it mean if it shows anything that's not zero? And to explain this to patients, I usually have to, again, pull out the pathology textbook and explain all of the things that happen before you would see calcification. So when you look at the stages of lesions, calcification is a very late process.

You described it earlier as basically the repair of damage. So if you have a calcium score of zero, does it mean you have perfect coronary arteries? You can't conclude. Yeah, this is a really important point. And to me, there's been a lot of work on sort of what people call the power of zero. So what does a calcium score of zero mean? To me, it's all about the context. So in a 25 year old, or my 15 year old daughter is going to have a calcium score of zero. It's meaningless for it gives you absolutely no additional risks ratification.

Conversely, when a 90 year old-old shows up and has a calcium score of zero, it's quite informative. And in fact, I have some patients in their 70s and 80s who I've taken off of statins because they had a calcium score of zero. And in those patients, their risk of having a heart attack is not zero, but it's low one person. I mean, again, let's remember that the biggest risk factor for having a heart attack is your age. So age supersedes everything else that supersedes all the other known risk factors that we use every day.

Your lipids, your blood pressure, the presence of absence. Although I will throw in my rant here, why is age the greatest risk factor? I don't know. It's a good question. I mean, I would argue as Alan Snyderman has argued that it's an area under the curve issue. It's an good question. I mean, I would argue, as Alan Snyderman has argued, that it's an area under the curve issue. It's an exposure question. So, age is the greatest risk factor for a number of diseases in which it's not entirely

clear why, but I think in atherosclerosis, you would have to argue that this area under the curve shows a monotonic progression in an individual, just as we see progression of polyp to cancer in the colon. So that's exactly why I think the older you are, the more interesting it is to have a zero calcium score. It's Bayes' theorem at its finest. You are acquiring more and more information as somebody goes on. So, you know, when I see 35-year-olds with zero calcium scores saying, see, I'm totally fine. I say, I have no goddamn clue. How do you know that?

But the contrast is that if you see a 35 year old who does have calcium, that's exactly right. That's informed. So there you have, the way I describe it is, it's a two by two. And there's only two quadrants that are interesting to me. Young people, meaning someone under say 45 or 50

who has calcification, and old people, and I'm sorry to use the term old, but older folks call it someone over 70 who has no calcification. If you're in those categories, Bayes' theorem is lighting up like ding ding ding ding ding ding ding ding if you're in the other two quadrants, I don't think I've learned anything. Mostly. So I started again up, frame this. I started off thinking there was no value calcium scans. I evolved to think, all right, well, there's going to be value in these two quadrature describe. I also think there's probably some value in the extremes in, say, I saw a patient recently

who was in his 50s, early 50s, who had a calcium score of 1300. You know, asymptomatic primary prevention. I have a 49 year old who just scored 4500. Right. So that, I mean, that to me is useful, right? So that takes us, again, not gonna ever be supported by clinical trials, but that takes us from, okay, now we all agree that you should be on,

at least statin for primary prevention, but maybe we wanna be even more aggressive, right? And so that's when you start thinking, this is actually gonna change what we do, or change at least in my head, the risk-benefit ratio. Anticdodal, I wanna tell you about that patient, because this is just getting off in the weeds a little bit.

This patient whose family history, if I shared it with you, you would say, oh, he's gonna have an elevated L.P. Little A. Father had first MI at 42, dead by 49, brother had MI in 40s, etc., etc. When you hear these stories, you say, well, it's elevated L.P. Little A for sure. You do an advanced blood test on them, normal L.P. Little A.

Anyone know something else? Lipids aren't even that crazy. It's not like he's got FH. It's not like he's got an APOB in the 99th percentile. Yeah, he's probably in the 70th percentile. But it's like, these are the patients that keep you up at night. And it's like when I was talking to Richard Isaacson about Alzheimer's disease, he's way more afraid of the patients with a ravaging family history of Alzheimer's disease who

have normal APOE. Because there's clearly something going on, and I don't even know what it is. And that's sort of how we feel about these patients of which we have many where it's not even like, you know, they're at the 70th or 80th percentile of risk by lipids and by other metrics, but by story and now by calcium and other tests. I mean, they're at the 99th percentile. I had a patient I talked about a lot on Twitter a couple weeks ago who ended up in his early 50s and ended up having like a very, very tight, proximal left main, like just the kind

of thing that you the so-called Widowmaker. You look at this thing and you think there's no way in the world this guy should have walked into my office and he did. And his first pass lipids were all completely normal, you know, his, you know, regular fasting lipid. He had no obvious risk factors and then we got his LPA back and it was high and I was relieved. And I was relieved because on the one hand, I knew I understood what was going on. On the other hand, we're still left with this. Well, we still don't really have a direct therapy to offer.

But at least we've got a couple of indirect things till Sam Tamekis is ASO's or around. Did you look at his aortic valve yet? It's normal. It is. That's so interesting. I would have guessed someone that young with such aggressive athero would also have something abnormal in his aortic valve. Interesting. All right.

So that's the calcium score. I've always found it very difficult to interpret the data on this because they tend to report it without clearly specifying the age cohort. So for example, everybody loves to quote a study that would say, a zero calcium score means your 10-year risk is 1.9% or something to that effect. But you can't actually say that without knowing the age of the cohort. Because a zero calcium score in a group of 30-year-olds probably has a 10-year risk of less than 1%, a zero calcium score in a cohort of 70- olds would clearly be five to 10% still.

So that's another thing that I just find very sloppy, but I don't have these discussions too much in social media because I find it so frustrating, but it's that you just want to have the time to explain that nuance to folks. It's a great point. And I use the Mesa calculator because it's a nice, you know, it has the traditional risk factors, and then you can add in the calcium score if you have it. I was talking about the multiethnic study of atherosclerosis. One of the two largest cohorts we have ever to study atherosclerosis along with framing

it. And then they'll give you the 10-year risk plus or minus. So they'll say, well, this is what the 10-year risk would have been without- We're either without the calcium. Yeah. And that's somewhat helpful. But again, it comes back to this being way more arthin science. I mean, this is at this point in private prevention. This is still very much art and not science and probably will be for our lifetime.

So we'll have to get used to that. So then CT-Anger Grams basically said like we're gonna do more or less what the NG Gram did in terms of providing anatomic detail because the calcium score doesn't really give you anatomic detail of the artery. It's basically just showing you show me every place where there was a disaster that's been repaired. The CTA says, well, now I'm going to actually show you both the negative and positive image of the artery. So you'll see everything that's going on. But it's in many ways even a better test than the angiogram because you get to see the wall and you can look for soft plaque or other forms of injury to the artery

that haven't yet reached the point of calcification. Assuming somebody doesn't have a lot of calcium, somebody has a lot of calcium then you can't really do it. And assuming that you can block the heart down, the scanners have gotten fast enough now that the quality of the data we get back from these is spectacular. And we get this information we never used to have unless you did Ivas. So Ivas is an interesting ultrasound. So when you do an angiogram, you don't get to see what's underneath the endothelium.

You have to infer it. So now you can see it. So you can see not just the plaque. So I'm fond. I have a strong family history of melanoma and I'm told by my dermatology colleagues that Nevi melanoma grows down before it grows up. So what's happening underneath the surface, you can't see. And then when it starts to grow,

you start to see other servers. That's right. Luminol narrowing is a very, very late consequence of atherosclerosis. So that's why I said, if we did a CTA on us or an average 50 year old, you'd see plaque. It may not narrow the loom in more than a couple percent if at all, it may just look like a normal variation

and sort of lumpy bumpiness, but you'll see plaque and that plaque grows down before it grows up. There's a ton of information. The question of course is, what is the value of that information and how does it change our management? That's a, to me, it just adds color to the discussion we already had. It adds great benefit on the negative and on the positive, depending on the age.

But you take that patient with a zero calcium score whose CT-NG gram is pristine. Their arteries are enormously patent and there's not a shred of evidence of soft plaque. It's still not a guarantee. I mean, we know that, right? Even Ivis could miss plaque or vulnerability. But it makes still not a guarantee. I mean, we know that, right? Even Ivis could miss plaque or vulnerability, but it makes you feel a bit more comfortable that your level of aggression

can be lower and the converse than is true as well. So then what's the cost, right? So other than the theoretical cost of the radiation, which is probably something and the... Yeah, right now, they're going so fast. These things are at a really good scanner so that the top shelf scanners here are doing CT angiograms at about two milli-ceverts of radiation. So for the listener, milli-ceverts, the unit in which we measure radiation, the NRC limits people or suggests an upper limit of 50 milli-ceverts for a year.

We want our patients to be below 20 milli-ceverts for a year. Living at sea level exposes you to maybe one millesever over the course of a year. Living in Denver probably exposes you to four or five milleseverts for a year. So that puts the two millesevers in context. The first generations of these Ethan, 20 milleseverts just for a CT angiogram. What's the chest X-ray? Incredibly low. It's less than one mille c-vert. So we can sort of dismiss that.

There's very little risk of the contrast and most people. Obviously, if you're older, you have kidney disease, something else that it becomes the definition. One of the greatest costs is the economic cost. It's rarely covered and it's a, I don't remember exact cost, but it's not trivial. It's probably $2,500. So it's a quite expensive study relative to the CT,

the calcium score, which I got to put a plug-in, by the way, your institution here needs to get its head out of its ass. I mean, jeez, us. I said in patients the Stanford. Stanford, Stanford's doing CT angiograms for like 100 bucks. And you coca-nuts here are charging like thousands of dollars. Don't get me started.

Well, I think it'll change now at the new guidelines. I think the price has to come down. But it's such an interesting example. I have to send patients from San Francisco to drive down to Stanford. They're pissed off, but I'm like, you know. I tell my patients, this is the one example of

they're actually being an efficient market in medicine, right? Because third party payers don't pay for it up until recently. They haven't paid for it. You have to pay for it out of pocket. So these guys realize the only way they're gonna get it, no one's gonna pay $3,000 to get it.

It's the same basic machine, same everything else. It's just that there's a market. It's a fixed cost is already sunk, and there's no variable cost. It's just, yeah, it's comical. The question then is sort of what is the risk of the CTA? And so from my perspective, the risk is with the right patient, the right doctor is zero.

The wrong patient, the wrong doctor, it could be high. And so the example I use is I've got patients, and I'm sure you have a lot too, who are anxious, and they can't, even though they don't anticipate that they're gonna be this way, they can't live with this sort of thing growing inside of them. I'm sure you had patients when you were doing

cancer surgery who just basically said, get this tumor in the hell out of me. I don't want cancer anymore, get it out. And even though prostate cancer is a great example, right? There are lots of ways to treat prostate cancer today, and some of them involve cutting the tumor out. Others that are equally as effective probably or close don't. But some people mentally can't get their head around living with cancer. And I think I have patients of mine who, when they get a CTA and they see there's plaque there, they just can't sleep because they think this thing is going, I'm going to die from

a heart attack. And no matter what we say, no matter what I say, just can't sleep because they think this thing is going, I'm going to die from a heart attack. And no matter what we say, no matter what I say, I can't dissuade them of that. That's to me is the one cause. So that's where I would sort of say, this is why I'm not going to, that and the economic thing is sort of why I'm not going to widely do this and everybody. But in certain people, it's spectacular. So before we leave this, let's just talk about what heart flow is, because that's something that's come on the scene and about the path. I want to say it's about

three years ago, maybe four years ago, it's a company here in the Bay Area, correct? And they're layering on an analysis to the CTNG Gram. Can you explain a little bit about what that is and where it came about? I'm going to try and keep it brief, because I got quoted in an article over the summer about heart flow. And I think I said something like, I don't wake up in the middle of the night dreaming about which patient I wanna use heart flow in. So I don't wanna be too harsh on them.

This is basically based on the idea that you can use physics to measure the percent narrowing of an artery by measuring the velocity across the lesion. So as anyone who puts their finger on the end of a garden hose knows, the velocity of the water that comes out of the garden hose goes up as you narrow the opening of the garden hose. So the same thing is true in an artery.

If you have a narrowing, then the velocity across that is going to be faster and there will be a pressure gradient. So you can actually measure pressure using a catheter with a pressure sensor on it. And you can measure pressure before and after the blockage and you can basically then infer how severe the blockage is. And that technique was first developed invasively in people who were going into the cath lab. And there were patients where you'd look at the artery

and you'd think, yeah, we're looking at this in two dimensions and we can't really see, it's hard to see exactly how severe this is. So there were a couple of these tools that were developed. One of them is this Intervascular Ultra Sound Ivis. And then the other one was this FFR, which is a way of measuring pressure and basically inferring the degree of blockage. So that fractional flow reserve is the calculation of P2, which is the pressure beyond the

occlusion over P1. Right. And they do it before and after administering a vasodilator. P2, which is the pressure beyond the occlusion over P1. Right, and they do it before and after administering a vasodilator. So they'll give a patient a vasodilator, and they can measure sort of maximal blood flow. And you can do that in a normal artery, a normal artery, you'll see it augment in a diseased artery, doesn't it? It goes down. And there are two big trials that looked at the use of invasive fractional flow reserve. One was called fame, the other was called fame too.

I'll spare everybody me looking up exactly what fame stood for again. What did those studies show? The take home, and again, there's controversy with almost anything in cardiology, there's controversy. The take home was that if you had an FFR that was less than 0.8, so you use a mathematical formula that would basically calculate, and if it was less than 0.8,

if you then put a stint in that artery, people did better. So it suggested that this could be a useful tool to help stratify who should be getting stints and who shouldn't be getting stints. And I think a lot of our interventional cardiology colleagues have been using it that way for the past few years. Again, there are questions. I don't want to get into the controversy. There are questions about the technique and about how they did it, and there are some questions about the validity of it. But it's mostly a useful tool and people do use it. But it's invasive, so you have to be having an angiogram to do it. So somebody came up with this idea that you could do the same thing using just a non-invasive CT scan, and you could basically measure the velocity and for the pressure using OMS law.

So they did the same thing they gave it based on dilator not and they can do this. And it goes law, sorry. Oils. Yeah, I don't know, you're the answer there. I'm not saying it's been a long way. So they did this and law and behold, they were able to measure this thing.

Not an invasive, you don't have to have a catheterization. You can do it all through CT. And then heart flow basically is selling the software as an add-on package to the CTA and they'll give you what's called a CTFFR, which is their calculated FFR. Is this changing your practice? Because when it came out, I started doing it. And then I realized, especially just based on orbita, that wasn't really going to change my management. So I have not done a heart flow study and probably over a year on anybody. That's the point.

Whereas the anatomy of sort of whether there's plaque there does help guide you about how aggressive to be with your medical therapy, it's not clear to me that we're learning anything from adding the heart flow on. So I have never ordered one. It doesn't mean that I won't order one in the future. I've done a lot of this where I've said I've never ordered one and then 10 years later, I in the future. I've done a lot of this where I've said, I've never ordered one, and then 10 years later, I've ordered one, I've ordered a lot. So I reserved the right to be wrong on this one,

but my instinct is, like you say, we have the information from these two other big trials that tell us that this is probably not gonna be a huge game changer, because what information is it adding and how are we gonna react to it? So their pitch from a business standpoint is that it saves unnecessary catheterizations. That's a business discussion that I think

I generally don't believe right now, but that's their case. And if you're an individual patient, what values are going to bring to you, or if you as a doctor, what value does it bring to you? I can't think of a big value today. Unless you had somebody who you were going to send to the Catholic, and you thought this would help sort of make you feel comfortable about not doing it.

Let's pivot for a second because we're sitting here in your office. We've been nerding out for two hours on preventative cardiology, but I'm looking at your very, very beautiful whiteboard. And I not only do I have tremendous whiteboard envy, but there's not a single thing on here that looks like it's about cardiology. If I didn't know better, I would think I was in the lab of David Sabatini or one of my other friends, you know, Lou Cantley. I mean, we've got insulin receptors, PI3K, we've got mTOR, you've even delineated between MTOR complex one, two pathways to a topogy. That's a growth hormone, IGF pathways, pancreas, liver.

Are we in your office? Whose office is this? I came here to San Francisco 21 years ago to study in the lab. The person who became my mentor was my boss until he left to go work in Nevadaartis a couple years ago, a year ago, two years ago, Sean Kaufland. And I came here because I was interested in the biology of blood clotting. And so when I left his lab and decided that I want to stay here in San Francisco, I had to find something that I wanted to do that would be not what he was doing because that would be done. And so at that time, I got very interested in the biology of six differences. And I don't want to spend seven hours describing it, but it's a really interesting literature.

And so I did a deep dive on it and thought, gosh, there's a lot of reasons to think that there may be significant differences in the way men and women behave clinically and biologically with regard to the clotting system. And there may be reasons to expect why that would be, right? We talked a little bit before about the pacenta and pregnancy. Men don't have to have this other thing living inside of them. And therefore could afford maybe to optimize more towards sort of wound healing defense strategy, right? Men, there's a difference in sort of the way you might, if you were to design a system, if you were to create evolution there, you may be able to optimize

it. This system for the two sexes differently. That is the most interesting idea I've ever heard because one of the questions I've always batted about in my mind is all things equal why are women less susceptible to cardiovascular disease or at least I wouldn't say that way. Why do women experience a phase shift? They get it later and you look at blood pressure differences, maybe women have lower blood pressure, another one is iron, women have less iron. For 30, 40 years of their life, they're basically doing a blood donation every month. I never once considered what you just said, which, as you say, it actually makes a lot of sense. Men would, in theory, evolve to heal from a wound much quicker, even at greater cost down the line

because of their role in a hunter-gatherer society, whereas the woman must evolve to protect the offspring much more, and you could see how that would be a lower immune response, a lower inflammatory response, a lower pro-thrombotic response. That's it. I can't believe I didn't even know that. Well, if you want to get really crazy, you can start to imagine, well, maybe women have

evolved to be the less masculine of the sexes. In other words, maybe they're the ones not going out and throwing spears and fighting because they have to carry pregnancy. So they're a little bit more susceptible to bleeding. And I had a sort of complication of menstruation, all these other things. So anyway, I thought, wow, this is a really interesting area. And the reason it was particularly interesting was that in the work that we had done primarily in mouse genetic models, it looked like there was a pretty significant difference in the rate of clotting between male and female mice. So I thought, well, this would be a really fun thing to study.

And of course, I did exactly what you did, which was I immediately kind of latched on to what must be sex hormones. And did some early kind of pilot studies looking at the role of estrogen aster receptor different. And it didn't pan out. And so I did more reading about sex dimorphism in general. And it turns out that mammals have this remarkable sexually dimorphic liver. So if you take the liver out of a mammal human or a mouse, there's a set of genes that are expressed dramatically different, even up to 100 full different males and females. And a lot of these genes or genes that regulate sex hormone sex or minding or modification. Others are sexually dimorphic for reasons we don't understand. But if you do a sort of array of gene expression,

whether you're using an old-fashioned chipper air, whether you're doing RNA-seq, you see this tremendous signature difference between the genes that are turned on in the liver of females and males. Well, where clotting factors made the liver? So I thought, well, this is what we're gonna do do. And so I set off to basically try and understand of how this happens. So what regulates the dimorphism of leveraging expression in mammals, turns out it's not sex hormones. That's actually secondary.

It turns out that it's a dimorphic pattern of growth hormone secretion. So it was described back in the 50s and 60s that there was a factor from the pituitary called feminizing factor, but it wasn't known what it was. So, we just ground up the extract of the pituitary and injected it into a male or female mouse, you could basically drive the expression of these genes. And ultimately, it was found in a beautiful paper, I think it was published in 1982 and sell by Richard Palmer's group.

It was found that that factor is growth hormone. And that if you, which by the way, is the last one I would have predicted. Like I would have said, oh, it's probably luteinizing hormone or follicle stimulating hormone. I wouldn't have guessed growth hormone. No, it's growth hormone.

So, you know, males have a more pulsatile pattern of growth hormone secretion. So they have longer intervals between the pulses. Females are more continuous. And so they have, they have very short. So the guys have these spikes that are less frequent and the women are putting.

Now, area under the curve about the same. Mean it's the same. So what's cool is you can actually take an intact normal wild type male rodent and put a pump in and deliver continuous growth hormone and you can completely reverse the signature of their gene expression in the liver. And you can do the opposite with a female mass, you take a female mass and because if you give exogenous growth hormone, you basically suppress endogenous growth hormone secretion from the pituitary, you can give the opposite with a female mass. Take a female mass, because if you give exogenous growth or when you basically suppress endogenous growth

or when it's a creation from the pituitary, you can give a couple of injections. I think it's just one or two a day to a female mass and you mask you, and I deliver. We live in a world where a lot of people have decided it's a good idea to prescribe growth hormone to reduce the effects of aging. I talked about this very briefly with near barzoli

on our podcast, and I would say that near's view from that was that there might be some benefit in men in certain circumstances in women less so. But is it safe to say that if a man and a woman are both receiving the same dose and same dosing pattern of exogenous growth hormone, you would evaporate that difference of gene expression in the liver because you would have suppressed the pituitary secretion. Yes.

You should. Have you done that experiment? In people? No, in mice. Yeah. Yeah. Yeah. Yeah.

We did that experiment. So I got into this because I was interested in clotting. And that makes sense as a cardiologist. I just, we just spent two hours talking about like clotting. Is it interesting to a cardiologist? So starting off my lab as a junior assistant professor, I thought, well, this is what I'm going to do. I'll understand the biological basis of sex differences of plotting, get into this growth hormone pattern. And so we started to do that. And we, as a lot of

people, by generation, do science is a little bit of a game of you do whatever else does and see what it comes out. And so we started knocking out different components of the growth hormone signaling pathway in mouse. And we got to this protein called Jack 2, which is a kinase, which basically adds a phosphate group to proteins. And it's important for other areas of medicine and science, but it's obligate signal transducer of growth hormone. So downstream of the receptor, growth hormone binds Jack 2 basically allows this signal to be transducer.

Is there a different receptor for growth hormone in the liver versus outside of the liver? No, GHR is the same everywhere. There are different isoforms. I think there's a soluble one which is basically a GH binding protein, but the GHR is the same. And that signal is transduced because growth hormone receptor itself is a type 1 psychoma receptor. It doesn't have any intrinsic tyrosine kinase activity. It has to partner with this other non-merceptive tyrosine kinase, Jack 2, to transuse the signal. So we eventually knocked out Jack 2 in the liver in hepatocytes. And I'll never forget that I had a technician working in the lab at the time. He actually, he was the only person working in the lab at the time.

It was just the two of us. And he came to me, he said, Ethan, there's something wrong with these livers. I don't even need to genotype them. And I'll show you a picture. But it turns out that the livers in the animals where we had selectively deleted jack two in hepatocytes were basically turned into natobost tissue. It was the most you were creating naffled D. Yes. So just something we're trying to understand what you're saying.

If you knock out jack two in a liver, you prevent growth hormone from exerting its transduction in the liver because you need Jack 2 as that second tyrosine kinase. So, it's basically like taking away growth hormone from the liver. And if you do that, you accumulate fat in the liver. 25 fold increase. 25 fold. So, it becomes clinically grotesque. I mean, you just basically create faggwa.ar in fact there was a moment in time where I thought well

This would be a fun side business. I'll just make for a girl because we can engineer it quick question Did the triglycerides go up or stay the same and I sure yes no they were the same so in other words you shut off Export it seems like significantly right there is no flux there's no outward you were basically not getting any VLD L or triglycerite out of those livers. Well, so we didn't know what we did at the beginning. We had no idea. In fact, I took the liver topopathologist

because I said, I don't know what this is because I didn't know what it was. And he said, Ethan, I'll look at another microscope for you, but I know what this is. And I said, what's that? He said, it's naffled. I said, what's naffled? And he said, it's non-alcoholic fatty liver.

And I said, okay. And so then, of course, I started with the very basic, like, all right, well, what are the causes of naffled? It's an increase in synthesis, so increase in DNA, the decrease in export, increase in uptake, or it's decrease in oxidation. So we started to go through this whole list and to make a very long story short, what we settled on and published, we published a model that I think mostly we validated to be true, although there's a little bit of controversy about it. And it comes back to what you said. So growth hormone signals and one of the products of growth hormone signaling in the hepatocytes and other cells is this protein called IGF1, insulin-like growth factor one. And 95% of circulating, if not more, of circulating IGF1 in the plasma,

so if you take blood of you or may come from the liver, so it's liver derived. So if you knock out growth hormone signaling in hepatocytes, you completely shut off and shut down circulating IGF1. There's still local IGF1 and cells and tissues, but circulating IGF1 goes to zero. And circulating IGF1 is the plasma biosensor for growth hormones. Growth hormone's half-life is extremely short. So we evolved the system to measure growth hormone levels, not by measuring growth hormone itself, but by measuring IGF1. So when IGF1 levels fall, the hypothalamus pituitary sense that, and then they turn on growth hormone.

That is so brilliant. Just as an engineer, I have to sort of reflect on that for a moment. Every time I hear something like what you just said, I'm so glad that I was not in charge of evolution, because I would so glad that I was not in charge of evolution. Because I would have screwed that one up. I would have said, make the growth hormone sensor sense growth hormone. And of course, you would get into a cyclic amplified response because of how short it sticks around.

But instead, luckily, evolution was in charge and not me. It said, no, no, no, no, no, no, no, no, that's going to be way too fluctuating. Let's look at something that's much more stable, that's a readout of growth hormone. Oh, hey, how about IGF and have that be the feedback loop? Goodness gracious. I love when nature is so smart. The fascinating thing is that circulating IGF1, I won't say it's all it does because it does a few other things, but the vast majority of its role is as a plasma

biosensite of a growth hormone. So it regulates growth hormone secretion. So what happens if you knock down IGF1, you get this huge increase in growth hormone secretion, you basically get acromegaly, but you get selective growth hormone resistance in the hepatocytes. So you probably remember the growth hormone has been described for a long time forever and ever to be prolipolytic. So it's actually one of two hormones is both's both catabolic and anabolic, but it turns on, it's a way to mobilize that from adipose tissue stores. Testosterone being the other

where you can be anabolic to muscle, catabolic to fat. And thyroid hormone, I think, is another one where you can be both. Unlike insulin, for example, which would be anabolic to both. Yep. Or cortisol, which would be,

actually cortisol is the reverse. It's catabolic to muscle, anabolic to fat, anabolic defense. Right. So in any case, if you give an animal growth hormone, if you have a patient who has a tumor that secrates growth hormone, what we disease called acro-megalene or gigantism, right? I wonder if the giant had gigantism.

Those people have a decrease in lean body mass, increase in muscle mass. That's basically because growth hormone mobilizes fat from adipose tissue stores. So we reasoned that what was happening was the growth hormone was turning on lipolusists and mobilizing all this fat and that fat was getting taken up by the liver. What was interesting was we did a relatively deep analysis of all the mouse models that have been made involving the receptor, GHR, downstream signaling components, including Jack 2

and another one called stat 5. And we looked at animals that have been engineered to be missing any of those components in the whole animal versus just in the liver. And what was interesting was that the animals where you knock out the pathway in the whole animal had a 1 to 2 fold increase in lipid in their liver, very modest, if hardly noticeable. Whereas if you knock out the receptor or this other molecule step 5 or Jack 2, selectively just in a patisite, you get this 20 to 25 fold increase. So that told us it's not just about having high growth hormone levels. It's about high growth hormone levels.

And those growth hormone levels acting on the periphery, there must be some other factor that is important here. And so we reasoned what people do, which we did at a gene expression array. We saw there was a molecule called CD36, which is also known as fatty acid translocase. And we saw that it was increased by, you know, 20 fold in these animals where we knocked out Jack too in the liver, and we thought, well, gosh,

this could be facilitating uptake. And so we did, you know, a series of following experiments after that where we knocked out CD36 just in a parasite and showed that we could make that get better. So we put together series of follow-on experiments after that where we knocked out CV 36 just in a padiside to ensure that we could make that get better. So we put together this model where growth hormone basically, growth hormone secretion is disenhibited at the level of hypothalamus pituitary. You get an increase, you get an increase in activity

in peripheral tissues, it's then mobilizing all this fat and then the fat is being taken up sort of preferentially or augmented rate of uptake by the up regulation of this molecule. Now, if you block Jack 2 and block the expression of CD36, do you eliminate the fat accumulation in over? Yeah, that's the experiment we did. It wasn't 100%, but we basically brought it back down to almost, you know, to instead

of it being 100 grams per milligram of tissue or something, it was like 20, where normal amounts would be 11 or 12. So it's near normalized. We also then did an experiment. We said, well, what happens if we block this pathway, the growth hormone signaling pathway in a dipocytes, since we're presuming that this must be a product of lipolysis? So what happens if we block this pathway in a dipocytes? So we went and made an animal where we knocked out Jack 2 in a dipocytes selectively, and then we crossed the two together and asked what would happen basically can you reduce the amount of lipid in the liver by knocking out both at the same time and we did. And that experiment we did almost 10 years ago and and what was so fascinating about

that experiment was we never intended to get into any of the insulin glucose homestasis stuff at all. But when you're doing these experiments, they're expensive. And so we did a bunch of things, you know, measured, we did, I think we did an insulin tolerance test for some reason on these mice. And we saw that the mice where we knocked out Jack II, Justinian Dibisites, had the most profound insulin sensitivity. Like we actually killed our mice because they died from hypoglycemia. We gave them the same amount of insulin that you gave a normal mouse, and they bottomed out, we couldn't rescue them, and they were super insulin-sensitive. And this was mostly glucose being disposed into the muscle?

No, it turns out, so we thought that was interesting, so we then went on to kind of dig deeper on what was going on. Again, here we'd knocked out this pathway just in a dipisites, and we saw that if you knock out the pathway in a dipisites. But And we saw that if you knock out the pathway in a dipisites. But I'm confused. So you knock out the pathway in a dipisites. When they're hypoglycemic, you're

putting that glucose very easily into muscle or into liver. I mean, you'd have to put it into one of those two wouldn't you to then, even if you want to then put it into fat into the fat cell. Yeah. So and what you're asking is a phenomenal question. And we had initially, I think, naively thought that this was a dipesite autonomous effect

that we thought, well, must be the dipesite. But then there's not that much glucose that's actually disposed into the dipesite on a per mass basis. And we thought, that doesn't make sense. So we ended up doing what you do, which is to clamp the animals. And it turns out that the defect is almost entirely in turning off EGP.

So basically what we do is we completely turn off endogenous glucose production from the liver. Which is really not an insulin sensitivity issue at all. It just masks or raids as profound insulin sensitivity, but you basically clamped the portal vein metaphorically and you kill an organism in five minutes if you stop hepatic glucose out. But how quickly did you see these animals die? It was within 30 minutes. Oh my god. Yeah

Yeah, it was really profound and and so this then sent us off in this like long What's now been a 10-year journey to try and understand how growth went regulates? insulin sensitivity or insulin glucose homie estasis and how that happens through the adipiside we won't get into all of it now, but it turned me on to the Kind of remarkable figure one of these figures in history that I didn't know before. I got into this that I am surprised. He's Guy Bernardo, who's a Argentine physician scientist who won the Nobel Prize. First Latin American to win the Nobel Prize, right?

I mean, this guy was unbelievable. I'll send you a link. There was a period of time in the 1930s. I think it was 1936 where he was the first or only author on 14 articles in the New England Journal of Medicine over five weeks. At one point, he had, it was the most unbelievably productive period of time ever seen.

And he had enough willing to know about prize. He shared the double prize with the choris of the choriscle, which I didn't know until recently. I was reviewing some of this stuff for our talk today and I didn't realize that they had collaborated on some stuff back in the 1930s, but he defined the diabetogenic nature of growth hormones. So he did these experiments that I think were really cool and basically got left behind because no one really paid attention to any of this stuff for a long time, but he defined that if you take an animal, the first thing I experienced he did was he took an animal and took the pituitary out and then gave the animal insulin and saw that the animal was,

he described it as they were more susceptible to being to the toxic effects of insulin so that they bought them their blood sugar out. He then did the opposite experiment where he took an animal, he'd lopped out the pancreas and then saw that if you got rid of the pituitary gland that they were less susceptible to the hyperglycemia that they basically had improved diabetes. Those experiments continued on for 60 years. So let me just make sure I understood. Take away growth hormone and you're going to become much more theoretically or appear insulin sensitive, but in reality, much more hypoglycemic.

Take away growth hormone in the absence of the pancreas and you actually tolerate hyperglycemia better. That's right. In fact, there were people in the 60s, I believe, who were doing hypophysectomies and people with very brittle type 2 diabetes. So severing the link between the hypothalamus and the pituitary? They were taking the pituitary right out. Yeah, wow.

And it was a very effective treatment, actually, except that it had a significant morbidity and mortality of the surgery. So at that time, they had perfected the art of taking the pituitary out. But even when they did, you're saying even now that they'd have to replace all of the thyroid and sex hormone and ACTH, the cortisol-related stuff, it still turned out to be better off. All things considered in how well it managed their diabetes. The ultimate killer experiment happened in 1983, or so. So they took patients with type 1 diabetes, who had an insulin pump. So they were getting a fixed dose of insulin. And then they gave them, I believe, one or two injections of growth hormone.

And you could see the insulin level go, like this, straight up. Basically, their insulin use, within a day spikes and stays up until they stop the GH injections. And it comes back down. And in fact, three out of the seven people in this one study got profoundly hypoglycemic when they stopped the growth hormone. So it turns out that there's a drug that blocks the growth hormone receptor that's used as a second line treatment for acromegaly. It's called somaferter, pygvisimmon. It's an analog of native wild type GH. It just has a few mutations in it that renders it basically as a dominant negative,

so it doesn't allow, basically shuts off the receptor. And it's used again clinically. And if you look at the package insert, the black box warning is, if you take any diabetes drugs, let your doctor know, because your risk of hypoglycemia is so high. So it actually reminds me a lot of the sort of low carb ketogenic diet in the sense that it has that same effect. And in that 1983 New England Journal of Paper, they actually talked about growth hormone secretion being as much the cause of brittle type 2 diabetes as the effect.

And for reasons that I don't understand, people just forgot about it. And so we set out to kind of try and understand, at least at the beginning at a cellular level, how is this regulated? And we're trying to dig down. It turns out that it all comes back to your favorite molecule, mTOR, and it looks like it converges

in this intersection between these two signaling pathways that evolved actually only, I mean, growth hormone doesn't exist pre-telios. So there's no growth hormone in phlasor worms. It's only in invertebrates and teliosts. And it co-evolved basically from insulin, which is not that surprising, right? IGF1 is basically the target molecule of GH. It's not surprising that GH and insulin

would have evolved in a similar way, even though they look very different, they act very different. So the way I think about it is that growth hormone is kind of retained a lot of the sort of metabolic effects of insulin and insulin, obviously has retained a lot of the growth promoting effects that used to be with growth hormone when they were all one molecule. And so the point is that I think that these two molecules act in concert and from our experiments it looks like that's happening in the adipocyte and that basically growth of one's acting as a break on insulin signaling and that that's controlling metabolism in the whole body at a distance.

And so that's what we've been working on. And again, we could probably talk about that for three hours, but it's been keeping us busy. So let me kind of think through this a little bit, because it's so interesting. Let's go back for a second, too. You didn't mention IGF binding proteins, but where do they fit into this?

The IGF BP's, as they're called, are also made by the liver, correct? So IGF is mostly made by the liver, IGF BP2, BP3, also made by the liver. These are interesting to most people listening to this because if they pay attention to any of the sort of epidemiology around longevity, there's so much controversy around this idea of IGF and its association with mortality. And you have such conflicting information, that's what makes this so challenging, right? So you have these people that have mutations in either the GHR or low GH secretion and

or low IGF due to a deficient GHR on the liver, and they seem to live longer or at least get less cancer, but then they also seem to get a bunch of other diseases that are kind of weird. But when you look at all cause mortality, it seems to nature at the 60th or 70th percentile for everything. But when you do it by disease, certain diseases seem to get better with higher IGF, like Alzheimer's disease, and I believe cardiovascular disease, you would know this. But others get worse, like cancer starts to go up.

So how does all of that make sense in terms of what you're learning at this level? Well, I'll say that the GH meetings are fascinating, because they're basically the room aligns in these two camps. There's one side of the room that believes that GH is the elixir that will promote longevity. And there's's one side of the room that believes that GH is the elixir that will promote longevity, and there's the other side of the room that believes that too much GH signaling will negatively impact longevity. It's really interesting the way these two things. I think for me, if you start with what we know from human genetics and animal genetics,

it's incontrovertible that excess GH signaling, at least at the levels that you see with transgenic animals are anachromagely, is one of the most potent ways to die, right? I mean, people with anachromagely, untreated acromagely die in their 30s and 20s, and the dive cardiovascular disease. So I think that's gain of function, and again, the animal is the same thing. It's a great way to shorten lifespan in any animal, whether it's a worm or a fly or increased signaling through this pathway and you'll shorten lifespan. And then the flip sides, he mentioned in the LaRone patients, right? Those patients don't have increased longevity per se, but they sure do have a decrease in their risk of metabolic disease.

It's a much decreased risk of developing type 2 diabetes, despite an increase in body fat, which you'd think would be dangerous. It turns out that they and the mice, so there's a mouse model of laryng syndrome. That's actually the longest lived mouse that's ever been engineered. There was a prize that I don't know if it still exists, but it's called the Methusel apprise. They used to give out, it was $5 million to an investigator.

If you could engineer the longest living mouse that's ever been made. And so this guy, Andre Barky, it's other than Illinois, engineered the mouse that's missing. Actually, he and John Coptic did it together, this experiment where they engineered the mouse that's missing GHR. And that mouse lived to be 1,819 days,

which is basically the equivalent of like 207 human years. Still to this day, the longest living mouse it's ever been made. And that meant it was without GHR and the liver forever. No, anywhere. Anywhere. And that means for its entire life. The whole life. So these are short and fat mice, and they live forever. But they have all the other problems that you'd have if you're missing growth hormone congenitally. So they're short, and they're

they're pretty fat. What's interesting is that that fat are they cognitively the same? The mice for the people. The mice, well, I guess both, but I think they are. It's a great question. I don't know how much has been done

on their cognitive abilities late in life, but they clearly are very resistant to these diseases that kill mice in labs. They're healthy by every stretch. They're extraordinarily insulin sensitive. I mean, again, same thing that was described before we ever did these experiments. What we demonstrated was that the insulin sensitivity is conferred by the absence of the signaling pathway in the adipose tissue, which is acting at a distance mostly on the

liver. So what do you think confers the protection to the Laurent's patients? I don't know. It's one of the things I think about every day, but at a very simple level, I think of it as an improvement in insulin sense, it's sensitivity to decrease in insulin and decrease in IGF1. I can't get better than that right now, but I think this circulating insulin levels

are nearly undetectable. And my lab's die of cancer, and I think there's probably just less insulin, less IGF1, and they just don't get cancer. Because this relationship between hyperinsulinemia and high glucose, you and I both are on an advisory board of a company called Verta Health, and that's how we actually met a few years ago. And I remember in one of the meetings we were discussing this idea that people need to understand the difference between managing glucose and managing insulin. If you manage glucose levels, if you keep glucose levels in the ideal range, by any means,

you control microvascular disease. You're less likely to go blind and less likely to have kidney failure and have an amputation. But if you do that with a strategy of high insulin, you trade it for macrobascular disease, atherosclerosis, coronary artery disease throughout the body, obviously, you know, in the coronary arteries and cerebral arteries, even the aorta, the large vessels, suggesting that even high insulin by itself can be problematic. So these patients are walking around with very low insulin, which you could see would protect them at the macrovascular level. Because of this, I still think of it as a paradox because I'm still struggling

to wrap my head around their insulin sensitivity, how they can be so insulin sensitive, but they also obviously have normal glucose levels. So their microvascular stuff is okay. And then on top of that, you're saying if insulin and IGF are pro, from a metabolic standpoint, pro-oncologic or pro-tumor, you also get that benefit, the one I've never understood is, aren't these things important neurotrophically? I mean, isn't IGF and GH important in the brain? And how are they avoiding those consequences? One of the voybles of doing what we do is that we look at what we look at and don't look at anything else.

So, again, I set out to do these experiments originally because I was interested in the clotting. It was only an accident that we noticed that the liver looked like fagra. We've never looked at the brain. And I don't know how much others have looked at the brain. And I'm not sure how much what happens in a mouse brain would guide us. But it's a great question. I think if you're just asking about the things

that I can measure. So metabolic disease, cardiovascular disease, cancer, and lifespan, it seems like everything aligns towards too much GH being bad and less GH being better. But I can't tell you about the neuro stuff. It could be the opposite there. And why is it that if the patients with loron syndrome are less likely to die or they get to phase shift and delay the onset of cardiovascular disease,

neurodegenerative disease, and cancer, they don't have a survival advantage? Well, the story that I, I mean, again, you're talking about pockets of a few hundred people. I think the one that's gotten the most attention is this one in Ecuador and there are 300 patients there. I think what's amazing is that the 30-year follow-up of that cohort of people, there was not one single case of cancer or diabetes. Over 30 years and 300 people compared to like 15% in their age-match relatives.

What I heard was that they were depressed and had an increased risk of alcoholism because they were basically ostracized for being fat dwarps. I mean, I hate to be harsh, but I think that was the most important thing. Yeah, and I also heard there was a higher incidence of accidental death and other things, which you could argue, well, you have to die of something. So if accidental death explains it, that should still show a survival advantage.

I think we're getting into the sort of trouble of trying to... Yeah, epidemiology just makes this very difficult. Especially in these small, like, in-bread communities, I think it just becomes almost impossible. So we talked about experiments we're never going to have answers to. We're never going to have a human longevity lifespan study that you or I will see the results of. And we just have to understand that. But at the meantime, we can talk about the other stuff.

And I mean, the insulin thing to me is interesting because I think there are some people out there in the Twitter sphere who are sort of fall into the category of statin denialists. I think there's this narrative that's developed out there that statins don't treat the underlying cause of cardiovascular disease, that the underlying cause of cardiovascular disease is insulin. And while I'm firmly in the camp and we'll ever expect to remain in the camp that lipids are fundamental and probably the most important driver of cardiovascular disease, of arthrochlorotic disease and events. I do think there's good evidence that insulin

actually does play a role. And in fact, there were some studies that were published over the years that showed that fasting insulin was an independent risk factor for cardiovascular disease. And it makes sense. Don't we also see this borne out in the type one literature that stratifies patients by insulin use? Yeah.

I think James O'Keefe published a paper on this about two years ago. Do you know James? No. Provincial cardiologist in Kansas, mostly his work is an exercise, and the role of too much exercise, actually, but actually published a paper in this a while ago. So, yeah, super interesting. This is clearly top 10 questions I get asked all the time is, should I be on growth hormone? My general answer is no. Mostly through the lens of,

I'm not convinced by any data that growth hormone will promote longevity. But on the flip side, I've also softened my tone. I used to just think on first principles it made no sense because of if nothing else, the cancer risk. But of course, the other thing that's odd is there's so many people taking growth hormone, especially athletes. And if there is a negative consequence of it, it's probably not as big as I would have guessed, and or it takes a lot longer to show up than I would have guessed, because we just don't see the trail of body bags that you would expect. I mean, that's the thing is you have very bonds of 25 or 28 taking a bunch of growth hormone. What do you expect?

So maybe his risk of having an MI is increased twofold or threefold. Would that be enough to see, don't you think, wouldn't a twofold increase show up? In a non-randomized cohort of athletes taking an illegal drug, I don't think we have to date. I don't feel confident. But what I've learned in this work is that these hormones are regulated in ways that we can't even begin to understand. I mean, that's so complicated.

And so I'm nervous to go in there and start perturbing it or replacing it if it's deficient. Because I just, I see all the different things that can happen and how complicated that can be. So I'm a little bit more of a minimalist, I guess, when it comes to these kinds of interventions. But my answer to my patients is every line of evidence I can see about GH at least is that if you're worried, if you're optimizing for longevity, it's hard to tell a story that that's going to help you. Now, if you're optimizing for, I want to feel better, I want to increase my lean muscle mass, I want to decrease my fat mass, I want to look better, go for it. If that's what you want. And so that's what I tell people is if this is something that you're willing to

understand that we have no evidence That it's probably an increased your lifespan it may more likely even decrease it But you like how it makes you feel and look then then sure so I would agree with all of that I think the one area where I would love to see more investigation and this is certainly amenable to a clinical trial is Does increasing IGF in patients with either very high risk for or early cognitive impairment to improve outcomes. I think the literature makes a plausible case that that could be the case, and that strikes me as a subset in patients, at least for me clinically, that I am most interested in

knowing the answer to that question. If we take our high risk dementia patients, or worse yet, patients who are already in the earliest stages of cognitive impairment and take the ones who are at lower levels, you know, the bottom quartile of IGF levels will GH provide benefit. Yeah, that's a great trial. What happens to your IGF when you fast? Oh, plummets. And the numbers are kind of irrelevant because it's all a function of your scale.

So when I was on a ketogenic diet for three years with no fluctuation, my IGF level resided at the 40th or 50th percentile for my age. So the lab that I use gives me not only my IGF level, but in five year increments, it gives me the distribution of it. So I can, you can very accurately peg where you are. So for me, constantly being on a ketogenic diet, put me at about the 40th to 50th percentile for IGF level, which is not really surprising when you consider that a ketogenic diet minimizes insulin and also for most people actually keeps protein lower than you would otherwise normally have it.

So methionine plays such an important role in this, of course. When I'm not on a ketogenic diet, which I'm not these days, except for in the perifasting period, my IGF probably lives closer to the 70th percentile. On our scale, that's about 200. When I do a fast, so I'll do a blood draw right before the fast, and then usually on day six or day seven of a complete water only fast, that IGF will be in the 80s and 90s, which is more than two standard deviations below the mean. What I find most interesting is how long it takes to rebound, and it takes about

six weeks to come back to normal. So, and if you ever, and it's measuring growth hormone is one of the hardest things to do, because it's so important. I've never measured it for that reason. I just, I, yeah. I mean, it might be so high that you would be able to see something. Let's talk about it because I'd love to figure out the problem is I only fast in New York, never in San Francisco, but maybe I'll do a fast up here and swing by the lab and we'll do daily bullet does or something. I guess we have to get an IRB these days. We can't do anything

for fun, but it's very interesting to see how much you can manipulate GH nutritionally. Well, that's what one of the things that we're really interested in understanding, like in the future, is understanding its role in this fasting-feeding transition. It goes up in fasting. But as you say, I do have one levels go down. So you get this selective GH resistance in the liver at least. The question of is whether you're getting GH resistance and other tissues as well. But why would you have this hormone go up and then lose its activity?

It's kind of a funny thing, right? And you see this in people with anorexia too. Yeah, I've never actually understood it as well as I feel like I do now based on the way you've told this story of, it's a great way to describe it, right? Selective GH resistance in the liver, IGF is plummeting GH's skyrocketing. Then the question, and we should know this, and eventually we will, what is GH activity and a dipisites? Is it actually maintained?

And so, are you basically trying to mobilize fat as a way of avoiding starvation? Is it basically you're trying to direct GH to act only on the periphery and not on the liver? By the way, if you believe that periodic fasting improves longevity, and I certainly do Valter Longo does, we might come at it from different ways. It also begs the question, is the benefit conferred by the reduction in IGF

or the transient rise in GH? Yeah, or something completely different. I never even really considered that the benefit could be conferred from the GH rise, although that seems less likely, given that it's hard to imagine you, I mean, who knows though, maybe there's something, I mean, if biology teaches us anything, it's to stop acting like we know what we're talking about.

Exactly. Exactly. Ethan, I want to go back to something because I know we've got to wrap up, you've got to, you've got to get back to stuff. You know, you talked about something at the beginning that I didn't know, which was you went off to Vassar to get as far away from science as you could, and yet you had an experience there that presented science in the right way, and I would argue the world is actually a better place for you doing what you're doing now, which is not to say that

you being the drummer of a band wouldn't have been equally impactful, but maybe I'm biased. This is an interesting topic to me because my biggest fear, or it's only one of my biggest fears in education, is a retreat from science. What could a parent think about out there as they think about their son or daughter? And I'm actually even more afraid of it in the case of girls where there's this ridiculous stupid, and I really think it is stupid and incorrect, that girls are just not going to be as good at science or math I think that most of that is actually a feed forward mechanism that's built into an expectation I mean, how do you think about this with your kids or how could I think about it with my kids or anybody else thinking about this like what can we do to

make science Is exciting as it can possibly be and if for no other reason it's not even say this to be, it's not because everyone has to become a scientist. It's an inability to understand science makes you a victim for the rest of your life, whether you want to admit it or not. If you can't at least have some understanding of science and think critically, you are going to be overrun with propaganda and nonsense. And the consequence of that is enormous and we see it. You it. I don't think this fact is necessarily correct today, but it was at the time that I knew it and it won't be directionally off. At the time of the statistic, there's what 565 members in the House of Representatives in the Senate. Five of them had degrees in science.

So less than one percent of the lawmakers of this country are trained scientifically. That just doesn't strike me as an appropriate balance. So what happened at Vassar and how can we reproduce it? So those are two things that I think about a lot. One is obviously we as a group of scientists need to do a better job of communicating what we do in an interesting and exciting way to people without dumbing it down. And honestly, I'm not just saying this to shove sunshine up your ass, but I've had so many calls from people, either people I do know or people I don't know

who've said, I just heard this great podcast. And I think what you're doing here is bold because you're not shying away from getting into the depth. It may be that a lot of the conversation that we had around the science was over the head of the average lay person who hasn't had science, but I still think it's valuable. And they're gonna go off and get littered about something and they're finding it interesting.

So I think we as a community need to do that, whether it's you or it's Ron Veil and Ibiology or other things, which if you haven't seen it, I highly recommend he's making these videos. In fact, they did one one day of Sabatini a series on Emptor. Yeah, I saw that one. Yeah, if we're going to get more people interested in science, we've got to make it more interesting. The second thing is there's this trend, and you know this because you've got kids, of hyper-specialization earlier and earlier in life. I could afford to go to medical school and making the decision as a sophomore in college. That's almost impossible to believe that that could happen today.

I mean, it could happen, you'd have to take time off. But what I find with our trainees is that people who don't, two things happen, one is people who get into science at a young age get burned out and don't like it by the time they get to be, you know, a fellow or a resident or attending. And the second thing is the people who don't get into science, like me, the Ethan Wises, who go to Vassar in 2019

and not 1991. Find it way too much of an obstacle to get in now. It's just too complicated and too many barriers. So one of the things that I'm passionate about, and I'm actually working on it, I can't really talk about it now, but we're gonna talk about it soon. We're working on some ways to help

MD-only medical students and beyond get exposed to real intensive two and and three year experiences in the lab So the kind of thing that used to happen routinely where people would go and work at an age Like you did or other things where they can get exposed to science in a meaningful way Even if their career is not going to be as a PI running a lab It will help increase the scientific literacy having being able to speak both these languages So that's something I'm super passionate about. Because traditional medical school is actually not scientific training.

That's gone. Now, so, you know, I've heard this saying, I don't know who this one gets distributed, but the gist of it is that we've taken the science out of medical school on the medicine out of graduate school, right? So our graduate students are craving more understanding of physiology in medicine. Our medical students are not really missing what they're not getting, but they're not learning science anymore. And so once that happens, then the likelihood that that student who's not done in PhD, who's never worked in a lab, is going to have the courage

or the ability to go work in a lab later on in life is close to zero. And the thing is, what was great about the way it happened for me was that I came to it without much preconceived notion and dog was so I came to it with just preconceived notion and dogmas. So I came to it with just native curiosity and sort of like how should things work? And look, I wish my basis of scientific knowledge was greater than it is. I'm jealous of people, like my MD PhD friends from Hopkins,

like Dave Sabotein, those guys. I'm totally jealous of how deep their knowledge is, but I have a different perspective and I bring the clinical work that I do and the things that I think about what I'm seeing patients and have thought about. So it's a different way. We didn't get a chance to talk about it,

but you've been really, I mean, as though everything we've described, your entire clinical career, your amazing stuff you're doing in the lab isn't enough to keep you busy and oh, by the way, you also have a family. You decided, like, I mean, I feel like you did it in a week, because I remember when you called me and told me about it, and then a week later, you had a prototype, and then two weeks later,

you had your next product, you started a company last year. Yeah. So can you tell us a little bit about that, because half my patience now are using this device? We could do an entire podcast on this, and maybe on a podcast. Maybe we should. A podcast and bring you on, because I do think there's some of this stuff. When I first called you, I remember calling you, it was like a Saturday or Sunday, and you were generous

to take the time to help me think about this. We talked a lot about the behavioral science, and the behavioral economics, which is something we've talked about a lot at our time on the verte advisory board. I think it's, to me, it's the most interesting part of this whole obesity story, right? We're talking about a behavior at its core and a change in behavior and how do we, at the absolute most basic level, how do we use technology to help people change their behavior? And that's something that I've been thinking about for a long time. And to make a really, really, really long story short, I got together with an amazing team

of people who'd been doing work in weight loss. And actually, when I told them what I wanted to do, they both told me to get lost. They said they're never going to do a weight loss startup again. They had started and sold a company to weight watchers and said, it's too hard. People say they want to lose weight, but they actually don't. They don't have the tools to do it. So short version of a long story, we thought, well, gosh, you know, one thing that is true, I think about weight loss in general for people who struggle is that we're not giving them the information

they need to be able to make the change in behavior. The only information that we give people is the information they get from stepping on their scale. That's an incredibly lagging indicator. I mean, you could have entire gallon of ice cream tonight at 11 o'clock and step on the scale tomorrow and you may not have any difference in your weight. So it's relatively useless on a day-to-day level. And by the time you actually get information, it's not actionable. I would add one more thing, which is the amount

of movement in water alone makes it almost impossible. For example, the average woman who is still experiencing a menstrual cycle can easily fluctuate by eight pounds in a month. It's a four kilogram average fluctuation in water weight. So can you imagine if a woman says, I want to lose 10 pounds in and she's using her scale, it's just impossible. And you know, you can build in, you know, moving averages and other things. But again, you're not giving them the information they need to be able to make the changes. If they want to make a change, so what's interesting and unique about...

So when I came to the Verde Advisory Board, I'd never done keto before. And frankly, I kind of thought it was a little bit weird. I don't know if you remember that first advisory board meeting we had at the Mexican restaurant down there, and I still joke about this. In fact, I think I've joke about it with Sam and Steve. That I show up at this thing, and there's bowls of guacamole there with spoons in them. And fajita dishes without wraps and there wasacal hydrate to be found on the table. I thought, this is like a cult. Like, this is weird. And I never really had any

curiosity about doing it. And then I tried it myself. And I realized that the one unique fact about this diet that's different from all other diets that I know of other than fasting for a week is it allows you to fall by marker. And that if you use that by marker as a guide to help your own adherence, it can help reinforce some of these behaviors. And maybe that would be sufficient. So we finally decided to try this thing. And one of the issues is you know better than anybody,

testing your ketone level, whether it's through blood or breath or urine, has all kinds of issues. And there's imperfection, but we figured if we could build a good sensor, I'm not talking about like a lab level sensor, but a good sensor that people could use, they could carry around that would be portable and accurate enough to help guide these behavioral changes that we could use that as the basis of basically replacing a lot of the human intervention that goes into programs like Verda, right? So Verda is successful at what they do in a different population, right?

The population of people not really primarily trying to lose weight, but more trying to manage their diabetes. But that takes a lot of human capital. So could this information help replace that and kind of make it more economically feasible? And so basically through just a series of incredibly fortunate accidents and beyond hard work from this team, we were able to get the sensor, swap out an alcohol sensor for an acetone specific sensor and got this thing to market quickly. It didn't feel like a day, but it was fast. I mean, we basically, I think you and I spoke in August. I had a prototype in October because I managed my calendar through my fasts, which are

always being in court. Then of course, my December had the version I have now, which is great, and that's the one that a number of my patients have. I think it was November. Yeah, we are doing this slow. Tell people, I don't even think we've mentioned the name of the company. What's the name of the company? It's spelled K-E-Y-T-O, and most people pronounce it keto as you would pronounce ketogenic diet.

But we were sort of intentional in being vague about whether you could call it keto if you wanted to, leaves it open to the idea that it could be more than just ketogenic diet. And so the company's organized around one is giving people the information they need through this sensor Which you know links up to an app to giving people information they need to be able to succeed at whatever they're doing So you know how to do keto you've done TED talks on keto But an average person hears about key to jack diet and they like I don't I don't know how to do that So we give people the information they need to be able to do the diet and then at some point and it won't be now But at some point we're gonna help't be now, but at some point, we're going to help people get to, you know what to do, you're measuring how well you're doing, but

how do you actually, and how can you enable that? How can you get people to food? So I cook 90% of the meals. I've got my lunch that I brought with me over there in a bag. But a lot of people don't have that luxury. And so they'll go out here, this food court, and I want to get lunch. And so can we help deliver that food to them at some point? So that's sort of the big picture of what we're doing. And it's been incredibly fun. I mean, I've been at UCSF now. I've been in this office for almost 10 years.

And I do think I'm like one of the luckiest people in the world to be able to do the things I do, both combining this clinical work, which is just a gift with this lab work, which is basically like a game. It's like a glorified living, breathing video game that we get to try and solve puzzles every day and I get paid to do it. But this thing has been fun to do and it happens at a different pace. As you said, a normal cycle

for me in the lab is like five years. This thing happened in three months and so it's fun to kind of exercise different muscles and think about business for the first time in my life. I mean, I haven't really thought about business before and it's fun. I actually enjoy it I think about I love thinking about the human psychology and And the behavior so it's been kind of a fun adventure. We'll see you awesome And you've got one for me to take back to one of my I'm seeing one of my patients next week who I was with the other day And I was talking about it with him like I had already given him one and he's like, what are you talking about? And I was like, well, I'm going to see Ethan. So I'll get you one.

You're someone that I follow on Twitter because I always enjoy. I mean, you know, for me, Twitter is just a great way to curate reading and stuff. And I love following your stuff. So where can people find you? That's probably my biggest place that I spend time social media wise. And my Twitter handles it at Ethan J. Wise. I have to say, I probably had a significant problem and my wife would say that I had a

more than significant problem with the amount of time I spend on there. I'm not there as much anymore just because I can't keep up that and my job and my family and this startup thing. But I do try to respond, you know, somebody sends me a message, I'll try to respond. Even if once a week there's a great study that you're highlighting, I find that super helpful. Yeah, it's fun. Look, Twitter actually went down there and visited a friend of mine as the CFO at the company Ned Siegel and he invited me to,

he said, you're so active, like you're a power user in science and medicine, you should come visit. And it was really sweet. He brought, he invited me to come down, we toured through the facility. I'd never been there before, but I think they have something going there. Like it, talk about increasing scientific literacy.

It's, and I know I, my own patients who follow me and they tell me they learn a lot. They learn a lot about medicine and science. They learn a lot from you. You don't have to be a stranger to, unless you've been in the Himalayas hunting Yeti for the past five years, you certainly realize that right now Twitter is under attack and I feel bad every time Jack Dorsey has to go on a podcast, it's just basically to get skewered. I understand why people are upset about the role of Twitter in politics

and fake news and stuff, and I think that's a super upsetting problem. Fortunately, in the world that we play in Twitter, I still find it more positive than negative. In the end, I've got a bunch of people I follow who basically curate some of the research I just wouldn't be able to keep up with, because I'm really narrow in what I do, but I need to know what's going on in these fields that are adjacent, and

that's a great way to do it. So, Ethan, I can't think enough has been awesome, and I suspect this won't be the last time we have to sit down and have a formal discussion, and we'll obviously have many more informal ones. Awesome, Peter. Thank you so much for coming up. You can find all of this information and more at peteratiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode.

You can also find my blog at peteratiamd.com. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email where I'll update you on what I've been up to the most interesting papers I've read and all things related to longevity, science, performance, sleep, etc. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID Peter Atiyah MD, but usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaim.

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